CA3064975A1

CA3064975A1 - Novel inhibitors of map4k1

Info

Publication number: CA3064975A1
Application number: CA3064975A
Authority: CA
Inventors: Vinod Patel; Venkateshwar REDDY; Laxmikant Atmaram Gharat; Sachin Sundarial Chaudhari; Sanjib Das; Ranganadh VELGALETI; Daisy Manish Shah; Malini Bajpai
Original assignee: Glenmark Pharmaceuticals SA
Current assignee: Ichnos Sciences SA
Priority date: 2017-05-26
Filing date: 2018-05-28
Publication date: 2018-11-29
Also published as: AU2018272986A1; EP3630778A1; EA201992584A1; JP2021506735A; WO2018215668A1; MX2019013922A; KR20200011965A; IL270844A; CN112601752A

Abstract

The invention relates to novel inhibitors of MAP4K1 (HPK1) useful for the treatment of diseases or disorders characterised by dysregulation of the signal transduction pathways associated with MAPK activation, including hyperproliferative diseases, diseases of immune system dysfunction, inflammatory disorders, neurological diseases, and cardiovascular diseases. The invention further relates to pharmaceutical compositions comprising the same and methods of treatment of said diseases and disorders. The inhibitors are of formula (I) wherein the definitions for A, D, E, F, R5, R6, R7, Z, ring Q, n, x and y are as given in the application.

Description

TECHNICAL FIELD
The present patent application is directed to novel inhibitors of the mitogen-activated protein kinase kinase kinase kinase 1, also known as MAP4K1 or HPK1 (hematopoietic progenitor kinase 1).
BACKGROUND OF THE INVENTION
Protein kinases represent a large family of proteins which play a variety of crucial roles in the regulation of a wide range of cellular processes. Such kinases include Akt, Axl, Aurora A, Aurora B, DYRK2, EPHAa2, FGFR3, FLT-3, VEGFr3, IGFLr, IKK2, JNK3, VEGFr2, MEK1, MET, P70s6K, Plkl, RSK1, Src, TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK, PDGFR, TAK1, LimK, Fltl, PDK1, Erk and RON.
Inhibition of various protein kinases, especially selective inhibition, has become an important strategy in treating many diseases and disorders.
MAP4K1 is a serine/threonine kinase of the 5te20 family. MAP4K enzymes (MAP
kinase kinases) are generally involved at the highest level of a largely linear kinase activation pathway. A MAP4K will phosphorylate and activate a particular substrate which is a MAP3K
(a MAP kinase kinase). A MAP3K in turn phosphorylates and activates a MAP2K (a MAP
kinase kinase). A MAP2K in turn phosphorylates and activates a MAPK (MAP
kinase). The MAP kinase is the final effector of the pathway and it in turn phosphorylates a substrate to control key cellular processes such as cell proliferation, cell differentiation, gene expression, transcription regulation, and apoptosis. The substrate of MAPK is generally a nuclear protein, such as nuclear factor kappa-B (NF-KB). Activation of the MAPK by its phosphorylation by an MAP2K results in translocation of this final enzyme in the cascade into the nucleus.
MAP4K1, also known as HPK1, is primarily expressed in the immune system's Tcells and B cells, which are critical in regulation of the immune system.
Overstimulation of T cell and B cell activation pathways can result in auto-immune diseases, while understimulation of these pathways can result in immune dysfunction, susceptibility to viral and bacterial infection and increased susceptibility to cancer. MAP4K1 is activated by its interaction with activated T cell receptors (TCRs) and B cell receptors (BCRs), so MAP4K1 activation serves to convey the cellular activation signal from the surface of a T or B cell to the effector proteins in the nucleus. There is also evidence that MAP4K1 can be activated via the TGF-I3 receptor, the erythropoietin receptor and the FAS protein (which is involved in apoptosis signaling). MAP4K1 activation ultimately results in activation of several identified nuclear effector proteins, including those involved in the NF-K1, AP-1, ERK2, and Fos signaling pathways.
MAP4K1 is considered a negative regulator of T cell receptor (TCR) activation signals, and it is one of the effector molecules that mediates immunosuppression of T cell responses upon exposure to prostaglandin E2 (PGE2). Studies have shown that activity dampens the strength of the T cell receptor signal transduction cascade, and thus, targeted genetic disruption of MAP4K1 results in strengthened TCR activation signals.
One particularly important pathway that MAP4K1 appears to be involved with is the JNK pathway. MAP4K1 regulates the MAP3K's MEKK1, TAK1 and MLK3. These in turn regulate the MAP2K's MKK4 and MKK7. These in turn regulate the MAPK JNK. JNK
then regulates important transcription factors and other proteins, including p53, SMAD4, NFAT-2, NFAT-4, ELK1, ATF2, HSF1, c-Jun, and JunD. JNK has been implicated in apoptosis, neurodegeneration, cell differentiation and proliferation, inflammatory conditions and cytokine production.
The JNK signal transduction pathway is activated in response to environmental stress and by the engagement of several classes of cell surface receptors, including cytokine receptors, serpentine receptors and receptor tyrosine kinases. In mammalian cells, the JNK
pathway has been implicated in biological processes such as oncogenic transformation and mediating adaptive responses to environmental stress. JNK has also been associated with modulating immune responses, including maturation and differentiation of immune cells, as well as effecting programmed cell death in cells identified for destruction by the immune system. Among several neurological disorders, JNK signaling is particularly implicated in ischemic stroke and Parkinson's disease, but also in other diseases as mentioned further below.
It is noteworthy that the MAPK p38a1pha was shown to inhibit cell proliferation by antagonizing the JNK-c-Jun-pathway. p38a1pha appears to be active in suppression of proliferation in both normal cells and cancer cells, and this strongly suggests the involvement of JNK in hyperproliferative diseases (see, e.g., Hui et al., Nature Genetics, Vol. 39, No. 6, June 2007). JNK signaling has also been implicated in diseases such as excitotoxicity of hippocampal neurons, liver ischemia, reperfusion, neurodegenerative diseases, hearing loss, deafness, neural tube birth defects, cancer, chronic inflammatory diseases, obesity, diabetes, in particular, insulin-resistant diabetes, and it has been proposed that selective JNK inhibitors

2 are needed for treatment of various diseases with a high degree of specificity and lack of toxicity.
Because MAP4K1 is an upstream regulator of JNK, effective inhibitors of MAP4K1 would be useful in treating the same diseases which have been suggested or implicated for INK inhibitors, especially where such disease or dysfunction is manifested in hematopoietic cells such as T cells and B cells.
Targeted disruption of MAP4K1 (HPK1) alleles has been shown to confer T cells with an elevated Thl cytokine production in response to TCR engagement.
Burakoff et al., Immunologic Research, 54(1): 262-265 (2012). HPK1¨/¨ T cells were found to proliferate more rapidly than the haplotype-matched wild-type counterpart and were resistant to prostaglandin E2 (PGE2)-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1¨/¨ T cells became resistant to lung tumor growth. Also, the loss of HPK1 from dendritic cells (DCs) endowed them with superior antigen presentation ability, enabling HPK1¨/¨ DCs to elicit a more potent anti-tumor immune response when used as cancer vaccine. It was considered probable that blocking the MAP4K1 kinase activity with a small molecule inhibitor may activate the superior antitumor activity of both cell types, resulting in a synergistic amplification of anti-tumor potential. Given that MAP4K1 is not expressed in any major organs, it is less likely that a selective inhibitor of MAP4K1 would cause any serious side effects.
The relationship between MAP4K1 and PGE2 is particularly noteworthy because PGE2 is the predominant eicosanoid product released by cancer cells, including lung, colon and breast cancer cells. Tumor-produced PGE2 is known to contribute significantly to tumor-mediated immune suppression.
Zhang et al., J. Autoimmunity, 37:180-189 (2011), described diminished HPK1 expression in CD4 T cells of lupus patients due to the selective loss of JMJD3 histone demethylase binding to the HPK1 locus. This suggests that HPK1 is one of the key molecules involved in the maintenance of peripheral tolerance. Peripheral tolerance is one of the major obstacles to the development of effective anti-tumor immunity.
Several small molecule inhibitors of MAP4K1 have been reported, but they do not inhibit MAP4K1 selectively, or even preferentially. Such inhibitors include staurosporine, bosutinib, sunitinib, lestaurtinib, crizotinib, foretinib, dovitinib and KW-2449. Staurosporine, for example, broadly inhibits a wide range of protein kinases across both the serine/threonine and tyrosine kinase families. Bosutinib is primarily an inhibitor of the tyrosine kinase BCR-Abl, with additional activity against the Src family tyrosine kinases.
Sunitinib is a broad

3 inhibitor of tyrosine kinases. Lestaurtinib is primarily an inhibitor of the FLT, JAK and TRK
family tyrosine kinases. Crizotinib is primarily an inhibitor of the c-met and ALK tyrosine kinases. Foretinib was under study as an inhibitor of the c-Met and VEGFR
tyrosine kinases.
Dovitinib is primarily an inhibitor of the FGFR receptor tyrosine kinase. KW-2449 is an experimental inhibitor primarily of the FLT3 tyrosine kinase.
Sunitinib inhibits MAP4K1 at nanomolar concentrations, but it is a broad-spectrum receptor tyrosine kinase inhibitor. Treating T-cells with sunitinib results in enhanced cytokine product similar to that observed with HPK1 ¨/¨ T cells, which suggests that in T cells a selective MAP4K1 inhibitor could produce the same enhanced immune response phenotype.
Currently, there is a largely unmet need for an effective way of treating disease and disorders associated disrupted protein kinase signaling. Autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, are all diseases and disorder which can be affected by dysfunctional protein kinase signaling. Improved therapeutic compounds, compositions and methods for the treatment for these disease and disorders are urgently required. MAP4K1 inhibition is an especially attractive target for cancer immunotherapy.
The major challenge currently faced in the field is the lack of MAP4K1 specific inhibitors. The present disclosure provides novel, highly effective small-molecule inhibitors of MAP4K1.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a compound of formula (I) (R6)n \
I X Y
L Q
Z
A..... R...'' E

R -r, N N / D
I
R7 (i) stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, wherein A is selected from CH and N;
D is selected from CR1R2 and CO;
E is selected from (CR3R4)m, NR' and CO;

4 F is selected from 0, CH2, CHOH and CO;
each occurrence of R5 is selected from hydrogen, halogen, cyano, hydroxyl and Ci-salkyl;
R7 is selected from hydrogen and Ci_salkyl;
each occurrence of R6 is selected from halogen, cyano, hydroxyl, Ci_salkyl, haloCi-salkyl, hydroxyCi_salkyl, C1-8alkoxy, Ci_salkoxyCi_salkyl, C3-6cycloalkyl and 6cycloalky1C1_8a1ky1;
Rl, R2, R3 and R4 which may be same or different, are each independently selected from hydrogen, amine, Ci_salkyl, C3_6cycloalkyl, haloCi_salkyl, hydroxyCi_salkyl, C3-6cycloalky1C1_8alkyl, C1_8alkoxy, 3-15 membered heterocyclyl, Ci_salky13-15 membered heterocyclyl and CRaRbNRaRb;
Ra and Rb, which may be the same or different, are each independently selected from hydrogen and Ci_salkyl;
Z is selected from 0, NH and S;
x NH 0 0 ./x N AN N
L is selected from o H ' 5 and =
NX,Y.

x and y represents point of attachment;
Ring Q is selected õ from - (R8) q (R10), )>. ,=
(R)p 0 _____________________________ and

5 5 5 Rio N
=
each occurrence of R8 is selected from halogen, cyano, cyanoCi_salkyl, cyanohaloCi-salkyl, cyanoC3-6cycloalkyl, Ci_salkyl, haloC1_8alkyl, hydroxyC1_8alkyl, hydroxyCi_shaloalkyl, and -SO2R1;

each occurrence of R9 is selected from halogen, cyano, hydroxyl, Ci_salkyl, haloCi-N
= N, ' f\L
salkyl, hydroxyCi_salkyl, Ci_salkoxy, N 0 NH = r I N----\
c____ i ,,,\,...õNõ..........,.--...... .....õ--N
N- 7................N
I N

\
/N---) 1 1 /5/õ..........õ.õ,N.,,,,........õ. N
N \
( \--NH 0 /-/............,,õN.,........õ.õ,...

5 5 5 _____ /
I I
..,,---N'5.õ.. ..../NN...., N
_N
5 0 ,õ,--.........N.,..... ...........N,....., 1 .
...õ."N======,..õ
1 =
N \ / .......,N.,........ /'^\ I
N N
I
N \N N
______________________ /N , 1 , r\l'/', 1 H

/N
N
N
N c ) C ) S . / 1 c ) \
/ % ' N

t 5 o o , I
I......-'N'-.......
N I
N I
N I ...../ N',.......
N
N N
c ) \ /
*N- X
N N-'''''N / 'OH A

6 :......,...,N,...õ....0 PCT/EP2018/063957 I
,../N,.õ, (N
I 0 c NI N

NH, ,' H <>
, , , I
I ..................................................................... 1 --,õ..,''N'....... ...õ/NN,....
,.=
N
H H \ ___ N\
F , \ , I ----------------- I I I ----- I --=N I
N -------------------------------------------------------------------- I
.õ..--N,.., ...õ...-'N',.,.., ..õ.....N,......40,0 / \
N

, /s:.
0 s I I I

N N 1 /ON N--"N/ N
1 1 ___________ N
\ 1 N NH
' , , , , I N%
N ' HNN<5.,õ.0 HN0 (N / ,, 0 <>
CN CN, \ , N )V NN/

7

8 N
/
( ....,..--,,,, i> N
I0 (:)NH2 CN ) /OH
HO
N u2N
N 5 5 " 5 5 5 5 5 CN HO and OH .

RM is selected from halogen, hydroxyl, cyano, Ci_salkyl, haloCi_salkyl, C3_6cycloalkyl and C6_14aryl; wherein C6_14aryl is optionally substituted with one or more substituents 5 selected from halogen, hydroxyl, cyano, amide or Ci_salkyl;
'm' is 1 or 2;
'n' is 0, 1 or 2;
`p' is 0 or 1;
'q' is 0 or 1; and T is 1 or 2.
The compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (I) as defined above wherein A is N (according to an embodiment defined below); F is 0 (according to another embodiment defined below); R7 is hydrogen (according to yet another embodiment defined below).
According to one embodiment specifically provided are compounds of formula (I), in which A is CH.
According to another embodiment specifically provided are compounds of formula (I), in which A is N.
According to yet another embodiment specifically provided are compounds of formula (I), in which D is CR1R2 or CO.

According to yet another embodiment specifically provided are compounds of formula (I), in which Rl is hydrogen or Ci_salkyl (e.g. methyl) and R2 is hydrogen, Ci_salkyl (e.g. methyl, ethyl or isopropyl), hydroxyCi_salkyl (e.g. hydroxyl methyl), C1_8alkoxyC1-N

salkyl (e.g. methoxymethyl), 3-15 membered heterocycly1C1-8alkyl (e.g.
) or CRaRbNRaRb. In this embodiment, Ra and Rb are independently hydrogen or methyl. In another embodiment, Ra and Rb are hydrogen. In yet another embodiment, Ra and RID are methyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which D is CH2, CH-CH3, CH-CH2-CH3, C(CH3)2, CH-CH(CH3)2, CH-HC

I
......./N".......
CH2OH, CH-CH2-0-CH3, 0 5 CH-CH2-N(CH3)2 or CO.
According to yet another embodiment specifically provided are compounds of formula (I), in which E is (CR3R4)m, NR' or CO.
According to yet another embodiment specifically provided are compounds of formula (I), in which R3 is hydrogen or Ci_salkyl (e.g. methyl) and R4 is hydrogen or Ci_salkyl (e.g. methyl) and 'm' is 1 or 2.
According to yet another embodiment specifically provided are compounds of formula (I), in which E is CH2, CH-CH3, C(CH3)2, (CH2)2, N-CH3 or CO.
According to yet another embodiment specifically provided are compounds of formula (I), in which F is 0, CH2, CHOH or CO.
According to yet another embodiment specifically provided are compounds of formula (I), in which R5 is hydrogen, halogen (e.g. chloro) or cyano.
According to yet another embodiment specifically provided are compounds of formula (I), in which R5 is hydrogen, chloro or cyano.
According to yet another embodiment specifically provided are compounds of formula (I), in which R7 is hydrogen or Ci_salkyl (e.g. methyl).
According to yet another embodiment specifically provided are compounds of formula (I), in which R7 is hydrogen or methyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which Z is 0.

9 According to yet another embodiment specifically provided are compounds of formula (I), in which Z is NH.
According to yet another embodiment specifically provided are compounds of formula (I), in which Z is S.
According to yet another embodiment specifically provided are compounds of formula (I), in which R6 is halogen (e.g. chloro or fluoro), Ci_salkyl (e.g.
methyl), haloCi-salkyl (e.g. trifluoromethyl) or Ci_salkoxy (e.g. methoxy).
According to yet another embodiment specifically provided are compounds of formula (I), in which R6 is chloro, fluoro, methyl, trifluoromethyl or methoxy.
According to yet another embodiment specifically provided are compounds of formula (I), in which 'n' is 0, 1 or 2.
According to yet another embodiment specifically provided are compounds of ..,,,<.....,...õ NH ...,...):,.,, formula (I), in which L is 0 ; x and y represents point of attachment.
According to yet another embodiment specifically provided are compounds of o ./x ,-"\N ' formula (I), in which L is H ' ; x and y represents point of attachment.
According to yet another embodiment specifically provided are compounds of o N N H
formula (I), in which L is H ; x and y represents point of attachment.
According to yet another embodiment specifically provided are compounds of formula (I), in which L is o o ; x and y represents point of attachment.
According to yet another embodiment specifically provided are compounds of formula (I), in which Ring Q is Rio , ) ' ,-- , ( R8)q 1 \N
..
-,____......
-- =-= >.
(R9)p .n ..
1 \ ( (Rio), N .......0 N Or .

According to yet another embodiment specifically provided are compounds of - )>.
formula (I), in which Ring Q is According to yet another embodiment specifically provided are compounds of (R8) q formula (I), in which Ring Q is (R9 )p =
According to yet another embodiment specifically provided are compounds of formula (I), in which R8 is halogen (e.g. chloro or bromo), cyano, cyanoCi_salkyl (e.g.
cyanomethyl or cyanoisopropyl), cyanohaloC1_8alkyl (e.g. cyanodifluoromethyl), cyanoC3_ 6 cycloalkyl (e.g. cyanocyclopropane), Ci_salkyl (e.g. methyl), haloC1_8alkyl (e.g.
trifluoromethyl or difluoromethyl), hydroxyCi_shaloalkyl (e.g. hydroxyl difluoromethyl) or -S02R1. In this embodiment, Rl is Ci_salkyl (e.g. methyl, ethyl or amine).
According to yet another embodiment specifically provided are compounds of formula (I), in which R8 is chloro, bromo, cyano, cyanomethyl, cyanoisopropyl, cyanodifluoromethyl, cyanocyclopropane, methyl, trifluoromethyl, difluoromethyl, hydroxyl difluoromethyl, -S02Me, -S02Et or -SO2NH2.
According to yet another embodiment specifically provided are compounds of formula (I), in which R9 is halogen (e.g. fluoro or bromo), cyano, hydroxyl, Ci_salkyl (e.g.
methyl), haloCi_salkyl (e.g. trifluoromethyl), Ci_salkoxy (e.g. methoxy), /N/
=
NH N

\ 5 FN]
= \
N NH 5 o \ __ 0 5 5 5 = 5 I I
...,,,N,...... ...,,,N.,....... I
N
I
N N \
/ \ N
= 0 5 5 5 5 5 5 r 5 I I
NI
N . I ..,,===N"...õ
I ..../\_ cN
N I S =,' N
\ N
H I
t F 0 0 ,' zN N N N
\ ) ) ..
N N
¨NI\ /1\I
N N¨

I I I ''"+
'NI N /
/N-NI
I
I I
N 0,.....N`...., N ,õ===== \
C ) N
N CN <
n , N 0 __ cN z\
X N 1 'OH F F \----NH 2''N H
V

I I I I I
N
.õ...õNõ...... ,,,,N,,.... I
cN .,:=cly N ( .....õ,.Nõ.....
\ 5 5 OH, H 5 H 5 F 5 I I
N I
....õ,. Nõ,... I
N )1 Ni 0 it] <õ NI
..õ===== `....stso \sõ..Ø0õ ,....,...

N \ /

H H

%
0 =
..õ..-"N`.,..
I I
N

¨N N
/ N
\ 0 I
I HN, _.0 = I I I
HN, _..0 11 I
HN0 (N) CN <>
0 N ' ...õ:õ1 CNõ.....,1 , NN
I
\ , I N N

OH
H2N/. 5 o 0NH5 5 5 HO 2 CN ) j , 5 5 5 / \ o CN HO

Or OH, According to yet another embodiment specifically provided are compounds of 5 formula (I), in which R9 is fluoro, bromo, cyano, hydroxyl, methyl, trifluoromethyl, methoxy, N N
/,,......N.,,....,....õ ,N............ ,,,N..õ......õ/õ..- "' ---Si____\ ----NH ..= 1 c_____ i -- \
/N
,, ----\
/ \. N N

7,.....,.....õ-N........,....
1 \ 5 ---/
NH, =;' N

--- \ ________________________________________________________________ N

,,N.........N,.......õ..õ...s.N.,,,.-../....õ,õõ,,N.,.........õ...õ. I :,''', 0 \ __ 0 0 , 0 .....õ.=N...õ..... ,.....,. N .õ.......
I
........, N --...õ, I I
....,,,N,....... ..,,,N,........ N/ \ N/
N
N
N
N

I ----------------------------- =
I
N
I

NN
S
N
1 1 F 0/ %0 N, 5 H 5 5 5 5 ' 5 I zN N N) '. .' N c ) C N
c ) \
'I\1 (NN
õ

I
N
I I I
o KN /N 1 ..õ..-- N =====..õ..
N N/ I
../1õ...../N
\ \ c ) . N
. - - x ________________________________________ n si \---NI-<
*N- N-/ / 1-_1 H F F A 5 5 5 5 I
..,....,- N ====.õ, N, N N õ,./N====õ,....

I
I

I N
N N rti iti j, , "1""/
N
Y N\ 5 5 5 0 1 I I I ..
.......,,N,...... I
...õN.,..õ.40, (:) N 1 __ 1 n -------------------- NO.N/
N
N N-N
/ \ 5 5 5 5 5 5 5 ../. s.
0 = I
N
I I
I =
\ ) HNN.........0 N¨NH(N /

N
, 101 N
1\ , 5 5 CN 5 CN, 5 I
I H I

)\1 , N'''...
NN I
) I N N hI2N0 ONH2 CN

I

OH
HO 5 5 CN HO or OH, According to yet another embodiment specifically provided are compounds of formula (I), in which Ring Q is CF3 = CF, CF3 CF3 CF, 0 CF3 L , ., = N 0 N . * N (NNH
õ..-....,,N...õ, NõNõ..) 1 ..............õ,N.,,, 5 ........,....õ.NH 5 0 5 i 0 CF3 =
N
.--='- s',..
., ./ , =
N'.---\
CF

CF, .
, NN NN
Br 5 0 5 5 5 , ,. CF, =
=

N1 , Nõ...............õ....õ, N...., I :,.. I. C F3 / 5 *

CF

, CF ..,' CF õ,, CF3 CF
........N...., .........N....., .........N.,...., c NN,.....
N
CF, N , 1....**..'N
[---.... ...-1.... , N.,.....õ....õ... "........
LV N'Th 1...,õõ....N...,..õ,....5 CF
, . *
CFe ........N.,,, ' .
, , = r N.,.....
.,,,k1...., . .
N . :
......õ.N.õ..õ,.....,,,N........, , CN
CN
I
.......,N,..... 5 I N
H

, ,' CF3 l' CF3 ,=
CF i ilo CF
=,'' CF3 , , (....,N .......A....., .'.
CN
N

, .
, CF,, . CF, i , CF
, . =
CF, , , F F * N
erN N
N
'.
CN

CF

i CF, , F
c ) \ ........( 0F3 / 0 CF3 .= el ./

, =
CF, , , i 40 CF3 / CF ,,,/ CF3 , , = /40 C F3 i , N
, ..,,..."N,....... ) OMe F 5 5 5 5 OH 1 \ /
0 \-N
---/

CF33 ,. 10) CF3 , / C Fs N , c , 5 5 5 ' 5 i CF / CF, . . , CF, .' õ' CF3 .
...õ,,,1\1,....
0 ....õõNõ...... , N erN
(:)....õ, NH
H A 6 \ ....-., ..,..--- 0 OH

. CF, / CF, I
. , . CF3 / Ili = =
. CF3 . ' . .=
CF, N

N.........N...., NH (N) : CF
= 0 3 i CF3 ri 0 CF3 ,== CF3 / CF3 N
cN ,,,,,, 0 N
N N
N''''''''', ' CF3 /
. 1110 CF3 N
N N N3m111111/
Ni....N/
N \ 5 5 5 5 5 ,I 0 CF3 CF3 , / 0 CF3 .
, .
, = .
0 . ' CF3 =
.õ..,N,..õ.
...õ.....".õ

. 0 .= N
N L.,3 5 F, C.\ 1 5 N¨NH 5 CN 5 CN 5 lio CF3 .,./ 0 CF
i 3 :" CF3 .=

=
, ,, HN
zN ./ CF3 =0 µI __ ( = CN
----,N.-------............ 5 ,, CF3 l'i CF3 CF3 i Iliiii N
<>./.....
`....., , 0 5 l' CF 5 5 : CF3 = .. . 1 0 , ,' CF3 cHs .........N . i N
..........N..õ, .
......õN.õ.... .. , , ,= 0 SO2Me 11 i .. ) I 41111 OH N

==1 Am SO2Me / CF

, F F
/ CH F2 .../ SO2 Et N
I

=
',/ SO2Me =,.." 0F3 .3...i CF3 ........,N,......
N 11 H ...../ õI
so2NH2 5 L.N. CN 5 HO OH 5 Or OH , According to yet another embodiment specifically provided are compounds of =
I
(R1 )t formula (I), in which Ring Q is . In this embodiment, Rl is Ci_salkyl (e.g.
methyl) or haloCi_salkyl (e.g. trifluoromethyl). In yet another embodiment, 't' is 2.
According to yet another embodiment specifically provided are compounds of formula (I), in which Ring Q is According to yet another embodiment specifically provided are compounds of formula (I), in which Ring Q is According to yet another embodiment specifically provided are compounds of Rio formula (I), in which Ring Q is According to yet another embodiment specifically provided are compounds of formula (I), in which Rl is Ci_salkyl (e.g. methyl) or C6_14aryl. In this embodiment, C6_14aryl is optionally substituted with one or more substituents selected from cyano, or amide.

According to yet another embodiment specifically provided are compounds of NN
/\
formula (I), in which Ring Q is Or tRN
According to yet another embodiment specifically provided are compounds of formula (I), in which `p' is 0 or 1.
According to yet another embodiment specifically provided are compounds of formula (I), in which `q' is 0 or 1.
According to yet another embodiment, specifically provided are compounds of formula (I), in which A is CH or N;
D is CH2, CH-CH3, CH-CH2-CH3, C(CH3)2, CH-CH(CH3)2, CH-CH2OH, CH-CH2-0-HC

CH3, 0, CH-CH2-N(CH3)2, CO or cycloalkyl;
E is CH2, CH-CH3, C(CH3)2, (CH2)2, N-CH3 or CO;
F is 0, CH2, CHOH or CO;
R5 is hydrogen, chloro or cyano;
R7 is hydrogen or methyl;
Z is 0, NH or S;
R6 is chloro, fluoro, methyl, trifluoromethyl or methoxy;
y N 'N "NH' Lis 0 H ' Or 0 0 =

Ring Q is ---(NN /
f----NN--- , r---NN------..

CF3 , .,' CF3 r.......µ CF30 , , ' NN......) N,N) i CF3 ., i 0 , ., , ., , -..,..............,õNH5 ..,.............,0 5 N.,....,,5) CF= 3 / CF, , ,....N..,1 , (NN\

5 Br 5 0 5 , CF3 21 ,' Br :; Iso CF 3 NN (NN

NN....) NN.....) ON

i/. CF3 /

, .,../N,.......
=
. , ..../N,....... , , === CF3 s ' . N
H ' , 0 CF305,..õ....., NN.,,,,......õõ...N.....õ

, 0 CF3 CFs , , ill CF, , , . . CFs L N I-.
= .....,N......., , .....,,N
Nrklõ...., '''NI...,v , CF, ........................,......
, , i N...,.........., H ...,,,,....,,,.N õ.........õ, 5 NI''' I
õ......N,...., 5 , CF , ; CF, , , / so C F3 3 / cFe CN
, , , /
' , r N...., , , , / NN CN
I N
H N
H

, , õ' CF
, , F F
erN ........N......, N \ ...Z N .
. ' CN ./
CN
I......,.S., .' "i' cFs . CF, , .
. õ CF, , I., CF3 õ
.
.
* / CF, ' N
\ ...Z c ) ) N
c ) c"
........( ) N¨ ¨1\1' ''F 5 / 5 I I I5 I

F ,/ oli CF3 //' 1= CFCF

3 / / ' ao CF35 /.1 . 11) CN OF3 5 CN OMe F

:

CF, / CF s ' CF
=

N erN
..,,,,N,....... C ) \ .........
.,../N,,,..

/ N¨

I X
F F

r:

' 0.........N.,.., c ) N
( ) ./.' CF3 NN......) (NN/Nõ.....CN
N N
5 tH 5 NH 5 H A

i CF
.' . .. CF, ,.' C ) .
./ 0 CF, ii CF3 == lei N trõN ..õ.../N,......
....õ..,N,......
(:)......,,NH
6 \ ........( NH
N */ N
% ........."....õ 5 .' CF, .
, . 3 õ' 0 CF3 , .
CF3 1.' CF . , O......õ..N,,, il CF CF, . 0 N ..õ..N.õ,.... cN 0 N
...õõ,N.3,.."
.........N.........
%,..õ.., ,...,...
Y N N N/ /

... 40 CF, / 0 CFs i Fs ,,, ,CF3 , ill CFs ... 0 CF, . , õN, ,....,N,....,.. ...........N...., N

N N N""'''''= N N/

I 5 I 5 I 5 I .--rN,.......

/,''' 410 CF3 , ,'. CF3 /
, , ' CF, , 0 , .. CF, .........."
, =
=
/NN
/ NO.......,.< O./
i \
\ 5 F 5 1 N-NH 5 , , , CF3 /

, / ail ,,./ CF3 , ..õ,...,N,.., N
III HN,.......0 N
µ _________________________________________________________ ( , / 0 CF3 ' CN CN 5 .............. 5 , .. 0 CF3 , . .
..= 0 c3 .
. ,..
CF, , , . CF3 11 , HN...,...0 . HN,.......0 N
CN
<> (.> ..----..
----..N../...

.....)õ,,,,N
N
..."'N',.. 5 H2N 0 , ; CF3 O
' CF ; , ' 3 .
, ' P
=
, CH3 / ........NN
N
11 C ) .........N...., 5 0 NH2 5 CN --'j I CF3 5 HO

; CF3 , /

, % OH 0 el SO2Me I I I
, .
% CHF2 I SO2Et . .
= .
.1 -,....., 010 -..,/ cF3 =, CF3 . OH 11 11 ' ..,, SO2Me , .; SO2Me 5/

,õ..,N".....õ, CF3 ...õ.'N"..,...
N C

, 1 N
I
5 OH, 5 5 1 5 N........0 I
/ ',............., N \
, ........RN ,/\.......N
1 \ N
A

5 Or / 5 5 `na' is 1 or 2; and 'n' is 0, 1 or 2.
According to an embodiment, specifically provided are compounds of formula (I) with an ICso value of less than 500 nM, preferably less than 100 nM, more preferably less than 50 nM, with respect to MAP4K1 inhibition.
Compounds of the present invention include the compounds in Examples 1-261. It should be understood that the formulas (I) structurally encompasses all geometrical isomers, stereoisomers, enantiomers and diastereomers, N-oxides, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
The present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described herein may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a tablet, capsule, sachet, paper or other container.
Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired. The compound may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation. In general, satisfactory results, e.g. for the treatment of diseases as hereinbefore set forth are indicated to be obtained on oral administration at dosages of the order from about 0.01 to 2.0 mg/kg. In larger mammals, for example humans, an indicated daily dosage for oral administration will accordingly be in the range of from about 0.75 to 300 mg, conveniently administered once, or in divided doses 2 to 4 times, daily or in sustained release form. Unit dosage forms for oral administration thus for example may comprise from about 0.2 to 75 or 150 mg or 300 mg, e.g. from about 0.2 or 2.0 to 10, 25, 50, 75, 100, 150, 200 or 300 mg of the compound disclosed herein, together with a pharmaceutically acceptable diluent or carrier therefor.
Pharmaceutical compositions comprising Compounds of the Invention may be prepared using conventional diluents or excipients and techniques known in the galenic art.
Thus oral dosage forms may include tablets, capsules, solutions, suspensions and the like.
DETAILED DESCRIPTION OF THE INVENTION
Definitions The terms "halogen" or "halo" means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
The term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci_salkyl), and which is attached to the rest of the molecule by a single bond, such as, but not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "C1_6alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. The term "C1_4alkyl" refers to an alkyl chain having 1 to 4 carbon atoms.
Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.
The term "alkoxy" denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. C1-8 alkoxy). Representative examples of such groups are -OCH3 and -0C2H5. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.
The term "alkoxyalkyl" or "alkyloxyalkyl" refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above (i.e.
Ci_salkoxyCi_salkyl or Ci_salkyloxyCi_salkyl). Example of such alkoxyalkyl moiety includes, but are not limited to, -CH2OCH3 (methoxymethyl) and -CH20C2H5 (ethoxymethyl). Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched.
The term "haloalkyl" refers to at least one halo group (selected from F, Cl, Br or I), linked to an alkyl group as defined above (i.e. haloCi_salkyl). Examples of such haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. The term "haloC1_4alkyl" refers to at least one halo group linked an alkyl chain having 1 to 4 carbon atoms. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms (i.e. haloCi_salkoxy). Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
Unless set forth or recited to the contrary, all haloalkoxy groups described herein may be straight chain or branched.
The term "hydroxyCi_salkyl" refers to a Ci_salkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCiAalkyl). Examples of hydroxyC1_4alkyl moieties include, but are not limited to -CH2OH and -C2H4OH.
The term "cyanoalkyl" refers to a alkyl group as defined above directly bonded to cyano group (i.e. cyanoCi_salkyl). Examples of such cyanoCi_salkyl moiety include, but are not limited to, cyanomethyl, cyanoethyl and cyanoisopropyl. Unless set forth or recited to the contrary, all cyanoalkyl groups described herein may be straight chain or branched.
The term "cyanohaloalkyl" refers to cyanoalkyl group substituted with one or more halogen atoms (i.e.cyanohaloCi_salkyl). Example of cyanohaloalkyl include but are not limited to cyanodifluoromethyl. Unless set forth or recited to the contrary, all cyanohaloalkyl groups described herein may be straight chain or branched.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, (i.e.C3_12cycloalkyl). Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapthyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. The term "C3_6cycloalkyl" refers to the cyclic ring having 3 to 6 carbon atoms.
Examples of "C3-6cyc10a1ky1" include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to an alkyl group (i.e.
C3_6cycloalkylC1_8alkyl). The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
The term "cyanocycloalkyl" refers to a cyclic ring-containing radical having 3 to about 6 carbon atoms directly attached to cyano group (i.e.
"cyanoC3_6cycloalkyl). Non-limiting example of such groups include cyanocyclopropane.
The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms (i.e. C6-',aryl), including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "heterocyclic ring" or "heterocycly1" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical (i.e.
3 to 15 membered heterocycly1) which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; also, unless otherwise constrained by the definition the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl or tetrahydrofuranyl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group (i.e. 3 to 15 membered heterocyclylCi_salkyl). The 20 heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
The term "heteroaryl" unless otherwise specified refers to 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, 0 or S (i.e. 5 to 14 membered heteroaryl). The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl and phthalazinyl.
The term "pharmaceutically acceptable salt" includes salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.
The term "treating" or "treatment" of a state, disorder or condition includes:
(a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
The compounds of formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolysing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of chiral HPLC
column. The chiral centres of the present invention can have the S or R
configuration as defined by the IUPAC 1974.
The terms "salt" or "solvate", and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers or racemates of the inventive compounds.
PHARMACEUTICAL COMPOSITIONS
The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical compositions described herein comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
The pharmaceutical compositions described herein may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application.
Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of such compounds or pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, and topical.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.

Topical dosage forms of the compounds include, but are not limited to, ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art.
METHODS OF TREATMENT
The compounds of Formula I, as described herein are highly effective inhibitors of the MAP4K1 kinase, producing inhibition at nanomolar concentrations. MAP4K1 inhibitors according to the invention are therefore useful for treatment and prophylaxis of diseases associated with protein kinase signaling dysfunction. Accordingly, without being bound by any theory, it is believed that inhibition of MAP4K1 could, for example, reverse or prevent the cellular dysfunction associated with perturbations of the INK signaling pathway, especially in T and B cells. Therefore, administration of a MAP4K1 inhibitor as described herein could provide a potential means to regulate MAPK signal transduction pathways, especially the INK pathway, and by extension provide a treatment for a variety of diseases and disorders including autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative, and cardiovascular diseases and disorders.
In addition, without being bound by theory, selective MAP4K1 inhibition, as provided by the Compounds of the Invention, may provide a novel means of cancer treatment.
Traditional signal transduction strategies relate to interference with the pathways that promote tumor cell proliferation or metastasis. The present invention provides instead a means of enhancing the activity and effectiveness of the body's T cells, for example, to overcome the immunosuppressive strategies used by many cancers. The U.S. Food and Drug Administration (FDA) has recently approved some monoclonal antibody-based treatments that achieve the same result by interfering with T-cell surface receptors which promote inhibition of TCR activity (e.g., anti-CTLA-4 and anti-PD-1 antibodies, marketed as Ipilimumab and Pembrolizumab, respectively). The success of the treatments demonstrate proof of the concept that cancer can be effectively treated by interfering with pathways which inhibit TCR signaling, Targeting these pathways using a small molecule inhibitor of MAP4K1 should produce improved results using more patient-friendly administration techniques.
Therefore, in the third aspect, the invention provides a method for the treatment or prophylaxis of a disease or disorder which may be ameliorated by modulating (e.g., inhibiting) MAP4K1-dependent signaling pathways, including the JNK pathway, e.g., autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative, and cardiovascular diseases and disorders, comprising administering to a patient in need thereof an effective amount of the compound of Formula I as described herein, in free or pharmaceutically acceptable salt form.
In particular embodiments, administration of the compound of Formula I results in enhanced T cell receptor (TCR) signaling, such as resulting in an enhanced T
cell-mediated immune response (e.g., increased T cell cytokine production).
In other particular embodiments, administration of the compound of Formula I
results in increased T cell resistance to PGE2-mediated T cell suppression.
The disease or disorder may be selected from the group consisting of:
neurodegenerative diseases, such as Parkinson's disease or Alzheimer's disease; stroke and associated memory loss; autoimmune diseases such as arthritis; allergies and asthma;
diabetes, especially insulin-resistant diabetes; other conditions characterized by inflammation, including chronic inflammatory diseases; liver ischemia;
reperfusion injury;
hearing loss or deafness; neural tube birth defects; obesity;
hyperproliferative disorders including malignancies, such as leukemias, e.g. chronic myelogenous leukemia (CML);
oxidative damage to organs such as the liver and kidney; heart diseases; and transplant rejections. In certain embodiments, the disease or disorder to be treated may also relate to impaired MAP4K1-dependent signaling. Impaired MAP4K1 signaling can lead to reduced immune cell, e.g. T and B cell, function which can permit or enhance the escape of nascent cancer cells from immune surveillance. Restoration of T and B cell function via treatment with a MAP4K1-inhibitor can therefore promote the clearance of carcinogenic and pre-carcinogenic cells from the body. Thus, in a particular embodiment, the invention provides a method for the treatment or prevention of hyperproliferative diseases, such as cancer, including melanomas, thyroid cancers, adenocarcinoma, breast cancer, central nervous system cancers such as glioblastomas, astrocytomas and ependymomas, colorectal cancer, squamous cell carcinomas, small and non-small cell lung cancers, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma and skin cancers. In particular embodiments, owing to the unique role of immune cell dysfunction in hematologic cancers, the invention provides a method of treatment or prevention of hematologic cancers such as leukemias, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, and multiple myeloma.
The MAP4K1 inhibitor compounds described herein for the treatment or prophylaxis of disease or disorder according to the foregoing methods may be used as a sole therapeutic agent or may be used in combination with one or more other therapeutic agents useful for the treatment of said diseases or disorders. Such other agents include inhibitors of other protein kinases in the JNK pathway, including, for example, inhibitors of INK (e.g., JNK1 or JNK2), MKK4, MKK7, p38, MEKK (e.g., MEKK1, MEKK2, MEKK5), and GCK, Therefore, in a particular embodiment, the MAP4K1 inhibitor of the invention may be administered in combination with inhibitors of INK (e.g., JNK1 or JNK2), MKK4, MKK7, p38, MEKK (e.g., MEKK1, MEKK2, MEKK5), and GCK.
In another aspect, the invention provides the following:
(0 the compound of Formula I as described herein, in free or pharmaceutically acceptable salt form, for use in any of the methods or in the treatment or prophylaxis of any disease or disorder as set forth herein, (ii) a combination as described hereinbefore, comprising a MAP4K1 inhibitor of the invention, e.g., the compound of Formula I as described herein, in free or pharmaceutically acceptable salt form and a second therapeutic agent useful for the treatment or prophylaxis of any disease or disorder set forth herein;
(iii) use of the compound of Formula I in free or pharmaceutically acceptable salt form, or the combination described herein, (in the manufacture of a medicament) for the treatment or prophylaxis of any disease or condition as set forth herein, (iv) the compound of Formula I in free or pharmaceutically acceptable salt form, the combination described herein or the pharmaceutical composition of the invention as hereinbefore described for use in the treatment or prophylaxis of any disease or condition as set forth herein.
GENERAL METHODS OF PREPARATION

The compounds, described herein, including those of general formula (I), intermediates and specific examples are prepared through the synthetic methods as depicted in Schemes 1 to 14. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling reagents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the present invention. The modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained using the general reaction sequences may be of insufficient purity. These compounds can be purified using any of the methods for purification of organic compounds known to persons skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.
General schemes A general approach for the preparation of compounds of the formulae (Ia) (wherein R5, R6, R7, A, E, F, D, Z, Q and n are as defined in the general description) is depicted in synthetic scheme 1.
Synthetic Scheme 1 Hal (R6)n WAN
' =R' (R6)n 0 r R7 (2) )1- elLX
'R' HZ substitution reaction 0 R N.6 (1) (3) 17 H2N,Q coupling coupling H2N.Q
(4 reaction reaction ) (4) Hal (R6)n n A)F'E
"Thr Q
(R6). R5): AN N.6 ZL
eLXFE
HZ .Q R7 (2) R5AN N.15 substitution reaction I7 (5) (la) The substitution reaction of compound of formula (1) (wherein R' = Me or Et) with halogen bearing compound of formula (2) in the presence of a suitable reagent and solvent yields the compound of formula (3). The reaction may be carried out in the presence of suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc., and the solvent can be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or a mixture thereof. The reaction can also be performed by Buchwald reaction using a suitable base such as tripotassium phosphate, sodium or potassium tert-butoxide, cesium carbonate, etc., in the presence of palladium acetate as catalyst and a suitable hindered ligand (eg.
XPhos, di-tBuXPhos, JohnPhos, DavePhos, Sphos, etc.) in an appropriate solvent such as toluene, 1,4-doxane, water or a mixture thereof (Ref: Angew. Chem. Int. Ed.
2006, 45, 4321) The coupling reaction of the ester of formula (3) with amine of formula (4) in the presence of a suitable reagent and solvent affords the compound of general formula (Ia).
The suitable base used in the reaction may be potassium tert-butoxide or trimethyl aluminium solution.
The coupling reaction may be carried out in a suitable solvent or mixture thereof. The suitable solvent may be selected from dichloromethane, THF, toluene, or a combination thereof Alternatively, the coupling reaction of compound of formula (1) with the amine of formula (4) gives amide of formula (5) which on substitution reaction with compound of formula (2) furnishes the compound of general formula (I).
A general approach for the preparation of compounds of the formulae (Ha) (wherein Rl, R2, R3, R4, R5, R6, A, F, Z, Q and n are as defined in the general description) (and P =
protecting group, like Boc or PMB) is depicted in synthetic scheme 2.
Synthetic Scheme 2 Hal R4 (R6)n AL
J:
(R6)n A-Fi2 4 Z 0 R N N Ri R p L .R, 15 (6) R31'' 1Link substitution reaction R1 N N R5 (1) 15 (7) H2N.r, coupling coupling H2N.Q
(4)-` reaction reaction (4) Hal R4 F'(--"R3 (R6 )n (R6)n I-' 6 ) R4 Z 0 HZ 0 i. substitution reaction deprotection R R1 NN:LR5 (5) H (Ha) The substitution reaction of compound of formula (1) (wherein R' = Me or Et) with halogen bearing compound of formula (6) in the presence of a suitable reagent and solvent yields the compound of formula (7). The reaction may be carried out in the presence of suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc., and the solvent can be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or a mixture thereof. The reaction can also be performed by Buchwald reaction using a suitable base such as tripotassium phosphate, sodium or potassium tert-butoxide, cesium carbonate, etc., in the presence of palladium acetate as catalyst and a suitable hindered ligand (eg.
XPhos, di-tBuXPhos, JohnPhos, DavePhos, Sphos, etc.) in an appropriate solvent such as toluene, 1,4-doxane, water or a mixture thereof The coupling reaction of the ester of formula (7) with amine of formula (4) in the presence of a suitable reagent and solvent directly affords the deprotected final compound of general formula (Ha). The suitable base used in the reaction may be potassium tert-butoxide or trimethyl aluminium solution. The coupling reaction may be carried out in a suitable solvent or mixture thereof The suitable solvent may be selected from dichloromethane, THF, toluene, or a combination thereof.
Alternatively, the coupling reaction of compound of formula (1) with the amine of formula (4) gives amide of formula (5) which on substitution reaction with compound of formula (6) followed by deprotection furnishes the compound of general formula (Ha). The reaction conditions for the alternative sequence may remain the same as described in scheme 1.
Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
A general approach for the preparation of compounds of the formulae (JIb) (wherein R5, R6, R7, A, E, F, D and n are as defined in the general description) is depicted in synthetic scheme 3.
Synthetic Scheme 3 F F
(R 6)n H2N OEt 6, (R 6, (9)0 /Or H F F (R \' I H F F
I OH N :Me0H NH2 0 coupling reaction 0 OEt NH3 HO N
TBDMS TBDMS o 0 (8) (10) (11) Hal (R6)n (R 6)n H F F
R5AN N b 117 (2) b ink)F'E 0 Burgess reagent 1.1 CN
in(ly'E
substitution R5 A N' X N. b reaction R5 N N' (12) R7 (11b) The benzoic acid derivative of formula (8) on coupling reaction with ethyl 2-(3-aminopheny1)-2,2-difluoroacetate (9) yields the amide derivative of formula

(10). The reaction may be carried out via acid chloride formation using oxalyl chloride or thionyl chloride followed by coupling with the amine in the presence of suitable base and solvent.
The suitable base for the reaction may be triethylamine, N,N-diisopropylethylamine, pyridine or DMAP and solvent may be selected from THF, chloroform, dichloromethane or 1,4-dioxane. The reductive amination and deprotection of compound of formula (10) using ammonia solution in methanol at elevated temperature (above 50 C) affords the compound of formula (11). Substitution of compound of formula (11) with halogen derivative (2) yields the compound of formula (12). The reaction may be carried out in the presence of suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc.;
and the solvent can be selected from DMF, DMSO, acetonitrile, 1,4-dioxane or a mixture thereof The amide group of compound of formula (12) converts to the nitrile group by reaction with Burgess Reagent to give compound of general formula (III)). The reaction may be carried out in a suitable solvent such as dichloromethane.
A general approach for the preparation of compounds of the formula (Ma) and (Mb) (wherein Rl, R2, R3, R4, R5, R6, A, F, Z, Q and n are as defined in the general description) (and wherein R' = Me or Et and P = protecting group, like Cbz, Boc or PMB) is depicted in synthetic scheme 4.
Synthetic Scheme 4 Hal eL,(1)1--R3 5)t 'L .-k-R2 1:1 N N Fit (6) HNQ (4) 1 ) (R6) 2 -, (R6), 0 i. triphosgene, solvent i. substitution reaction Z
ii. deprotection HZ H H ii. deprotection (13') (14') /
Hal ), )n protection ink)LxFLRR43 (R
A , 1µ-R2 H (R 0 .
(R6)n R- N N. R1 04 7 -12N0NyTh 'R0 N. , lr Q R4 -NH L
H H
P (6) R 3"¨r FlA i. (4) ' or (4) 0 ... R3_),FINA

, 0.
HZ substitution reaction R2---L J1, 5 ii.
deprotection R24 AR 5 (13) 15 (14) H
(111a) coupling HOAQ
reaction (4') (R6), (R6), , K
z'CNAQ z0N Q H
R4 H deprotection R4 E
R301' Link LA
R----c,I õ.:1...,5 R)r õ.(r.,5 RI N iN ri R 1 N iN ri 1) (15) H
(111b) The amino phenol compound of formula (13) on reaction with compound of formula (6) yields the compound of formula (14). The reaction may be carried out in the presence of suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride etc.; and the solvent can be selected from DMF, DMSO, toluene, acetonitrile, 1,4-dioxane or a mixture thereof. The amine compound of formula (14) on step wise reaction with triphosgene and amine of formula (4) in THF; followed by deprotection yields the urea derivative of general formula (Ma). Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc. Alternatively, Compound of general formula (Ma) may be synthesized by the reaction of a carbamate derivative of amine (4') with compound (14) in the presence of a suitable base and solvent. The suitable base for the reaction may be triethylamine, DIPEA, etc. and the suitable solvent may be DMSO. Compound of general formula (Ma) can also be synthesized by an alternative sequence of reaction starting from Z-protected analogue (13') of compound (13). The compound of formula (13') on step wise reaction with triphosgene and amine of formula (4) in THF; followed by Z-deprotection yields the urea derivative of formula (14'). Compound (14') on reaction with compound of formula (6) yields the compound general formula (Ma). The reaction conditions may remain same as discussed above.
Alternatively, the amine of formula (14) on reaction with acid compound of formula (4') yields the amide compound of formula (15). The coupling reaction may be carried out in the presence of suitable coupling agent such as HATU, EDCI.HC1 with or without HOBt, T3P or DCC. The reaction may be carried out in suitable solvent selected from THF, dichloromethane, dichloroethane, chloroform, 1,4-dioxane or a mixture thereof The compound of formula (16) on deprotection yields the compound of general formula (Mb).
Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
A general approach for the preparation of compounds of the formula (IIc) (wherein Rl, R2, R3, R4, R5, R6, A, F, Q and n are as defined in the general description) (and wherein R' = Me or Et; P = protecting group, like Boc or PMB) is depicted in synthetic scheme 5.
Synthetic Scheme 5 (R6)n H2N.Q (R6)n, (R6),, (4) nitro reduction _H2N..._TrH
" -rr N,Q
021N 0 coupling 02N Q

reaction (16) (17) (18) Hal (R6)n, (R6)n, ^¨R2 4 Q Q
,R F n FO
deprotection `---1\
catalyst, base, solvent Fit N 171 P H (19) (11c) The coupling reaction of the nitro ester of formula (16) with amine of formula (4) in the presence of a suitable reagent and solvent affords the compound of general formula (17).
The suitable base used in the reaction may be potassium tert-butoxide or trimethyl aluminium solution. The coupling reaction may be carried out in a suitable solvent or mixture thereof.
The suitable solvent may be selected from dichloromethane, THF, toluene, or a combination thereof Nitro reduction compound of formula (17) yields the amine of formula (18). The reaction may be carried out using iron powder in the presence of acetic acid or ammonium chloride in appropriate solvent such as methanol, ethanol, THF, water or a mixture thereof.
The substitution reaction of compound of formula (18) with halogen bearing compound of formula (6) in the presence of a suitable reagent and solvent yields the compound of formula (19). The reaction may be performed using Buchwald coupling method in the presence of suitable base, catalyst, ligand and solvent. The reaction may be performed using base such as sodium or potassium tert-butoxide, cesium or potassium carbonate, etc.
palladium acetate can be used as a catalyst along with a suitable ligand (eg. XPhos, t-BuXPhos, JohnPhos) and appropriate solvent can be selected from 1,4-dioxane, toluene, water or a mixture thereof.
The compound of formula (19) on deprotection yields the compound of general formula (IIc).
Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
A general approach for the preparation of compounds of the formula (lid) and (He), (III) and (IIg) (wherein 1V, R25 R35 R45 R55 65 K A, Q and n are as defined in the general description) (and P = protecting group, like Boc or PMB) is depicted in synthetic scheme 6.
Synthetic Scheme 6 n, Hal ?
51F..y (1,16) Hal 0 RR42 (1,16)n.
H H
(R6)11, B 3 .
H R5 N N (3c N,c) .0_11,11,Q
H R N N Ri 3y(x.,1,, 0 4 OH 0 base HO 0 substitution reaction Ri N N R5 Me0H
R iN R5 Boc õ1,...., solvent

11 N R- (24) (5a) P (21) p (22) H
i. methylamine soln 1 ii. deprotection deprotection i.
trimethylsilane, TEA
ii. deprotection (1,16)n, (1,16) 6 n.
(R6)n> H h (R)õ,,, H
H
--''---rr"µQ
....iiN,_ 4 OH 0--3-110 NµQ R4 0 0 0 R4 o- 0 Q

0 5 R H 0 Q NaBEI4 3 ^ R3..rk R1 NRNR-1 N:..R5 R 1.2 --.. -N N H
H
(11g) (Ile) (11d) R1 HN Not) 1,1' The compound of formula (5a) with phenolic hydroxyl group on substitution with halogen bearing compound of formula (20) yields the ether of formula (21). The reaction may be carried out in the presence of suitable base and solvent. Suitable base may be potassium carbonate, cesium carbonate, cesium fluoride etc. and the suitable solvent may be DMF, DMSO, 1,4-dioxane, etc. The compound of formula (21) on N-deprotection affords the compound of general formula (lid). Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
Alternatively compound of formula (21) on reaction with sodium borohydride in a suitable solvent yields the gives the hydroxyl derivative of formula (22). The suitable solvent for the reaction may be THF, methanol or a mixture thereof. The compound (22) undergoes further reduction in the presence of trimethylsilane and trifluoroacetic acid followed by N-deprotection to furnish the compound of general formula (III). Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
The compound of general formula (lid) on reduction using sodium borohydride yields the compound of general formula (lie). The suitable solvent for the reaction may be THF, methanol or a mixture thereof In another embodiment the compound of formula (5a) on reaction with formyl derivative of formula (23) in the presence of base and solvent affords the compound of formula (24). Suitable base may be potassium carbonate, cesium carbonate, cesium fluoride etc. and the suitable solvent may be DMF, DMSO, 1,4-dioxane, etc.
The reaction of compound of formula (24) with methylamine solution in the presence of catalytic amount of acetic acid followed by N-deprotection yields the compound of general formula (hg). Deprotection reaction may be carried out using hydrochloric acid or trifluoroacetic acid in suitable solvent such as methanol, ethanol, ethyl acetate, 1,4-dioxane, dichloroethane, etc.
A general approach for the preparation of compounds of the formula (2a) (wherein Rl, R2, R3 and R4 are as defined in the general description) (and P =
protecting group, like Boc or PMB) is depicted in synthetic scheme 7.
Synthetic Scheme 7 CI

Rli<OH N
CI HN R3 CI Ri CI
N JJ:0 (26) R40 BBr3 N N 2 H R N-protecting 0 R4 p 1 R2 agent N
:(_Rs' I base, solventl I I>c ,OH solvent CI (28) R1 Lz.., N CI N N base, solvent N N
H R3 Ra NjC9-1 1; R-(25) (27) I R> I<Br N N (2a) H R3 Fe (29) 4,6-Dichloro-5-methoxypyrimidine (25) on reaction with appropriately substituted ethanolamine derivative of formula (26) in the presence of suitable base and solvent yields the compound of formula (27). The suitable base for the reaction may be potassium carbonate and solvent may be DMF or 1,4-dioxane. In attempt to cyclize the compound of formula (27) using boron tribromide in a suitable solvent such as THF, affords either of the compound of formula (28) or (29) or a mixture thereof in varied ratio, which on reaction with a suitable protecting agent in the presence of a suitable base and solvent furnishes the compound of formula (2a). The N-protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-C1). The suitable base for the reaction may be triethylamine, DIPEA, DMAP, or a mixture thereof and solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF or a mixture thereof A general approach for the preparation of compounds of the formula (2b) (wherein R3 and R4 are as defined in the general description) is depicted in synthetic scheme 8.
Synthetic Scheme 8 CI CI
H01)(0 CI 0 CI
N

AlC13 OH R3R4 (31) N
A NOR
PMBA R-NCI DCE I TPP, DEAD, solvent R3 R4 base, solvent I
N CI N -CI N N
PMB
(25) (30) (32) (2b) The demethylation reaction of 4,6-dichloro-5-methoxypyrimidine (25) with aluminium chloride in a suitable solvent such as dichloroethane yields 4,6-dichloropyrimidin-5-ol (30) which on reaction with appropriately substituted glycolate ester of formula (31) under Mitsunobu condition affords the ethyloxy-ester of formula (32). The Mitsunobu reaction may be carried out in the presence of triphenylphosphine, diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) in THF as a solvent. The compound of formula (32) on reaction with 4-methoxybenzylamine (PMBA) in the presence of a suitable base and solvent at elevated temperature (more than 100 C) affords the cyclized compound of formula (2b). The suitable base for the reaction may be triethylamine, DIPEA, DMAP, or a mixture thereof and solvent can be selected from DMF, 1,4-dioxane, DMSO or a mixture thereof A general approach for the preparation of compounds of the formula (2d) (wherein Rl and R2, are as defined in the general description) (and P = protecting group, like Boc or PMB) is depicted in synthetic scheme 9.
Synthetic Scheme 9 Rõ1 R2 H2N)OH CI 1 CI
N'(:) (26a), Ne-CfRi R2 OH , B131-3 NI pi R`
k substitution I )10H solvent N CI reaction N N )\IN)C)11 H H
(25) (27a) (33) Cl CI
N-protecting H J
, c,0 agent N 1IRNI ' TPP, DEAD N
I el R ' I
base, solvent N " '-'OH THF N^N<R2 P
(34)1" (2d) 4,6-Dichloro-5-methoxypyrimidine (25) on reaction with appropriately substituted ethanolamine derivative of formula (26a) in the presence of suitable base and solvent yields the compound of formula (27a). The suitable base for the reaction may be potassium carbonate and solvent may be DMF or 1,4-dioxane. In attempt to cyclize the compound of formula (27a) using boron tribromide in a suitable solvent such as THF, affords the compound of formula (33) which on N-protection with a suitable protecting agent in the presence of suitable base and solvent furnishes the compound of formula (34).
The N-protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-C1). The suitable base for the reaction may be triethylamine, DIPEA, DMAP, or a mixture thereof and solvent can be selected from THF, dichloromethane, 1,4-dioxane, DMF
or a mixture thereof The compound of formula (34) on self-Mitsunobu reaction yields the cyclized compound of formula (2d).

A general approach for the preparation of compounds of the formula (2e) and (21) (wherein P = protecting group, like Boc or PMB) is depicted in synthetic scheme 10.
Synthetic Scheme 10 Br N-protecting Br Br OH bromination OH Br 'Br (37) agent n (1(:) C 1 , 1 j , 1 j N NH2 base, solvent N N
base, solvent N N
HBr N H
(35) (36) (38) (2e) ClAci base, solvent (39) Br Br N-protecting 0 agent 0 1 1 1 1 N 0 base, solvent N N 0 N

(40) (2f) Bromination of 2-aminopyridin-3-ol (35) using bromine in absolute ethanol yields the hydrobromide salt of 2-amino-4-bromopyridin-3-ol (36). The compound (36) on reaction with dibromoethane (37) in the presence of suitable base and solvent at elevated temperature (>50 C) yields 8-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (38). The suitable base for the reaction may be potassium or cesium carbonate and solvent can be selected from acetonitrile, dichloromethane, 1,4-dioxane, THF or a mixture thereof Compound (38) on N-protection with a suitable protecting agent in the presence of suitable base and solvent furnishes the compound of formula (2e). The N-protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-C1). The suitable base for the reaction may be LiHMDS, triethylamine, DIPEA, DMAP, or a mixture thereof The suitable solvent 15 can be selected from THF, dichloromethane, 1,4-dioxane, DMF or a mixture thereof.
Alternatively, 2-amino-4-bromopyridin-3-ol hydrobromide (36) undergoes cyclization with chloroacetyl chloride (39) at elevated temperature (> 50 C) in the presence of suitable base solvent to yield 8-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (40). The suitable base for the reaction may be sodium bicarbonate and solvent may be 2-butanone, water or a mixture thereof Compound (40) on N-protection with a suitable protecting agent in the presence of suitable base and solvent furnishes the compound of formula (2f). The N-protecting agent can be tert-butyl dicarbonate (Boc anhydride) or 4-methoxybenzylchloride (PMB-C1).
The suitable base for the reaction may be cesium carbonate, and solvent can be selected from THF, 1,4-dioxane, DMF or a mixture thereof.
A general approach for the preparation of compounds of the formula (2g) is depicted in synthetic scheme 11.

Synthetic Scheme 11 ci ci OH CI 0 CI 0 CI, Mg õ, /
N 0 (42) " 1 oxidation N 1 PMBA N
N CI solvent ks.tzõ. 1 solvent, ht N CI N CI ven ea N N
(41) (43) (44) (2g) PMB
4,6-Dichloropyrimidine-5-carbaldehyde (41) on reaction with vinylmagnesium chloride (42) in THF affords 1-(4,6-dichloropyrimidin-5-yl)prop-2-en- 1 -ol (43) which on oxidation yields 1-(4,6-dichloropyrimidin-5-yl)prop-2-en-1-one (44). The oxidation reaction may be carried out using Des -Martin periodinane in dichloromethane. The compound of formula (44) on reaction with 4-methoxybenzylamine in the presence of a suitable base (optional) and solvent at elevated temperature (> 45 C) affords the cyclized compound of formula (2g). The suitable base for the reaction may be triethylamine, DIPEA, DMAP, or a mixture thereof and solvent can be selected from DMF, 1,4-dioxane, DMSO or a mixture thereof A general approach for the preparation of compounds of the formula (la) (wherein R6 and n are as defined in the general description) and X is halogen is depicted in synthetic scheme 12.
Synthetic Scheme 12 (R6)n \ 16 OH (R6)nv (R 6 i \
(46) n Me0H/H+ , 4r0, 'W 0H
Ph 0 xl>1(3F1 base, solve: Ph(:) 0 0 (48) 0 ( (45) 47) 1 H2/Pd n (R6) (R6) HO ...
nrcy HO
f>
OH Me0H/H+
N inr0, (49) (1a) The compound of formula (45) on reaction with benzyl alcohol (46) in the presence of suitable base and solvent yields the compound of formula (47). The suitable base for the reaction may be potassium tert-butoxide and solvent may be DMSO. The compound of formula (47) undergoes esterification using sulfuric acid in methanol under reflux conditions to give the compound of formula (48) which on palladium (palladium on carbon 5-10%, 50%
wet) catalyzed hydrogenation affords the compound of formula (la). The hydrogenation reaction may be performed in a suitable solvent such as ethanol, methanol, ethyl acetate, or a combination thereof Alternatively, the benzoic acid of formula (49) on esterification reaction using sulfuric acid in methanol affords the methyl ester of formula (la).

A general approach for the preparation of compounds of the formula (la) (wherein R6 and n are as defined in the general description) and X is halogen is depicted in synthetic scheme 13.
Synthetic Scheme 13 (R6) (R6)n (R6)n, n 0 H H2N (i) NaNO2, HCI
+
HS2 I Me0H/H
I
HS

(51) (50) (52) (1 b) Et0S- K+
The amino benzoic acid derivative of formula (50) on diazotization reaction using sodium nitrite and hydrochloric acid followed by reaction with potassium ethyl xanthate (51) in the presence of a suitable base such as sodium bicarbonate yields the thiophenol-benzoic acid of formula (52). The suitable solvent for the reaction is water. The benzoic acid of .. formula (52) on esterification reaction using sulfuric acid in methanol affords the methyl ester of formula (lb).
A general approach for the preparation of compounds of the formula (4a) (wherein R8 and R9 are as defined in the general description) is depicted in synthetic scheme 14.
Synthetic Scheme 14 p18 H
nitro H2N R8 9 reduction Hal ___________________________ (54) JI
substitution reaction (53) (55) (4a) The compound of formula (53) (wherein 'hal' = halogen) on reaction with compound of formula (54) affords the compound of formula (55). The reaction may be done in the presence of suitable base and solvent. The suitable base may be sodium, potassium or cesium carbonate, sodium or potassium tert-butoxide, sodium hydride, cesium fluoride, etc. The solvent may be selected from THF, DMF, toluene, DMSO, chloroform, dichloromethane, acetonitrile, dichloroethane, 1,4-dioxane or a mixture thereof Nitro reduction of compound (55) yields the compound of formula (4a). The reaction may be carried out using iron powder in the presence of acetic acid or ammonium chloride in appropriate solvent such as methanol, ethanol, THF, water or a mixture thereof. Nitro reduction can also be done by palladium (palladium on carbon 5-10%, 50% wet) catalyzed hydrogenation. The hydrogenation reaction may be performed in a suitable solvent such as ethanol, methanol, ethyl acetate, or a combination thereof Intermediates Methods for the Synthesis of Intermediate A
Intermediate Al tert-Butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate CI
NICI
k j N N
Boc Step 1: 2((6-Chloro-5-methoxypyrimidin-4-yl)amino)ethanol CI
NCNNOH
H
To a stirred solution of 4,6-dichloro-5-methoxypyrimidine (10 g, 55.8 mmol) in 1,4-dioxane (100 mL) were added ethanolamine (3.42 mL, 56.9 mmol) and potassium carbonate (9.26 g, 67.0 mmol) and the mixture was refluxed at 125 C for 8 h. The mixture was cooled to RT
and partitioned between ethyl acetate and water. The organic layer was separated and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to yield 10.5 g of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 3.44 (t, J =
5.6 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 3.72 (s, 3H), 4.80-4.85 (br s, 1H), 7.55 (s, 1H), 8.04 (s, 1H); ESI-MS (m/z) 204 (M+H)+.
Step 2: 4-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine CI
N0j I
N N
H
A mixture of 2((6-chloro-5-methoxypyrimidin-4-yl)amino)ethanol (step 1 intermediate) (6.0 g, 29.4 mmol) and boron tribromide in dichloromethane (1.0M, 100 mL) was refluxed for 3-4 h. The mixture was concentrated and the residue was diluted with water. The solution was .. neutralized with saturated sodium bicarbonate solution and the product was extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 4.0 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 4.02 (t, J
= 10.4 Hz, 2H), 4.66 (t, J= 10.0 Hz, 2H), 8.46 (s, 1H), 10.31 (br s, 1H).
Step 3: tert-Butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate To a stirred solution of 4-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (step 2 intermediate) (4.0 g, 23.3 mmol) in dichloromethane (40 mL) were added di-tert-butyl dicarbonate (Boc anhydride) (7.6 g, 34.9 mmol) at 0 C followed by triethylamine (9.7 mL) and the mixture was stirred at 0 C for 3 h and then 1 h at RT. DMAP (1.4 g, 11.6 mmol) was added in small portions to the reaction mixture at 0 C and stirred for 1 h at RT. The solvent was evaporated under reduced pressure and the residue was diluted with ice-water mixture.
The aqueous mixture was neutralized using sodium bicarbonate solution and the product was extracted in dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 1.5 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.49 (s, 9H), 3.92 (t, J= 4.8 Hz, 2H), 4.12 (t, J= 4.4 Hz, 2H), 8.31 (s, 1H).
Intermediate A2 4-Chloro-8-(4-methoxybenzy1)-6H-pyrimido [5,4-b] [1,4] oxazin-7(8H)-one CI
NO
k 1 N LBO
Step 1: 4,6-Dichloropyrimidin-5-ol CI
NOH
I
N CI
A suspension of 4,6-dichloro-5-methoxypyrimidine (2.0 g, 11.2 mmol) and aluminum chloride (2.0 g, 15.0 mmol) in DCE (10 mL) was heated to reflux for 3-4 h. The mixture was concentrated under reduced pressure, cooled to 0 C and quenched with ice-water. The mixture was diluted with 1M HC1 (10 mL). The precipitated solid was filtered and dried well to yield 1.0 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 8.39 (s, 1H), 11.67 (br s, 1H).
Step 2: Ethyl 2-((4,6-dichloropyrimidin-5-yl)oxy)acetate 0, N
I
N CI
To a mixture of 4,6-dichloropyrimidin-5-ol (step 1 intermediate) (4.0 g, 24.2 mmol), ethyl glycolate (3.02 g, 29.1 mmol) and triphenylphosphine (12.7 g, 48.5 mmol) in THF (40 mL) was slowly added diethyl azodicarboxylate (DEAD) (9.8 g, 48.5 mmol) at RT. The mixture was stirred overnight at RT. The mixture was diluted with diethyl ether and filtered off the precipitated solid. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 450 mg of the desired compound. 1H
NMR (400 MHz, DMSO-d6) 6 1.34 (t, J= 7.2 Hz, 3H), 4.31 (q, J= 7.2 Hz, 2H), 4.80 (s, 2H), 8.51 (s, 1H).

Step 3: 4-Chloro-8-(4-methoxybenzy1)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one To a solution of ethyl 2((4,6-dichloropyrimidin-5-yl)oxy)acetate (step 2 intermediate) (1.0 g, 3.98 mmol) in DMF (10 mL) were added 4-methoxybenzylamine (818 mg, 5.97 mmol) followed by DIPEA (513 g, 3.98 mmol) at 0 C. The mixture was stirred overnight at RT and the 1 h at 130 C. The mixture was cooled and quenched with water. The aqueous mixture was extracted twice with dichloromethane. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to yield 660 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 3.71 (s, 3H), 5.05 (s, 2H), 5.12 (s, 2H), 6.86 (d, J= 8.8 Hz, 2H), 7.29 (d, J= 8.8 Hz, 2H), 8.44 (s, 1H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 1.
Table 1: Chemical name, structure and analytical data of Intermediates A15-A17 Intermediate No. Chemical Name and Structure Analytical Data CI
1H NMR (400 MHz, DMSO-d6) 6 1.56 Al5 N:X 1 N NO (d, J = 6.8 Hz, 3H), 3.71 (s, 3H), 5.12 PMB (d, J = 6.8 Hz, 3H), 6.86 (d, J = 8.4 Hz, (R)-4-Chloro-8-(4-methoxybenzy1)- 2H), 7.27 (d, J = 8.8 Hz, 2H), 8.47 (s, 6-methyl-6H-pyrimido [5,4 - 1H); APCI-MS (m/z) 320 (M+H)+.
b][1,4]oxazin-7(8H)-one CI
Nicc' 1H NMR (400 MHz, DMSO-d6) 6 1.66 r (d, J = 6.8 Hz, 3H), 3.79 (s, 3H), 4.90 N
PMB (q, J= 6.8 Hz, 1H), 5.24 (s, 2H), 6.83-(S)-4-Chloro-8-(4-methoxybenzy1)- 6.86 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H), 6-methyl-6H-pyrimido [5,4 - 8.45 (s, 1H); APCI-MS (m/z) b][1,4]oxazin-7(8H)-one (M+H)+.
CI
NIC):( N N 0 1H NMR (400 MHz, DMSO-d6) 6 1.61 Al7 (s, 6H), 3.79 (s, 3H), 5.24 (s, 2H), 6.84 PMB (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 4-Chloro-8-(4-methoxybenzy1)-6,6- 2H), 8.44 (s, 1H); APCI-MS (m/z) 334 dimethy1-6H-pyrimido [5,4- (M+H)+.
b][1,4]oxazin-7(8H)-one Intermediate A3 (S)-tert-Butyl 4-chloro-6-methyl-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate CI
N
I
N N
60c Step 1: (S)-1-((6-Chloro-5-methoxypyrimidin-4-yl)amino)propan-2-ol CI
NrO
N N'()E1 H I
To a stirred solution of 4,6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol) in 1,4-dioxane (50 mL) were added potassium carbonate (4.6 g, 33.5 mmol) followed by (S)-(+)-1-amino-2-propanol (2.3 g, 30.7 mmol) at RT. The resultant mixture was stirred at 125 C
for 8 h. The mixture was cooled to RT and diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 4.85 g of the desired compound.
1H NMR (400 MHz, DMSO-d6) 6 1.05 (d, J = 6.4 Hz, 3H), 3.28-3.34 (m, 2H), 3.73 (s, 3H), 3.78-3.87 (m, 1H), 4.77 (d, J = 4.8 Hz, 1H), 7.46 (t, J = 5.6 Hz, 1H), 8.04 (s, 1H); ESI-MS
(m/z) 218 (M+H)+.
Step 2: (S)-4-((2-Bromopropyl)amino)-6-chloropyrimidin-5-ol CI
NOH
N Br H I
A mixture of (S)-1-((6-chloro-5-methoxypyrimidin-4-yl)amino)propan-2-ol (step 1 intermediate) (4.8 g, 22.1 mmol) and boron tribromide (1M in dichloromethane, 25 mL) was heated at 80 C for 18 h. The solvent was removed under reduced pressure and the residue was quenched with ice-cooled water. The aqueous solution was neutralized using sodium bicarbonate and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 3.9 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.63 (d, J= 6.4 Hz, 3H), 3.58-3.64 (m, 1H), 3.72-3.79 (m, 1H), 4.39-4.47 (m, 1H), 7.48 (t, J= 5.6 Hz, 1H), 7.86 (s, 1H), 9.99 (br s, 1H).
Step 3: (S)-tert-Butyl 4-chloro-6-methyl-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate The titled compound was prepared by the reaction of (S)-4-((2-bromopropyl)amino)-6-chloropyrimidin-5-ol (step 2 intermediate) (500 mg, 2.69 mmol) with di-tert-butyl dicarbonate (881 mg, 4.84 mmol) in the presence of DMAP (296 mg, 2.48 mmol) in dichloromethane (10 mL) as per the procedure described in step 3 of Intermediate Al to yield 154 mg of the compound. 41 NMR (400 MHz, DMSO-d6) 6 1.50 (s, 9H), 1.63 (d, J =
6.8 Hz, 3H), 3.57-3.63 (m, 1H), 3.75-3.81 (m, 1H), 4.39 (q, J= 6.8 Hz, 1H), 8.27-8.33 (m, 1H); ESI-MS (m/z) 285 (M)+.
The chemical structure, name and analytical data of the intermediate prepared by .. following the procedure described above are given below in Table 2.
Table 2: Chemical name, structure and analytical data of Intermediate A10 Intermediate No. Chemical Name and Structure Analytical Data CI
N y:' ) = 'N
I 1H NMR (400 MHz, DMSO-d6) 6 1.51 Al 0 N N
(s, 9H), 1.63 (d, J= 6.8 Hz, 3H), 3.57-6oc (R)-tert-Butyl 4-chloro-6-methyl- ' (q J =6.8 Hz, 1H), 8.30-8.34 (m, 1H).
6H-pyrimido[5,4-b][1,4]oxazine- ' 8(7H)-carboxylate Intermediate A4 tert-Butyl 4-chloro-7,7-dimethy1-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate CI
N ,C).
I
N N
I3oc Step 1: 246-Chloro-5-methoxypyrimidin-4-yl)amino)-2-methylpropan-1-ol N CXO
I V
N N.,OH
H
To a stirred solution of 4,6-dichloro-5-methoxypyrimidine (5.0 g, 27.9 mmol) in 1,4-dioxane (50 mL) were added potassium carbonate (4.6 g, 33.5 mmol) followed by 2-amino-methylpropanol (2.71 mL, 28.4 mmol) at RT. The resultant mixture was stirred at 125 C for 8 h. The mixture was cooled to RT and diluted with ethyl acetate and water.
The layers were separated and the organic layer was washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 3.5 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.37 (s, 6H), 3.50 (d, J = 5.6 Hz, 2H), 3.74 (s, 3H), 5.10 (t, J= 6.0 Hz, 1H), 6.30 (s, 1H), 8.06 (s, 1H).
Step 2: 4-Chloro-6-((1-hydroxy-2-methylpropan-2-yl)amino)pyrimidin-5-ol CI
NOH
I V
N N,OH
H
To a solution of 2-((6-chloro-5-methoxypyrimidin-4-yl)amino)-2-methylpropan-1-01 (step 1 intermediate) (3.5 g, 15.1 mmol) in dichloromethane (35 mL) was added boron tribromide (1M in THF, 75.8 mL) at 0 C and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with methanol at 0 C and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution.
The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to yield 2.5 g of the desired compound.
41 NMR (400 MHz, DMSO-d6) 6 1.36 (s, 6H), 3.48 (s, 2H), 5.13-5.15 (br s, 1H), 6.11 (s, 1H), 7.88 (s, 1H), 9.97 (s, 1H).
Step 3: tert-Butyl (6-chloro-5 -hydroxypyrimidin-4-y1)(1 -hydroxy-2-methylprop an-2-yl)carbamate CI
NOH
I K,OH
N N
60c To a stirred solution of 4-chloro-6-((1-hydroxy-2-methylpropan-2-yl)amino)pyrimidin-5-ol (step 2 intermediate) (2.5 g, 11.4 mmol) in dichloromethane (25 mL) were added di-tert-butyl dicarbonate (2.5 g, 11.4 mmol) at 0 C followed by triethylamine (2.4 mL, 17.1 mmol) and the mixture was stirred at RT for 15 h. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 1.9 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.36 (br s, 6H), 1.50 (br s, 9H), 3.50 (d, J= 6.0 Hz, 2H), 5.06 (t, J= 10.0 Hz, 1H), 6.55 (s, 1H), 8.20 (s, 1H).
Step 4: tert-Butyl 4-chloro-7,7-dimethy1-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate To a stirred solution of tert-butyl (6-chloro-5-hydroxypyrimidin-4-y1)(1-hydroxy-2-methylpropan-2-yl)carbamate (step 3 intermediate) (1.9 g, 5.97 mmol) in anhydrous THF (20 mL) were added triphenylphosphine (1.88 g, 7.18 mmol) and diisopropyl azodicarboxylate (DIAD) (1.39 mL, 7.17 mmol) at 0 C under nitrogen atmosphere. The mixture was stirred for 1 h at 0 C. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 350 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.36 (s, 6H), 1.51 (s, 9H), 4.13 (s, 2H), 8.19 (s, 1H); ESI-MS (m/z) 300 (M+H)+.

The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 3.
Table 3: Chemical name, structure and analytical data of Intermediates A5-A6 and All-A14 Intermediate Chemical Name and Structure Analytical Data No.
CI
k N (),, lti NMR (400 MHz, DMSO-d6) 6 1.33 AS
(d, J = 5.6 Hz, 3H), 1.52 (s, 9H), 4.24 N N
60c (dd, J1 = 2.0 Hz, J2 = 11.2 Hz, 1H), (R)-tert-Butyl 4-chloro-7-methyl- 4.36-4.39 (m, 1H), 4.58-4.61 (m, 1H), 6H-pyrimido[5,4-b][1,4]oxazine- 8.55 (s, 1H).
8(7H)-carboxylate CI
NC)l 1F1 NMR (400 MHz, DMSO-d6) 6 1.34 J, ). (d, J = 5.2 Hz, 3H), 1.50 (s, 9H), 4.24 A6 N N "i/ (dd, J1 = 2.0 Hz, J2 = 11.2 Hz, 1H), Boc 4.36-4.39 (m, 1H), 4.58-4.61 (m, 1H), (S)-tert-Butyl 4-chloro-7-methyl-8' 55 (s' ' 1H). ESI-MS (m/z) 285 6H-pyrimido[5,4-b][1,4]oxazine- +
(M+H) .
8(7H)-carboxylate CI
NJ:CI
1 Al 1 1F1 NMR (400 MHz, DMSO-d6) 6 0.97 (t, J = 7.6 Hz, 3H), 1.51 (s, 9H), 1.75-N N
Boc 1.79 (m, 1H), 2.50-2.58 (br s, 2H), (R)-tert-Butyl 4-chloro-7-ethyl-6H- 4.40-4.52 (br s, 2H), 8.55 (s, 1H); ESI-PYrimido[5,4-b][1,4]oxazine-8(7H)- MS (m/z) 300 (M+H)t carboxylate Cl 1F1 NMR (400 MHz, DMSO-d6) 6 0.91 N:i ) (t, J = 7.6 Hz, 3H), 1.50 (s, 9H), 2.49-Al2, N N ." 2.59 (m, 2H), 4.26 (dd, J1 = 2.4 Hz, .1-2 Boc = 11.2 Hz, 1H), 4.42 (t, J = 6.8 Hz, (S)-tert-Butyl4-chloro-7-ethy1-6H- 1H), 4.50 (dd, J1 = 1.2 Hz, J2 = 11.2 pyrimido[5,4-b][1,4]oxazine-8(711)- Hz, 1H), 8.55 (s, 1H); ESI-MS (m/z) carboxylate 300 (M+H)+.
CI
1F1 NMR (400 MHz, DMSO-d6) 6 0.93 NtC
N N
1 (d, J = 6.8 Hz, 3H), 1.04 (d, J =
6.8 Hz, A13, 3H), 1.49 (s, 9H), 1.72-1.74 (m, 1H), Boc (R)-tert-Butyl 4-chloro-7-isopropyl-2.38 (d, J = 3.6 Hz, 2H), 2.43 (d, J =
6H-pyrimido[5,4-b][1,4]oxazine-6.4 Hz, 1H),+ 8.55 (s, 1H); ESI-MS
8(711)-carboxylate (m/z) 313 (MY.
CI
NA0 ), 1F1 NMR (400 MHz, DMSO-d6) 6 0.93 Al4 N N õr (d, J = 6.8 Hz, 3H), 1.05 (d, J =
6.8 Hz, Boc 3H), 1.51 (s, 9H), 1.70-1.80 (m, 2H), (S)-tert-Butyl 4-chloro-7-isopropyl- 2.50-2.51 (m, 2H), 8.55 (s, 1H); ESI-6H-pyrimido[5,4-b][1,4]oxazine- MS (m/z) 314 (M+H)+.
8(7H)-carboxylate Intermediate A7 tert-Butyl 8-bromo-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate Br .,0 1 j 1\111 Boc Step 1: 2-Amino-4-bromopyridin-3-ol hydrobromide Br OH
, 1 -1\1NH2 HBr To a solution of 2-aminopyridin-3-ol (45 g, 409 mmol) in absolute ethanol (225 mL) at 0-10 C was drop wise added bromine (64 mL, 818 mmol) and the mixture was stirred for 3 days at RT. The solvent was removed under reduced pressure at low temperature and the residue was cooled to 0 C. Ethyl acetate was added to the residue and stirred for 1 h. The solid was filtered and dried well to yield 48 g of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 5.94 (br s, 2H), 6.65 (d, J = 5.6 Hz, 1H), 7.23 (d, J= 5.6 Hz, 1H).
Step 2: 8-Bromo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine Br k j N N
H
To a solution of 2-amino-4-bromopyridin-3-ol hydrobromide (step 1 intermediate) (15 g, 58.6 mmol) in acetonitrile (150 mL) were added cesium carbonate (57.1 g, 175 mmol) followed by 1,2-dibromoethane (16.4 g, 87.7 mmol) and the mixture was refluxed for 48 h.
The mixture was filtered and the filtrates was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 3.0 g of the titled compound. 1H NMR (400 MHz, DMSO-d6) 6 3.33-3.43 (m, 2H), 4.13-4.20 (m, 2H), 6.71 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 7.40 (d, J = 5.2 Hz, 1H); ESI-MS (m/z) 215 (M+H)+.
Step 3: tert-Butyl 8-bromo-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate To a solution of 8-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (step 2 intermediate) (2.1 g, 9.76 mmol) in anhydrous THF (20 mL) were dropwise added lithium bis(trimethylsilyl)amide (LiHMDS) (1M, 11.6 mL, 11.7 mmol) followed by di-tert-butyl dicarbonate (3.3 mL, 14.6 mmol) at 0 C and the mixture was stirred at the same temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 2.4 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.46 (s, 9H), 3.86 (d, J = 4.4 Hz, 2H), 4.35 (d, J = 4.4 Hz, 2H), 7.38 (d, J = 5.2 Hz, 1H), 7.81 (d, J= 5.2 Hz, 1H);
ESI-MS (m/z) 316 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 4.
Table 4: Chemical name, structure and analytical data of Intermediates A26 Intermediate No. Chemical Name and Structure Analytical Data BrO
1H NMR (400 MHz, DMSO-d6) 6 1.46 N N
(s, 9H), 3.81-3.86 (m, 2H), 4.23-4.28 A26 Boc (m, 2H), 7.59 (d, J = 2.4 Hz, 1H), 8.04 tert-Butyl 7-bromo-2H-pyrido[3' 2-(d, J = 2.0 Hz, 1H); ESI-MS (m/z) 215 b][1 ,4]oxazine- 4 (3 H)-c arb oxylate (M+H-Boc)+.
Intermediate A8 8-Bromo-4-(4-methoxybenzy1)-2H-pyrido [3,2-b] [1,4]oxazin-3 (4H)-one Br I
1\1 N
PM B
Step 1: 8-Bromo-2H-pyrido [3,2-b] [1,4]oxazin-3(4H)-one Br I
) H
To a solution of 2-amino-4-bromopyridin-3-ol hydrobromide (step 1-Intermediate A7) (12 g, 63.4 mmol) in a mixture of 2-butanone and water (1:1, 120 mL) was added aqueous solution of sodium bicarbonate (16 g, 190 mmol) at 0 C and the mixture was stirred for 10 min. Chloroacetyl chloride (7.16 g, 63.4 mmol) was added to the mixture and stirred for 3-4 h at 0 C. Then the mixture was heated to 80 C and stirred for 10 h. The mixture was cooled to RT and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 2.5 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 4.77 (s, 2H), 7.26 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 11.44 (s, 1H); ESI-MS (m/z) 229 (M+H)+.

Step 2: 8-Bromo-4-(4-methoxybenzy1)-2H-pyrido [3,2-b] [1,4]oxazin-3 (4H)-one To a solution of 8-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (step 1 intermediate) (250 mg, 1.09 mmol) in DMF (5.0 mL) were added cesium carbonate (709 mg, 2.18 mmol) followed by 4-methoxybenzyl chloride (256 mg, 1.63 mmol) and the mixture was stirred for 3 h at RT. The mixture was quenched with water and the product was extracted twice in ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 270 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 3.78 (s, 3H), 4.80 (s, 2H), 5.30 (s, 2H), 6.83 (d, J = 5.2 Hz, 2H), 7.16 (d, J = 5.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.86 (d, J= 5.2 Hz, 1H).
Intermediate A9 4-Chloro-8-(4-methoxybenzy1)-7,8-dihydropyrido [2,3 -d]pyrimidin-5 (6H)-one N
I
NI\I
PMB
Step 1: 1-(4,6-Dichloropyrimidin-5-yl)prop-2-en-1-ol CI OH
N ' I
N CI
To a stirred solution of 4,6-dichloropyrimidine-5-carbaldehyde (10 g, 56.5 mmol) in anhydrous THF (100 mL) was slowly added vinylmagnesium chloride (1M, 67.6 mL, 67.8 mmol) at -20 C and the mixture was stirred for 3 h at RT. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate.
The solution was filtered and concentrated to yield 5.0 g of the desired compound. 1H NMR
(400 MHz, DMSO-d6) 6 5.36-5.39 (m, 1H), 5.43 (s, 1H), 5.90-5.92 (br s, 1H), 6.15-6.23 (m, 1H), 8.73 (s, 1H).
Step 2: 1-(4,6-Dichloropyrimidin-5-yl)prop-2-en-1-one ci 0 ))N ' I
N CI
To a stirred solution of 1-(4,6-dichloropyrimidin-5-yl)prop-2-en-1-ol (step 1 intermediate) (100 mg, 0.49 mmol) in dichloromethane (5.0 mL) was added Dess¨Martin periodinane (415 mg, 0.97 mmol) at 0 C and the mixture was stirred overnight at RT. The mixture was filtered through celite and the filtrate was washed with water. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to yield 20 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 6.10 (d, J = 17.6 Hz, 1H), 6.33 (d, J = 10.8 Hz, 1H), 6.62-6.69 (m, 1H), 8.89 (s, 1H).
Step 3: 4-Chloro-8-(4-methoxybenzy1)-7,8-dihydropyrido [2,3 -d]pyrimidin-5 (6H)-one To a solution of 1-(4,6-dichloropyrimidin-5-yl)prop-2-en-1-one (step 2 intermediate) (1.1 g, 5.40 mmol) in DMF (28 mL) was added 4-methoxybenzylamine (1.1 g, 8.12 mmol) at RT.
The mixture was stirred overnight at 50 C. The mixture was cooled and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate.
The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to yield 900 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 3.29 (t, J = 6.0 Hz, 2H), 3.78-3.82 (m, 5H), 4.66 (d, J = 5.6 Hz, 2H), 6.89 (dd, ./i = 2.0 Hz, .1-2 = 6.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 8.38 (s, 1H).
Intermediate A 1 8 (R)-te rt-Butyl 4-chloro-7-(morpholinomethyl)-6H-pyrimido [5,4-b] [1,4]
oxazine-8 (7 H)-carboxylate ci N:r\j(NDLI
Boo N
Co) Step 1: (R)-Methyl 2-((tert-butoxycarbonyl)amino)-3-((methylsulfonyl)oxy)propanoate o-(:)Nls To a stirred solution (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate (2.0 g, 9.13 mmol) in dichloromethane (20 mL) were added DIPEA (3.9 mL, 22.8 mmol) followed by methanesulfonyl chloride (Mesyl chloride) (850 L, 10.9 mmol) at 0 C and the mixture was stirred at 0 C for 1 h. The mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to yield 2.95 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.41 (s, 9H), 3.20 (s, 3H), 3.67 (s, 3H), 4.35-4.45 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H).
Step 2: (R)-Methyl 2-((tert-butoxycarbonyl)amino)-3-morpholinopropanoate >01.r N...}Ø..._ ,C, To a stirred solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-((methylsulfonyl)oxy)propanoate (step 1 intermediate) (2.9 g, 9.76 mmol) in dichloromethane (20 mL) were added morpholine (1.7 mL, 19.5 mmol) followed by N,N-diisopropylethylamine (DIPEA) (3.3 mL, 19.5 mmol) at 0 C. The mixture stirred at RT for 18 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography to yield 1.46 g of the desired product.
1H NMR (400 MHz, DMSO-d6) 6 0.96 (t, J= 7.2 Hz, 3H), 2.28-2.51 (m, 10H), 3.72 (s, 2H), 8.09 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.51 (dd, ./i = 2.4 Hz, J2 = 8.8 Hz, 1H).
Step 3: (R)-te rt-Butyl (1-hydroxy-3-morpholinopropan-2-yl)carbamate H
If o H
0 r\i To a solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-morpholinopropanoate (step 2 intermediate) (1.4 g, 4.86 mmol) in THF (15 mL) was added DIBAL solution (1M
in toluene, 19.4 mL, 19.4 mmol) at -78 C and the mixture was stirred at the same temperature for 2 h.
The reaction was quenched with brine and stirred for 1 h. The solution was filtered and washed with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 1.2 g of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.38 (s, 9H), 2.20-2.38 (m, 6H), 3.52-3.60 (m, 6H), 4.60 (t, J = 5.6 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.32 (s, 1H); ESI-MS (m/z) 260 (M+H)+.
Step 4: (R)-te rt-Butyl (1-((4,6-dichloropyrimidin-5 -yl)oxy)-3 -morpho linoprop an-2-yl)carbamate N N
CI CI
(31 0 Boo. N.1.,4,,N ,>
H
The titled compound was prepared by the reaction of (R)-tert-butyl (1-hydroxy-morpholinopropan-2-yl)carbamate (step 3 intermediate) (1.2 g, 4.61 mmol) with 4,6-dichloropyrimidin-5-ol (step 1 of Intermediate A2) (912 mg, 5.51 mmol) in the presence of DIAD (1.4 g, 6.92 mmol) and triphenylphosphine (1.8 g, 6.92 mmol) in THF (10 mL) as per the procedure described in step 2 of Intermediate A2 to yield 2.96 g of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 1.18 (d, J = 6.0 Hz, 9H), 2.50-2.51 (m, 4H), 3.50-3.55 (m, 4H), 3.90-4.0 (m, 1H), 4.09-4.13 (m, 1H), 4.21-4.23 (m, 1H), 4.74-4.80 (m, 2H), 8.32 (s, 1H);
ESI-MS (m/z) 406 (M+H)+.
Step 5: (R)-1-((4,6-Dichloropyrimidin-5-yl)oxy)-3-morpholinopropan-2-amine hydrochloride NN
CI )1LCI

HCI
To a solution of (R)-te rt-butyl (1-((4,6-dichloropyrimidin-5-yl)oxy)-3-morpholinopropan-2-yl)carbamate (step 4 intermediate) (2.9 g, 7.13 mmol) in ethyl acetate (10 mL) was added hydrochloric acid in 1,4-dioxane (4M, 40 mL) and the mixture was stirred at RT
for 3 h. The mixture was concentrated under reduced pressure to give 536 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 3.28-3.66 (m, 6H), 3.90-4.05 (m, 4H), 4.44-4.48 (m, 3H), 8.76 (s, 1H), 9.01 (br s, 3H).
Step 6: (R)-4-Chloro-7-(morpholinomethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine ci H-C

To a solution of (R)-1-((4,6-dichloropyrimidin-5-yl)oxy)-3-morpholinopropan-2-amine hydrochloride (step 5 intermediate) (520 mg, 1.51 mmol) in DMF (5.0 mL) was added DIPEA (2.6 mL, 15.1 mmol) and the mixture was stirred overnight at RT. The mixture was quenched with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue obtained was purified by column chromatography to yield 271 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 2.38-2.46 (m, 4H), 2.49-2.51 (m, 2H), 3.57 (t, J = 4.8 Hz, 4H), 3.77-3.82 (m, 1H), 4.15-4.16 (s, 2H), 7.89 (s, 1H), 8.09 (s, 1H); ESI-MS (m/z) 271 (M+H)+.
Step 7: (R)-te rt-Butyl 4-chloro-7-(morpholinomethyl)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate The titled compound was prepared by the reaction of (R)-4-chloro-7-(morpholinomethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (step 6 intermediate) (260 mg, 0.96 mmol) with di-tert-butyl dicarbonate (230 mg, 1.05 mmol) in the presence of DMAP (106 mg, 0.86 mmol) in dichloromethane (20 mL) as per the procedure described in step 3 of Intermediate Al to yield 231 mg of the compound. lti NMR (400 MHz, DMSO-d6) 6 1.50 (s, 9H), 3.51-2.29 (m, 6H), 3.52 (d, J = 4.4 Hz, 4H), 4.03 (q, J = 7.2 Hz, 1H), 4.21 (dd, ./i = 2.4 Hz, J2 = 11.2 Hz, 1H), 8.27-8.33 (m, 1H); ESI-MS (m/z) 285 (M)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 5.
Table 5: Chemical name, structure and analytical data of Intermediate A23-A25 Intermediate Chemical Name and Structure Analytical Data No.
CI

1F1 NMR (400 MHz, DMSO-d6) 6 1.51 N I N ) ,O.
(s, 9H), 3.27 (s, 3H), 3.34-3.40 (m, 60c 2H), 4.24-4.28 (m, 1H), 4.51-4.56 (m, (R)-tert-Butyl 4-chloro-7-1H), 4.63-4.69 (m, 1H), 8.31 (s, 1H);
(methoxymethyl)-6H-pyrimido [5,4- ESI-MS (m/z) 316 (M+H)+.
b][1,4]oxazine-8(7H)-carboxylate CI

N I N1','NI
1F1 NMR (400 MHz, DMSO-d6) 6 1.50 A24 0c (s, 9H), 2.20 (s, 6H), 2.35-2.41 (m, (R)-tert-Butyl 4-chloro-7-2H), 4.16-4.22 (m, 1H), 4.54-4.61 (m, ((dimethylamino)methyl)-6H-2H), 8.31 (s, 1H); ESI-MS (m/z) 329 (M+H)+.
pyrimido[5,4-b] [1,4]oxazine-8(7H)-carboxylate CI
N CI
:XI ) 1F1 NMR (400 MHz, CDC13) 6 1.60 (s, 60c 9H), 3.96-4.00 (m, 2H), 4.38-4.42 (m, tert-Butyl 2,4-dichloro-6H- 2H); ESI-MS (m/z) 307 (M+H)+.
pyrimido[5,4-b] [1,4]oxazine-8(7H)-carboxylate Intermediate A19 (S)-tert-Butyl 7-(((tert-butoxyc arbonyl)oxy)methyl)-4-chloro-6H-pyrimido [5,4-b][1,4]oxazine-8(7H)-carboxylate CI
0,N
1 Boc0,,=CNj NI"
thoc Step 1: N-(6-Chloro-5-hydroxypyrimidin-4-yl)acetamide CI
N c.CDH
NxI

To a solution of 4-amino-6-chloropyrimidin-5-ol (1.5 g, 10.3 mmol) in dichloromethane (15 mL) was added acetyl chloride (0.8 mL, 10.3 mmol) followed by dropwise addition of triethylamine (4.2 mL, 30.9 mmol) at 0 C and the mixture was stirred at RT
for 3 h. The mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 790 mg of the desired compound. ESI-MS (m/z) 188 (M+H)+.
Step 2: (S)-1-(4-Chloro-7-(hydroxymethyl)-6H-pyrimido [5,4-b] [1,4]
oxazin-8 (7 H)-yl)ethanone CI
N
N N
(D
To a suspension of potassium carbonate (1.47 g, 10.7 mmol) in acetonitrile (20 mL) were added N-(6-chloro-5-hydroxypyrimidin-4-yl)acetamide (step 1 intermediate) (500 mg, 2.67 mmol) followed by (2R)-(-)-glycidyl tosylate (669 mg, 2.93 mmol) and the mixture was refluxed for 24 h. The mixture was cooled to RT and diluted with ethyl acetate and water.
The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 270 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 2.12 (s, 3H), 3.96-4.16 (m, 1H), 4.16-4.30 (m, 4H), 6.23 (s, 1H), 8.06 (s, 1H).
Step 3: (S)-(4-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-7-yl)methanol CI
NYO
I N N (9. OH
A solution of (S)-1-(4-chloro-7-(hydroxymethyl)-6H-pyrimido[5,4-b][1,4]oxazin-8 (7 H)-yl)ethanone (step 2 intermediate) (150 mg, 0.62 mmol) in hydrochloric acid in 1,4-dioxane (3.0 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure and the residue was diluted with water. The aqueous mixture was basified using saturated sodium bicarbonate solution till pH 8-9 at -20 C. The mixture was extracted twice with ethyl acetate.
The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 170 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 3.34-3.41 (m, 1H), 3.47-3.57 (m, 2H), 4.11-4.32 (m, 2H), 5.09 (t, J = 5.6 Hz, 1H), 7.88 (s, 1H), 8.21-8.22 (br s, 1H).
Step 4: (S)-tert-Butyl 7-(((tert-butoxycarbonyl)oxy)methyl)-4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate The titled compound was prepared by the reaction of (S)-(4-chloro-7,8-dihydro-pyrimido[5,4-b][1,4]oxazin-7-yl)methanol (step 3 intermediate) (170 mg, 0.84 mmol) with di-tert-butyl dicarbonate (476 mg, 2.18 mmol) in the presence of DMAP (246 mg, 2.01 mmol) in dichloromethane (10 mL) as per the procedure described in step 3 of Intermediate Al to yield 100 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.37 (s, 9H), 1.50 (s, 9H), 4.02-4.13 (m, 1H), 4.15-4.35 (m, 1H), 4.31 (dd, J, = 2.8 Hz, .1-2 = 11.2 Hz, 1H), 4.55-4.79 (m, 1H), 4.80-4.81 (m, 1H), 8.33 (s, 1H).
Intermediate A20 tert-Butyl 9-bromo-3 ,4-dihydropyrido [3,2-b] [1,4] oxazepine-5 (2H)-carboxylate Br _0 N^N
Boc Step 1: 4-Bromo-3 -(3 -chloropropoxy)pyridin-2-amine Br CI
I

The titled compound was prepared by the reaction of 2-amino-4-bromopyridin-3-ol hydrobromide (step 1 of Intermediate A7) (1.0 g, 3.90 mmol) and 1-bromo-3-chloropropane (925 mg, 5.80 mmol) in the presence of cesium carbonate (3.8 g, 11.7 mmol) in acetonitrile (10 mL) as per the procedure described in step 2 of Intermediate A7 to yield 400 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.19-2.25 (m, 2H), 3.95 (t, J = 6.0 Hz, 2H), 4.39 (t, J= 5.6 Hz, 2H), 6.17 (s, 2H), 6.74 (d, J= 5.6 Hz, 1H), 7.55 (d, J =
5.6 Hz, 1H).
Step 2: 9-Bromo-2,3 ,4,5 -tetrahydropyrido [3,2-b] [1,4] oxazepine Br 0 To a stirred solution of 4-bromo-3-(3-chloropropoxy)pyridin-2-amine (step 1 intermediate) (400 mg, 1.20 mmol) in DMF (5.0 mL) was added sodium hydride (60% w/w, 96 mg, 2.40 mmol) at RT. The mixture stirred at 80 C for 1 h. The reaction mixture was quenched with water and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over anhydrous sodium, filtered and concentrated under reduced pressure to yield 250 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.94-1.98 (m, 2H), 3.25-3.29 (m, 2H) 4.15 (t, J =
6.0 Hz, 2H), 6.39 (br s, 1H), 6.86 (d, J = 5.6 Hz, 1H), 7.52 (d, J= 5.2 Hz, 1H), Step 3: tert-Butyl 9-bromo-3,4-dihydropyrido [3,2-b] [1,4] oxazepine-5 (2H)-carboxylate The titled compound was prepared by the reaction of 9-bromo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepine (step 2 intermediate) (2.0 g, 8.77 mmol) and di-tert-butyl dicarbonate (2.84 g, 13.0 mmol) in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) (1M, 11 mL, 10.6 mmol) in anhydrous THF (20 mL) as per the procedure described in step 3 of .. Intermediate A7 to yield 2.1 g of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.35 (s, 9H), 1.94-1.97 (m, 2H), 3.60-3.63 ( br s, 2H), 4.12-4.14 (br s, 2H), 7.63 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 5.2 Hz, 1H).
Intermediate A21 tert-Butyl 8-bromo-7-nitro-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate Br I j N N
60c Step 1: 8-Bromo-7-nitro-3,4-dihydro-2H-pyrido [3,2-b] [1,4]oxazine Br 02N ko k 1\1 N
To a solution of 8-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (step 2 of Intermediate A7) (802 mg, 3.73 mmol) in trifluoroacetic acid (5.0 mL) was added potassium nitrate (415 mg, 4.10 mmol) at 0 C. The mixture was gradually warmed to RT and stirred overnight at RT. The mixture was quenched with ice-water and neutralized with aqueous sodium hydroxide solution at 0 C. The precipitated solid was filtered, washed with water and dried.
The crude solid was triturated with diethyl ether and dried well to yield 732 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 3.52 (t, J = 4.0 Hz, 2H), 4.26 (t, J =
4.0 Hz, 2H), 8.46 (s, 1H), 8.60 (s, 1H).
Step 2: tert-Butyl 8-bromo-7-nitro-2H-pyrido [3,2-b] [1,4]oxazine-4(3H)-carboxylate The titled compound was prepared by the reaction of 8-bromo-7-nitro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (step 1 intermediate) (875 mg, 3.36 mmol) with di-tert-butyl dicarbonate (1.15 mL, 5.04 mmol) in the presence of triethylamine (0.94 mL, 6.72 mmol) and DMAP (41 mg, 0.34 mmol) in dichloromethane (20 mL) as per the procedure described in step 3 of Intermediate A4 to yield 1.02 g of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.49 (s, 9H), 3.94 (t, J= 4.4 Hz, 2H), 4.46 (t, J= 4.4 Hz, 2H), 8.58 (s, 1H).
Methods for the Synthesis of Intermediate B
Intermediate B1 Preparation of methyl 4-chloro-3-hydroxybenzoate CI al 0, HO

To a stirred solution of 4-chloro-3-hydroxybenzoic acid (690 mg, 4.00 mmol) in methanol (8.0 mL) was added sulfuric acid (10 L, 0.20 mmol) and the mixture was heated at 75 C for 14 h. The mixture was concentrated, residue was cooled to 0 C and neutralized using aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate.
The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to yield 902 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 3.91 (s, 3H), 5.66 (d, J = 4.4 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.3, 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H); ESI-MS
(m/z) 187 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 6.
Table 6: Chemical name, structure and analytical data of Intermediates B2-B12 Intermediate No. Chemical Name and Structure Analytical Data B2 HO 00 0, ESI-MS (m/z) 153 (M+H)+.

Methyl 3-hydroxybenzoate 1H NMR (400 MHz, CDC13) 6 2.30 (s, B3 HO 40 0, 3H), 3.90 (s, 3H), 5.33 (s, 1H), 7.18 (d, 0 J = 8.1 Hz, 1H), 7.52-7.53 (m, 2H);
Methyl 3-hydroxy-4- ESI-MS (m/z) 167 (M+H)+.

Intermediate Chemical Name and Structure Analytical Data No.
methylbenzoate F
B4 a HO 0, CAS # 214822-96-5; ESI-MS (m/z) O 171(M+H)+.
Methyl 4-fluoro-3-hydroxybenzoate CI

1I-1 NMR (400 MHz, DMSO-d6) 6 3.95 101 (s, 3H), 6.12 (br s, 1H), 7.10 (s, 1H), O 7.49 (s, 1H), 7.60 (s, 1H).
Methyl 3-chloro-5-hydroxybenzoate 40 0, 1I-1 NMR (400 MHz, DMSO-d6) 6 2.48 B6 HO (s, 3H), 3.91 (s, 3H), 7.15-7.25 (m, 1H), 7.43 (dd, Ji = 0.8 Hz, .12 = 8.0 Hz, Methyl 3-hydroxy-2-1H).
methylbenzoate CI al 1I-1 NMR (400 MHz, DMSO-d6) 6 2.42 0, B7 HO (s, 3H), 3.81 (s, 3H), 7.25 (d, J =
8.0 O Hz, 1H), 7.31 (dd, ./1 = 0.8 Hz, .12 = 8.8 Methyl 4-chloro-3-hydroxy-2-Hz, 1H), 9.50 (s, 1H).
methylbenzoate al a 1I-1 NMR (400 MHz, DMSO-d6) 6 3.83 B8 HO 0, (s, 3H), 6.95 (dd, Ji = 2.8 Hz, .12 = 8.8 O Hz, 1H), 7.16 (s, 1H), 7.35 (d, J = 8.8 Methyl 2-chloro-5-hydroxybenzoate Hz, 1H), 10.08 (s, 1H).
,0 a 0, 1I-1 NMR (400 MHz, DMSO-d6) 6 3.83 (s, 6H), 7.01 (d, J = 8.4 Hz, 1H), 7.36 O (s, 1H), 7.43 (dd, Ji = 2.0 Hz, .12 = 8.0 Methyl 3-hydroxy-4- Hz, 1H), 9.44 (s, 1H).
methoxybenzoate CF3 1I-1 NMR (400 MHz, DMSO-d6) 6 3.87 (s, 3H), 7.31-7.32 (m, 1H), 7.60-7.62 B10 HO 1.1 0 , (m, 2H), 10.67 (s, 1H).

Methyl 3-hydroxy-5-(trifluoromethyl)benzoate B11 al F
iCo 1I-1 NMR (400 MHz, DMSO-d6) 6 3.83 HO (s, 3H), 6.99-7.03 (m, 1H), 7.12-7.22 O (m, 2H), 9.79 (s, 1H).
Methyl 2-fluoro-5-hydroxybenzoate B12 a al o' CAS # 3964-57-6; ESI-MS (m/z) 187 HO (M+H)+.
Methyl 3-chloro-4-hydroxybenzoate Intermediate B13 Methyl 3-hydroxy-4-(trifluoromethyl)benzoate F3c HO 0, Step 1: Methyl 3-(benzyloxy)-4-(trifluoromethyl)benzoate io 0 A mixture of 3-fluoro-4-(trifluoromethyl)benzoic acid (1.0 g, 4.80 mmol) and benzyl alcohol (3.67 mL, 36.4 mmol) and potassium tert-butoxide (1.58 g, 14.2 mmol) in DMSO
was stirred at RT for 2 days. The mixture was diluted with ethyl acetate and water. The aqueous layer was separated and acidified with conc. HC1 and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated. The residue was dissolved in methanol (5.0 mL). Sulfuric acid (0.5 mL) was added to the mixture and refluxed for 3 h. The mixture was concentrated, residue was cooled to 0 C and neutralized using aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to yield 510 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 3.97 (s, 3H), 5.27 (s, 2H), 7.35-7.50 (m, 5H), 7.69-7.70 (m, 2H), 7.74 (s, 1H).
Step 2: Methyl 3-hydroxy-4-(trifluoromethyl)benzoate A solution of methyl 3-(benzyloxy)-4-(trifluoromethyl)benzoate (step 1 intermediate) (500 mg, 2.27 mmol) in methanol (5.0 mL) with catalytic amount of 10% palladium on carbon (50% wet) was hydrogenated at RT for 16 h. The mixture was filtered through celite and the celite bed was rinsed with methanol. The combined filtrate and washings were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 400 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 3.87 (s, 3H), 7.47 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.66 (d, J= 8.0 Hz, 1H), 11.12 (br s, 1H).
Intermediate B14 Methyl 3-mercapto-4-methylbenzoate el 0, HS

Step 1: 3-Mercapto-4-methylbenzoic acid SI O
HS H

To a stirred suspension of 3-amino-4-methylbenzoic acid (2.0 g, 13.22 mmol) in conc.
hydrochloric acid (8.0 mL) and water (20 mL) at 0 C was added a solution of sodium nitrite (958 mg, 13.88 mmol) in water (20 mL) over a period of 20 min. The diazotization mixture was added lot wise to a stirred mixture of potassium ethyl xanthate (2.5 g, 15.8 mmol) and 2M aqueous sodium carbonate solution (22 mL, 43.6 mmol) over a period of 20 min. The mixture was heated for 1 h at 45 C. The mixture was acidified with conc.
hydrochloric acid and the product was extracted twice in ethyl acetate. The combined organic extracts were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removal of solvents was refluxed overnight with potassium hydroxide (2.9 g, 52.9 mmol) in a mixture of ethanol and water (1:1, 20 mL). The reaction mixture was cooled to RT and acidified with conc. hydrochloric acid and extracted thrice with ethyl acetate. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to yield 760 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 2.23 (s, 3H), 5.64 (s, 1H), 7.29 (d, J= 8.0 Hz, 1H), 7.60 (dd, J, = 1.6 Hz, J2 = 8.0 Hz, 1H), 7.98 (s, 1H), 12.90 (s, 1H);
ESI-MS (m/z) 167 (M-H)-.
Step 2: Methyl 3-mercapto-4-methylbenzoate To a stirred solution of 3-mercapto-4-methylbenzoic acid (760 g, 4.52 mmol) in methanol (10 mL) was added sulfuric acid (250 L) and the mixture was refluxed for 2 h. The mixture was concentrated, residue was cooled to 0 C and neutralized using aqueous sodium bicarbonate solution. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to yield 502 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 2.28 (s, 3H), 3.83 (s, 3H), 5.75 (s, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.62 (dd, = 1.6 Hz, .1-2 = 7.6 Hz, 1H), 8.01 (s, 1H).
Methods for the Synthesis of Intermediate C
Intermediate Cl 4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline H2N CFr,, N
1\1,) Step 1: 1-(Bromomethyl)-4-nitro-2-(trifluoromethyl)benzene Br To a solution of 2-methyl-5-nitrobenzotrifluoride (10 g, 48.5 mmol) and AIBN
(800 mg, 4.85 mmol) in ethylene dichloride (150 mL) was added N-bromosuccinimide (8.6 g, 48.5 mmol) at RT and the reaction mixture was refluxed for 18 h. The mixture was concentrated and the residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated.
The residue obtained was purified by silica gel column chromatography to yield 6.21 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 4.88 (s, 2H), 8.04 (d, J = 8.4 Hz, 1H), 8.43 (s, 1H), 8.54 (dd, ./i = 2.4 Hz, .1-2 = 8.4 Hz, 1H).
Step 2: 1-Ethyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine r N
N) To a stirred solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (step 1 intermediate) (4.0 g, 14.1 mmol) in dichloromethane (40 mL) were added N-ethylpiperazine (1.88 mL, 14.7 mmol) followed by N,N-diisopropylethylamine (DIPEA) (3.27 mL, 19.1 mmol) at RT. The mixture stirred at RT for 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution followed by brine.
The organic layer was dried over anhydrous sodium, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 3.5 g of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 0.96 (t, J = 7.2 Hz, 3H), 2.28-2.51 (m, 10H), 3.72 (s, 2H), 8.09 (d, J= 8.4 Hz, 1H), 8.40 (s, 1H), 8.51 (dd, ./1 = 2.4 Hz, J2 = 8.8 Hz, 1H).
Step 3: 4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline A solution of 1-ethyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (step 2 intermediate) (800 mg, 2.52 mmol) in methanol (20 mL) with catalytic amount of 10% palladium on carbon (50% wet) was hydrogenated at RT for 16 h. The mixture was filtered through celite and the celite bed was rinsed with methanol. The combined filtrate and washings were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 600 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 0.97 (t, J
= 7.2 Hz, 3H), 2.26-2.51 (m, 10H), 3.38 (s, 2H), 5.44 (s, 2H), 6.74 (dd, ./i = 2.4 Hz, J2 = 8.4 Hz, 1H), 6.85 (s, 1H), 7.29 (t, J = 8.4 Hz, 1H).

The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 7.
Table 7 Chemical name, structure and analytical data of Intermediates C2-C15 Intermediate Chemical Name and Structure Analytical Data No.
H2N 0cFrN.... lti NMR (400 MHz, DMSO-d6) 6 2.19 N,) (s, 3H), 2.51 (br s, 8H), 3.33 (s, 2H), 4-((4-Methylpiperazin-1-yl)methyl)- 5.44 (s, 2H), 6.75 (dd, ./1 = 2.0 Hz, J2 =
3-(trifluoromethyl)aniline 8.0 Hz, 1H), 6.84 (s, 1H), 7.29 (d, J =
8.0 Hz, 1H).
1F1 NMR (400 MHz, DMSO-d6) 6 0.95 H2N cFN,1.1 I. N) (d, J = 6.4 Hz, 6H), 2.33-2.60 (m, 9H), C3 4-((4-Isopropylpiperazin-1-3.37 (d, J = 9.9 Hz, 2H), 5.43 (s, 2H), 6.75 (dd, ./1 = 1.6 Hz, J2 = 8.0 Hz, 1H), yl)methyl)-3-6.84 (s, 1H), 7.29 (d, J = 11.6 Hz, 1H).
(trifluoromethyl)aniline 1F1 NMR (400 MHz, DMSO-d6) 6 0.88 (d, J = 6.4 Hz, 3H), 1.05-1.15 (m, 2H), H2N 0cFr----.....---1.29-1.34 (m, 1H), 1.54 (d, J = 12.0 N.,,,..- Hz, 2H), 1.86 (d, J = 11.2 Hz, 2H), 4-((4-Methylpiperidin-1-yl)methyl)- 2.72 (d, J= 11.6 Hz, 2H), 3.34 (s, 2H), 3-(trifluoromethyl)aniline 5.42 (s, 2H), 6.75 75 (dd, ./1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 6.84 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H); ESI-MS (m/z) 273 (M+H)+.
1F1 NMR (400 MHz, DMSO-d6) 6 2.31 H2N 40cFro (br s, 4H), 3.17 (d, J = 5.2 Hz, 2H), N,.) 3.39 (s, 2H), 3.55 (t, J = 4.4 Hz, 2H), 4-(Morpholinomethyl)-3-5.46 (s, 2H), 6.75 (dd, ./1 = 2.0 Hz, J2 =
(trifluoromethyl)aniline 8.4 Hz, 1H), 6.86 (s, 1H), 7.30 (d, J =
8.4 Hz, 1H); ESI-MS (m/z) 261 (M+H)+.
1FI NMR (400 MHz, DMSO-d6) 6 1.39 H2N iocFr.N.Boc (s, 9H), 2.27 (d, J = 4.8 Hz, 4H), 2.60 N,.) (d, J = 5.2 Hz, 4H), 3.20-3.40 (m, 2H), tert-Butyl 4-(4-amino-2-5.76 (s, 2H), 6.75 (dd, ./1 = 2.0 Hz, J2 =
(trifluoromethyl)benzyl)piperazine- 8.0 Hz, 1H), 6.85 (s, 1H), 7.30 (d, J =
1-carboxylate 8.0 Hz, 1H); ESI-MS (m/z) 360 (M+H)+.
1F1 NMR (400 MHz, DMSO-d6) 6 0.96 H2N C7 0 1\1) r.N
(t, J= 4.8 Hz, 3H), 2.11-2.51 (m, 13H), , 4-((4-Ethylpiperazin-1-yl)methyl)-3.21 (s, 2H), 4.85 (s, 2H), 6.29 (dd, ./1 = 2.4 Hz, J2 = 8.0 Hz, 1H), 6.35 (s, 3-methylaniline 1H), 6.78 (d, J = 8.0 Hz, 1H).

NMR (400 MHz, DMSO-d6) 6 1.97 C8 H2N so cFrN,Ic (s, 3H), 2.27 (t, J = 4.8 Hz, 2H), 2.33 N1) (t, J = 4.8 Hz, 2H), 3.33-3.42 (m, 6H), Intermediate Chemical Name and Structure Analytical Data No.
1-(4-(4-Amino-2- 5.76 (s, 2H), 6.77 (dd, J, = 2.0 Hz, .1-2 =
(trifluoromethyl)benzyl)piperazin-1- 10.0 Hz, 1H), 6.86 (s, 1H), 7.32 (t, J =
yl)ethanone 8.4 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 0.83 (t, J= 7.2 Hz, 3H), 1.38-1.43 (m, 2H), C9 2.18-2.46 (m, 12H), 5.76 (s, 2H), 6.75 4-((4-Propylpiperazin-1-yl)methyl)-(d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 7.28 3-(trifluoromethyl)aniline (d, J = 8.4 Hz, 1H); ESI-MS (m/z) 302 (M+H)+.
1H NMR (400 MHz, DMSO-d6) 6 0.95 cF3 (t, J= 3.6 Hz, 3H), 2.30-2.51 (m, 8H), 1\1,) 3.17-3.58 (m, 4H), 5.76 (s, 2H), 6.71 H2N (s, 1H), 6.78 (s, 1H), 6.85 (s, 1H); ESI-3-((4-Ethylpiperazin-1-yl)methyl)- MS (m/z) 288 (M+H)+.
5-(trifluoromethyl)aniline cF3 1H NMR (400 MHz, DMSO-d6) 6 2.13 C11 (s, 6H), 3.29 (s, 2H), 5.0-5.3 (s, 2H), H2N 6.69 (s, 1H), 6.72 (s, 1H), 6.76 (s, 1H);
34(Dimethylamino)methyl)-5- ESI-MS (m/z) 219 (M+H)+.
(trifluoromethyl)aniline 1H NMR (400 MHz, DMSO-d6) 6 H2N = 1.07-1.61 (m, 2H), 1.60-1.91 (m, 3H), 2.13 (s, 6H), 2.28-2.49 (m, 2H), 2.55-2.61 (m, 1H), 2.69-2.71 (m, 1H), 5.42 1-(4-Amino-2- (s, 2H), 6.75 (d, J, = 2.0 Hz, Ji = 8.8 (trifluoromethyl)benzy1)-N,N- Hz, 1H), 6.84 (s, 1H), 7.28 (d, J =
8.4 dimethylpyrrolidin-3-amine Hz, 1H); ESI-MS (m/z) 288 (M+H)+.
H2N = cF(s) I
,)"=N\

(S)-1-(4-Amino-2- ESI-MS (m/z) 288 (M+H)+.
(trifluoromethyl)benzy1)-N,N-dimethylpyrrolidin-3-amine \1¨
H NMR (400 MHz, DMSO-d6) 6 H2N = ,) 1.81-2.03 (m, 4H), 2.25 (s, 6H), 2.54-C14 11 2.89 (m, 5H), 3.88 (q, J = 16.0 Hz, (R)-1-(4-Amino-2- 2H), 8.09 (d, J= 8.4 Hz, 1H), 8.39 (dd, (trifluoromethyl)benzy1)-N,N- J, = 2.4 Hz, Ji = 8.4 Hz, 1H), 8.51 (s, dimethylpyrrolidin-3-amine 1H).
0 1H NMR (400 MHz, DMSO-d6) 6 0.98 (:) CF3.N (t, J= 7.2 Hz, 3H), 2.31-2.51 (m, 10H), C15 N1,) 3.67 (s, 2H), 3.89 (s, 3H), 7.96 (d, J =
Methyl 4-((4-ethylpiperazin-1- 8.0 Hz, 1H), 8.17 (s, 1H), 8.22 (d, J =
yl)methyl)-3- 8.4 Hz, 1H); ESI-MS (m/z) 331 (trifluoromethyl)benzoate (M+H)+.

Intermediate No. Chemical Name and Structure Analytical Data H2N SO2Me 1H NMR (400 MHz, DMSO-d6) 6 0.96 (t, J = 7.2 Hz, 3H), 2.27 (q, J = 7.2 Hz, 2H), 2.32-2.38 (m, 6H), 3.32-3.43 (m, C N
2H), 3.41 (s, 3H), 3.64 (s, 2H), 5.63 (s, 2H), 6.74 (dd, Ji = 2.4, .1-2 = 8.0 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H),7.21 (d, J
4-((4-ethylpiperazin-1-yl)methyl)-3- - 2.4 Hz, 1H).
(methylsulfonyl)aniline Intermediate C16 4-(2-(Dimethylamino)ethoxy)-3-(trifluoromethyl)aniline H2N oF3 N
Step 1: N,N-Dimethy1-2-(4-nitro-2-(trifluoromethyl)phenoxy)ethanamine 02N is cF3 To a stirred solution of N,N-dimethylethanolamine (2.9 mL, 48.6 mmol) in DMF
(10 mL) was added sodium hydride (60% w/w, 421 mg, 10.5 mmol) at 0 C and stirred for 30 min. 1-Fluoro-4-nitro-2-(trifluoromethyl)benzene (2.0 g, 9.56 mmol) was added to the mixture and stirred at RT for 2 h. The reaction mixture was quenched with water extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine, dried over anhydrous sodium, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 2.3 g of the desired product. The compound was as such taken forward to the next step without characterization.
Step 2: 4-(2-(Dimethylamino)ethoxy)-3-(trifluoromethyl)aniline The titled compound was prepared by the catalytic hydrogenation reaction of N,N-dimethy1-2-(4-nitro-2-(trifluoromethyl)phenoxy)ethanamine (2.2 g, 7.91 mmol) in methanol (15 mL) as per the procedure described in step 3 of Intermediate Cl to yield 1.8 g of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 2.20 (s, 6H), 2.58 (t, J = 6.0 Hz, 2H), 4.0 (t, J =
6.0 Hz, 2H), 5.03 (s, 2H), 6.77 (dd, J, = 2.8 Hz, J1 = 8.4 Hz, 1H), 6.81-6.82 (br s, 1H), 6.97 (d, J = 8.8 Hz, 1H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 8.
Table 8: Chemical name, structure and analytical data of Intermediates C17 and Intermediate No. Chemical Name and Structure Analytical Data 1F1 NMR (400 MHz, DMSO-d6) 6 0.97 (t, J= 7.2 Hz, 3H), 1.59-1.63 (m, 2H), 1.84-1.90 (m, 2H), 2.19 (br s, 2H), 2.32 (q, J = 7.2 Hz, 2H), 2.50-2.63 (m, 4-((1-Ethylpiperidin-4-yl)oxy)-3-2H), 4.28-4.30 (m, 1H), 5.02 (br s, (trifluoromethyl)aniline 2H), 6.74-6.81 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H); ESI-MS (m/z) 289 (M+H)+.
H2N = cF3 NMR (400 MHz, DMSO-d6) 6 1.73-1.78 (m, 2H), 1.93-1.98 (m, 2H), 2.28-2.51 (m, 5H), 2.74 (br s, 2H), 4.46 LNJ
(br s, 1H), 5.15 (s, 2H), 6.79 (dd, J, =
1.2 Hz, J2 = 8.0 Hz, 1H),6.97 (d, J =
2-((1-Methylpiperidin-4-yl)oxy)-5- 8.4 Hz, 1H), 8.09 (s, 1H); APCI-MS
(trifluoromethyl)aniline (m/z) 275 (M+H)+.
Intermediate C18 3 -(4-Isopropylpip erazin-l-y1)-5 -(trifluoromethyl)aniline cF3 H2N NTh LN
To a stirred solution of 3-bromo-5-(trifluoromethyl)aniline (1.5 g, 6.25 mmol) in DMF (10 mL) were added 1-isoprpylpiperazine (3.6 mL, 24.4 mmol), cesium carbonate (4.06 g, 12.5 mmol), copper (I) iodide (595 mg, 3.12 mmol) and 8-hydroxyquinoline (272 mg, 1.87 mmol) at RT. The mixture was heated in a sealed tube at 120 C for 16 h. The reaction mixture was cooled to RT and diluted with ethyl acetate. The solution was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography to yield 660 mg of the desired product. 1I-1 NMR (400 MHz, DMSO-d6) 6 1.00 (d, J
= 6.4 Hz, 6H), 2.50-2.55 (m, 4H), 2.62-2.69 (m, 1H), 3.07 (t, J= 4.8 Hz, 4H), 5.33-5.35 (br s, 2H), 6.28 (s, 1H), 6.32 (s, 2H); ESI-MS (m/z) 288 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 9.
Table 9: Chemical name, structure and analytical data of Intermediates C29-C23 Intermediate ChemicalNo. Name and Structure Analytical Data Intermediate Chemical Name and Structure Analytical Data No.

C19 = N 1H NMR (400 MHz, DMSO-d6) 6 H2N 2.22 (s, 3H), 2.43-2.50 (m, 4H), 3.09 (t, J = 4.8 Hz, 4H), 5.33 (s, 2H), 6.29 3-(4-Methylpiperazin-1-y1)-5- (s, 1H), 6.33 (s, 2H).
(trifluoromethyl)aniline CF3 1H NMR (400 MHz, DMSO-d6) 1.02 (t, J= 3.2 Hz, 3H), 2.31-2.38 (m, 2H), C20 H2N 2.46-2.51 (m, 4H), 3.09 (t, J=
4.8 Hz, 4H), 5.34 (s, 2H), 6.29 (s, 1H), 6.33 3-(4-Ethylpiperazin-1-y1)-5- (s, 2H); ESI-MS (m/z) 274 (M+H)+.
(trifluoromethyl)aniline CF3 1H NMR (400 MHz, DMSO-d6) 0.85 (t, J= 7.6 Hz, 3H), 1.34-1.49 (m, 2H), C21 2.17-2.34 (m, 2H), 2.44-2.54 (m, 4H), 3.09 (br s, 4H), 5.36 (s, 2H), 1 6.28-\1.7\
6.32 (br s 3-(4-Propylpiperazin-1-y1)-5-" 3H). ESI-MS (m/z) 288 +
(trifluoromethyl)aniline (M+H).
CF3 1H NMR (400 MHz, DMSO-d6) 0.10 (m, 2H), 0.45-0.50 (m, 2H), 0.83-0.87 (m, 1H), 2.19-2.22 (m, 2H), A
2.49-2.55 (m, 4H), 3.10 (t, J= 4.8 Hz, 3-(4- 4H), 5.36 (s, 2H), 6.29 (s,1H), 6.33 (s, (Cyclopropylmethyl)piperazin-1- 2H); ESI-MS (m/z) 300 (M+H)+.
y1)-5-(trifluoromethyl)aniline 1H NMR (400 MHz, DMSO-d6) 0.92 (d, J = 6.4 Hz, 3H), 1.12-1.23 (m, C23 40 H2N Na 2H), 1.47-1.53 (m, 1H), 1.64-1.67 (m, 2H), 2.65 (dt, J, = 2.4 Hz, J2 = 12.4 Hz, 2H), 3.58-3.61 (m, 2H), 5.31 (s, 3-(4-Methylpiperidin-1-y1)-5- 2H), 6.25 (s, 1H), 6.32 (d, J =
10.8 (trifluoromethyl)aniline Hz, 2H).
Intermediate C24 4-(4-Methylpiperazin-1-y1)-3-(trifluoromethyl)aniline LN
Step 1: 1-Methyl-4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine 02N rdi., CF3 LN

A mixture of 2-fluoro-5-nitrobenzotrifluride (5.0 g, 23.9 mmol) and 1-methylpiperazine (7.18 g, 71.7 mmol) in DMSO (20 mL) was heated at 100 C for 5 h. The mixture was cooled to RT and diluted with ethyl acetate and water. The organic layer was separated;
and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water followed by brine and concentrated under reduced pressure to give 5.2 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 2.23 (s, 3H), 2.45-2.51 (m, 4H), 3.13 (t, J= 4.8 Hz, 4H), 7.54 (d, J= 8.8 Hz, 1H), 8.38 (d, J= 2.8 Hz, 1H), 8.40 (d, J=
1.6 Hz, 1H).
Step 2: 4-(4-Methylpip erazin-l-y1)-3 -(trifluoromethyl)aniline The titled compound was prepared by the catalytic hydrogenation reaction of 1-methyl-4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine (step 1 intermediate) (5.0 g, 17.3 mmol) in methanol (200 mL) as per the procedure described in step 3 of Intermediate Cl to yield 4.12 g of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.19 (s, 3H), 2.49-2.51 (m, 4H), 2.71 (t, J = 4.4 Hz, 4H), 5.34 (s, 2H), 6.76 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H); ESI-MS
(m/z) 260 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 10.
Table 10: Chemical name, structure and analytical data of Intermediates C25-Intermediate No. Chemical Name and Structure Analytical Data H2N cF3 1H NMR (400 MHz, DMSO-d6) 6 2.70 (d, J = 4.4 Hz, 4H), 3.64 (t, J

= 3.6 Hz, 4H), 5.37 (s, 2H), 6.78 (dd, J, = 2.4 Hz, J2 = 8.4 Hz, 4-Morpholino-3-1H), 6.82 (s, 1H), 7.25 (d, J = 8.8 (trifluoromethyl)aniline Hz, 1H) ; ESI-MS (m/z) 247 (M+H)+.
cF3 H2N 40 N 1H NMR (400 MHz, DMSO-d6) 3.06 (d, J = 4.8 Hz, 4H), 3.71 (d, Lo J = 4.8 Hz, 4H), 5.39 (s, 2H), 3 -Morpho lino-5 - 6.32-6.34 (m, 3H).
(trifluoromethyl)aniline Intermediate C27 tert-Butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate H2N cF3 C,N'Boc Step 1: tert-Butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 02N 40 cF3 N' L,....õ N.
Boc To a stirred solution of 2-fluoro-5-nitrobenzotrifluride (5.0 g, 23.9 mmol) in acetonitrile (50 mL) were added potassium carbonate (6.6 g, 47.8 mmol) and tert-butyl piperazine-l-carboxylate (4.9 g, 26.3 mmol) at RT and the mixture refluxed 24 h. The mixture was cooled to RT and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water followed by brine and concentrated under reduced pressure to give 5.23 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.43 (s, 9H), 3.06 (t, J = 5.2 Hz, 4H), 3.47 (t, J
= 4.4 Hz, 4H), 7.61 (d, J = 8.8 Hz, 1H), 8.39-8.45 (m, 2H).
Step 2: tert-Butyl 4-(4-amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate The titled compound was prepared by the catalytic hydrogenation reaction of tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (step 1 intermediate) (3.0 g, 8.00 mmol) in methanol (200 mL) as per the procedure described in step 3 of Intermediate Cl to yield 2.3 g of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.41 (s, 9H), 2.66 (t, J = 4.8 Hz, 4H), 3.34 (s, 4H), 5.38 (m, 2H), 6.75 (dd ./1 = 2.4 Hz, J2 = 8.4 Hz, 1H), 6.81 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H); ESI-MS (m/z) 346 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 11.
Table 11: Chemical name, structure and analytical data of Intermediates C99 Intermediate No. Chemical Name and Structure Analytical Data H2N 40 c _F3 1H NMR (400 MHz, DMSO-d6) 6 2.24 (s, 3H), 2.84-2.92 (m, 8H), C99 (1\1 5.10 (s, 2H), 6.85 (d, J = 1.2 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 2-(4-Methylpiperazin-1-y1)-5- 7.01 (d, J = 8.0 Hz, 1H); ESI-MS
(trifluoromethyl)aniline (m/z) 260 (M+H)+.
Intermediate C28 4-((4-Ethylpiperazin-1-yl)methyl)aniline N,) Step 1: 1-Ethyl-4-(4-nitrobenzyl)piperazine N...) The titled compound was prepared by the reaction of 1-(bromomethyl)-4-nitrobenzene (1.8 g, 8.32 mmol) with N-ethylpiperazine (1.16 mL, 9.16 mmol) in the presence of N,N-diisopropylethylamine (DIPEA) (2.15 mL, 12.5 mmol) in dichloromethane (10 mL) as per the procedure described in step 2 of Intermediate Cl to yield 1.23 g of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 0.98 (t, J = 7.2 Hz, 3H), 2.34-2.40 (m, 10H), 3.59 (s, 2H), 7.58 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.4 Hz, 2H).
Step 2: 4-((4-Ethylpiperazin-1-yl)methyl)aniline To a stirred solution of 1-ethyl-4-(4-nitrobenzyl)piperazine (step 1 intermediate) (200 mg, 0.88 mmol) in a mixture of methanol and water (1:1, 20 mL) were added ammonium chloride (215 mg, 4.08 mmol) followed by iron powder (224 mg. 4.028 mmol) in small portions at 100 C. The mixture was stirred at 100 C for 2 h. The mixture was concentrated and the residue was diluted with a mixture of ethyl acetate and water. The organic layer was separated and washed with water followed by brine and dried over anhydrous sodium sulfate.
The solution was filtered, concentrated and the residue obtained was purified by column chromatography to yield 3.5 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 0.95 (t, J = 7.2 Hz, 3H), 2.24-2.29 (m, 10H), 3.23 (s, 2H), 4.93 (br s, 2H), 6.48 (d, J= 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 12.
Table 12: Chemical name, structure and analytical data of Intermediates C29-C32 and C77-Intermediate No. Chemical Name and Structure Analytical Data 1H NMR (400 MHz, DMSO-d6) 6 H2N 0 CI r=Nr,-..
0.97 (t, J = 7.2 Hz, 3H), 2.27-N.,.) 2.35 (m, 10H), 3.34 (s, 2H), 5.29 3-C hloro-4-((4-ethylpiperazin-1-(s, 2H), 6.47 (dd, ./1 = 2.4 Hz, J2 yl)methyl)aniline = 8.4 Hz, 1H), 6.57 (s, 1H), 7.02 (d, J= 8.0 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) 6 0.97 (t, J = 6.8 Hz, 3H), 2.28-H2N 0 Br -N,-2.36 (m, 7H), 3.33 (d, J = 5.6 Hz, C30 N,) 5H), 5.26 (s, 2H), 6.51 (dd, ./i =
3-Bromo-4-((4-ethylp ip erazin-1-2.0 Hz, J2 = 10.0 Hz, 1H), 6.77 yl)methyl)aniline (s, 1H), 7.02 (d, J = 8.4 Hz, 1H);
ESI-MS (m/z) 299 (M+H)+.

Intermediate Chemical Name and Structure Analytical Data No.
cF=3 (R) Boc 1H NMR (400 MHz, DMSO-d6) N-NõNj 1.42-1.57 (m, 11H), 2.90 (s, 3H), 3.02 (s, 2H), 3.08-3.14 (m, 2H), 3.64-3.71 (m, 3H), 7.28-7.34 (m, (R)-te rt-butyl (1-(4-amino-2-1H), 7.55 (dd, Ji = 2.0 Hz, .1-2 =
(trifluoromethyl)benzyl)pyrrolidin-3-8.0 Hz, 1H), 7.78 (s, 1H).
yl)(methyl)carbamate cF3 (S) Boc C32 H2N =
ESI-MS (m/z) 274 (M+H-Boc).
(S)-te rt-butyl (1-(4-amino-2-(trifluoromethyl)benzyl)pyrrolidin-3-yl)(methyl)carbamate H2N cF3 1H NMR (400 MHz, DMSO-d6) 6 1.62-1.66 (m, 1H), 1.85-1.91 (m, 1H), 2.11 (s, 6H), 2.28-2.76 (m, l_j \
4H), 3.35-3.54 (br s, 3H), 5.76 (s, (R)-1-(3-Amino-5-2H), 6.69 (s, 1H), 6.71 (s, 1H), (trifluoromethyl)benzy1)-N,N-6.76 (s, 1H).
dimethylpyrrolidin-3-amine H2N cF3 1H NMR (400 MHz, DMSO-d6) 6 2.00-2.23 (m, 2H), 2.55 (s, 6H), C78 l_ 2.61-2.67 (m, 1H), 2.79-2.85 (m, j \
3H), 3.34-3.37 (m, 1H), 3.60 (d, J
(S)-1-(3-Amino-5-= 3.2Hz, 2H), 6.81 (s, 1H), 6.87 (trifluoromethyl)benzy1)-N,N-(s, 1H), 6.91 (s, 1H).
dimethylpyrrolidin-3-amine Intermediate C33 N1-(4-Amino-2-(trifluoromethyl)benzy1)-N1,N2,N2-trimethylethane-1,2-diamine Step 1: tert-Butyl (4-methyl-3-(trifluoromethyl)phenyl)carbamate Boc'N CF3 To a solution of 4-methyl-3-(trifluoromethyl)aniline (2.5 g, 14.2 mmol) in a mixture of 1,4-dioxane (20 mL) and water (20 mL) were added sodium carbonate (2.3 g, 21.3 mmol) and di-tert-butyl dicarbonate (3.72 g, 17.0 mmol) and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 3.85 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.48 (s, 9H), 2.35 (s, 3H), 7.31 (d, J= 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 9.59 (s, 1H).
.. Step 2: tert-Butyl (4-(bromomethyl)-3-(trifluoromethyl)phenyl)carbamate Boc'N CF3 Br To a solution of tert-butyl (4-methyl-3-(trifluoromethyl)phenyl)carbamate (step 1 intermediate) (3.8 g, 13.8 mmol) in carbon tetrachloride (30 mL) were added N-bromosuccinimide (4.13 g, 27.6 mmol) and AIBN (226 mg, 1.38 mmol) at RT and the .. reaction mixture was refluxed for 16 h. The mixture was concentrated and the residue was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine.
The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 3.05 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.49 (s, 9H), 4.62 (s, 2H), 6.68 (s, 1H), 7.49-7.57 (m, 2H), 7.71 (s, 1H).
Step 3: tert-Butyl (4-4(2-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)phenyl)carbamate Boc CF3'N 40 .. To a solution of tert-butyl (4-(bromomethyl)-3-(trifluoromethyl)phenyl)carbamate (step 2 intermediate) (200 mg, 0.56 mmol) in THF (10 mL) were added N,N,N'-trimethylethylenediamine (176 L, 1.35 mmol) and triethylamine (236 L, 1.69 mmol) at RT
and the reaction mixture was stirred at RT for 2 h. The mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 315 mg of the desired compound. 1H
NMR (400 MHz, DMSO-d6) 6 1.48 (s, 9H), 2.12 (s, 9H), 2.35 (q, J = 4.4 Hz, 2H), 2.41-2.44 (m, 2H), 3.53 (s, 2H), 7.62 (s, 2H), 7.87 (s, 1H), 9.66 (s, 1H); ESI-MS (m/z) 376 (M+H)+.
Step 4: N1-(4-Amino-2-(trifluoromethyl)benzy1)-N1,N2,N2-trimethylethane-1,2-diamine To a solution of tert-butyl (4-4(2-(dimethylamino)ethyl)(methyl)amino)methyl)-(trifluoromethyl)phenyl)carbamate (step 3 intermediate) (300 mg, 0.80 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (2.0 mL) and the mixture was stirred at RT for 3 h. The reaction mixture was diluted with ethyl acetate and the organic solution was washed with saturated sodium bicarbonate solution followed by water and brine.
The solution was dried over anhydrous sodium sulfate, filtered and concentrated to yield 102 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 2.11 (s, 9H), 2.34-2.39 (m, 4H), 3.33-3.40 (br s, 2H), 5.42 (s, 2H), 6.75 (dd, ./i = 2.0 Hz, .1-2 = 8.0 Hz, 1H), 6.85 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H).
Intermediate C34 N1-(2-(Dimethylamino)ethyl)-N1-methy1-5-(trifluoromethyl)benzene-1,3-diamine cF3 FI2N N1') Step 1: Di-tert-butyl (3-bromo-5-(trifluoromethyl)phenyl)imidodicarbonate c3 (Boc)2N Br 15 The titled compound was prepared by the reaction of 3-bromo-5-trifluoromethylaniline (5.0 g, 20.8 mmol) with di-tert-butyl dicarbonate (11.3 g, 52.1 mmol) in the presence of DMAP
(254 mg, 2.08 mmol) in dichloromethane (20 mL) as per the procedure described in step 3 of Intermediate Al to yield 3.8 g of the product. 1H NMR (400 MHz, DMSO-d6) 6 1.41 (s, 18H), 7.77 (d, J= 6.0 Hz, 1H), 7.93-7.96 (m, 1H), 8.05 (s, 1H).
20 Step 2: Di-tert-butyl (3 -42-(dimethylamino)ethyl] (methyl)amino)-5 -(trifluoromethyl)phenyl)imidodicarbonate cF3 =' (Boc)2N N1 To a solution of di-tert-butyl (3-bromo-5-(trifluoromethyl)phenyl)imidodicarbonate (step 1 intermediate) (2.2 g, 4.89 mmol) in 1,4-dioxane (20 mL) were added N,N,N' -25 trimethylethylenediamine (636 L, 4.89 mmol), sodium tert-butoxide (1.40 g, 14.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (447 mg, 0.49 mmol) and (2-biphenyl)di-tert-butylphosphinetriethylamine (JohnPhos) (37 mg, 1.47mmol) at RT and the reaction mixture was stirred at 45 C for 4 h. The mixture was cooled to RT
and filtered through celite. The filtrate was concentrated and the residue was dissolved in ethyl acetate.
The organic solution was washed with 0.1 N HC1 followed by water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 2.01 g of the desired compound. The compound was as such carried forward to the next step without characterization.
Step 3: N1-(2-(Dimethylamino)ethyl)-N1-methy1-5-(trifluoromethyl)benzene-1,3-diamine The titled compound was prepared by the reaction of di-tert-butyl (34(2-(dimethylamino)ethyll(methyl)amino)-5-(trifluoromethyl)phenyl)imidodicarbonate (step 2 intermediate) (100 mg, 0.22 mmol) with trifluoroacetic acid (0.5 mL) in dichloromethane (3.0 mL) as per the procedure described in step 4 of Intermediate C33 to yield 50 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.17 (s, 6H), 2.34 (t, J = 7.2 Hz, 2H), 3.3-3.37 (m, 5H), 5.29 (s, 2H), 6.07 (s, 1H), 6.10 (s, 1H), 6.14 (s, 1H); ESI-MS (m/z) 262 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 13.
Table 13: Chemical name, structure and analytical data of Intermediate C35 Intermediate No. Chemical Name and Structure Analytical Data cF3 1H NMR (400 MHz, DMSO-d6) 6 H2N N 1.41-1.47 (m, 2H), 1.81 (d, J
= 12.8 C35 Hz, 2H), 2.21 (s, 7H), 2.62-2.69 (m, 2H), 3.64 (d, J= 12.8 Hz, 2H), 5.34 (s, 1 -(3 -Amino-5 - 2H), 6.26 (s, 1H), 6.33 (d, J
= 7.2 Hz, (trifluoromethyl)pheny1)-N,N- 2H); ESI-MS (m/z) 288 (M+H)+.
dimethylpiperidin-4-amine Intermediate C36 1-(3 -Aminophenyl)cycloprop anecarbonitrile ON
Step 1: 1-(3-Nitrophenyl)cyclopropanecarbonitrile o2N =ON
To a stirred solution of 2-(3-nitrophenyl)acetonitrile (500 mg, 3.08 mmol) in DMSO (10 mL) were added 1,2-dibromoethane (266 L, 3.08 mmol) and sodium hydride (60% w/w, 123 mg, 3.08 mmol) at RT. The mixture stirred at RT for 16 h. The reaction mixture was quenched with aqueous sodium sulfate solution, diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over anhydrous sodium, filtered and concentrated under reduced pressure.
The residue obtained was purified by column chromatography to yield 635 mg of the desired product. 41 NMR (400 MHz, DMSO-d6) 6 1.69 (t, J = 2.8 Hz, 2H), 1.87 (t, J= 2.8 Hz, 2H), 7.70 (t, J=
8.0 Hz, 1H), 7.78-7.80 (m, 1H), 8.17-8.19 (m, 2H).
Step 2: 1-(3 -Aminophenyl)cycloprop ane carbonitrile To a stirred solution of 1-(3-nitrophenyl)cyclopropanecarbonitrile (step 1 intermediate) (630 mg, 3.35 mmol) in a mixture of ethyl acetate and water (1:1, 20 mL) were added ammonium chloride (1.79 g, 33.4 mmol) followed by iron powder (747 mg. 13.4 mmol) in small portions at 100 C. The mixture was stirred at 100 C for 2 h. The mixture was concentrated and the residue was diluted with a mixture of ethyl acetate and water. The organic layer was separated and washed with water followed by brine and dried over anhydrous sodium sulfate.
The solution was filtered, concentrated and the residue obtained was purified by column chromatography to yield 350 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.36 (t, J = 4.8 Hz, 2H), 1.66 (t, J = 4.8 Hz, 2H), 5.22 (br s, 2H), 6.36-6.38 (m, 1H), 6.46-6.48 (m, 1H), 6.57 (s, 1H), 6.99 (t, J = 4.0 Hz, 1H).
Intermediate C37 (S)-3 -(3 -F luoropyrrolidin-1 -y1)-5 -(trifluoromethyl)aniline cF3 0 No....

Step 1: (S)-3 -F luoro-1-(3 -nitro-5 -(trifluoromethyl)phenyl)pyrro lidine cF3 40 02N 0....
F
The titled compound was prepared by the reaction of 1 -bromo-3 -nitro-5 -(trifluoromethyl)benzene (1.2 g, 4.44 mmol) with (5)-3-fluoropyrrolidine (593 mg, 6.66 mmol) in the presence of cesium carbonate (4.34 g, 13.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (81 mg, 0.09 mmol) and ( )-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (rac-BINAP) (83 mg, 0.13 mmol) in 1,4-dioxane (20 mL) as per the procedure described in step 2 of Intermediate C34 to yield 109 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 2.16-2.22 (m, 1H), 2.27-2.33 (m, 1H), 3.47-3.58 (m, 1H), 3.60-3.67 (m, 2H), 3.72 (s, 1H), 5.43-5.57 (m, 1H), 7.20 (s, 1H), 7.52 (s, 1H), 7.62 (s, 1H); ESI-MS (m/z) 279 (M+H)+.
Step 2: (S)-3 -(3 -F luoropyrro lidin-l-y1)-5 -(trifluoromethyl)aniline The titled compound was prepared by the catalytic hydrogenation of (S)-3-fluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)pyrrolidine (step 1 intermediate) (100 mg, 0.36 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) as per the procedure described in step 3 of Intermediate Cl to yield 55 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 2.10-2.26 (m, 2H), 3.27-3.57 (m, 4H), 5.33-5.36 (br s, 2H), 5.49 (br s, 1H), 5.98 (s, 2H), 6.18 (s, 1H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 14.
Table 14: Chemical name, structure and analytical data of Intermediates C38-Intermediate No. Chemical Name and Structure Analytical Data cF3 C38 H2N , F
The crude amine was as such carried forward to the next step.
(R)-3 -(3 -F luoropyrrolidin-l-y1)-5 -(trifluoromethyl)aniline cF3 1H NMR (400 MHz, DMSO-d6) 6 1.44 (s, 9H), 3.07 (t, J = 5.2 Hz, 4H), 3.43 LN.Boc (t, J = 4.4 Hz, 4H), 5.39 (s, 2H), 6.32-tert-Butyl 4-(3-amino-5-6.35 (m, 3H).
(trifluoromethyl)phenyl)piperazine-1-c arbo xylate Intermediate C40 tert-Butyl 4-(3 -amino-5 -(trifluoromethyl)phenyl)pip eridine-l-carboxylate c3 N.Boc Step 1: tert-Butyl 4-(3 -nitro-5 -(trifluoromethyl)pheny1)-5 ,6-dihydropyridine-1(2H)-carboxylate 02N I*
I N.Boc To a solution of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (1.0 g, 3.70 mmol) in 1,4-dioxane (35 mL) were added tert-butyl 4-(4,4,5 ,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-5,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 3.70 mmol), tetrakis(triphenylphosphine)palladium(0) (213 mg, 0.18 mmol) and saturated aqueous sodium bicarbonate solution (15 mL) and the mixture was heated at 120 C for 6 h. The mixture was cooled to RT and diluted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 891 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.52 (s, 9H), 2.60 (br s, 2H), 3.71 (t, J
= 5.6 Hz, 2H), 4.18 (br s, 2H), 6.32 (br s, 1H), 7.94 (s, 1H), 8.39 (s, 1H), 8.42 (s, 1H).
Step 2: tert-Butyl 4-(3 -amino-5 -(trifluoromethyl)phenyl)pip eridine-1 -carboxylate The titled compound was prepared by the catalytic hydrogenation of tert-butyl 4-(3-nitro-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate (step 1 intermediate) (880 mg, 2.35 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) (catalytic) as per the procedure described in step 3 of Intermediate Cl to yield 728 mg of the compound. 1H NMR
(400 MHz, DMSO-d6) 6 1.50 (s, 9H), 1.55-1.66 (m, 2H), 1.82 (d, J= 12.4 Hz, 2H), 2.58-2.66 (m, 1H), 2.80 (t, J= 12.0 Hz, 2H), 4.26 (br s, 2H), 6.69 (s, 1H), 6.78 (s, 1H), 6.86 (s, 1H).
Intermediate C41 3 -(1 -Methylpip eridin-4-y1)-5 -(trifluoromethyl)aniline cF3 To a stirred suspension of lithium aluminium hydride (275 mg, 7.25 mmol) in THF (20 mL) was slowly added a solution of tert-butyl 4-(3-amino-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate (Intermediate C40) (500 mg, 1.45 mmol) in THF (20 mL) at RT and the mixture was heated at 90 C for 18 h. The mixture was cooled to RT and quenched with saturated aqueous sodium sulfate solution. The mixture was filtered and the filtrate was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 181 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.56-1.59 (m, 2H), 1.62-1.71 (m, 2H), 1.89-1.90 (m, 2H), 2.17 (s, 3H), 2.3-2.51 (m, 1H), 2.83 (d, J = 7.6 Hz, 2H), 5.48 (s, 2H), 6.29 (s, 1H), 6.73 (s, 2H).
Intermediate C42 4-(3 -Amino-5 -(trifluoromethyl)phenyl)thiomorpholine 1,1-dioxide S=C:1 'b Step 1: 4-(3 -Nitro-5 -(trifluoromethyl)phenyl)thiomorpholine v211 1011 m The titled compound was prepared by the reaction of 1 -bromo-3 -nitro-5 -(trifluoromethyl)benzene (2.0 g, 7.40 mmol) with thiomorpholine (1.1 g, 11.1 mmol) in the presence of cesium carbonate (7.2 g, 22.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (135 mg, 0.15 mmol) and ( )-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (rac-BINAP) (138 mg, 0.22 mmol) in 1,4-dioxane (30 mL) as per the procedure described in step 2 of Intermediate C34 to yield 1.05 g of the desired compound. 1H NMR
(400 MHz, DMSO-d6) 6 2.66-2.69 (m, 4H), 3.79-3.81 (m, 4H), 7.60 (s, 1H), 7.69 (s, 1H), 7.86 (s, 1H).
Step 2: 4-(3 -Nitro-5 -(trifluoromethyl)phenyl)thiomorpholine 1,1-dioxide cF3 sr(D
'b To a solution of 4-(3-nitro-5-(trifluoromethyl)phenyl)thiomorpholine (step 1 intermediate) (1.0 g, 3.42 mmol) in dichloromethane (20 mL) was added mCPBA (1.7 g, 10.3 mmol) at RT
and the mixture was stirred at RT for 2 h. The mixture was diluted with saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to yield 523 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 3.19 (t, J= 5.2 Hz, 4H), 4.01 19 (t, J= 5.2 Hz, 4H), 7.75 (s, 1H), 7.97 (s, 1H), 8.0 (s, 1H).
Step 3: 4-(3 -Amino-5 -(trifluoromethyl)phenyl)thiomorpholine 1,1-dioxide The titled compound was prepared by the catalytic hydrogenation of 4-(3-nitro-(trifluoromethyl)phenyl)thiomorpholine 1,1-dioxide (step 2 intermediate) (510 mg, 1.57 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) (catalytic) as per the procedure described in step 3 of Intermediate Cl to yield 346 mg of the compound. 1H NMR
(400 MHz, DMSO-d6) 6 3.12 (s, 4H), 3.72 (s, 4H), 5.43 (s, 2H), 6.35 (s, 1H), 6.42 (d, J= 6.8 Hz, 2H).
Intermediate C43 4-Amino-N-(2-(dimethylamino)ethyl)-2-(trifluoromethyl)benzamide H2N cF3 Step 1: N-(2-(Dimethylamino)ethyl)-4-nitro-2-(trifluoromethyl)benzamide o2N cF3 PH
To a stirred solution of 4-nitro-2-(trifluoromethyl)benzoic acid (500 mg, 2.12 mmol) in dichloromethane (20 mL) were added triethylamine (612 L, 4.24 mmol), N1,N1-dimethylethane-1,2-diamine hydrochloride (633 L, 5.0 mmol) followed by HATU
(967 mg, 2.54 mmol) at RT. The mixture was stirred at RT for 18 h before quenching it with water.
The layers were separate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate.
The solution was filtered and concentrated under reduced pressure to yield 311 mg of the titled compound. 1H NMR (400 MHz, DMSO-d6) 6 2.23 (s, 6H), 2.45-2.50 (m, 2H), 3.33-3.38 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 8.49 (s, 1H), 8.56 (dd, J, = 2.0 Hz, .1-2 = 8.4 Hz, 1H), 8.76 (t, J = 5.2 Hz, 1H); ESI-MS (m/z) 306 (M+H)+.
Step 2: 4-Amino-N-(2-(dimethylamino)ethyl)-2-(trifluoromethyl)benzamide The titled compound was prepared by the catalytic hydrogenation of N-(2-(dimethylamino)ethyl)-4-nitro-2-(trifluoromethyl)benzamide (step 1 intermediate) (300 mg, 0.98 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) in methanol (10 mL) as per the procedure described in step 3 of Intermediate Cl to yield 151 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.16 (s, 6H), 2.33 (t, J= 7.2 Hz, 2H), 3.18-3.26 (m, 2H), 5.79 (s, 2H), 6.73 (dd, Ji = 2.0 Hz, .12 = 10 Hz, 1H), 6.87 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 8.0 (t, J= 5.6 Hz, 1H); ESI-MS (m/z) 276 (M+H)+.
Intermediate C44 (4-Amino-2-(trifluoromethyl)phenyl)(4-ethylpip erazin-l-yl)methanone H2N is CF3r,-...N..-õ, Step 1: (4-Ethylpiperazin-1-y1)(4-nitro-2-(trifluoromethyl)phenyl)methanone 02N sCFrN
N,) To a stirred solution of 4-nitro-2-(trifluoromethyl)benzoic acid (2.0 g, 8.51 mmol) in dichloromethane (20 mL) were added triethylamine (8.5 mL, 59.5 mmol), N-ethylpiperazine .. (1.24 mL, 9.35 mmol) followed by T3P (11.1 mL, 18.7 mmol) at RT. The mixture was stirred at RT for 16 h before quenching it with water. The layers were separate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 2.2 g of the titled compound. 1H NMR (400 MHz, DMSO-d6) 6 0.99 (d, J
= 6.8 Hz, 3H), 2.19-2.50 (m, 6H), 3.03-3.16 (m, 2H), 3.58-3.72 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 8.53-8.58 (m, 2H).
Step 2: (4-Amino-2-(trifluoromethyl)phenyl)(4-ethylpiperazin-1-y1)methanone The titled compound was prepared by the catalytic hydrogenation of (4-ethylpiperazin-1-yl)(4-nitro-2-(trifluoromethyl)phenyl)methanone (step 1 intermediate) (2.0 g, 6.04 mmol) in the presence of 10% palladium on carbon (50% wet) in methanol (50 mL) as per the procedure described in step 3 of Intermediate Cl to yield 1.9 g of the compound. 1H NMR
(400 MHz, DMSO-d6) 6 0.98 (t, J= 7.2 Hz, 3H), 2.19-2.50 (m, 6H), 3.09-3.18 (m, 2H), 3.57-3.58 (m, 2H), 5.78 (s, 2H), 6.78 (dd, ./1 = 2.0 Hz, .12 = 8.4 Hz, 1H), 6.88 (s, 1H), 7.01 (d, J =
8.0 Hz, 1H).
Intermediate C45 Ethyl 2-(3-aminopheny1)-2,2-difluoroacetate F F

Step 1: Ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate F F
02N is0 To a stirred suspension of 1-iodo-3-nitrobenzene (5.0 g, 20.1 mmol) and copper powder (5.0 g, 80.3 mmol) in DMSO (20 mL) was added ethyl 2-bromo-2,2-difluoroacetate (5.1 mL, 40.2 mmol) at RT. The mixture was stirred overnight at 60 C in a sealed tube. The reaction mixture was cooled to RT and quenched with aqueous ammonium chloride solution.
The aqueous mixture was poured into water and extracted twice with ethyl acetate.
The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to yield 3.2 g of the desired product. 41 NMR (400 MHz, DMSO-d6) 6 1.23 (t, J =
7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 7.89 (t, J = 8.4 Hz, 1H), 8.09 (dd, ./1 = 0.8 Hz, .12 = 8.0 Hz, 1H), 8.33 (t, J = 2.0 Hz, 1H), 8.47 (dd, ./i = 0.8 Hz, .12 = 6.8 Hz, 1H); ESI-MS (m/z) 245 (M+H)+.
Step 2: Ethyl 2-(3-aminopheny1)-2,2-difluoroacetate The titled compound was prepared by the reaction of ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate (step 1 intermediate) (600 mg, 2.44 mmol) with iron powder (567 mg, 10.2 mmol) and ammonium chloride (1.30 g, 24.4 mmol) in a mixture of ethyl acetate and water (7:2, 9.0 mL) as per the procedure described in step 2 of Intermediate C28 to yield 350 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.23 (t, J = 7.2 Hz, 3H), 4.20 (q, J =
7.2 Hz, 2H), 5.53 (br s, 2H), 6.65 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.75 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H); ESI-MS (m/z) 216 (M+H)+.
Intermediate C46 3 -(4,4-Difluoropip eridin-l-y1)-5 -(trifluoromethyl)aniline F F
Step 1: 4,4-Difluoro-1-(3 -nitro-5 -(trifluoromethyl)phenyl)pip eridine F F
The titled compound was prepared by the reaction of 1-bromo-3 -nitro-5 -(trifluoromethyl)benzene (250 mg, 0.93 mmol) with 4,4-difluoropiperidine (354 mg, 2.77 mmol) in the presence of sodium tert-butoxide (140 mg, 1.45 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (44 mg, 0.05 mmol) and 1,1-bis(diphenylphosphinoferrocene (54 mg, 0.10 mmol) in 1,4-dioxane (3.0 mL) as per the procedure described in step 2 of Intermediate C34 to yield 150 mg of the desired compound.
1H NMR (400 MHz, DMSO-d6) 6 2.06 2.09 (m, 4H), 3.60 (t, J = 5.60 Hz, 4H), 7.72 (s, 1H), 7.67 (s, 1H), 7.97 (s, 1H).
Step 2: 3 -(4,4-Difluoropip eridin-l-y1)-5 -(trifluoromethyl)aniline The titled compound was prepared by the catalytic hydrogenation of 4,4-difluoro-1-(3-nitro-5-(trifluoromethyl)phenyl)piperidine (step 1 intermediate) (220 mg, 0.71 mmol) in the presence of palladium on carbon (10% w/w, 50% wet) in methanol (5.0 mL) as per the procedure described in step 3 of Intermediate Cl to yield 70 mg of the compound. 1H NMR
(400 MHz, DMSO-d6) 6 1.97-2.07 (m, 4H), 3.28-3.33 (m, 4H), 5.39 (s, 2H), 6.32 (s, 1H), 6.40 (s, 2H); ESI-MS (m/z) 281 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 15.
Table 15: Chemical name, structure and analytical data of Intermediates C47-C49 and C63 Intermediate No. Chemical Name and Structure Analytical Data H2N 0 CF 3 1H NMR (400 MHz, DMSO-d6) 6 0.33-0.33 (m, 2H), 0.43-0.45 (m, 2H), N 1.62-1.67 (m, 1H), 2.64-2.65 (m, 4H), C47 CN) 3.05 (t, J= 4.8 Hz, 4H), 5.35 (s, 2H), A 6.28 (s, 1H), 6.32 (s, 2H);
ESI-MS
(m/z) 286 (M+H)+.
3 -(4-Cyc lopropylpip erazin-l-y1)-5 -(trifluoromethyl)aniline H2N s 0F3 1H NMR (400 MHz, DMSO-d6) 6 1.72-1.79 (m, 2H), 1.88-1.98 (m, 2H), ,N, 3.06-3.10 (m, 2H), 3.11-3.34 (m, 2H), C48 4.76-4.98 (m, 1H), 5.36 (s, 2H), 6.23 Y (s, 1H), 6.36 (s, 2H).
F
3 -(4-F luoropip eridin-l-y1)-5 -(trifluoromethyl)aniline H2N 0 c3 1H NMR (400 MHz, DMSO-d6) 6 1.88-1.99 (m, 1H), 2.01-2.02 (m, 1H), 2.54 (s, 2H), 3.02 (d, J= 10.0 Hz, 1H), C49 c1\12,,R) 3.19-3.34 (m, 2H), 4.37 (m, 1H), 5.27 OH (br s, 2H), 5.91-5.92 (br s, 2H), 6.12 (s, (R)-1-(3 -Amino-5 - 1H); ESI-MS (m/z) 247 (M+H)+.
(trifluoromethyl)phenyl)pyrrolidin-3-ol Intermediate No. Chemical Name and Structure Analytical Data H2N c3 1H NMR (400 MHz, DMSO-d6) 6 1.16 (d, J = 10.0 Hz, 6H), 2.23 (t, J = 10.8 Hz, 2H), 3.50 (d, J = 12.0 Hz, 2H), C63 C 3.64-3.68 (m, 2H), 5.36 (s, 2H), 6.30 s' 0 (s, 1H), 6.35 (d, J = 11.2 Hz, 2H); ESI-3-((2R,6S)-2,6- MS (m/z) 275 (M+H)+.
Dimethylmorpholino)-5-(trifluoromethyl)aniline Intermediate C50 N-(3 -Amino-5 -(trifluoromethyl)phenyl)acrylamide cF3 5 To a stirred solution of 5-(trifluoromethyl)benzene-1,3-diamine (200 mg, 1.13 mmol) in dichloromethane (9.0 mL) were added triethylamine (164 L, 1.13 mmol) followed by acryloyl chloride (31 L, 0.34 mmol) at 0 C. The mixture was stirred overnight at RT. The mixture was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine and dried over anhydrous sodium 10 sulfate. The solution was filtered, concentrated and the residue was purified by silica gel column chromatography to yield 60 mg of the desired product. ESI-MS (m/z) 231 (M+H)+.
Intermediate C51 6-Methyl-5 -(trifluoromethyl)pyridin-3 -amine 15 Step 1: Diethyl 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)malonate CO2Et CO2Et To a stirred solution of diethylmalonate (5.0 g, 23.5 mmol) in THF (25 mL) was added potassium tert-butoxide (1M in THF, 70.5 mmol) at -10 C and the mixture was stirred 10 min at the same temperature followed by 30 min at RT. A solution of 2-chloro-5-nitro-3-20 (trifluoromethyl)pyridine (5.0 g, 23.52 mmol) in THF (25 mL) was added slowly to the mixture at 0 C and the resultant mixture was stirred for 4-5 h at RT. The mixture was quenched with aqueous ammonium chloride solution and extracted twice with ethyl acetate.

The combined organic layers were washed with water followed by brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to yield 5.1 g of the desired product. The crude amine was as such carried forward to the next step.
Step 2: 2-Methyl-5 -nitro-3 -(trifluoromethyl)pyridine 02NcF3 A solution of diethyl 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)malonate (step 1 intermediate) (5.0 g, 14.3 mmol) in 50% sulfuric acid (50 mL) was heated at 85-90 C for 2-3 h. The mixture was cooled to 0 C and basified with 3N NaOH solution. The aqueous solution was extracted twice with diethyl ether. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated to yield 3.2 g of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 2.79 (s, 3H), 8.73 (d, J = 2.4 Hz, 1H), 9.50 (d, J = 2.4 Hz, 1H).
Step 3: 6-Methyl-5 -(trifluoromethyl)pyridin-3 -amine The titled compound was prepared by the reaction of 2-methyl-5-nitro-3-(trifluoromethyl)pyridine (250 mg, 1.21 mmol) with iron powder (679 mg, 12.1 mmol) and ammonium chloride (519 mg, 9.70 mmol) in a mixture of ethanol and water (6:1, 3.5 mL) as per the procedure described in step 2 of Intermediate C28 to yield 170 mg of the compound.
1H NMR (400 MHz, DMSO-d6) 6 2.41 (s, 3H), 5.57 (br s, 2H), 7.19 (d, J= 2.8 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H).
Intermediate C52 tert-Butyl 4-(3 -amino-5 -(trifluoromethyl)pheny1)-1,4- diazep ane-1 -carboxylate 'Boc Step 1: tert-Butyl 4-(3 -nitro-5 -(trifluoromethyl)pheny1)-1,4-diazep ane-1 -c arbo xylate 02N io cF3 'Boc The titled compound was prepared by the reaction of 1 -bromo-3 -nitro-5 -(trifluoromethyl)benzene (100 mg, 0.37 mmol) with tert-butyl 1,4-diazepane- 1 -carboxylate (222 mg, 1.11 mmol) in the presence of sodium tert-butoxide (53 mg, 0.55 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (20 mg, 0.02 mmol) and 1,1-bis(diphenylphosphinoferrocene (24 mg, 0.04 mmol) in 1,4-dioxane (1.0 mL) as per the procedure described in step 2 of Intermediate C34 to yield 85 mg of the desired compound.
1H NMR (400 MHz, DMSO-d6) 6 1.42 (s, 9H), 1.630 (br s, 2H), 1.99-2.02 (m, 2H), 3.30-3.40 (m, 2H), 3.67-3.69 (m, 4H), 7.14 (s, 1H), 7.66 (s, 1H), 7.74 (s, 1H).
Step 2: tert-Butyl 4-(3 -amino-5 -(trifluoromethyl)pheny1)-1,4-diazep ane-l-carboxylate The titled compound was prepared by the reaction of tert-butyl 4-(3-nitro-5-(trifluoromethyl)pheny1)-1,4-diazepane-l-carboxylate (step 1 intermediate )(80 mg, 0.21 mmol) with iron powder (114 mg, 2.05 mmol) and ammonium chloride (88 mg, 1.64 mmol) in ethanol (2.0 mL) as per the procedure described in step 2 of Intermediate C28 to 35 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.34 (s, 9H), 1.71-1.99 (m, 2H), 3.16-3.32 (m, 2H), 3.45-3.56 (m, 4H), 5.23-5.24 (m, 4H), 6.12-6.15 (m, 3H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 16.
Table 16: Chemical name, structure and analytical data of Intermediates C53-056 and C69-Intermediate No. Chemical Name and Structure Analytical Data H2N cF3 1H NMR (400 MHz, CDC13): 6 1.29 (d, J = 6.8 Hz, 3H), 1.30 (s, 9H), 2.81(dt, = 3.6 Hz, .12 = 7.6 Hz, 1H), 3.0 (dd , C53 C(a J, = 4.0 Hz, J2 = 12.0 Hz, 1H), 3.27 oc (dt, ./1 = 3.6 Hz, J2 = 7.6 Hz, 1H), B
(S)-tert-Butyl 4-(3-amino-5-3.36-3.39 (m, 1H), 3.50-3.53 (m, 1H), (trifluoromethyl)pheny1)-2-3.93-3.96 (m, 1H), 4.35 (br s, 1H), 6.33 methylpiperazine-l-carboxylate (s, 1H), 6.44 (s, 1H), 6.52 (s, 1H).

1H NMR (400 MHz, CDC13): 6 1.28 (d, J = 6.8 Hz, 3H), 1.30 (s, 9H), 2.81(dt, = 3.6 Hz, .12 = 7.6 Hz, 1H), 3.0 (dd , C54 4R), = 4.0 Hz, J2 = 12.0 Hz, 1H), 3.27 (dt, ./1 = 3.6 Hz, J2 = 7.6 Hz, 1H), 6oc (R)-tert-Butyl 4-(3-amino-5-3.36-3.39 (m, 1H), 3.50-3.53 (m, 1H), (trifluoromethyl)pheny1)-2-3.93-3.96 (m, 1H), 4.35 (br s, 1H), 6.33 methylpiperazine-l-carboxylate (s, 1H), 6.44 (s, 1H), 6.52 (s, 1H).

Intermediate Chemical Name and Structure Analytical Data No.

1H NMR (400 MHz, DMSO-d6) 6 1.34 (s)r, (s, 9H), 1.90 (br s, 2H), 2.92 (t, J= 9.6 C55 N2(s) Hz, 1H), 3.18 (t, J = 8.0 Hz, 1H), 3.51 Boc (t, J = 8.4 Hz, 2H), 4.37-4.43 (m, 2H), (1S,4S)-tert-Butyl 5-(3-amino-5-5.03 (s, 2H), 6.00 (d, J = 10.8 Hz, 2H), (trifluoromethyl)pheny1)-2,5-6.17 (s, 1H).
diazabicyclo[2.2.1]heptane-2-carboxylate C56 c(s) ESI-MS (m/z) 247 (M+H)+.
OH
(S)-1-(3-Amino-5-(trifluoromethyl)phenyl)pyrrolidin-3-ol H2N c3 1H NMR (400 MHz, DMSO-d6) 6 0.91 (d, J = 6.4 Hz, 3H), 1.42 (s, 9H), 2.80-3.0 (m, 2H), 3.30-3.40 (m, 2H), 3.60-Boc 3.65 (m, 2H), 3.90 (br s, 1H), 5.37 (s, (S)-tert-Butyl 4-(3-amino-5- 2H), 6.28-6.29 (br s, 3H).
(trifluoromethyl)pheny1)-3-methylpiperazine-1-carboxylate The crude amine was as such carried C70 (N) forward to the next step due to poor solubility and instability in solution Boo (R)-tert-Butyl 4-(3-amino-5- form.
(trifluoromethyl)pheny1)-3-methylpiperazine-1-carboxylate Intermediate C57 3-(4-Methy1-1,4-diazepan-1-y1)-5-(trifluoromethyl)aniline H2N ao CF3 N\
Step 1: 1-(3-Nitro-5-(trifluoromethyl)pheny1)-1,4-diazepane cN.,) NH
A solution of tert-butyl 4-(3 -nitro-5 -(trifluoromethyl)pheny1)-1,4-diaz epane-1 -carboxylate (step 1-Intermediate C52) (600 mg, 1.54 mmol) in hydrochloric acid in 1,4-dioxane (5.0 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure and the residue was diluted with water. The aqueous mixture was basified using saturated sodium bicarbonate solution till pH 8-9 at -20 C. The mixture was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 250 mg of the desired product. The crude amine was as such carried forward to the next step.
Step 2: 1-Methyl-4-(3 -nitro-5 -(trifluoromethyl)pheny1)-1,4-diazep ane N\
To a stirred solution of 1-(3-nitro-5-(trifluoromethyl)pheny1)-1,4-diazepane (step 1 intermediate) (250 mg, 0.87 mmol) in acetonitrile (35 mL) were added methyl iodide (126 mg, 0.89 mmol) and potassium carbonate (125 mg, 0.91 mmol) at 0 C and the mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 160 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 1.90-1.92 (m, 2H), 2.26 (s, 3H), 2.26-2.51 (m, 2H), 2.64 (t, J
= 4.8 Hz, 2H), 3.55 (t, J= 6.0 Hz, 2H), 3.65 (t, J= 4.8 Hz, 2H),7.32 (s, 1H), 7.56 (s, 1H), 7.63 (t, J =
2.0 Hz, 1H); ESI-MS (m/z) 304 (M+H)-1.
Step 3: 3 -(4-Methyl-1,4-diazep an-1 -y1)-5 -(trifluoromethyl)aniline The titled compound was prepared by the reaction of 1-methy1-4-(3-nitro-5-(trifluoromethyl)pheny1)-1,4-diazepane (step 2 intermediate) (180 mg, 0.59 mmol) with iron powder (331 mg, 5.92 mmol) and ammonium chloride (253 mg, 4.73 mmol) in ethanol (3.0 mL) as per the procedure described in step 2 of Intermediate C28 to 140 mg of the compound. The crude amine was as such carried forward to the next step due to poor solubility and instability in solution form.

The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 17.
Table 17: Chemical name, structure and analytical data of Intermediate C58 Intermediate No. Chemical Name and Structure Analytical Data H2N u3 1H NMR (400 MHz, DMSO-d6) 6 2.56 (t, J = 5.2 Hz, 4H), 3.12 (t, J = 4.8 Hz, 4H), 3.32-3.34 (br s, 3H), 5.36 (s, 2H), C58 CN) 6.29 (s, 1H), 6.34 (s, 2H); ESI-MS
(m/z) 284 (M+H)+.
3 -(4-(Prop-2-yn-1 -yl)pip erazin-1 -y1)-5 -(trifluoromethyl)aniline Intermediate C59 3 -(4-(Oxetan-3 -yl)pip erazin-l-y1)-5 -(trifluoromethyl)aniline 40 H2N NTh \-6 Step 1: 1-(3 -Nitro-5 -(trifluoromethyl)pheny1)-4-(oxetan-3 -yl)pip erazine cF3 N^i \-6 A mixture of zinc chloride (277 mg, 2.03 mmol) and molecular sieves (200 mg) was dried under vacuum followed with addition of 1-(3-nitro-5-(trifluoromethyl)phenyl)piperazine hydrochloride (100 mg, 0.40 mmol) and oxetan-3-one (150 mg, 2.08 mmol) in methanol (1.0 mL). The resultant mixture was stirred at RT for 2 h. The mixture was cooled to 0 C and was added sodium cyanoborohydride (126 mg, 2.08 mmol) in small portions. The mixture was stirred for 2 h at RT. The mixture was filtered through celite and the filtrate was diluted with sodium bicarbonate solution. The mixture was again passed through celite and the filtrate was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography to yield 90 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 2.42-2.51 (m, 4H), 3.43-3.47 (m, 4H), 4.34-4.37 (m, 1H), 4.48 (t, J= 6.0 Hz, 2H), 4.56-4.68 (m, 2H), 7.64 (s, 1H), 7.75 (s, 1H), 7.90 (t, J=
2.0 Hz, 1H).

Step 2: 3 -(4-(Oxetan-3 -yl)pip erazin-l-y1)-5 -(trifluoromethyl)aniline The titled compound was prepared by the reaction of 1-(3-nitro-5-(trifluoromethyl)pheny1)-4-(oxetan-3-yl)piperazine (step 1 intermediate ) (100 mg, 0.30 mmol) with iron powder (179 mg, 3.19 mmol) and ammonium chloride (138 mg, 2.55 mmol) in ethanol (4.0 mL) as per the procedure described in step 2 of Intermediate C28 to 70 mg of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 2.388 (t, J = 4.8 Hz, 4H), 3.12 (t, J = 4.8 Hz, 4H), 3.42-3.45 (m, 1H), 4.47 (t, J = 5.6 Hz, 2H), 4.56 (t, J = 6.4 Hz, 2H), 5.37 (s, 2H), 6.30 (s, 1H), 6.34 (s, 2H).
Intermediate C60 (R)-1-(3 -Amino -5 -(trifluoromethyl)pheny1)-N,N-dimethylpyrro lidin-3 -amine H2N I* CF3 ^
N-/
To a stirred solution of 3-bromo-5-(trifluoromethyl)aniline (200 mg, 0.83 mmol) and (R) -N ,N - dime thy 1py r r oli din -3 - amin e (200 mg, 1.75 mmol) in DMF (2.0 mL) were added copper iodide (83 mg, 0.44 mmol) followed by 8-hydroxyquinoline (40 mg, 0.26 mmol) at RT in a sealed tube. The mixture was stirred overnight at 120 C. The mixture was cooled to RT and diluted with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 80 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.73-1.83 (m, 1H), 2.12-2.17 (m, 6H), 2.74-2.78 (m, 1H), 2.98 (t, J =
8.4 Hz, 1H), 3.16-3.22 (m, 1H), 3.33-3.41 (m, 4H), 5.28 (s, 2H), 5.95 (s, 1H), 6.14 (s, 1H); ESI-MS (m/z) 274 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 18.
Table 18: Chemical name, structure and analytical data of Intermediate C61 Intermediate No. Chemical Name and Structure Analytical Data H2N . cF3 1H NMR (400 MHz, DMSO-d6) 6 1.77-1.83 (m, 1H), 2.12-2.20 (m, 5H), C61 (..N
2.49-2.99 (m, 1H), 2.99 (t, J = 8.4 Hz, \ i(S) 1H), 3.15-3.41 (m, 5H), 5.28 (s, 2H), N-5.94 (s, 2H), 76.14 (s, 1H); ESI-MS
/
(S)-1-(3 -Amino-5 - (m/z) 274 (M+H)+.

(trifluoromethyl)pheny1)-N,N-dimethylpyrro lidin-3 -amine Intermediate C62 tert-Butyl 3 -amino-5 -(trifluoromethyl)b enzyl(isopropyl)carb amate N.Boc Step 1: N-(3 -Nitro-5 -(trifluoromethyl)b enzyl)propan-2-amine 02N so CFNH
A solution of 2-propanamine (408 mg, 7.04 mmol) in dichloromethane (5.0 mL) was cooled to 0 C and to that was slowly added a solution of 1-(bromomethyl)-3-nitro-5-(trifluoromethyl)benzene (500 mg, 1.76 mmol) in dichloromethane (5.0 mL). The mixture was warmed to RT and stirred for 18 h. The mixture was poured into water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 170 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 1.13 (d, J = 6.0 Hz, 6H), 2.96 (br s, 1H), 4.11 (br s, 2H), 8.32 (s, 1H), 8.43 (s, 1H), 8.64 (s, 1H).
Step 2: tert-Butyl isopropy1(3-nitro-5-(trifluoromethyl)benzyl)carbamate 02N 40 cF3 N.Boc The titled compound was prepared by the reaction of N-(3 -nitro-5 -(trifluoromethyl)benzyl)propan-2-amine (step 1 intermediate) (170 mg, 0.65 mmol) with di-tert-butyl dicarbonate (156 mg, 0.71 mmol) in the presence of DIPEA (168 mg, 1.30 mmol) in dichloromethane (5.0 mL) as per the procedure described in step 3 of Intermediate Al to yield 240 mg of the product. 1H NMR (400 MHz, DMSO-d6) 6 1.15 (d, J = 6.8 Hz, 6H), 1.57 (s, 9H), 4.47 (br s, 3H), 7.85 (s, 1H), 8.32 (s, 1H), 8.38 (s, 1H).
Step 3: tert-Butyl 3-amino-5-(trifluoromethyl)benzyl(isopropyl)carbamate The titled compound was prepared by the reaction of tert-butyl isopropy1(3-nitro-5-(trifluoromethyl)benzyl)carbamate (step 2 intermediate ) (235 mg, 0.65 mmol) with iron powder (363 mg, 6.50 mmol) and ammonium chloride (278 mg, 5.20 mmol) in ethanol (5.0 mL) and water (1.5 mL) as per the procedure described in step 2 of Intermediate C28 to 170 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.05 (d, J = 6.8 Hz, 6H), 1.42 (s, 9H), 4.21 (br s, 3H), 5.56 (s, 2H), 6.62 (s, 1H), 6.67 (d, J= 8.4 Hz, 2H).
Intermediate C64 3 -(1-Methyl-1H-pyrazol-4-y1)-5 -(trifluoromethyl)aniline N-N
Step 1: 4-(3 -Nitro-5 -(trifluoromethyl)pheny1)-1-(tetrahydro-2H-pyran-2-y1)-1H-pyrazo le 02N is cF3 7, N-N
THF;
The titled compound was prepared by the reaction of 1-bromo-3 -nitro-5 -(trifluoromethyl)benzene (1.0 g, 3.70 mmol) with 1-(tetrahydro-2H-pyran-2-y1)-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-pyrazole (1.12 g, 4.07 mmol) in the presence of cesium carbonate (1.80 g, 5.50 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (150 mg, 0.18 mmol) in 1,4-dioxane (10 mL) and water (2.0 mL) as per the procedure described in step 2 of Intermediate C34 to yield 730 mg of the desired compound1H NMR (400 MHz, DMSO-d6) 6 1.53-1.68 (m, 2H), 1.69-1.74 (m, 1H), 1.95-2.0 (m, 2H), 2.07-2.10 (m, 1H), 3.65-3.70 (m, 1H), 3.94-3.97 (m, 1H), 5.45 (dd , ./i = 2.4 Hz, .1-2 = 10.0 Hz, 1H), 7.86 (s, 1H), 8.32 (s, 1H), 8.51 (s, 1H), 8.75 (s, 1H), 8.87 (s, 1H).
Step 2: 4-(3 -Nitro-5 -(trifluoromethyl)pheny1)-1H-pyrazo le o2N is cF3 7, HN-N
The titled compound was prepared by the reaction of 4-(3-nitro-5-(trifluoromethyl)pheny1)-1-(tetrahydro-2H-pyran-2-y1)-1H-pyrazole (step 1 intermediate) (350 mg, 1.03 mmol) with hydrochloric acid in ethyl acetate (10 mL) in methanol (5.0 mL) as per the procedure described in step 1 of Intermediate C57 to yield 257 mg of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 8.25 (s, 1H), 8.29 (s, 1H), 8.65 (s, 1H), 8.71 (s, 1H), 8.72 (d, J= 2.0 Hz, 1H), 13.24 (s, 1H).
Step 3: 1-Methyl-4-(3 -nitro-5 -(trifluoromethyl)pheny1)-1H-pyrazo le 02N cF3 N-N
The titled compound was prepared by the reaction of 4-(3-nitro-5-(trifluoromethyl)pheny1)-1H-pyrazole (step 2 intermediate) (100 mg, 0.39 mmol) with methyl iodide (82 mg, 0.58 mmol) in the presence of sodium hydride (60% w/w, 17 mg, 0.42 mmol) in DMF
(5.0 mL) as per the procedure described in step 2 of Intermediate C57 to yield 60 mg of the compound.
1H NMR (400 MHz, DMSO-d6) 6 3.89 (s, 3H), 8.24 (s, 2H), 8.41 (s, 1H), 8.59 (s, 1H), 8.66 (s, 1H).
Step 4: 3 -(1-Methyl-1H-pyrazol-4-y1)-5 -(trifluoromethyl)aniline The titled compound was prepared by the catalytic hydrogenation of 1-methy1-4-(3-nitro-5-(trifluoromethyl)pheny1)-1H-pyrazole (step 3 intermediate) (55 mg, 0.20 mmol) in the presence of palladium on carbon (10% w/w, 50% wet, 20 mg) in methanol (5.0 mL) and THF
(2.0 mL) as per the procedure described in step 3 of Intermediate Cl to yield 35 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 3.85 (s, 3H), 5.56 (s, 2H), 6.68 (s, 1H), 6.95 (s, 2H), 7.79 (s, 1H), 8.12 (s, 1H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above (step 1 and 4) are given below in Table 19.
Table 19: Chemical name, structure and analytical data of Intermediate C65 Intermediate No. Chemical Name and Structure Analytical Data H2N cF3 1H NMR (400 MHz, DMSO-d6) 6 1.54-1.56 (m, 2H), 1.63-1.70 (m, 1H), 1.71-1.96 (m, 2H), 2.08-2.17 (m, 1H), 3.61-3.67 (m, 1H), 3.92-3.95 (m, 1H), N-N
THF;
5.40 (dd , ./i = 2.8 Hz, .1-2 = 10.0 Hz, 3-(1-(Tetrahydro-2H-pyran-2-y1)-1H), 5.55 (s, 2H), 6.71 (s, 1H), 7.00 (s, 1H-pyrazol-4-y1)-5-1H), 7.04 (s, 1H), 7.87 (s, 1H), 8.35 (s, (trifluoromethyl)aniline 1H) Intermediate C66 3 -((l-Methylazetidin-3 -yl)oxy)-5 -(trifluoromethyl)aniline H2N C_F3 Step 1: tert-Butyl 3 -(3 -nitro-5 -(trifluoromethyl)phenoxy)azetidine-l-c arboxylate 02N 401 cF3 O
\.-N.Boc The titled compound was prepared by the reaction of 3-nitro-5-(trifluoromethyl)phenol (1.0 g, 4.83 mmol) with N-Boc-3-hydroxyazetidine (1.0 g, 5.80 mmol) in the presence of triphenylphosphine (1.9 g, 7.20 mmol) and diisopropyl azodicarboxylate (DIAD) (1.35 mL, 7.20 mmol) in THF (10 mL) as per the procedure described in step 2 of Intermediate A2 to yield 1.52 g of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.39 (s, 9H), 3.84-3.88 (m, 2H), 4.36 (br s, 2H), 5.27-5.32 (m, 1H), 7.82 (s, 1H), 7.88-7.90 (m, 1H), 8.11 (s, 1H).
Step 2: 3 -(3 -Nitro-5 -(trifluoromethyl)phenoxy)az etidine hydrochloride 02N is \--NH HCI
The titled compound was prepared by the reaction of tert-butyl 3-(3-nitro-5-(trifluoromethyl)phenoxy)azetidine-1-carboxylate (step 1 intermediate) (1.50 g, 5.73 mmol) with hydrochloric acid in ethyl acetate (20 mL) in ethyl acetate (4.0 mL) as per the procedure described in step 1 of Intermediate C57 to yield 918 mg of the compound (isolated a hydrochloride salt). 1H NMR (400 MHz, DMSO-d6) 6 4.02-4.06 (m, 2H), 4.46-4.51 (m, 2H), 5.39-5.42 (m, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.95 (t, J = 2.0 Hz, 1H), 8.14 (s, 1H), 9.68 (br s, 2H); ESI-MS (m/z) 263 (M+H-HCl).
Step 3: 1-Methyl-3 -(3 -nitro-5 -(trifluoromethyl)phenoxy)azetidine Toa stirred solution of 3-(3-nitro-5-(trifluoromethyl)phenoxy)azetidine hydrochloride (step 2 intermediate) (900 mg, 3.01 mmol) in dichloroethane (10 mL) were added formaldehyde (37%, 135 mg, 4.52 mmol) and sodium triacetoxyborohydride (STAB) (958 mg, 4.52 mmol) and the mixture was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 790 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.29 (s, 3H), 3.02-3.06 (m, 2H), 3.72-3.76 (m, 2H), 5.08 (t, J = 5.6 Hz, 1H), 7.67 (s, 1H), 7.85 (t, J = 2.0 Hz, 1H), 8.07 (s, 1H); ESI-MS (m/z) 277 (M+H)+.
Step 4: 3 -((l-M ethylazetidin-3 -yl)oxy)-5 -(trifluoromethyl)aniline The titled compound was prepared by the reaction of 1-methy1-3-(3-nitro-5-(trifluoromethyl)phenoxy)azetidine (step 3 intermediate ) (780 mg, 2.82 mmol) with iron powder (780 mg, 14.1 mmol) and ammonium chloride (1.5 g, 28.2 mmol) in methanol (10 mL) and water (10 mL) as per the procedure described in step 2 of Intermediate C28 to 623 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.27 (s, 3H), 2.92-2.95 (m, 2H), 3.69 (dt, ./i =2.0 Hz, ./i = 6.0 Hz, 2H), 4.67-4.70 (m, 1H), 5.61 (s, 2H), 6.17 (s, 1H), 6.23 (t, J= 1.6 Hz, 1H), 6.45 (s, 1H); ESI-MS (m/z) 247 (M+H)+.
Intermediate C68 1-((4-Fluorophenyl)carbamoyl)cyclopropanecarboxylic acid HO
0 0 [W
To a stirred solution of cyclopropane-1,1-dicarboxylic acid (400 mg, 3.05 mmol) in dichloromethane (10 mL) were added thionyl chloride (222 L, 3.05 mmol) followed by catalytic amount of DMF and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in THF (10 mL). The solution was cooled to 0 C; 4-fluoroaniline (0.29 mL, 3.05 mmol) was added to the reaction mixture followed by triethylamine (0.43 mL, 3.08 mmol). The resultant mixture was stirred overnight at RT. The mixture was diluted with water and extracted twice with ethyl acetate.
The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by column chromatography to yield 270 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.41 (s, 4H), 7.12-7.17 (m, 2H), 7.61-7.64 (m, 2H), 10.51 (s, 1H), 12.81 (s, 1H).
Intermediate C71 3 -((1S,4S)-5 -M ethy1-2,5-diazabicyclo [2 .2 .1]heptan-2-y1)-5-(trifluoromethyl)aniline H2N c_F3 (s)c%
N (s) Step 1: (1S,4S)-tert-Butyl 5 -(3 -nitro-5 -(trifluoromethyl)pheny1)-2,5 -diazabicyclo[2.2.1]heptane-2-carboxylate 02N 0_ F3 (s)1 (s) Boc The titled compound was prepared by the reaction of 1-bromo-3 -nitro-5 -(trifluoromethyl)benzene (2.7 g, 13.6 mmol) with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 2.52 mmol) in the presence of sodium tert-butoxide (350 mg, 3.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (138 mg, 0.15 mmol) and Xantphos (175 mg, 0.30 mmol) in toluene (10 mL) as per the procedure described in step 2 of Intermediate C34 to yield 840 mg of the desired compound.
1H NMR (400 MHz, DMSO-d6) 6 1.60 (s, 9H), 2.06 (d, J = 5.2 Hz, 2H), 3.26-3.51 (m, 4H), 4.52 (s, 1H), 4.61-4.75 (m, 1H), 6.99 (s, 1H), 7.51 (s, 1H), 7.76 (s, 1H).
Step 2:
(1S,4S)-2-(3 -Nitro-5 -(trifluoromethyl)pheny1)-2,5 -diaz abicyclo [2 .2 .1]heptane hydrochloride 02N so CF3 (s) H HCI
The titled compound was prepared by the reaction of (1S,4S)-tert-butyl 5-(3-nitro-5-(trifluoromethyl)pheny1)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (step 1 intermediate) (400 mg, 1.13 mmol) with hydrochloric acid in 1,4-dioxane (4.0 mL) in ethanol (8.0 mL) as per the procedure described in step 1 of Intermediate C57 to yield 280 mg of the compound.
The crude amine was as such carried forward to the next step.
Step 3:
(1S,4S)-2-Methy1-5 -(3 -nitro-5 -(trifluoromethyl)pheny1)-2,5-diazabicyclo[2.2.1]heptane 02N u3 (s) The titled compound was prepared by the reaction of (1S,4S)-2-(3-nitro-5-(trifluoromethyl)pheny1)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (step 2 intermediate) (275 mg, 0.94 mmol) with methyl iodide (147 mg, 1.03 mmol) in the presence of potassium carbonate (142 mg, 1.03 mmol) in acetonitrile (12 mL) as per the procedure described in step 2 of Intermediate C57 to yield 60 mg of the compound. The crude amine was as such carried forward to the next step.
Step 4: 3 -((1S,4S)-5 -Methyl-2,5 -diaz abicyclo [2 .2 .1]heptan-2-y1)-5 -(trifluoromethyl)aniline The titled compound was prepared by the catalytic hydrogenation of (1S,4S)-2-methy1-5-(3-nitro-5-(trifluoromethyl)pheny1)-2,5-diazabicyclo[2.2.1]heptane (step 3 intermediate) (60 mg, 0.19 mmol) in the presence of palladium on carbon (10% w/w, 50% wet, 20 mg) in methanol (10 mL) as per the procedure described in step 3 of Intermediate Cl to yield 60 mg (crude) of the compound. The crude amine was as such carried forward to the next step due to poor solubility and instability in solution form.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 20.
Table 20: Chemical name, structure and analytical data of Intermediate C72-C73 and C75-Intermediate No. Chemical Name and Structure Analytical Data H2N cF3 The crude amine was as such carried C72 C (s forward to the next step due to poor solubility and instability in solution form.
(S)-3 -(2,4-Dimethylpip erazin-l-y1)-5 -(trifluoromethyl)aniline H2N c_F3 1H NMR (400 MHz, DMSO-d6) 6 1.01 (d, J = 6.4 Hz, 3H), 2.02 (td , J, = 3.6 Hz, J2 = 11.2 Hz, 1H), 2.20 (d, J = 3.6 C Hz, 3H), 2.61-2.64 (m, 1H), 2.76-2.79 (m, 2H), 2.94 (dt, J, = 3.2 Hz, J2 = 11.6 Hz 1H) 3.18-3.21 (m, 1H), 3.89-3.92 (R)-3-(2,4-Dimethylpiperazin-1-y1)- "
(m, 1H), 5.32 (s, 2H), 6.25 (s, 1H), 5 -(trifluoromethyl)aniline 6.29 (d, J = 1.6 Hz, 2H).
H2N c _F3 1H NMR (400 MHz, DMSO-d6) 6 1.04 (d, J = 6.0 Hz, 3H), 2.06-2.17 (m, 1H), 2.20 (s, 3H), 2.32-2.37 (m, 2H), 2.68-C ( 2.81 (m, 2H), 3.42-3.48 (m, 2H), 5.35 (s, 2H), 6.28 (s, 1H), 6.33 (s, 2H) ESI-(R)-3-(3,4-Dimethylpiperazin-1-y1)-MS (m/z) 274 (M+H)+.
5 -(trifluoromethyl)aniline Intermediate No. Chemical Name and Structure Analytical Data H2N c_F3 1H NMR (400 MHz, DMSO-d6) 6 1.04 C
(d, J = 5.6 Hz, 3H), 2.08-2.16 (m, 1H), 2.20 (s, 3H), 2.22-2.37 (m, 1H), 2.68-2.80 (m, 3H), 3.43-3.48 (m, 2H), 5.35 (S)-3-(3,4-Dimethylpiperazin-1-y1)- (s, 2H), 6.28 (s, 1H), 6.33 (s, 2H).
-(trifluoromethyl)aniline Intermediate C74 4-(3 -Amino-5 -(trifluoromethyl)phenyl)morpho lin-3 -one H2N c _ F3 0,1\H
5 Step 1: 4-(3 -Nitro-5 -(trifluoromethyl)phenyl)morpholine 02N so c3 (o) The titled compound was prepared by the reaction of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (2.0 g, 7.40 mmol) with morpholine (1.61 g, 18.5 mmol) in the presence of N,N-diisopropylethylamine (DIPEA) (2.7 mL, 14.8 mmol) in DMSO (10 mL) as per the procedure described in step 2 of Intermediate Cl to yield 1.1 g of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 3.36 (t, J = 5.2 Hz, 4H), 3.75 (t, J = 4.8 Hz, 4H), 7.64 (s, 1H), 7.78 (s, 1H), 7.91 (t, J = 2.4 Hz, 1H).
Step 2: 4-(3 -Nitro-5 -(trifluoromethyl)phenyl)morpho lin-3 -one 02N is c3 Oy\H
401) A suspension of 4-(3-nitro-5-(trifluoromethyl)phenyl)morpholine (step 1 intermediate) (1.1 g, 3.98 mmol), benzyltributylammonium chloride (7.5 g, 23.9 mmol) and K1VIn04 (3.77 g, 23.9 mmol) in dichloromethane (70 mL) was heated overnight at 70 C. The mixture was cooled to RT and diluted with ethyl acetate. The suspension was filtered through celite and the bed was washed with ethyl acetate. The combined filtrate and washings were concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 340 mg of the desired compound. 41 NMR (400 MHz, DMSO-d6) 6 3.91-3.94 (m, 2H), 3.94-4.03 (m, 2H), 4.29 (s, 2H), 8.37 (d, J= 10.8 Hz, 2H), 8.66 (t, J =
1.6 Hz, 1H).
Step 3: 4-(3 -Amino-5 -(trifluoromethyl)phenyl)morpho lin-3 -one The titled compound was prepared by the reaction of 4-(3-nitro-5-(trifluoromethyl)phenyl)morpholin-3-one (step 2 intermediate ) (300 mg, 1.14 mmol) with iron powder (636 mg, 11.3 mmol) and ammonium chloride (487 mg, 9.10 mmol) in ethanol (10 mL) and water (4.0 mL) as per the procedure described in step 2 of Intermediate C28 to 150 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 3.69 (t, J = 5.2 Hz, 2H), 3.95 (t, J=4.8 Hz, 2H), 4.19 (s, 2H), 5.72 (s, 2H), 6.76 (s, 2H), 6.82 (d, J= 12.4 Hz, 2H).
Intermediate C79 3'-Amino-5'-(trifluoromethyl)-[1,1'-bipheny1]-4-carbonitrile ON
Step 1: 3'-Nitro-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbonitrile ON
To a solution of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (250 mg, 0.92 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) were added 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)benzonitrile (215 mg, 0.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (39 mg, 0.05 mmol) and potassium carbonate (269 mg, 1.95 mmol) and the mixture was heated at 100 C for 18 h. The mixture was cooled to RT and diluted with ethyl acetate.
The solution was filtered through celite. The filtrate was washed with water followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield 350 mg of the desired compound. 1H
NMR (400 MHz, DMSO-d6) 6 8.03 (dd, ./i = 1.6 Hz, .12 = 3.6 Hz, 2H), 8.14 (dd, ./i = 2.0 Hz, .12 = 6.4 .. Hz, 2H), 8.60 (s, 2H), 8.81 (t, J = 1.6 Hz, 1H).
Step 2: 3'-Amino-5'-(trifluoromethy1)41,1'-biphenyl]-4-carbonitrile The titled compound was prepared by the reaction of 3'-nitro-5'-(trifluoromethy1)41,1'-biphenyl]-4-carbonitrile (step 2 intermediate) (150 mg, 0.51 mmol) with iron powder (286 mg, 5.13 mmol) and ammonium chloride (219 mg, 4.10 mmol) in ethanol (5.0 mL) and water (2.0 mL) as per the procedure described in step 2 of Intermediate C28 to 50 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 5.80 (s, 2H), 6.92 (s, 1H), 7.08 (s, 1H), 7.12 (s, 1H), 7.82 (d, J= 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 21.
Table 21: Chemical name, structure and analytical data of Intermediate C80 Intermediate No. Chemical Name and Structure Analytical Data H2N cF3 1H NMR (400 MHz, DMSO-d6) 6 5.75 (s, 2H), 6.91 (s, 1H), 7.11 (s, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.84-7.87 (m, 1H), 7.96 (dt, ./i = 1.2 Hz, .1-2 CN
= 6.8 Hz, 1H), 8.11 (s, 1H); ESI-MS
3 '-Amino-5 '-(trifluoromethyl)- [1,1'- (m/z) 261 04-Hy.
biphenyl] -3 -carbonitrile Intermediate C81 4-(1-(4-Ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)aniline H2N CF _ 3 (Nj Nc Stepl : 1 -(4-Nitro-2-(trifluoromethyl)phenyl)ethanone To a stirred solution of 1-bromo-4-nitro-2-(trifluoromethyl)benzene (500 mg, 1.85 mmol) and tributy1(1-ethoxyvinyl)tin (806 mg, 2.22 mmol) in DMF (5.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (136 mg, 0.09 mmol) after purging argon for 15 min. The mixture was heated at 90 C for 18 h. The mixture was cooled to RT
and poured into dilute hydrochloric acid (50 mL). The solution was stirred at RT for 1 h.
The aqueous mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 125 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 2.65 (s, 3H), 7.66 (d, J= 8.4 Hz, 1H), 8.50 (m, 1H), 78.60 (s, 1H).
Step 2: 1-(4-Nitro-2-(trifluoromethyl)phenyl)ethanol _ 3 OH
To a solution of 1-(4-nitro-2-(trifluoromethyl)phenyl)ethanone (step 1 intermediate) (120 mg, 0.52 mmol) in methanol (5.0 mL) was added sodium borohydride (20 mg, 0.52 mmol) at 0 C
and the mixture was stirred at RT for 3 h. The reaction was quenched with acetone (2.0 mL) and diluted with water. The aqueous mixture was extracted twice with chloroform. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 120 mg of the desired compound.
1H NMR (400 MHz, CDC13) 6 1.53 (d, J = 6.4 Hz, 3H), 2.15 (d, J = 2.8 Hz, 1H), 5.42-5.43 (br s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.46 (dd, J, = 2.4 Hz, J2 = 8.8 Hz, 1H), 8.52 (s, 1H).
Step 3: 1-Ethy1-4-(1-(4-nitro-2-(trifluoromethyl)phenyl)ethyl)piperazine 02N so cF3 cNj To a stirred solution of 1-(4-nitro-2-(trifluoromethyl)phenyl)ethanol (step 2 intermediate) (600 mg, 2.56 mmol) in dichloromethane (5.0 mL) were added triethylamine (1.0 mL, 7.68 mmol) followed by methanesulfonyl chloride (Mesyl chloride) (587 mg, 5.12 mmol) at 0 C
and the mixture was stirred at RT for 1 h. The reaction was quenched with ice-water mixture and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 25 C. The residue was dissolved in DMF
(10 mL) and cooled to 0 C. To that solution were added potassium carbonate (706 mg, 5.12 mmol) followed by N-ethylpiperazine (292 mg, 2.56 mmol) and the mixture was stirred overnight at RT. The reaction was quenched with ice-water mixture and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 320 mg of the desired compound. 1H NMR (400 MHz, CDC13) 6 1.09 (t, J= 7.2 Hz, 3H), 1.32 (d, J= 10.4 Hz, 3H), 2.30-2.46 (m, 10H), 3.77 (q, J = 4.8 Hz, 1H), 8.15 (d, J= 8.8 Hz, 1H), 8.40 (dd, J, = 2.4 Hz, J2 = 8.8 Hz, 1H), 8.51 (s, 1H).
Step 4: 4-(1-(4-Ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)aniline The titled compound was prepared by the reaction of 1-ethy1-4-(1-(4-nitro-2-(trifluoromethyl)phenyl)ethyl)piperazine (step 3 intermediate ) (220 mg, 0.66 mmol) with iron powder (371 mg, 6.64 mmol) and ammonium chloride (283 mg, 5.31 mmol) in ethanol (5.0 mL) and water (1.0 mL) as per the procedure described in step 2 of Intermediate C28 to .. 80 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.03 (t, J= 6.4 Hz, 3H), 1.17-1.23 (m, 5H), 2.51-2.92 (m, 7H), 3.36 (m, 2H), 5.76 (s, 2H), 6.78-6.81 (br s, 2H), 7.38 (d, J = 8.4 Hz, 1H).
Intermediate C82 N-(3 -Amino-5 -(trifluoromethyl)phenyl)propionamide HN,f0 Step 1: N-(3 -Bromo-5 -(trifluoromethyl)phenyl)propionamide Br CF _ 3 HN,f0 To a stirred mixture of propionic acid (1.54 g, 20.8 mmol) and 3-bromo-5-(trifluoromethyl)aniline (5.0 g, 20.8 mmol) in dichloromethane (15 mL) were added EDCI.
HC1 (7.9 g, 41.6 mmol), HOBt (2.8 g, 20.8 mmol) and DIPEA (7.0 mL, 41.6 mmol) at 0 C.
The mixture was stirred at RT for 3 h. The mixture was diluted with water and ethyl acetate.
The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine. The solution was dried over anhydrous sodium sulfate, fileted and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 2.3 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 0.90 (t, J = 7.2 Hz, 3H), 2.36 (q, J =
7.6 Hz, 2H), 7.60 (s, 1H), 7.98 (s, 1H), 8.11 (s, 1H), 10.35 (s, 1H).
Step 2: N-(34(Diphenylmethylene)amino)-5-(trifluoromethyl)phenyl)propionamide Ph N CF3 Ph 1.1 HN,f0 The titled compound was prepared by the reaction of N-(3 -bromo-5 -(trifluoromethyl)phenyl)propionamide (step 1 intermediate) (1.0 g, 3.37 mmol) with benzophenone imine (918 mg, 5.06 mmol) in the presence of cesium carbonate (2.2 g, 6.76 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (232 mg, 0.25 mmol) and ( )-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (rac-BINAP) (105 mg, 0.16 mmol) in 1,4-dioxane (10 mL) as per the procedure described in step 2 of Intermediate C34 to yield 1.05 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.05 (t, J = 7.6 Hz, 3H), 2.30 (q, .. J= 7.6 Hz, 2H), 6.61 (s, 1H), 7.17-7.36 (m, 3H), 7.47-7.69 (m, 9H), 1.06 (s, 1H); ESI-MS
(m/z) 397 (M+H)+.
Step 3: N-(3 -Amino-5 -(trifluoromethyl)phenyl)propionamide The titled compound was prepared by the reaction of N-(3-((diphenylmethylene)amino)-5-(trifluoromethyl)phenyl)propionamide (step 2 intermediate) (1.0 g, 2.53 mmol) with .. hydrochloric acid in 1,4-dioxane (5.0 mL) in THF (10 mL) as per the procedure described in step 1 of Intermediate C57 to yield 431 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.06 (t, J = 7.6 Hz, 3H), 2.29 (q, J = 7.6 Hz, 2H), 5.58 (s, 2H), 6.51 (s, 1H), 7.07 (s, 1H), 7.10 (s, 1H), 9.84 (s, 1H).
Intermediate C83 244-Amino-2-(trifluoromethyl)pheny1)-2-methylpropanenitrile CN
Step 1: 2-(4-Nitro-2-(trifluoromethyl)phenyl)acetonitrile o2N 0 c _ F3 CN
A mixture of 2-chloro-5-nitrobenzotrifluoride (3.0 g, 13.3 mmol), potassium carbonate (367 mg, 2.66 mmol), potassium iodide (3.3 g, 19.9 mmol) and ethyl cyanoacetate (1.80 g, 15.9 mmol) in DMF (20 mL) was stirred at RT for 72 h. The mixture was quenched with 10%
aqueous citric acid solution and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in a mixture of water (25 mL) and acetic acid (10 mL) and was added 37% hydrochloric acid at RT. The mixture was heated at 100 C for h. The reaction mixture was cooled to RT and quenched with 10% aqueous potassium carbonate solution. The aqueous mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column 30 chromatography to yield 2.3 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 4.40 (s, 2H), 8.02 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 8.60 (dd, Ji = 2.4 Hz, J2 = 8.4 Hz, 1H) ;
ESI-MS (m/z) 229 (M-H)-.
Step 2: 2-Methyl-2-(4-nitro-2-(trifluoromethyl)phenyl)propanenitrile CN
To a stirred solution of 2-(4-nitro-2-(trifluoromethyl)phenyl)acetonitrile (step 1 intermediate) (500 mg, 2.17 mmol) in THF (15 mL) were added methyl iodide (925 mg, 6.51 mmol) followed by potassium tert-butoxide solution (1M, 6.5 mL, 6.51 mmol) at 0 C
and the mixture was stirred at RT for 18 h. The mixture was diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
The residue obtained was purified by silica gel column chromatography to yield 70 mg of the desired compound (Fraction-1) along with 400 mg of 2-(4-nitro-2-(trifluoromethyl)phenyl)propanenitrile (Fraction-2). The fraction-2 (400 mg, 1.64 mmol) was further reacted with methyl iodide (465 mg, 3.27 mmol) in the presence of potassium tert-butoxide solution (1M, 3.27 mL, 3.27 mmol) in THF (20 mL) as per the procedure described above to yield 310 mg of the titled compound. 1H NMR (400 MHz, DMSO-d6) 6 1.88 (s, 6H), 8.11 (d, J= 9.2 Hz, 1H), 8.55 (s, 2H).
Step 3: 2-(4-Amino-2-(trifluoromethyl)pheny1)-2-methylpropanenitrile The titled compound was prepared by the reaction of 2-methyl-2-(4-nitro-2-(trifluoromethyl)phenyl)propanenitrile (step 2 intermediate) (300 mg, 1.15 mmol) with iron powder (321 mg, 5.76 mmol) and ammonium chloride (308 mg, 5.76 mmol) in methanol (10 mL) and water (10 mL) as per the procedure described in step 2 of Intermediate C28 to 137 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.72 (s, 6H), 5.71 (s, 2H), 6.79 (dd, = 1.6 Hz, .1-2 = 8.4 Hz, 1H), 6.99 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H); ESI-MS
(m/z) 229 (M+H)+.
Intermediate C84 N-(3 -Amino-5 -(trifluoromethyl)pheny1)-2-(dimethylamino)acetamide H2N io HN,e0 LI\J

The titled compound was prepared by the reaction of 5-(trifluoromethyl)benzene-1,3-diamine (1.1 g, 6.26 mmol) with N,N-dimethylglycine (644 mg, 6.25 mmol) in the presence of EDCI.
HC1 (2.39 mg, 12.5 mmol), HOBt (843 mg, 6.25 mmol) and DIPEA (2.15 mL, 12.5 mmol) in dichloromethane (10 mL) as per the procedure described in step 1 of Intermediate C82 to yield 230 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.62 (s, 6H), 3.04 (s, 2H), 5.60 (s, 2H), 6.52 (s, 1H), 7.13 (s, 1H), 7.18 (s, 1H), 9.72 (s, 1H); ESI-MS
(m/z) 3261(M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 22.
Table 22: Chemical name, structure and analytical data of Intermediate C85 Intermediate No. Chemical Name and Structure Analytical Data cF3 1H NMR (400 MHz, DMSO-d6) 6 0.84 (d, J = 6.0 Hz, 6H), 2.27-2.30 (m, 1H), 3.12-3.15 (m, 1H), 3.22-C85 H2N 14 N)CC
H N T., 3.26 (m, 1H), 3.37-3.41 (m, 3H), 5.61 (s, 2H), 6.52 (s, 1H), 7.05 (s, N-(3 -Amino-5 -1H), 7.12 (s, 1H), 9.89 (s, 1H); ESI-(trifluoromethyl)pheny1)-1- MS (m/z) 302 (M+H)+.
isopropylazetidine-3 -carboxamide Intermediate C86 1-(3 -Amino-5 -(trifluoromethyl)pheny1)-N,N-dimethylazetidin-3 -amine H2N 0 cF3 N
?
N
Step 1: N,N-Dimethy1-1-(3 -nitro-5 -(trifluoromethyl)phenyl)azetidin-3 -amine 02N 40 cF3 N
?
The titled compound was prepared by the reaction of 1-bromo-3 -nitro-5 -(trifluoromethyl)benzene (200 mg, 0.74 mmol) with N,N-dimethylazetidin-3-amine hydrochloride (256 mg, 1.48 mmol) in the presence of sodium tert-butoxide (355 mg, 3.70 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (34 mg, 0.04 mmol) and Xantphos (30 mg, 0. 05 mmol) in 1,4-dioxane (4.0 mL) as per the procedure described in step 2 of Intermediate C34 to yield 155 mg of the desired compound. 1H NMR
(400 MHz, DMSO-d6) 6 2.13 (s, 6H), 3.24-3.27 (m, 1H), 3.79 (t, J = 5.2 Hz, 2H), 4.08 (t, J = 7.6 Hz, 2H), 7.07 (s, 1H), 7.37 (s, 1H), 7.63 (s, 1H); ESI-MS (m/z) 290 (M+H)+.
Step 2: 1-(3 -Amino-5 -(trifluoromethyl)pheny1)-N,N-dimethylazetidin-3 -amine The titled compound was prepared by the reaction of N,N-dimethy1-1-(3-nitro-5-(trifluoromethyl)phenyl)azetidin-3-amine (step 1 intermediate) (150 mg, 0.52 mmol) with iron powder (290 mg, 5.19 mmol) and ammonium chloride (222 mg, 4.15 mmol) in ethanol (4.0 mL) and water (2.0 mL) as per the procedure described in step 2 of Intermediate C28 to 95 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 2.14 (s, 6H), 3.13-3.18 (m, 1H), 3.50 (t, J = 5.6 Hz, 2H), 3.86 (t, J = 7.2 Hz, 2H), 5.36 (s, 2H), 5.82 (s, 2H), 6.19 (s, 1H); ESI-MS (m/z) 260 (M+H)+.
Intermediate C87 (E)-3 -(3 -Amino-5 -(trifluoromethyl)phenyl)acrylamide H2N cF3 Step 1: 3 -(3 -nitro-5 -(trifluoromethyl)phenyl)propiolamide 02N is 0F3 To a solution of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (1.0 g, 3.70 mmol) in degassed DMF (10 mL) were added propiolamide (511 mg, 7.40 mmol), bis(triphenylphosphine)palladium(II)dichloride (129 mg, 0.18 mmol), copper(II)iodide (71 mg, 0.37 mmol) and triethylamine (1.54 mL, 11.1 mmol) at RT. The resultant mixture was heated at 120 C for 30 min in a microwave reactor. The mixture was cooled to RT and quenched with water. The product was extracted in ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 480 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 7.92 (br s, 2H), 8.32 (s, 1H), 8.46 (s, 1H), 8.57-8.66 (m, 1H).
Step 2: (E)-3 -(3 -Amino-5 -(trifluoromethyl)phenyl)acrylamide To a stirred solution of 3-(3-nitro-5-(trifluoromethyl)phenyl)propiolamide (step 1 intermediate) (201 mg, 0.78 mmol) in a mixture of methanol and water (3:1, 10 mL) was added ammonium chloride (416 mg, 7.78 mmol) and the mixture was heated to 80 C. Zinc dust (254 mg, 3.84 mmol) was added to the mixture in small portions and stirred at for 1 h at 80 C. The mixture was cooled to RT and diluted with ethyl acetate. The solution was filtered through celite. The filtrate was washed with ethyl acetate and the combined organic layers were washed with water, followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 65 mg of the desired compound. 41 NMR (400 MHz, DMSO-d6) 6 5.73 (s, 2H), 6.58 (d, J= 16.0 Hz, 1H), 6.84 (s, 1H), 6.95 (d, J= 7.6 Hz, 2H), 7.16 (s, 1H), 7.30 (d, J= 15.6 Hz, 1H), 7.55 (s, 1H).
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 23.
Table 23: Chemical name, structure and analytical data of Intermediate C88, C93, C96, C102-103, and 105 Intermediate No. Chemical Name and Structure Analytical Data F3c 1H NMR (400 MHz, DMSO-d6) 6 41 = \ N 5.87 (s, 2H), 6.94 (s, 1H), 6.99 (s, I C88 2H), 7.54 (d, J = 6.0 Hz, 2H), 8.64 H2N (d, J = 6.4 Hz, 2H), ESI-MS
(m/z) 3 -(Pyridin-4-ylethyny1)-5 - 263 (M+H)+.
(trifluoromethyl)aniline F3c 1H NMR (400 MHz, DMSO-d6) 6 41. = OH 1.44 (s, 6H), 5.49 (s, 1H), 5.73 (s, C93 H2N 2H), 6.71 (s, 1H), 6.81 (dd, J = 5.6, 1.6 Hz, 2H).
443 -Amino-5 -(trifluoromethyl)pheny1)-2-methylbut-3 -yn-2-ol F3c 1H NMR (400 MHz, DMSO-d6) 6 . ¨ 4.28 (d, J = 6.0 Hz, 2H), 5.36 (t, J=
C96 H2N OH 6.0 Hz, 1H), 5.76 (s 2H), 6.76 (s, 3 -(3 -Amino-5 - 1H), 6.84 (dd, J = 5.6, 1.6 Hz, 2H).
(trifluoromethyl)phenyl)prop-2-yn-1-ol F3c 1H NMR (400 MHz, DMSO-d6) 6 C102 . ¨ OH 1.37 (d, J = 5.2 Hz, 3H), 4.57 (br s, 1H), 5.49 (s, 1H), 5.75 (s, 2H), 6.74 4-(3 -amino-5 - (s, 1H), 6.80-6.84 (m, 2H).
(trifluoromethyl)phenyl)but-3-yn-2-ol Intermediate No. Chemical Name and Structure Analytical Data 1H NMR (400 MHz, DMSO-d6) 6 CF 3 1.35 (d, J = 6.4 Hz, 3H), 4.54 (t, J =
6.0 Hz, 1H),5.36 (d, J = 5.2 Hz, 1H), C103 H2N . OH 5.93 (s, 2H), 6.72 (dd, J1 = 2.0 Hz, .12 4-(4-Amino-2-= 8.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 7.24 (d, (trifluoromethyl)phenyl)but-3-yn-2-ol J = 8.4 Hz, 1H); ESI-1H NMR (400 MHz, DMSO-d6) 2.49 .5__/ _cF3 (t, J = 6.8 Hz, 2H), 3.54 (q, J = 6.8 C105 H 2N \ /
OH
Hz, 2H), 4.84 (t, J = 5.6 Hz, 1H), =
5.86 (s, 2H), 6.70 (dd, J1 = 2.0 Hz, .12 4-(4-Amino-2-= 8.0 Hz, 1H), 6.86 (d, J = 2.4 Hz, (trifluoromethyl)phenyl)but-3-yn-1-ol 1H), 7.23 (d, J = 8.4 Hz, 1H); ESI-MS (m/z) 230 (M+H)+.
Intermediate C89 3 -(3 -Amino-5 -(trifluoromethyl)phenyl)propio lamide The titled compound was prepared by the reaction of 3 -(3 -nitro-5 -(trifluoromethyl)phenyl)propiolamide (Intermediate C87-step 1 intermediate) (200 mg, 0.77 mmol) with iron powder (216 mg, 3.87 mmol) and ammonium chloride (42 mg, 0.77 mmol) in a mixture of ethanol, THF and water (2:1:1, 10 mL) as per the procedure described in step 2 of Intermediate C28 to yield 110 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 5.90 (s, 2H), 714-7.21 (m, 3H), 7.71 (s, 1H), 8.17 (s, 1H).
Intermediate C90 (E)-3 -(3 -Amino-5 -(trifluoromethyl)phenyl)acrylonitrile H2N 0 cF3 CN
To a solution of 3-bromo-5-(trifluoromethyl)aniline (502 mg, 2.09 mmol) in degassed DMF
(5.0 mL) were added acrylonitrile (97 L, 2.51 mmol), tetrakis(triphenylphosphine)palladium(0) (121 mg, 0.10 mmol), and triethylamine (0.87 mL, 6.27 mmol) at RT. The resultant mixture was heated at 130 C for 30 min in a microwave reactor. The mixture was cooled to RT and quenched with water. The product was extracted in ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 206 mg of the desired compound.

(400 MHz, DMSO-d6) 6 5.79 (s, 2H), 7.44 (d, J= 16.8 Hz, 1H), 7.92-7.96 (m, 2H), 7.12 (s, 1H), 7.59 (d, J = 16.8 Hz, 1H).
Intermediate C91 445 -Amino-3 -(tert-butyl)-1H-pyrazol-1-y1)b enzonitrile ON

To a solution of 4-hydrazinylbenzonitrile (3.0 g, 22.55 mmol) in ethanol (30 mL) were added pivaloyl acetonitrile (3.38 g, 37.1 mmol) followed by PTSA (6.42 g, 33.8 mmol) and the mixture was heated to reflux using Dean-Stark apparatus for 16 h. The precipitated solid was filtered and dried to yield 3.5 g of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.22 (s, 9H), 5.50 (s, 2H), 7.83-7.93 (m, 5H); ESI-MS (m/z) 241 (M+H)+.
Intermediate C92 3 -(5 -Amino-3 -(tert-butyl)-1H-pyrazol-1-y1)benzonitrile CN
H2N \NIN
To a solution of 3-hydrazinylbenzonitrile (500 mg, 3.75 mmol) in hydrochloric acid in 1,4-dioxane (10 mL) was added pivaloyl acetonitrile (565 mg, 4.51 mmol) and the mixture was heated to reflux for 16 h. The mixture was cooled to RT and diluted with water. The solution was basified using saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 830 mg of the desired compound.
1H NMR (400 MHz, DMSO-d6) 6 1.22(s, 9H), 5.45 (s, 2H), 7.62-7.73 (m, 2H), 7.94-8.03 (m, 3H); ESI-MS (m/z) 241 (M+H)+.
Intermediate C94 3 -(methylsulfonyl)aniline 0, Step 1: 1-(Methylsulfony1)-3-nitrobenzene o2N sso, To a solution of 1-iodo-3-nitrobenzene (500 mg, 2.01 mmol) in degassed DMSO
(5.0 mL) were added sodium methanesulfinate (413 mg, 4.01 mmol), N,N-dimethylethylenediamine (106 mg, 1.20 mmol) copper(I)trifluoromethane sulfonate toluene complex (311 mg, 0.60 mmol) and the mixture was evacuated and flushed with nitrogen for thrice. The mixture was heated at 120 C for 3 h. The mixture was cooled to RT, quenched with saturated ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 360 mg of the desired compound. The compound was as such taken forward to the next step without characterization.
Step 2: 3-(methylsulfonyl)aniline The titled compound was prepared by the catalytic hydrogenation of 1-(methylsulfony1)-3-nitrobenzene (step 1 intermediate) (351 mg, 1.74 mmol) in the presence of 10%
palladium on carbon (50% wet, 150 mg) in methanol (5.0 mL) as per the procedure described in step 3 of Intermediate Cl to yield 230 mg of the compound. ESI-MS (m/z) 172 (M+H)+.
The chemical structure, name and analytical data of the intermediate prepared by following the procedure described above are given below in Table 24.
Table 24: Chemical name, structure and analytical data of Intermediate C98 Intermediate No. Chemical Name and Structure Analytical Data 0, j 1H NMR (400 MHz, DMSO-d6) 6 1.09 (t, J = 7.2 Hz, 3H), 3.16 (q, J =

7.2 Hz, 2H), 5.67 (s, 2H), 6.85 (d, J =
7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3 -(Ethylsulfonyl)aniline 7.03 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H).
Intermediate C95 3 -(3 -Methoxyprop-1 -yn-1 -y1)-5 -(trifluoromethyl)aniline '0 Step 1: 3 -(3 -Nitro-5 -(trifluoromethyl)phenyl)prop-2-yn-1-01 02N c3 HO
The titled compound was prepared by the reaction of 1-bromo-3 -nitro-5 -(trifluoromethyl)benzene (502 mg, 1.86 mmol) with propargyl alcohol (219 L, 3.72 mmol) in the presence of bis(triphenylphosphine)palladium(II)dichloride (65 mg, 0.09 mmol), copper iodide (35 mg, 0.18 mmol) and triethylamine (0.8 mL, 5.58 mmol) in DMF
(5.0 mL) as per the procedure described in step 1 of Intermediate C87 to yield 205 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 4.37 (d, J = 6.0 Hz, 2H), 5.50 (t, J =
6.0 Hz, 1H), 8.26 (s, 1H), 8.46 (d, J = 2.0 Hz, 2H).
Step 2: 1-(3 -Methoxyprop-1-yn-l-y1)-3 -nitro-5 -(trifluoromethyl)b enzene 02N c3 '0 The titled compound was prepared by the reaction of 3 -(3 -Nitro-5 -(trifluoromethyl)phenyl)prop-2-yn-l-ol (step 1 intermediate) (738 mg, 3.01 mmol) with methyl iodide (0.37 mL, 6.02 mmol) in the presence of sodium hydride (60%w/w, 240 mg, 6.02 mmol) in THF (10 mL) as per the procedure described in step 2 of Intermediate C57 to yield 390 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 3.38 (s, 3H), 4.41 (s, 2H), 8.36 (s, 1H), 8.49 (s, 1H), 8.53 (s, 1H).
Step 3: 3 -(3 -Methoxyprop-1-yn-l-y1)-5 -(trifluoromethyl)aniline The titled compound was prepared by the reaction of 1-(3-methoxyprop-1-yn-1-y1)-3-nitro-5-(trifluoromethyl)benzene (step 2 intermediate) (465 mg, 1.79 mmol) with iron powder (501 mg, 8.97 mmol) and ammonium chloride (95 mg, 1.79 mmol) in a mixture of ethanol, THF
and water (3:2:1, 12 mL) as per the procedure described in step 2 of Intermediate C28 to yield 312 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 3.34 (s, 3H), 4.31 (s, 2H), 5.78 (s, 2H), 7.54 6.81 (s, 1H), 6.86 (s, 1H), 6.87 (s, 1H); ESI-MS (m/z) 230 (M+H)-1.

Intermediate C97 3 -(Difluoromethyl)aniline Step 1: 1 -(Difluoromethyl)-3 -nitrobenzene 02N I* CHF2 To a stirred solution of 3-nitrobenzaldehyde (506 mg, 3.35 mmol) in anhydrous dichloromethane (10 mL) was dropwise added DAST (1.32 mL, 10.04 mmol) at -78 C. The mixture was gradually warmed up to RT and stirred for 3 h. The mixture was quenched with saturated sodium bicarbonate solution and extracted twice with ethyl acetate.
The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to yield 332 mg of the desired compound. The compound was as such taken forward to the next step without characterization.
Step 2: 3-(Difluoromethyl)aniline The titled compound was prepared by the catalytic hydrogenation of 1-(difluoromethyl)-3-nitrobenzene (step 1 intermediate) (320 mg, 1.85 mmol) in the presence of 10%
palladium on carbon (50% wet, 100 mg) in methanol (5.0 mL) as per the procedure described in step 3 of Intermediate Cl to yield 160 mg of the compound. ESI-MS (m/z) 144 (M+H)+.
Intermediate C100 2-(3 -Aminopheny1)-2,2-difluoro ethanol F F

Step 1: 2,2-Difluoro-2-(3-nitrophenyl)ethanol F F

The titled compound was prepared by the reaction of ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate (Step 1 of C45) (408 mg, 1.66 mmol) with sodium borohydride (126 mg, 3.32 mmol) in ethanol (10 mL) as per the procedure described in step 2 of Intermediate C81 to yield 271 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 3.89-4.01 (m, 2H), 5.76 (t, J= 6.4 Hz, 1H), 7.82 (t, J= 7.6 Hz, 1H), 8.01 (dd, ./1 = 0.4 Hz, .1-2 =
7.6 Hz, 1H), 8.31 (s, 1H), 8.36-8.41 (m, 1H).

Step 2: 2-(3-Aminopheny1)-2,2-difluoroethanol The titled compound was prepared by the catalytic hydrogenation of 2,2-difluoro-2-(3-nitrophenyl)ethanol (step 1 intermediate) (260 mg, 1.28 mmol) in the presence of 10%
palladium on carbon (50% wet, 100 mg) in methanol (8.0 mL) as per the procedure described in step 3 of Intermediate Cl to yield 75 mg of the compound. 1H NMR (500 MHz, DMSO-d6) 6 3.70-3.77 (m, 2H), 5.31 (s, 2H), 5.53 (s, 1H), 6.58-6.65 (m, 2H), 6.68 (s, 1H), 7.05-7.10 (m, 1H); ESI-MS (m/z) 174 (M+H)+.
Intermediate C101 3 -(3 -Amino-5 -(trifluoromethyl)phenyl)propio lonitrile H2N cF3 CN
Step 1: 3 -(3 -Nitro-5 -(trifluoromethyl)phenyl)propiolonitrile 02N cF3 CN
To a stirred solution of 3-(3-nitro-5-(trifluoromethyl)phenyl)propiolamide (step 1 of C87) (100 mg, 0.38 mmol) in anhydrous dichloromethane (5.0 mL) was added Burgess reagent (110 mg, 0.46 mmol) at 0 C and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 60 mg of the titled compound. 1H NMR (400 MHz, DMSO-d6) 6 8.72 (d, J = 1.2 Hz, 1H), 8.77 (s, 1H), (d, J = 1.2 Hz, 1H), 8.99 (dd, J, =
1.6 Hz, J2 = 2.4 Hz, 1H).
Step 2: 3 -(3 -Amino-5 -(trifluoromethyl)phenyl)propio lonitrile The titled compound was prepared by the reaction of 3-(3-nitro-5-(trifluoromethyl)phenyl)propiolonitrile (step 1 intermediate) (251 mg, 1.04 mmol) with iron powder (292 mg, 5.22 mmol) and ammonium chloride (56 mg, 1.04 mmol) in a mixture of ethanol, THF and water (2:2:1, 25 mL) as per the procedure described in step 2 of Intermediate C28 to yield 121 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 6.04 (s, 2H), 7.06-7.11 (m, 2H), 7.20 (s, 1H).
Intermediate C106 3 -(4-Methylpip erazin-l-y1)-5 -(methylsulfonyl)aniline H2N SO2Me cNj Step 1: 1-(3-Iodo-5-nitropheny1)-4-methylpiperazine cNj The titled compound was prepared by the reaction of 1-fluoro-3-iodo-5-nitrobenzene (1.0 g, 3.75 mmol) 1-methylpiperazine (1.9 g, 18.7 mmol) in DMSO (10 mL) as per the procedure described in step 1 of Intermediate C24 to yield 901 mg of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 2.20 (s, 3H), 2.40-2.45 (m, 4H), 3.25-3.30 (m, 4H), 7.61-7.67 (m, 2H), 7.77-7.80 (m, 1H); ESI-MS (m/z) 348 (M+H)+.
Step 2: 1-Methyl-4-(3-(methylsulfony1)-5-nitrophenyl)piperazine 02N SO2Me (Nj The titled compound was prepared by the reaction of 1-(3-iodo-5-nitropheny1)-4-methylpiperazine (step 1 intermediate) (481 mg, 1.38 mmol) with sodium methanesulfinate (282 mg, 2.77 mmol), in the presence of N,N-dimethylethylenediamine (73 mg, 0.83 mmol) and copper(I)trifluoromethane sulfonate toluene complex (215 mg, 0.42 mmol) as per the procedure described in step 1 of Intermediate C94 to yield 310 mg of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 2.20 (s, 3H), 2.44-2.49 (m, 4H), 2.54 (s, 3H), 3.38-3.42 (m, 4H), 7.74-7.77 (m, 1H), 7.89-7.94 (m, 2H); ESI-MS (m/z) 300 (M+H)+.
Step 3: 3 -(4-Methylpip erazin-l-y1)-5 -(methylsulfonyl)aniline The titled compound was prepared by the catalytic hydrogenation of 1-methyl-4-(3-(methylsulfony1)-5-nitrophenyl)piperazine (step 2 intermediate) (301 mg, 1.00 mmol) in the presence of 10% palladium on carbon (50% wet, 150 mg) in methanol (10 mL) as per the procedure described in step 3 of Intermediate Cl to yield 110 mg of the compound. 1H NMR
(400 MHz, DMSO-d6) 6 2.22 (s, 3H), 2.41-2.47 (m, 4H), 3.08 (s, 3H), 3.09-3.14 (m, 4H), 5.45 (s, 2H), 6.36-6.39 (m, 1H), 6.51-6.57 (m, 2H); ESI-MS (m/z) 270 (M+H)+.

Examples General procedures for the synthesis of the examples are described in Method A-R. All the examples were prepared by following either of the methods described below from the combination of appropriate intermediates. Name, structure, Intermediate/method used and characterization data for individual examples are given in Table 25.
Method A
Preparation of 3 -((7, 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-N-(4-((4-ethylpip erazin-1 -yl)methyl)-3 -(trifluoromethyl)phenyl)b enzamide 0 N s CFrN
N,) N C'C) 0 NJ.NJ
H
Step 1:
N-(4-((4-Ethylpip erazin-1 -yl)methyl)-3 -(trifluoromethyl)p heny1)-3 -hydroxybenzamide HO N 0 CFrNI, 0 1\1) A mixture of 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (Intermediate Cl) (500 g, 1.74 mmol) and methyl 3-hydroxybenzoate (Intermediate B2) (317 mg, 1.91 mmol) in anhydrous THF (5.0 mL) was cooled to -20 C and added potassium tert-butoxide (1M, 10 mL, 10.44 mmol). The mixture was stirred at RT for 3 h. The reaction mixture was cooled to -20 C and quenched with saturated sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate and the combined organic layers were washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 220 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 0.98 (t, J = 6.8 Hz, 3H), 2.31-2.50 (m, 8H), 2.51 (br s, 2H), 3.56 (s, 2H), 6.98-7.01 (br d, 1H), 7.31-7.35 (m, 2H), 7.39 (d, J = 6.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.21 (s, 1H), 9.79 (s, 1H), 10.42 (s, 1H); ESI-MS (m/z) 408 (M+H)+.
Step 2: tert-Butyl 4-(3-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenoxy)-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7 H)-carboxylate so H
O N 0 CFrN
NO 0 N,) I j N N
6oc To a stirred solution of N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-3-hydroxybenzamide (step 1 intermediate) (200 mg, 0.49 mmol) and tert-butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (Intermediate Al) (134 mg, 0.49 mmol) in DMF (5.0 mL) was added cesium carbonate (241 mg, 0.74 mmol) and the mixture was stirred at 130 C for 2 h. The mixture was cooled to RT and diluted with a mixture of ethyl acetate and water. The organic layer was separated and washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 245 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 0.98 (t, J =
7.2 Hz, 3H), 1.50 (s, 9H), 2.39-2.50 (m, 10H), 3.56 (s, 2H), 3.91 (t, J= 4.0 Hz, 2H), 4.39 (t, J = 4.0 Hz, 2H), 7.46 (dd , ./1 = 1.6 Hz, .1-2 = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.88 (d, J= 7.6 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 8.20 (s, 1H), 10.52 (s, 1H); ESI-MS (m/z) 643 (M+H)+.
Step 3: 3 -((7,8-dihydro-6H-pyrimido [5 ,4-b] [1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpip erazin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)b enz amide To a stirred solution of tert-butyl 4-(3-((4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenoxy)-6H-pyrimido [5,4-b] [1,4] oxazine-8 (7 H)-carboxylate (step 2 intermediate) (220 mg, 0.34 mmol) in ethanol (3.0 mL) was added hydrochloric acid in 1,4-dioxane (7.0 mL) at 0 C and the mixture was stirred at RT for 3 h.
The mixture was diluted with ethyl acetate and water. The organic layer was washed with water, saturated sodium bicarbonate solution followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 105 mg of the desired product.
Method B
Preparation of 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(42-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide CI
H

N C) 0 N,---..N.--I, ) I
N N
H

Step 1: tert-Butyl 4-(2-chloro-5-(methoxycarbonyl)phenoxy)-6H-pyrimido [5,4-b.] [1,4]oxazine-8(7H)-carboxylate ci a 0, NO

1 ) NN
Boo To a stirred solution of methyl 4-chloro-3-hydroxybenzoate (Intermediate B1) (226 mg, 1.21 mmol) and tert-butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (Intermediate Al) (300 mg, 1.10 mmol) in DMF (10 mL) was added cesium carbonate (540 mg, 1.65 mmol) and the mixture was stirred at 130 C for 3 h. The mixture was cooled to RT
and quenched with saturated aqueous solution of sodium bicarbonate. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 334 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.50 (s, 9H), 3.86 (s, 3H), 3.94 (t, J= 4.4 Hz, 2H), 4.40 (t, J= 4.0 Hz, 2H), 7.79 (d, J =
8.4 Hz, 1H), 7.85-7.88 (m, 2H), 8.04 (s, 1H).
Step 2: 4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(42-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide The titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5-(methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1 intermediate) (100 mg, 0.24 mmol) and N1-(4-amino-2-(trifluoromethyl)benzy1)-N1,N2,N2-trimethylethane-1,2-diamine (Intermediate C33) (58 mg, 0.22 mmol) in the presence of potassium tert-butoxide (1M, 1.42 mL, 1.42 mmol) in anhydrous THF (20 mL) as per the procedure described in step 1 of Method A to yield 20 mg of the product.
Method B' Preparation of 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-N-(3 -(pip erazin-l-y1)-5 -(trifluoromethyl)phenyl)b enzamide ci a H
N 0 cF3 0 w ,,, 0 NO
, 1 j NN
(N
H ) N
H

Step 1: tert-Butyl 4-(3-(4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)b enzamido)-5 -(trifluoromethyl)phenyl)pip erazine-l-carboxylate ci Ai H
N
0 so cF3 N:CX10) 0 N N
H N
ci ri Boc The titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5-(methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1-Method B) (150 mg, 0.34 mmol) and tert-butyl 4-(3-amino-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate (Intermediate C39) (107 mg, 0.31 mmol) in the presence of potassium tert-butoxide (1M, 2.0 mL, 2.06 mmol) in anhydrous THF (10 mL) as per the procedure described in step 1 of Method A to yield 118 mg of the product. 1H
NMR (400 MHz, DMSO-d6) 6 1.43 (s, 9H), 3.19-3.21 (m, 4H), 3.46-3.52 (m, 6H), 4.21 (t, J
= 4.0 Hz, 2H), 6.99 (s, 1H), 7.61-7.89 (m, 7H), 10.40 (s, 1H); ESI-MS (m/z) 635 (M+H)+.
Step 2: 4-Chloro-3-((7,8-dihydro-6H-pyrimido [5 ,4-b] [1,4] oxazin-4-yl)oxy)-N-(3-(pip erazin-1-y1)-5 -(trifluoromethyl)phenyl)b enz amide The titled compound was prepared by the reaction of tert-butyl 4-(3-(4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)b enzamido)-5 -(trifluoromethyl)phenyl)piperazine-l-carboxylate (step 1 intermediate) (110 mg, 0.17 mmol) with hydrochloric acid in 1,4-dioxane (4M, 20 mL) in ethanol (4.0 mL) as per the procedure described in step 3 of Method A to yield 54 mg of the product.
Method C
Preparation of 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)amino)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)b enz amide H
HN N 0 CFn\j.=
NjC0) 0 N, N N
H
Step 1:
4-C hloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -nitrobenzamide H

0 N, To a stirred solution of 4-chloro-3-nitrobenzoic acid (1.0 g, 4.97 mmol) in dichloromethane (10 mL) were added oxalyl chloride (500 L, 5.30 mmol) followed by catalytic amount of DMF and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The solution was cooled to 0 C;
4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (Intermediate Cl) (1.0 g, 3.30 mmol) was added to the reaction mixture followed by DIPEA (1.5 mL, 8.30 mmol).
The resultant mixture was stirred overnight at RT. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by column chromatography to yield 1.43 g of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 0.98 (t, J = 7.2 Hz, 3H), 2.28-2.39 (m, 10H), 3.57 (s, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.98-8.04 (m, 2H), 8.16 (s, 1H), 8.27 (dd, ./i = 2.4 Hz, .12 = 8.4 Hz, 1H), 8.65 (s, 1H), 10.77 (s, 1H).
Step 2:
3 -Amino-4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)phenyl)benzamide CI a H
H2N N 0 oFrN, 0 I\1.) To a stirred solution of 4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3-(trifluoromethyl)pheny1)-3-nitrobenzamide (step 1 intermediate) (1.4 g, 2.97 mmol) in a mixture of ethyl methanol and water (1:1, 60 mL) were added ammonium chloride (1.6 g, 29.7 mmol) followed by iron powder (830 mg. 14.8 mmol) in small portions at 80 C. The mixture was stirred at 80 C for 2 h. The mixture was cooled to RT, filtered and concentrated.
The residue was diluted with a mixture of ethyl acetate and water. The organic layer was separated and washed with water followed by brine and dried over anhydrous sodium sulfate.
The solution was filtered, concentrated and the residue obtained was purified by column chromatography to yield 732 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 0.98 (t, J = 7.2 Hz, 3H), 2.28-2.39 (m, 10H), 3.55 (s, 2H), 5.60 (s, 2H), 7.13 (dd, ./i = 2.4 Hz, .12 = 8.4 Hz, 1H), 7.35 (d, J= 8.4 Hz, 2H), 7.69 (d, J= 8.4 Hz, 1H), 8.01 (dd, ./i = 2.0 Hz, .12 = 8.8 Hz, 1H), 8.18 (s, 1H), 10.41 (s, 1H); ESI-MS (m/z) 441 (M+H)+.
Step 3: tert-Butyl 4-((2-chloro-5-((4-((4-ethylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)carbamoyl)phenyl)amino)-6H-pyrimido [5,4-b] [1,4]
oxazine-8 (7 H)-carboxylate CI a H
HN N CFrN
..0 0 IW I\1) k ) N N
I3oc To a stirred solution of 3 -amino-4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-(trifluoromethyl)phenyl)benzamide (step 2 intermediate) (150 mg, 0.34 mmol) and tert-butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (Intermediate Al) (102 mg, 0.37 mmol) in toluene (5.0 mL) were added sodium tert-butoxide (36 mg, 0.37 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (12 mg, 0.01 mmol) and ( )-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (rac-BINAP) (13 mg, 0.02 mmol) and the mixture was stirred at 140 C for 25 h in a sealed tube. The mixture was diluted with ethyl acetate and the organic mixture was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 67 mg of the desired compound. 1H
NMR (400 MHz, DMSO-d6) 6 0.98 (t, J = 6.8 Hz, 3H), 1.49 (s, 9H), 2.30-2.39 (m, 10H), 3.57 (s, 2H), 3.90 (t, J= 8.0 Hz, 2H), 4.15 (t, J= 8.0 Hz, 2H), 7.72 (t, J= 7.2 Hz, 2H), 7.78 (m, 1H), 8.02-8.04 (m, 2H), 8.20 (s, 1H), 8.43 (s, 1H), 8.55 (s, 1H), 10.56 (s, 1H); ESI-MS
(m/z) 674 (M-H)-.
Step 4:
4-Chloro-3 -47,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)amino)-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)phenyl)b enzamide The titled compound was prepared by the reaction of tert-Butyl 4-((2-chloro-5-((4-((4-ethylpiperazin-l-yl)methyl)-3 -(trifluoromethyl)phenyl)carb amoyl)phenyl)amino)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 3 intermediate) (60 mg, 0.09 mmol) with hydrochloric acid in 1,4-dioxane (4.0 mL) in ethanol (4.0 mL) as per the procedure described in step 3 of Method A to yield 19 mg of the product.
Method D
Preparation of 4-chloro-N-(3-(cyanomethyl)pheny1)-3-47,8-dihydro-6H-pyrimido [5,4-b][1,4]oxazin-4-yl)oxy)benzamide ci AI
H
N

iNic,0 0 NJ.NJ
H

To a stirred solution of tert-butyl 4-(2-chloro-5-(methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (Step 1-Method B) (100 mg, 0.24 mmol) in toluene (5.0 mL) were added 2-(3-aminophenyl)acetonitrile (31 mg, 0.24 mmol) and trimethyl aluminium solution (2M, 237 L, 0.47 mmol) at 0 C. The mixture was stirred at RT for 2 h. The mixture was poured into ice-water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate.
The solution was filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 68 mg of the desired product.
Method E
Preparation of 4-chloro-N-(3 -(cyano difluoromethyl)pheny1)-3 47, 8-dihydro-6H-pyrimido [5 ,4-b] [1,4] oxazin-4-yl)oxy)b enzamide ci H F F
N

, 0 NAC21 j N N
H
Step 1: Ethyl 2-(3 -(3 -((te rt-butyldimethylsilyl)oxy)-4-chlorob enz amido)pheny1)-2,2-difluoroacetate ci H F F
0 WI N la C) TBDMS 0 'W 0 To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-4-chlorobenzoic acid (600 mg, 2.09 mmol) in dichloromethane (10 mL) were added oxalyl chloride (364 L, 4.19 mmol) followed by catalytic amount of DMF and the mixture was stirred at RT for 2 h.
The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (10 mL). The solution was cooled to 0 C; ethyl 2-(3-aminopheny1)-2,2-difluoroacetate (Intermediate C45) (495 mg, 2.30 mmol) was added to the reaction mixture followed by DIPEA (1.12 mL, 6.27 mmol). The resultant mixture was stirred overnight at RT.
The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated.
The residue thus obtained was purified by column chromatography to yield 655 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 0.27-0.35 (m, 6H), 1.02 (s, 9H), 1.27 (t, J= 6.8 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.51-7.64 (m, 4H), 7.97 (d, J =
8.4 Hz, 1H), 8.21 (s, 1H), 10.54 (s, 1H); ESI-MS (m/z) 484 (M+H)-1.

Step 2: N-(3 -(2-Amino-1,1-difluoro-2-oxo ethyl)pheny1)-4-chloro-3 -hydroxyb enzamide ci al H F F

HO

A mixture of ethyl 2-(3-(3-((tert-butyldimethylsilyl)oxy)-4-chlorobenzamido)pheny1)-2,2-difluoroacetate (step 1 intermediate) (650 mg, 1.34 mmol) and ammonia solution (7M in methanol, 10 mL) was heated at 80 C for 4 h in a sealed tube. The reaction mixture was cooled and concentrated under reduced pressure to yield 560 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 7.32 (d, J = 8.0 Hz, 1H), 7.43-7.53 (m, 4H), 7.92 (d, J = 8.4 Hz, 1H), 8.03 (s, 2H), 8.37 (s, 1H), 10.47 (s, 1H), 10.51 (s, 1H); ESI-MS
(m/z) 341 (M+H)+.
Step 3:
N-(3 -(2-Amino-1,1-difluoro-2-oxo ethyl)pheny1)-4-chloro-3 -47,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)benzamide ci al H F F
N ao NH2 0 w N0) 0 0 I
N N
H
To a stirred solution of N-(3-(2-amino-1,1-difluoro-2-oxoethyl)pheny1)-4-chloro-3-hydroxybenzamide (step 2 intermediate) (250 mg, 0.73 mmol) and tert-butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (Intermediate Al) (200 mg, 0.74 mmol) in DMF (5.0 mL) was added cesium carbonate (360 mg, 1.10 mmol) and the mixture was stirred at 130 C for 3 h. The mixture was cooled to RT and quenched with saturated aqueous solution of sodium bicarbonate. The aqueous mixture was extracted twice with ethyl acetate.
The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 45 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 3.51 (br s, 2H), 4.19-4.22 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.66-7.91 (m, 6H), 7.94 (d, J =
8.0 Hz, 1H), 8.07 (m, 1H), 8.38 (s, 1H), 10.52 (s, 1H); ESI-MS (m/z) 476 (M+H)+.
Step 4: 4-C hloro-N-(3 -(cyano difluoromethyl)pheny1)-3 -47,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)oxy)benzamide To a solution of N-(3 -(2-amino-1,1-difluoro-2-oxo ethyl)pheny1)-4-chloro-3 -((7,8-dihydro-6H-pyrimido [5,4-b][1,4]oxazin-4-yl)oxy)benzamide (step 3 intermediate) (40 mg, 0.08 mmol) in dichloromethane (3.0 mL) was added Burgess reagent (76.8 mg, 0.32 mmol) and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography to yield 7.0 mg of the desired compound.
Method F
Preparation of 4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-N-(3 -hydroxy-5-(trifluoromethyl)phenyl)benzamide CI a H
N

C) 3 k N Nj OH
H
Step 1: 4-Chloro-3-((7,8-dihydro-6H-pyrimido [5 ,4 -b.] [1,4] oxazin-4-yl)oxy)-N-(3 -methoxy-5 -(trifluoromethyl)phenyl)benzamide CI a H
N CF $ 3 V 1 j N N
H
The titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5-(methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1-Method B) (100 mg, 0.24 mmol) and 3-methoxy-5-(trifluoromethyl)aniline (45 mg, 0.24 mmol) in the presence of potassium tert-butoxide (1M, 1.42 mL, 1.42 mmol) in anhydrous THF (3.0 mL) as per the procedure described in step 1 of Method A to yield 75 mg of the product. 1H NMR (400 MHz, DMSO-d6) 6 3.51 (br s, 2H), 3.83 (s, 3H), 4.20 (t, J
= 4.0 Hz, 2H), 7.00 (s, 1H), 7.69-7.90 (m, 7H), 10.56 (s, 1H); ESI-MS (m/z) 481 (M+H)+.
Step 2: 4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-N-(3 -hydroxy-5 -(trifluoromethyl)phenyl)benzamide To a solution of 4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)benzamide (step 1 intermediate) (70 mg, 0.14 mmol) in dichloromethane (2.0 mL) was added boron tribromide (1M in dichloromethane, 1.2 mL, 1.16 mmol) at 0 C and the mixture was stirred at RT for 4 h. The reaction mixture was quenched with methanol at 0 C and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by flash column chromatography to yield 25 mg of the desired compound.

Method G
Preparation of 4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -((5 -oxo-5 ,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)b enz amide CI Al 0 N CFrN
N-3::) 0 N,) /
HN
Step 1: 4-C
hloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -hydroxybenzamide CI opHO N CFN
0 Ir N,) The titled compound was prepared by the reaction of methyl 4-chloro-3-hydroxybenzoate (Intermediate B 1) (260 mg, 1.39 mmol) and 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (Intermediate Cl) (400 mg, 1.39 mmol) in the presence of potassium tert-butoxide (1M, 8.4 mL, 8.39 mmol) in anhydrous THF (8.0 mL) as per the procedure described in step 1 of Method A to yield 200 mg of the product. 1H NMR (400 MHz, DMSO-d6) 6 0.98 (t, J = 7.2 Hz, 3H), 2.33-2.55 (m, 6H), 3.33 (br s, 4H), 3.56 (s, 2H), 7.42-7.53 (m, 3H), 7.70 (d, J = 8.4 Hz, 1H), 8.01 (dd, ./i = 2.0 Hz, .1-2 = 8.4 Hz, 1H),8.32 (s, 1H), 10.50 (s, 1H), 10.60 (br s, 1H).
Step 2: 4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 4(844-methoxyb enzy1)-5 -oxo-5 ,6,7,8-tetrahydropyrido [2,3 -d] pyrimidin-4-yl)oxy)b enzamide CI Ai 0 N) /
Pmd To a stirred solution of 4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3-(trifluoromethyl)pheny1)-3-hydroxybenzamide (step 1 intermediate) (872 mg, 1.97 mmol) and 4-chloro-8-(4-methoxybenzy1)-7,8-dihydropyrido [2,3 -d]pyrimidin-5 (6H)-one (Intermediate A9) (600 mg, 1.97 mmol) in DMF (20 mL) was added cesium carbonate (3.2 g, 9.85 mmol) and the mixture was stirred at 50 C for 3 h. The mixture was cooled to RT and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 400 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 0.99 (t, J = 7.2 Hz, 3H), 2.40-2.51 (m, 10H), 2.68 (t, J = 7.6 Hz, 2H), 3.57 (s, 2H), 3.65 (t, J = 6.8 Hz, 2H), 3.74 (s, 3H), 4.90 (s, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.8 Hz, 1H), 7.78 (d, J =
8.0 Hz, 1H), 7.91-7.94 (br s, 2H), 8.04 (dd, Ji = 1.6 Hz, .1-2 = 8.4 Hz, 1H), 8.18 (s, 1H), 8.24 (s, 1H), 10.58 (s, 1H); ESI-MS (m/z) 709 (M+H)+.
Step 3: 4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -45 -oxo-5,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4 -yl)oxy)b enzamide A solution of 4-chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-3-((8-(4-methoxyb enzy1)-5 -oxo-5 ,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)b enz amide (step 2 intermediate) (40 mg, 0.06 mmol) in a mixture of dichloroethane and trifluoroacetic acid (1:1, 600 L) was stirred overnight at 80 C. The mixture was cooled to RT and then to 0 C before the addition of aqueous sodium bicarbonate solution till pH 7-8.
The aqueous mixture was extracted twice with dichloromethane and the combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 12 mg of the desired product.
Method G' Preparation of 4-chloro-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)pheny1)-3 -47-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)oxy)benzamide CI
H
N 0 u3 0 Wi .ciD

1\l'N'.0 C\ij H
N
I
Step 1:
4-C hloro-3 -hydroxy-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)benzamide ci HO IN H
N
I 40 cF3 (Nj N
I
.. The titled compound was prepared by the reaction of methyl 4-chloro-3-hydroxybenzoate (Intermediate B1) (3.6 g, 19.3 mmol) and 3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)aniline (Intermediate C19) (5.0 g, 19.3 mmol) in the presence of potassium tert-butoxide (1M, 115 mL, 115 mmol) in anhydrous THF (50 mL) as per the procedure described in step 1 of Method A to yield 2.6 g of the product. 1H NMR (400 MHz, DMSO-d6) 6 2.23 (s, 3H), 2.47 (s, 4H), 3.21 (br s, 4H), 6.95 (s, 1H), 7.42-7.44 (m, 1H), 7.51-7.53 (m, 2H), 7.60 (s, 1H), 7.65 (s, 1H), 10.32 (s, 1H), 10.60 (s, 1H).
Step 2:
4-Chloro-3 -48-(4-methoxyb enzy1)-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b][1,4] oxazin-4-yl)oxy)-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)b enz amide ci NC'' N N-0 rN
PMBN) To a stirred solution of 4-chloro-3 -hydroxy-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)benzamide (step 1 intermediate) (80 mg, 0.19 mmol) and 4-chloro-8-(4-methoxybenzy1)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (Intermediate A2) (118 mg, 0.38 mmol) in DMSO (0.5 mL) was added cesium fluoride (88 mg, 0.58 mmol) and the mixture was stirred at 118 C for 5-7 h. The mixture was cooled to RT and quenched with water. The precipitated solid was collected through filtration and dried under vacuum. The crude compound was purified by flash column chromatography to yield 110 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 2.24 (s, 3H), 2.52-2.56 (m, 4H), 3.18-3.22 (m, 4H),3.72 (s, 3H), 5.04 (s, 2H), 5.15 (s, 2H), 6.88 (d, J= 8.8 Hz, 2H), 6.97 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.59 (s, 1H), 7.64 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.93-7.98 (m, 2H), 8.22 (s, 1H), 10.41 (s, 1H).
Step 3: 4-Chloro-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)pheny1)-3 dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)b enzamide The titled compound was prepared by the reaction of 4-chloro-3-48-(4-methoxybenzy1)-7-oxo-7,8-dihydro-6H-pyrimido [5 ,4-b] [1,4]oxazin-4-yl)oxy)-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)benzamide (step 2 intermediate) (100 mg, 0.15 mmol) with trifluoroacetic acid (2.0 mL) as per the procedure described in step 3 of Method G to yield 40 mg of the product.
Method H
Preparation of 4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -45,6,7,8-tetrahydropyrido [2,3 -d] pyrimidin-4-yl)oxy)b enzamide CI AI
H
N 0 CFrN
N 0 1W N,) k N N
H
Step 1: 4-C hloro-N-(4-((4-ethylp ip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -45-hydroxy-8-(4-methoxyb enzy1)-5 ,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)b enzamide ci a H
OH 0 N CFrN
)11\1 0 Ir N,.) I
1\1N
1;1\AB
To a solution of 4-chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-3-((8-(4-methoxybenzy1)-5-oxo-5,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)b enz amide (Step 2-Method G) (500 mg, 0.76 mmol) in THF (5.0 mL) at 0 C were added sodium borohydride (54 mg, 0.71 mmol) followed by added methanol (1.0 mL) dropwise.
The mixture was stirred for 3-4 h at RT. The reaction was quenched with water and extracted twice with chloroform. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 400 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) (t, J = 7.2 Hz, 3H), 1.70-1.74 (m, 1H), 1.92 (d, J = 2.8 Hz, 1H), 2.45-2.56 (m, 10H), 3.50-3.60 (m, 4H), 3.78 (s, 3H), 4.77 (d, J = 14.8 Hz, 1H), 4.89 (d, J =
15.2 Hz, 1H), 5.03 (br s, 1H), 5.26 (d, J = 4.4 Hz, 1H), 6.90 (dd, ./i = 2.0 Hz, ./i = 6.8 Hz, 2H), 7.24 (d, J=
8.8 Hz, 2H), 7.71-8.18 (m, 7H), 10.59 (s, 1H); ESI-MS (m/z) 711 (M+H)+.
Step 2: 4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-3-((8-(4-methoxybenzy1)-5,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)b enzamide CI a H
O N CFrN
0 ir N,) I
NI\I

To a stirred mixture of 4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3-(trifluoromethyl)pheny1)-3 -45 -hydroxy-8-(4-methoxyb enzy1)-5 ,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)benzamide (step 1 intermediate) (400 mg, 0.56 mmol) in triethylsilane (16 mL) at 0 C was added trifluoroacetic acid (8.0 mL) dropwise and the mixture was stirred for 3-4 h at RT. The mixture was cooled to 0 C and neutralized using aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with chloroform.
The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 200 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.09 (m, 3H), 1.89 (m, 2H), 2.50 (br s, 10H), 2.76 (m, 2H), 3.51-3.62 (m, 4H), 3.73 (s, 3H), 4.78 (s, 2H), 6.90 (d, J
= 8.4 Hz, 2H), 7.22 (d, J= 8.8 Hz, 2H), 7.71-7.92 (m, 4H), 8.00 (s, 1H), 8.06 (d, J= 7.2 Hz, 1H), 8.18 (s, 1H), 10.57 (s, 1H); ESI-MS (m/z) 695 (M+H)+.
Step 3: 4-C hloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -45,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)b enzamide The titled compound was prepared by the reaction of 4-chloro-N-(444-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-348-(4-methoxybenzy1)-5,6,7,8-tetrahydropyrido [2,3 -d]pyrimidin-4-yl)oxy)benzamide (step 2 intermediate) (100 mg, 0.14 mmol) with trifluoroacetic acid (2.0 mL) as per the procedure described in step 3 of Method G to yield 25 mg of the product.
Method I
Preparation of 1-(4-chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)oxy)pheny1)-3 -(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)phenyl)urea ci 0 NA SI N
O CF-'1\i'=
NO H H
I j NN
H
Step 1: tert-Butyl 4-(5-amino-2-chlorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8 (7 H)-carboxylate CI A

c, t 1 j NII
Boc The titled compound was prepared by the reaction of 5-amino-2-chlorophenol (80 mg, 0.55 mmol) and tert-butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (Intermediate Al) (150 mg, 0.55 mmol) in the presence of cesium carbonate (540 mg, 1.65 mmol) in DMF (3.0 mL) as per the procedure described in step 2 of Method G to yield 130 mg of the compound. 41 NMR (400 MHz, DMSO-d6) 6 1.50 (s, 9H), 3.92 (t, J = 4.4 Hz, 2H), 4.37 (t, J = 4.0 Hz, 2H), 5.44 (s, 2H), 6.41 (d, J = 6.4 Hz, 1H), 6.47 (dd, ./i = 2.4 Hz, J2 = 8.4 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 8.04 (s, 1H); ESI-MS (m/z) 379 (M+H)-1.
Step 2: te rt-Butyl 4-(2-chloro-5 -(3 -(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)phenyl)ureido)phenoxy)-6H-pyrimido [5,4-b] [1,4] oxazine-8(7H)-carboxylate ci 0 lei0 N
A r,I\L
N N CF3 ¨
,0 H H
NC 1 ) NN
6oc To a stirred solution of 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (Intermediate Cl) (150 mg, 0.52 mmol) in THF (20 mL) was added triphosgene (54 mg, 0.18 mmol) and the resulting mixture was stirred at 70 C. After 1 h of heating the mixture was concentrated under reduced pressure and the residue was dissolved in THF (20 mL). That solution was added dropwise to a stirred mixture of tert-butyl 4-(5-amino-2-chlorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1 intermediate) (150 mg, 0.40 mmol) and triethylamine (172 L, 1.19 mmol) in THF (20 mL) at RT. The resultant mixture was stirred for 2 h at 70 C. The mixture was cooled to RT and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 100 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 1.09 (t, J= 7.2 Hz, 3H), 1.50 (s, 9H), 2.42-2.51 (m, 10H), 3.54 (br s, 2H), 3.94 (t, J= 8.4 Hz, 2H), 4.40 (t, J= 7.6 Hz, 2H), 7.29 (dd, ./i = 2.4 Hz, .1-2 = 8.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.55-7.94 (m, 3H), 7.95 (s, 1H), 8.05 (s, 1H), 9.15 (s, 1H), 9.20 (s, 1H).
Step 3: 1-(4-Chloro-3-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)oxy)pheny1)-3 -(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)phenyOurea The titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5-(3-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenoxy)-6H-pyrimido [5,4-b][1,4]oxazine-8(7H)-carboxylate (step 2 intermediate) (100 mg, 0.14 mmol) with hydrochloric acid in 1,4-dioxane (2.0 mL) as per the procedure described in step 3 of Method A to yield 52 mg of the product.
Method I' Preparation of 1-(4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)pheny1)-3 -(3 -(trifluoromethyl)phenyl)urea H H

NO

I ) NN
Step 1: Benzyl (4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl) carbonate H H

Cbz0 , W 0 The titled compound was prepared by the reaction of 3-(trifluoromethyl)aniline (218 mg, 1.34 mmol), triphosgene (138 mg, 0.47 mmol) and 4-aminophenylbenzylcarbonate (250 mg, 0.89 mmol) in the presence of triethylamine (361 mg, 3.57 mmol) in THF (5.0 mL) as per the procedure described in step 2 of Method I to yield 200 mg of the titled compound. 1H NMR
(400 MHz, DMSO-d6) 6 5.07 (s, 2H), 6.95 (d, J = 2.0 Hz, 2H), 7.29-7.57 (m, 10H), 8.01 (s, 1H), 8.61 (s, 1H), 8.98 (s, 1H).
Step 2: 1-(4-Hydroxypheny1)-3 -(3 -(trifluoromethyl)phenyl)urea H H
NN c3 A solution of benzyl (4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)carbonate (step 1 intermediate) (200 mg, 0.47 mmol) in methanol (5.0 mL) with catalytic amount of 10%
palladium on carbon (50% wet, 200 mg) was hydrogenated at RT for 18 h. The mixture was diluted with chloroform filtered through celite and the celite bed. The filtrate was concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 48 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 6.69 (d, J
= 6.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.48-7.53 (m, 2H), 8.0 (s, 1H), 8.44 (s, 1H), 8.91 (s, 1H), 9.11 (s, 1H); ESI-MS (m/z) 397 (M+H)+.
Step 3: tert-Butyl 44443 -(3 -(trifluoromethyl)phenyl)ureido)phenoxy)-6H-pyrimido [5,4-[1,4]oxazine-8(7H)-carboxylate H H

N:CC3') N N
13oc The titled compound was prepared by the reaction of 1-(4-hydroxypheny1)-3-(3-(trifluoromethyl)phenyl)urea (step 2 intermediate) (50 mg, 0.17 mmol) and tert-butyl 4-chloro-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (Intermediate Al) (59 mg, 0.22 mmol) in the presence of cesium carbonate (109 mg, 0.34 mmol) in DMF (0.5 mL) as per the procedure described in step 2 of Method G to yield 30 mg of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 1.48 (s, 9H), 3.34-3.39 (m, 1H), 3.91 (t, J= 4.4 Hz, 2H), 4.36 (t, J= 4.0 Hz, 2H), 7.10-7.12 (m, 2H), 7.50-7.58 (m, 4H), 8.02-8.04 (br s, 2H), 8.67 (s, 1H), 9.07 (s, 1H); ESI-MS (m/z) 432 (M+H)-1.
Step 4:
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b] [1,4]o xazin-4-yl)oxy)pheny1)-3 -(3 -(trifluoromethyl)phenyl)urea The titled compound was prepared by the reaction of tert-butyl 4444343-(trifluoromethyl)phenyl)ureido)phenoxy)-6H-pyrimido [5,4-b] [1,4] oxazine-8(7H)-carboxylate (step 3 intermediate) (30 mg, 0.06 mmol) with hydrochloric acid in 1,4-dioxane (1.0 mL) as per the procedure described in step 3 of Method A to yield 11 mg of the product.
Method I"
Preparation of 1-(3-(tert-buty1)-1-(4-cyanopheny1)-1H-pyrazol-5-y1)-3-(4-43,4-dihydro-2H-pyrido [3 ,2-b] [1,4] oxazin-8-yl)oxy)phenyl)urea CN
4Ik H H

N N N Is 1 ,N

ri:)) N N
H
Step 1: tert-Butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-2H-pyrido [3,2-b] [1,4]oxazine-4(3H)-carboxylate H

0 'S

x ,0 N N
Boc A suspension of tert-butyl 8-bromo-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (Intermediate A7) (400 mg, 1.27 mmol), benzyl (4-hydroxyphenyl)carbamate (370 mg, 1.52 mmol) and tripotassium phosphate (966 mg, 4.56 mmol) in toluene (10 mL) was degassed and added palladium acetate (52 mg, 0.24 mmol) followed by 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos) (129 mg, 0.30 mmol) at RT. The mixture was refluxed at 120 C for 16 h. The mixture was cooled to RT, diluted with diethyl ether and filtered through celite. The filtrate was concentrated and the residue thus obtained was purified by flash column chromatography to yield 198 mg of the desired product. 'I-1 NMR
(400 MHz, DMSO-d6) 6 1.47 (s, 9H), 3.86 (t, J= 4.4 Hz, 2H), 4.27 (t, J = 4.4 Hz, 2H), 5.16 (s, 2H), 6.45 (d, J = 5.6 Hz, 1H), 7.04-7.09 (m, 2H), 7.34-7.46 (m, 5H), 7.52 (d, J = 8.8 Hz, 2H), 7.79 (d, J= 5.6 Hz, 1H), 9.86 (s, 1H); ESI-MS (m/z) 478 (M+H)+.
Step 2: tert-Butyl 8-(4-aminophenoxy)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate Ai NH2 1 ) N N
Lc The titled compound was prepared by the hydrogenation reaction of tert-butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-2H-pyrido [3,2-b] [1,4] oxazine-4(3H)-carboxylate (step 1 intermediate) (230 mg, 0.48 mmol) I the presence of 10% palladium on carbon (50%
wet, 40 mg) as per the procedure described in step 2 of Method I' to yield 127 mg of the desired compound. The compound was as such taken forward to the next step without characterization.
Step 3: tert-Butyl 84443 -(3 -(tert-butyl)-1-(4-cyanopheny1)-1H-pyrazol-5 -yl)ureido)phenoxy)-2H-pyrido [3,2-b] [1,4] oxazine-4(3H)-c arbo xylate ON

H H
Al NyN . NIN

I CILJ
N N
60c To a stirred solution of 4-(5-amino-3-(tert-buty1)-1H-pyrazol-1-y1)benzonitrile (Intermediate C91) (50 mg, 0.21 mmol) in a mixture of dichloromethane (6.0 mL) and saturated sodium bicarbonate solution (4.0 mL) at 0 C was added diphosgene (100 L, 0.83 mmol) and the mixture was stirred at RT for 1.5 h. The mixture was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the isocyanate. The isocyanate intermediate was suspended in a mixture of THF (10 mL) and acetonitrile (1.0 mL) and cooled 0 C. To that mixture were added tert-butyl 8-(4-aminophenoxy)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (step 2 intermediate) (71 mg, 0.21 mmol) followed by DIPEA (142 L, 0.83 mmol) and the resultant mixture was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 52 mg of the desired compound. ESI-MS (m/z) 610 (M+H)+.
Step 3: 1-(3 -(tert-Butyl)-1-(4-cyanopheny1)-1H-pyrazol-5 -y1)-3 -(443 ,4-dihydro-2H-pyrido [3 ,2-b] [1,4] oxazin-8-yl)oxy)phenyl)urea The titled compound was prepared by the reaction of tert-butyl 8-(4-(3-(3-(tert-buty1)-1-(4-cyanopheny1)-1H-pyrazol-5-yOureido)phenoxy)-2H-pyrido [3,2-b] [1,4] oxazine-4(3H)-carboxylate (step 2 intermediate) (50 mg, 0.08 mmol) with hydrochloric acid in 1,4-dioxane (3.0 mL) in methanol (0.5 mL) as per the procedure described in step 3 of Method A to yield 7.0 mg of the product.
Method J
Preparation of 4-chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -47-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)oxy)benzamide CI al O WI NNO CFri\j.=

k NNO
Step 1: Methyl 4-chloro-3-48-(4-methoxybenzy1)-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b][1,4]oxazin-4-yl)oxy)benzoate ci O WI 0, C) N

I;MB
The titled compound was prepared by the reaction of 4-chloro-8-(4-methoxybenzy1)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (Intermediate A2) (330 mg, 1.08 mmol) and 4-chloro-3-hydroxybenzoate (Intermediate B1) (261 mg, 1.40 mmol) in the presence of cesium fluoride (328 mg, 2.16 mmol) in DMSO (2.0 mL) as per the procedure described in step 2 of Method G' to yield 210 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 3.72 (s, 3H), 3.86 (s, 3H), 5.02 (s, 2H), 5.14 (s, 2H), 6.87 (dd, ./1 = 2.0 Hz, .1-2 = 6.4 Hz, 2H), 7.31 (d, J=
6.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.88-7.90 (m, 2H), 8.19 (s, 1H).

Step 2: 4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 4(844-methoxyb enzy1)-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)b enzamide CI
o N CFrN

I ,L

PMB
To a solution of methyl 4-chloro-348-(4-methoxybenzy1)-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzoate (step 1 intermediate) (210 mg, 0.46 mmol) and 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (Intermediate Cl) (110 mg, 0.38 mmol) in toluene (3.0 mL) was dropwise added trimethyl aluminium solution (2M in toluene, 768 L, 1.54 mmol) at RT. The mixture was stirred for 3-5 h at RT.
The mixture was quenched with aqueous ammonium chloride solution and extracted twice in ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 115 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 0.99 (t, J = 7.2 Hz, 3H), 2.40-2.51 (m, 10H), 3.57 (s, 2H), 3.72 (s, 3H), 5.04 (s, 2H), 5.15 (s, 2H), 6.87 (dd, ./i =
2.0 Hz, .1-2 = 6.4 Hz, 2H), 7.31 (d, J= 8.8 Hz, 2H), 7.72 (d, J= 8.4 Hz, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.94-8.0 (m, 3H), 8.17 (s, 1H), 8.22 (s, 1H), 10.58 (s, 1H); ESI-MS (m/z) 711 (M+H)+.
Step 3: 4-Chloro-N-(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -47-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)oxy)benzamide The titled compound was prepared by the reaction of 4-chloro-N-(444-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-3-48-(4-methoxybenzyl)-7-oxo-7,8-dihydro-pyrimido [5,4 -b][1,4]oxazin-4-yl)oxy)benzamide (step 2 intermediate) (100 mg, 0.14 mmol) with trifluoroacetic acid (3.0 mL) as per the procedure described in step 3 of Method G to yield 29 mg of the product.
Method .1' Preparation of N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-4-methyl-3-47-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4]oxazin-4-yl)oxy)benzamide O NH CFrN
N 0 ir I
NNO

Step 1: Methyl 3 -48 -(4-methoxyb enzy1)-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b]
[1,4] oxazin-4-yl)oxy)-4-methylbenzoate 40 0 , .,c) 0 N
I

PMB
A suspension of 4-chloro-8-(4-methoxybenzy1)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (Intermediate A2) (370 mg, 1.21 mmol), methyl 3-hydroxy-4-methylbenzoate (Intermediate B3) (261 mg, 1.57 mmol) and tripotassium phosphate (513 mg, 2.42 mmol) in toluene (4.0 mL) was degassed and added palladium acetate (54 mg, 0.24 mmol) followed by 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-BuXPhos) (77 mg, 0.18 mmol) at RT. The mixture was refluxed for 3-5 h. The mixture was cooled to RT, diluted with diethyl ether and filtered through celite. The filtrate was concentrated and the residue thus obtained was purified by flash column chromatography to yield 309 mg of the desired product. 1H NMR
(400 MHz, DMSO-d6) 6 2.19 (s, 3H), 3.72 (s, 3H), 3.83 (s, 3H), 5.01 (s, 2H), 5.14 (s, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.79 (dd, ./i = 2.0 Hz, .1-2 = 8.0 Hz, 1H), 8.17 (s, 1H).
Step 2: N-(4-((4-Ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)pheny1)-3 4(844-methoxyb enzy1)-7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-4-methylbenzamide 0N cFn\j..

I

PMB
The titled compound was prepared by the reaction of methyl 3-48-(4-methoxybenzy1)-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b] [1,4]oxazin-4-yl)oxy)-4-methylb enzo ate (step 1 intermediate) (270 mg, 0.62 mmol) with 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (Intermediate Cl) (140 mg, 0.49 mmol) in the presence of trimethyl aluminium solution (2M in toluene, 970 L, 1.94 mmol) in toluene (3.0 mL) as per the procedure described in step 2 of Method J to yield 210 mg of the compound. 1H
NMR (400 MHz, DMSO-d6) 6 0.98 (t, J= 8.4 Hz, 3H), 2.19 (s, 3H), 2.40-2.51 (m, 10H), 3.56 (br s, 2H), 3.72 (s, 3H), 5.02 (s, 2H), 5.15 (s, 2H), 6.88 (d, J = 8.4 Hz, 2H), 7.32 (d, J
= 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.86 (d, J= 8.0 Hz, 1H), 8.04 (d, J= 7.2 Hz, 1H), 8.17-8.19 (br s, 2H), 10.44 (s, 1H).

Step 3: N-(4-((4-ethylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)pheny1)-4-methy1-3-((7-oxo-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)b enzamide The titled compound was prepared by the reaction of N-(444-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-3-48-(4-methoxybenzyl)-7-oxo-7,8-dihydro-6H-pyrimido [5,4-.. b] [1,4]oxazin-4-yl)oxy)-4-methylbenzamide (step 2 intermediate) (150 mg, 0.22 mmol) with trifluoroacetic acid (3.0 mL) as per the procedure described in step 3 of Method G to yield 18 mg of the product.
Method K
Preparation of 4-chloro -N-(4-((4-(2-cyano ac etyl)pip erazin-1 -yl)methyl)-3 -(trifluoromethyl)pheny1)-3 -47, 8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)benzamide ci oi 0 WI N 0 CFrN-11.õCN
N o N.,..) 1 ) To a solution of 2-cyanoacetic acid (20 mg, 0.18 mmol) in acetonitrile (5.0 mL) were added DIPEA (0.1 mL, 0.56 mmol) followed by TBTU (50 mg, 0.18 mmol) at 0 C and the mixture was stirred for 30 min. 4-Chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide (dihydro chloride salt) (80 mg, 0.14 mmol) was added to the mixture and stirred for 3 h at RT. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 6.0 mg of the desired product.
Method L
Preparation of 4-chloro-348-methy1-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3 -(4-methylpip erazin-1 -y1)-5 -(trifluoromethyl)phenyl)b enz amide ci al H
N
0 wi so cF3 N *11:: 0 I j N
N N
I CN) I
Step 1: Methyl 4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzoate CI AI

1\jc.,0 0 Nk NJ
H
The titled compound was prepared by the reaction of tert-butyl 4-(2-chloro-5-(methoxycarbonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1-Method B) (500 mg, 1.18 mmol) with hydrochloric acid in ethyl acetate (25 mL) in methanol (5.0 mL) as per the procedure described in step 3 of Method A to yield 307 mg of the product. 1H NMR (400 MHz, DMSO-d6) 6 3.83-3.87 (m, 2H), 4.04 (s, 3H), 4.17-4.21 (m, 2H), 7.68-7.74 (m, 3H), 7.81 (br s, 2H).
Step 2: Methyl 4-chloro-3-48-methy1-7,8-dihydro-6H-pyrimido [5,4-b]
[1,4] oxazin-4-yl)oxy)benzoate ci Ai 0, r\ic.,0, 0 NI.N J
I
To a stirred solution of methyl 4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzoate (step 1 intermediate) (300 mg, 0.93 mmol) in DMF (5.0 mL) were added methyl iodide (132 mg, 0.93 mmol) followed by sodium hydride (60% w/w, 41 mg, 1.03 mmol) at 0 C and the mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 105 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 3.34 (s, 3H), 3.58 (t, J =
4.8 Hz, 2H), 3.85 (s, 3H), 4.27 (t, J = 4.4 Hz, 2H), 7.71-7.78 (m, 2H), 7.80-7.83 (m, 2H).
Step 3: 4-Chloro-3-48-methy1-7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)b enz ami de The titled compound was prepared by the reaction of methyl 4-chloro-348-methy1-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzoate (step 2 intermediate) (100 mg, 0.30 mmol) and 3-(4-methylpiperazin-1-y1)-5-(trifluoromethyl)aniline (Intermediate C19) (78 mg, 0.30 mmol) in the presence of potassium tert-butoxide (1M, 1.9 mL, 1.8 mmol) in anhydrous THF (5.0 mL) as per the procedure described in step 1 of Method A to yield 81 mg of the product.

Method M
Preparation of N-(4-((7,8-dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-3 -fluoropheny1)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide F EAr 0 . 00 110 F
),,0 INC I j N N
H
Step 1: tert-Butyl 4-(4-amino-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8 (7 H)-carboxylate NiC ) N N
eoc The titled compound was prepared by the reaction of tert-butyl 4-chloro-6H-pyrimido[5,4-b.] [1,4]oxazine-8(7H)-carboxylate (Intermediate Al) (500 mg, 1.83 mmol) with 4-amino-2-fluorophenol (350 mg, 2.76 mmol) in the presence of cesium carbonate (1.2 g, 3.67 mmol) in DMF (10 mL) as per the procedure described in step 2 of Method A to yield 361 mg of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.49 (s, 9H), 3.90 (t, J= 4.4 Hz, 2H), 4.35 (t, J
= 4.0 Hz, 2H), 5.36 (s, 2H), 6.36 (dd, ./i = 2.5 Hz, J2 = 6.8 Hz, 1H), 6.48 (dd, ./i = 2.8 Hz, J2 = 13.2 Hz, 1H), 6.92 (t, J= 8.8 Hz, 1H),7.95 (s, 1H); ESI-MS (m/z) 363 (M+H)+.
Step 2: tert-Butyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)-6H-pyrimido [5,4-b.] [1,4]oxazine-8(7H)-carboxylate F 1 NF 1 A r Fr\-1 I

F

N: ) N N
6oc To a stirred solution of tert-butyl 4-(4-amino-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazine-8(7H)-carboxylate (step 1 intermediate) (161 mg, 0.45 mmol) in dichloromethane (5.0 mL) were added DIPEA (138 L, 0.80 mmol), 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (Intermediate C68) (100 mg, 0.45 mmol mmol) followed by HATU (305 mg, 0.80 mmol) at RT. The mixture was stirred at RT
for 18 h before quenching it with water. The layers were separate and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to yield 75 mg of the titled compound. . 1H NMR (400 MHz, DMSO-d6) 6 1.45-1.46 (br s, 4H), 1.49 (s, 9H), 3.92 (t, J= 4.4 Hz, 2H), 4.38 (t, J= 3.6 Hz, 2H), 7.15 (t, J
= 9.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.62- 7.89 (m, 3H), 8.03 (s, 1H), 10.02 (s, 1H), 10.30 (s, 1H).
Step 3: N-(4-((7,8-Dihydro-6H-pyrimido [5,4-b] [1,4] oxazin-4-yl)oxy)-3 -fluoropheny1)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide The titled compound was prepared by the reaction of tert-Butyl 4-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxamido)phenoxy)-6H-pyrimido [5,4-b][1,4]oxazine-8(7H)-carboxylate (step 2 intermediate) (65 mg, 0.11 mmol) with hydrochloric acid in 1,4-dioxane (8.0 mL) in ethanol (5.0 mL) as per the procedure described in step 3 of Method A to yield 20 mg of the product.
Method N
Preparation of 4-chloro-3-43-methy1-2-oxo-1,2,3,4-tetrahydropyrido [2,3 -d]pyrimidin-5 -yl)oxy)-N-(3-(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)b enz ami de CI
H
N
0 is u3 I , ONN N
CN) H
I
Step 1: tert-Butyl (4-(2-chloro-5-((3-(4-methylpiperazin-1-y1)-5-(trifluoromethyl)phenyl)carbamoyl)phenoxy)-3-formylpyridin-2-yl)carbamate ci ai H
0 0 N so u3 Boc. I I ) N
H
NI\r CN) I
To a solution of 4-chloro-3-hydroxy-N-(3-(4-methylpiperazin-1-y1)-5-(trifluoromethyl)phenyl)benzamide (Step 1-Method G') (200 mg, 0.48 mmol) in DMF (3.0 mL) was added cesium carbonate (314 mg, 0.97 mmol) and the mixture was stirred for 30 min. The solution was cooled to 0 C and added with tert-butyl (3-chloro-2-formylphenyl)carbamate (CAS# 1260667-07-9) (186 mg, 0.73 mmol) at the same temperature. The resultant mixture was stirred overnight at RT. The reaction was quenched with ice and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography to yield 220 mg of the desired compound. 'H NMR (400 MHz, DMSO-d6) 6 1.48 (s, 9H), 2.23 (s, 3H), 2.45-2.51 (m, 4H), 3.21 (t, J= 4.8 Hz, 4H), 6.45 (d, J = 6.0 Hz, 1H), 6.98 (s, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 7.91 (d, J= 8.4 Hz, 1H), 8.01 (dd, ./i = 2.0 Hz, .1-2 = 8.4 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 5.6 Hz, 1H), 10.40 (s, 2H), 10.48 (s, 1H); ESI-MS (m/z) 534 (M+H-B0C)+.
Step 2: 4-chloro-3 -methy1-2-oxo-1,2,3 ,4-tetrahydropyrido [2,3 -d]pyrimidin-5 -yl)oxy)-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)b enz amide To a stirred solution of tert-butyl (4-(2-chloro-5-((3-(4-methylpiperazin-1-y1)-5-(trifluoromethyl)phenyl)carbamoyl)phenoxy)-3-formylpyridin-2-yl)carbamate (step 1 intermediate) (50 mg, 0.08 mmol) in THF (1.0 mL) were added methylamine solution (33%
in ethanol, 0.1 mL, 0.8 mmol) followed by a drop of acetic acid and the mixture was stirred overnight at RT. The precipitated solid was filtered, dried and purified by silica gel column chromatography to yield 12 mg of the desired compound.
Method 0 Preparation of 4-chloro-3-((3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl)oxy)-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)b enzamide ci 0 io N N CJ
Step 1: 8-Bromo-7-nitro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (Nitro adduct) Br 02N rcj:0 I j N N
H .NO2 To a stirred solution of 8-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (Step 2-Intermediate A7) (2.0 g, 9.30 mmol) in sulfuric acid (8 mL) was dropwise added a mixture of sulfuric acid and nitric acid (1:1, 14 mL) at 0 C over a period of 15 min.
The mixture was poured on crushed ice and stirred to give yellow solid. An aqueous solution of sodium hydroxide was added to the mixture till pH 8-9. The solid was filtered, washed with water and dried well. The crude solid was purified by recrystallization from acetone to yield 1.2 g of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 4.50-4.52 (m, 2H), 4.56-4.59 (m, 2H), 8.76 (s, 1H).

Step 2: 4-Chloro-N-(3 -(4-methylpip erazin-1 -y1)-5 -(trifluoromethyl)pheny1)-3-47-nitro -3 ,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl)oxy)b enzamide ci 02N,c,0 0 NN CN) To a stirred solution of 8-bromo-7-nitro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (Nitro adduct) (step 1 intermediate) (202 mg, 0.66 mmol) and 4-chloro-3-hydroxy-N-(3-(4-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamide (Step 1-Method G') (246 mg, 0.59 mmol) in DMF (12 mL) was added potassium carbonate (275 mg, 1.98 mmol) and the mixture was stirred at 105 C for 2 h. The mixture was cooled to RT and quenched with water. The aqueous mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water followed by brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to yield 368 mg of the desired product. 1H
NMR (400 MHz, DMSO-d6) 6 2.32 (s, 3H), 2.51-2.59 (br s, 4H), 3.23 (br s , 4H), 4.40-4.42 (m, 2H), 4.46-4.48 (m, 2H), 6.97 (s, 1H), 7.41 (d, J= 1.6 Hz, 1H), 7.55 (s, 1H), 7.59 (s, 1H), 7.78-7.83 (m, 2H), 8.99 (s, 1H), 10.40 (s, 1H).
Step 3: tert-Butyl 8-(2-chloro-5 -((3 -(4-methylpip erazin-1 -y1)-5 -(trifluoromethyl)phenyl)c arb amoyl)phenoxy)-7-nitro-2H-pyrido [3,2-b] [1,4]
oxazine-4 (3H)-carboxylate CI Ai 0 wi so 0F3 02N0, 0 j N Neloc CN) To a solution of 4-chloro-N-(3 -(4-methylpip erazin-1 -y1)-5 -(trifluoromethyl)p heny1)-3 nitro-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)benzamide (step 2 intermediate) (361 mg, 0.66 mmol) in dichloromethane (15 mL) were added triethylamine (183 L, 1.31 mmol) followed by di-tert-butyl dicarbonate (227 L, 0.99 mmol) and the mixture was stirred for 5 min before the addition of DMAP (8 mg, 0.06 mmol) at RT. The resultant mixture was stirred for 30 min at RT. The reaction mixture was diluted with dichloromethane and washed with water and brine. The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue thus obtained was purified by silica gel column chromatography to yield 287 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.52 (s, 9H), 2.22 (s, 3H), 2.40-2.51 (m, 4H), 3.16-3.20 (m, 4H), 3.91 (d, J= 4.4 Hz, 2H), 4.28 (d, J= 4.0 Hz, 2H), 6.94 (s, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.57 (s, 1H), 7.77-7.81 (m, 2H), 8.80 (s, .. 1H), 10.36 (s, 1H).
Step 4: tert-Butyl 7-amino-8-(2-chloro-5-((3-(4-methylpiperazin-1-y1)-5-(trifluoromethyl)phenyl)carbamoyl)phenoxy)-2H-pyrido [3,2-b] [1,4]oxazine-4(3H)-carboxylate CI Ai H N
0 wi io 0F3 H2N,c,0 0 , 1 j (1\1 1\11 Boc LN) I
To a stirred solution of tert-butyl 8-(2-chloro-5-((3-(4-methylpiperazin-l-y1)-(trifluoromethyl)phenyl)carbamoyl)phenoxy)-7-nitro-2H-pyrido [3,2-b]
[1,4]oxazine-4(3H) carboxylate (step 3 intermediate) (280 mg, 0.40 mmol) in a mixture of methanol and water (3:1, 20 mL) was added ammonium chloride (215 mg, 4.05 mmol) and the mixture was heated to 80 C. Zinc dust (135 mg, 2.06 mmol) was added in small portions and the mixture was stirred at for 1 h at 80 C. The mixture was cooled to RT and poured in to aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with 5%
mixture of methanol in chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 174 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.45 (s, 9H), 2.24 (s, 3H), 2.40 (br s, 4H), 3.21 (br s, 4H), 3.72 (t, J= 4.4 Hz, 2H), 4.08 (t, J= 4.0 Hz, 2H), 5.15 (s, 2H), 6.94 (s, 1H), 7.14 (s, 1H), 7.55-7.75 (m, 5H), 10.38 (s 1H).
Step 5: 4-C hloro-3 -((3 ,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl)oxy)-N-(3 -(4-methylpip erazin-l-y1)-5 -(trifluoromethyl)phenyl)b enzamide To a stirred solution of tert-butyl 7-amino-8-(2-chloro-5-((3-(4-methylpiperazin-1-y1)-5-(trifluoromethyl)phenyl)carbamoyl)phenoxy)-2H-pyrido [3,2-b] [1,4]oxazine-4(3H)-carboxylate (step 4 intermediate) (119 mg, 0.18 mmol) in dichloromethane (5.0 mL) at -20 C was added BF3-etherate (50%, 135 L, 0.54 mmol) and the mixture was stirred for 5 min.
Thereafter, a solution of tert-butyl nitrite (43 L, 0.36 mmol) in DCM (5.0 mL) was added dropwise to the reaction mixture over a period of 10 min. The resultant mixture was stirred at -20 C for 30 min. The mixture was allowed to warm up to 10 C and the solvent was removed by blowing nitrogen gas. The crude black residue was dissolved in DMF
(5.0 mL) and added to a stirred solution of iron sulfate (55 mg, 0.19 mmol) in DMF (5.0 mL) and the mixture was stirred for 5 min at RT. The poured in to aqueous sodium bicarbonate solution and the product was extracted twice in ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 28 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 2.27 (s, 3H), 2.44-2.47 (br s, 4H), 3.19-3.21 (br s, 4H), 3.43 (br s, 2H), 4.10 (t, J
= 4.0 Hz, 2H), 6.10 (d, J = 5.6 Hz, 1H), 6.96 (s, 2H), 7.53 (d, J= 5.6 Hz, 1H), 7.59 (s, 3H), 7.78-7.85 (m, 2H), 10.38 (s, 1H); ESI-MS (m/z) 548 (M+H)+.
Method P
Preparation of 1-(4-((7-cyano-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl)oxy)pheny1)-3 -(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)phenyl)urea H H

N N so CF3 Yo NCO
N
cj N N N
H
Step 1: tert-Butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-7-nitro-2H-pyrido [3 ,2-b] [1,4]oxazine-4(3H)-carboxylate r0 0 40 'o 02N Lo , I ) 1\1N
Boc The titled compound was prepared by the reaction of tert-butyl 8-bromo-7-nitro-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (Intermediate A22) (1.5 g, 4.16 mmol) and benzyl (4-hydroxyphenyl)carbamate (1.11 mg, 4.58 mmol) in the presence of cesium fluoride (1.9 g, 12.5 mmol) in DMSO (40 mL) as per the procedure described in step 2 of Method G' to yield 1.39 g of the compound. 1H NMR (400 MHz, DMSO-d6) 6 1.51 (s, 9H), 3.89 (t, J =
4.4 Hz, 2H), 4.25 (t, J = 4.0 Hz, 2H), 5.14 (s, 2H), 6.92 (d, J = 9.2 Hz, 2H), 7.34-7.43 (m, 7H), 8.69 (s, 1H), 9.72 (s, 1H).
Step 2: tert-Butyl 7-amino-8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-2H-pyrido[3,2-b] [1,4]oxazine-4(3H)-carboxylate H
N ((:) 40 wi 8 o H2N o, I j. , N N
lioc The titled compound was prepared by the reaction of tert-Butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-7-nitro-2H-pyrido [3,2-b] [1,4] oxazine-4(3H)-carboxylate (step 1 intermediate) (1.35 g, 2.58 mmol) with zinc dust (844 mg,

12.9 mmol) and ammonium chloride (1.38 g, 25.8 mmol) in a mixture of methanol and water (3:1, 40 mL) as per the procedure described in step 4 of Method 0 to yield 921 mg of the product. 1H
NMR (400 MHz, DMSO-d6) 6 1.45 (s, 9H), 3.73 (t, J= 4.4 Hz, 2H), 4.07 (t, J=
4.0 Hz, 2H), 4.94 (s, 2H), 5.13 (s, 2H), 6.79 (d, J= 9.2 Hz, 2H), 7.34-7.39 (m, 7H), 8.32 (s, 1H), 9.64 (s, 1H); ESI-MS (m/z) 492 (M+H)+.
Step 3: tert-Butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-7-iodo-2H-pyrido [3,2-b] [1,4]oxazine-4(3H)-carboxylate H

o 0 ) N N
6oc To a stirred suspension of tert-butyl 7-amino-8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (step 2 intermediate) (200 mg, 0.41 mmol) in acetonitrile (8.0 mL) was added PTSA (232 mg, 1.22 mmol) and stirred at RT
for 10-15 min. To that mixture a solution of sodium nitrite (56 mg, 0.81 mmol) and potassium iodide (169 mg, 1.05 mmol) in water (1.0 mL) was added at 10-15 C. The reaction mixture was gradually allowed to attain RT and poured on an aqueous solution of sodium bicarbonate.
The aqueous mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 102 mg of the desired compound. 1H NMR (400 MHz, DMSO-d6) 6 1.48 (s, 9H), 3.83 (t, J= 4.4 Hz, 2H), 4.16 (t, J= 3.6 Hz, 2H), 5.13 (m, 2H), 6.79 (d, J = 8.8 Hz, 2H), 7.34-7.43 (m, 7H), 8.27 (s, 1H),9.70 (s, 1H).
Step 4: tert-Butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-7-cyano-2H-pyrido[3,2-b] [1,4]oxazine-4(3H)-carboxylate H

wi 8 NC j0 I j N N
iioc To a solution of tert-butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-7-iodo-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (step 3 intermediate) (52 mg, 0.08 mmol) in DMF (5.0 mL) were added zinc cyanide (10 mg, 0.09 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.017 mmol) followed by water (10 L) and the mixture was degassed for 5 min before adding tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (8.0 mg, 0.008 mmol). The resultant mixture was heated to 145 C for 15 min in a microwave reactor. The reaction mixture cooled to RT and poured on to water. The mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by column chromatography to yield 19 mg of the Boc-deprotected compound. The Boc-group was restored by the reaction of the compound with di-tert-butyl dicarbonate (1.5 eq.) in the presence of LiHMDS (1.5 eq.) in THF (5.0 vol.) as per the procedure described in step 3 of Intermediate A7 to yield the titled compound. 1H NMR (400 MHz, DMSO-d6) 6 6 1.50 (s, 9H), 3.88 (t, J= 3.6 Hz, 2H), 4.21 (t, J= 4.4 Hz, 2H), 5.14 (m, 2H), 6.97 (d, J= 8.0 Hz, 2H), 7.33-7.44 (m, 7H), 8.41 (s, 1H), 9.78 (s, 1H).
Step 5: tert-Butyl 8-(4-aminophenoxy)-7-cyano-2H-pyrido[3,2-b][1,4]oxazine-4(3 H)-carboxylate Ai NH2 NC rc(0, I j N N
6(:)c A solution of tert-butyl 8-(4-(((benzyloxy)carbonyl)amino)phenoxy)-7-cyano-2H-pyrido[3,2-b] [1,4]oxazine-4(3H)-carboxylate (step 4 intermediate) (120 mg, 0.24 mmol) in methanol (12 mL) with catalytic amount of 10% palladium on carbon (50% wet, 60 mg) was hydrogenated at RT for 1 h. The mixture was filtered through celite and the celite bed was rinsed with methanol. The combined filtrate and washings were concentrated and the residue thus obtained was purified by silica gel column chromatography to yield 48 mg of the desired product. 1H NMR (400 MHz, DMSO-d6) 6 1.50 (s, 9H), 3.87 (t, J = 4.4 Hz, 2H), 4.22 (t, J =
4.0 Hz, 2H), 6.92 (dd, Ji = 2.0 Hz, .1-2 = 6.8 Hz, 2H), 7.41 (d, J= 8.8 Hz, 2H), 9.34 (s, 1H).
Step 6: tert-Butyl 7-cyano-8-(4-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenoxy)-2H-pyrido [3,2-b] [1,4] oxazine-4(3H)-carboxylate H H

40 1r 40 NC,x0j N
CN) N N
Boc The titled compound was prepared by the reaction of tert-butyl 8-(4-aminophenoxy)-7-cyano-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (step 5 intermediate) (45 mg, 0.12 mmol) with 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (Intermediate Cl) (35 mg, 0.12 mmol) by using triphosgene (13 mg, 0.04 mmol) and triethylamine (71 L, 0.37 mmol) in THF (10 mL) as per the procedure described in step 2 of Method Ito yield 53 mg of the compound. ESI-MS (m/z) 682 (M+H)+.
Step 7: 1-(4-((7-Cyano-3,4-dihydro-2H-pyrido [3,2-b] [1,4]oxazin-8-yl)oxy)pheny1)-3 -(4-((4-ethylpip erazin-l-yl)methyl)-3 -(trifluoromethyl)phenyl)urea The titled compound was prepared by the reaction of tert-butyl 7-cyano-8-(4-(3-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenoxy)-2H-pyrido [3,2-b][1,4]oxazine-4(3H)-carboxylate (step 6 intermediate) (52 mg, 0.07 mmol) with hydrochloric acid in 1,4-dioxane (2.5 mL) in 1,4-dioxane (2.0 mL) and methanol (0.5 mL) as per the procedure described in step 3 of Method A to yield 11 mg of the product. 1H NMR
(400 MHz, DMSO-d6) 6 1.01 (t, J= 7.2 Hz, 3H), 2.42 (br s, 10H), 3.33 (br s, 2H), 3.54 (br s, 2H), 4.04 (d, J= 8.0 Hz, 2H), 6.91 (d, J= 9.2 Hz, 2H), 7.41 (d, J = 9.2 Hz, 2H), 7.57 (d, J =
8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 8.10 (s, 2H), 8.79 (s, 1H), 9.04 (s, 1H);
ESI-MS (m/z) 582 (M+H)+.
Method Q
Preparation of 1-(3 -(tert-buty1)-1-(3 -cyanopheny1)-1H-pyrazol-5 -y1)-3 -(443 ,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-8-yl)oxy)phenyl)urea * CN
H H

N N N x 1 IN

eC)) NN
H

Step 1: Phenyl (3 -(te rt-buty1)-1-(3 -cyanopheny1)-1H-pyrazol-5 -yl)carb amate * ON
H

) 1 IN
To a stirred solution of 3-(5-amino-3-(tert-buty1)-1H-pyrazol-1-y1)benzonitrile (Intermediate C92) (150 mg, 0.62 mmol) and pyridine (0.1 mL, 1.25 mmol) in THF (10 mL) was added phenyl chloroformate (0.12 mL, 0.94 mmol) at 0 C. The mixture was stirred at RT for 2 h and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solution of filtered, concentrated and the residue obtained was purified by silica gel column chromatography to yield 79 mg of the desired product ESI-MS
(m/z) 361 (M+H)+.
Step 2: tert-Butyl 84443 -(3 -(tert-buty1)-1-(3 -cyanopheny1)-1H-pyrazol-5 -yl)ureido)phenoxy)-2H-pyrido [3,2-b] [1,4] oxazine-4(3H)-c arbo xylate H H
AI NisN 1 NAT
IN

CIC)) N N
Boa To a cooled (10 C) solution of tert-butyl 8-(4-aminophenoxy)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (step 2 of Method I") (60 mg, 0.17 mmol) in DMSO (5.0 mL) were added triethylamine (75 L, 0.53 mmol) followed by phenyl (3-(tert-buty1)-1-(3-cyanopheny1)-1H-pyrazol-5-y1)carbamate (step 1 intermediate) (70 mg, 0.19 mmol) and the mixture was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and washed with water, saturated ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue obtained was purified .. by silica gel column chromatography to yield 69 mg of the desired product.
1H NMR (400 MHz, DMSO-d6) 6 1.30 (s, 9H), 1.47 (s, 9H), 3.86 (t, J= 4.0 Hz, 2H), 4.27 (t, J = 4.0 Hz, 2H), 6.41 (s, 1H), 6.47 (d, J= 3.2 Hz, 1H), 7.03 (d, J= 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.71-7.77 (m, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 8.53 (s, 1H), 9.10 (s, 1H); ESI-MS (m/z) 610 (M+H)+.
Step 3: 1-(3 -(tert-Buty1)-1-(3 -cyanopheny1)-1H-pyrazol-5 -y1)-3 -(443 ,4-dihydro-2H-pyrido [3 ,2-b] [1,4] oxazin-8-yl)oxy)phenyl)urea To a stirred solution of tert-butyl 8-(4-(3-(3-(tert-buty1)-1-(3-cyanopheny1)-1H-pyrazol-5-y1)ureido)phenoxy)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxylate (step 2 intermediate) (64 mg, 0.11 mmol) in acetonitrile (10 mL) was added PTSA (200 mg, 1.05 mmol) followed by few drops of methanol and the mixture was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine.
The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue obtained was purified by silica gel column chromatography to yield 21 mg of the desired product.
Method R
Preparation of 1-(3 -(te rt-buty1)-1 -(4-cyanopheny1)-1H-pyrazol-5 -y1)-3 -(2-fluoro-442,3 ,4,5 -tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)phenyl)urea (Example 228) ON

Ai NyN 1 NIN

0---\
IN N
H
Step 1: tert-Butyl 94443 -(3-(te rt-buty1)-1 -(4-cyanopheny1)-1H-pyrazol-5-yOureido)-3 -fluorophenoxy)-3 ,4-dihydropyrido [3,2-b] [1,4] oxazepine-5 (2H)-c arboxylate ON

NõN N
NN
BoC
To a solution of 4-(5-amino-3-(tert-buty1)-1H-pyrazol-1-y1)benzonitrile (Intermediate 91) (120 mg, 0.34 mmol) in dichloromethane (10 mL) was added 1,1'-carbonyldiimidazole (CDI) (55 mg, 0.34 mmol) and the mixture was stirred at 50 C for 1 h followed by overnight at RT.
To that mixture was added 2-fluoro-4-((2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)aniline (prepared by procedure described in case of step 1 and 2 of method I") (81 mg, 0.34 mmol) at RT and stirred for 16 h. The reaction was quenched with water and extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to yield 60 mg of the titled compound. 41 NMR (400 MHz, DMSO-d6) 6 1.29 (s, 9H), 1.36 (s, 9H), 1.90-1.93 (m, 2H), 3.60-3.68 (m, 2H), 3.96-4.02 (m, 2H), 6.42 (s, 1H), 6.66 (d, J= 5.6 Hz, 1H), 7.05 (d, J= 8.8 Hz, 2H), 7.48 (d, J = 9.2 Hz, 2H), 7.80 (d, J =
8.4 Hz, 2H), 7.97-8.02 (m, 2H), 8.58 (s, 1H), 9.14 (s, 1H); ESI-MS (m/z) 541 (M+H-Boc)+.
Step 2: 1-(3-(tert-Buty1)-1-(4-cyanopheny1)-1H-pyrazol-5-y1)-3-(2-fluoro-442,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-y1)oxy)phenyl)urea The titled compound was prepared by the reaction of tert-butyl 9-(4-(3-(3-(tert-buty1)-1-(4-cyanopheny1)-1H-pyrazol-5-yOureido)-3-fluorophenoxy)-3,4-dihydropyrido[3,2-b][1,4]
oxazepine-5(2H)-carboxylate (step 1 intermediate) (50 mg, 0.08 mmol) with hydrochloric acid in 1,4-dioxane (5.0 mL) as per the procedure described in step 3 of Method A to yield 18 mg of the product.
Table 25: Structure, Chemical name, Method used and analytical data of Examples No. Intermed Analytical Data Structure and Name iates and Method 1. 0 H
Al, B2, 1I-1 NMR (400 MHz, DMSO-d6) O N r CFrN
Cl 6 0.98 (t, J = 6.8 Hz, 3H), 2.28-0 IW NI,) 2.51 (m, 10H), 3.33-3.51 (br s, I j Method A 4H), 4.17 (d, J = 4.0 Hz, 2H), NN
H
7.36-7.37 (m, 1H), 7.56 (d, J =
3-((7,8-Dihydro-6H-pyrimido[5,4-8.0 Hz, 1H), 7.68-7.82 (m, 5H), b] [1,4]oxazin-4-yl)oxy)-N-(4-((4-8.03 (d, J= 2.0 Hz, 1H), 8.20 (s, ethylpiperazin-l-yl)methyl)-3-1H), 10.42 (s, 1H); ESI-MS (m/z) (trifluoromethyl)phenyl)benzamid 543 (M+H)+.
e 2. F
H
Al, B4, 1I-1 NMR (400 MHz, DMSO-d6) ow No c3 Cl 6 0.98 (t, J = 6.8 Hz, 3H), 2.28-j,(D cl 2.44 (m, 10H), 3.51-3.56 (m, 1 j N Method A 4H), 4.20 (t, J = 8.4 Hz, 2H), NN
C ) 7.52-7.72 (m, 3H), 7.80 (br s, H
N 1H), 7.91-7.95 (m, 2H), 8.03 (dd, Ji = 1.6 Hz, J2 = 8.4 Hz, 1H), 3-((7,8-Dihydro-6H-pyrimido[5,4-8.18 (s, 1H), 10.50 (s, 1H); ESI-b] [1,4]oxazin-4-yl)oxy)-N-(4-((4- MS (m/z) 561 (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)pheny1)-4-fluorobenzamide 3. ci Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 6 2.15-2.38 (m, 11H), 3.51-3.56 O VI Ed cFrNi.
, (br s, 4H), 4.20 (t, J = 4.0 Hz, N:):()) 0 IW N) Method A 2H), 7.68-7.71 (br s, 2H), 7.72 (t, NI N
J= 10.4 Hz, 2H), 7.87-7.89 (br s, H
2H), 8.02 (d, J = 7.2 Hz, 1H), 4-Chloro-3-((7,8-dihydro-6H-8.16 (s, 1H), 10.45 (s, 1H); ESI-No. Intermed Analytical Data Structure and Name iates and Method pyrimido[5,4-b][1,4]oxazin-4- MS (m/z) 563 (M+H)t yl)oxy)-N-(4-((4-methylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)benzamid e 4. a gib H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N cFr...N. C3 6 0.95 (d, J = 6.4 Hz, 6H), 2.38-o IW N,) Method A 2.62 (m, 9H), 3.51-3.54 (m, 4H), 4.20 (t, J = 4.4 Hz, 2H), 7.69-1\IN 7.79 (m, 4H), 7.88-7.90 (m, 2H), H
4-Chloro-3-((7,8-dihydro-6H- 8.02 (dd, Ji = 8.4 Hz, .1-2 = 10.0 pyrimido[5,4-b][1,4]oxazin-4- Hz, 1H), 8.17 (s, 1H), 10.53 (s, yl)oxy)-N-(4-((4- 1H); ESI-MS (m/z) 591 (M+H)+.
isopropylpiperazin-l-yl)methyl)-(trifluoromethyl)phenyl)benzamid e 5. ci H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O wi N 0 CF C4 6 0.89 (d, J = 6.4 Hz, 3H), 1.11-, oj 0 N........õ,- 1.19 (m, 2H), 1.34 (br s, 1H), It Method A 1.58 (d, J = 12.0 Hz, 2H), 1.95 (t, N N J = 11.6 Hz, 2H), 2.74 (d, J =
H
4-Chloro-3-((7,8-dihydro-6H- 11.2 Hz, 2H), 3.52-3.53 (br s, pyrimido[5,4-b][1,4]oxazin-4- 4H), 4.20 (t, J = 4.0 Hz, 2H), yl)oxy)-N-(4-((4-methylpiperidin- 7.69-7.80 (m, 4H), 7.88-7.90 (m, 1-yl)methyl)-3- 2H), 8.02 (d, J = 8.8 Hz, 1H), (trifluoromethyl)phenyl)benzamid 8.16 (s, 1H), 10.53 (s, 1H); ESI-e MS (m/z) 562 (M+H)+.
6. a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) ow No cF CS
6 2.33-2.45 (m, 4H), 3.28-3.39 , (31 0 N, (m, 2H), 3.41-3.60 (m, 6H), 4.20 NJC Method A (t, J = 4.4 Hz, 2H), 7.69-7.87 N N (m, 4H), 7.88-7.90 (m, 2H), 8.05 H
4-Chloro-3-((7,8-dihydro-6H- (dd, J1 = 1.6 Hz, J2 = 8.4 Hz, pyrimido[5,4-b][1,4]oxazin-4- 1H), 8.18 (s, 1H), 10.55 (s, 1H);
yl)oxy)-N-(4-(morpholinomethyl)- ESI-MS (m/z) 550 (M+H)+.
3-(trifluoromethyl) phenyl)benzamide 7. a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) ow No cFr...NH C6 6 2.31 (br s, 4H), 2.71 (br s, 4H), NA, o 0 N,) 3.52 (br s, 4H), 4.20 (br s, 2H), j Method A 7.69-7.88 (m, 7H), 8.02 (d, J =
N N 7.2 Hz, 1H), 8.16 (s, 1H), 10.54 H
4-Chloro-3-((7,8-dihydro-6H- (s, 1H); ESI-MS (m/z) 549 pyrimido[5,4-b][1,4]oxazin-4- (M+H)+.
yl)oxy)-N-(4-(piperazin-1-No. Intermed Analytical Data Structure and Name iates and Method ylmethyl)-3-(trifluoromethyl)phenyl)benzamid e 8. CI
H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O VI N la CF C33 6 2.16 (s, 9H), 2.37-2.50 (m, N(:))0 4H), 3.51-3.59 (m, 4H), 4.20 (br j( IW NI' 1\I
I Method B s, 2H), 7.69-7.99 (m, 4H), 7.88 N N (s, 1H), 8.02 (d, J = 7.2 Hz, 1H), H
4-Chloro-3-((7,8-dihydro-6H- 8.16 (s, 2H), 10.54 (s, 1H); ESI-pyrimido[5,4-b][1,4]oxazin-4- MS (m/z) 565 (M+H)+.
yl)oxy)-N-(4-(((2-(dimethylamino)ethyl)(methyl)am ino)methyl)-3-(trifluoromethyl)phenyl)benzamid e 9. CI Ai H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O N r" CF3 C24 6 2.22 (s, 3H), 2.45-2.51 (br s, 4H), 2.84 (t, J = 4.0 Hz, 4H), N:,CI CI) N
,N, Method A 3.51-3.51 (br s, 2H), 4.20 (t, J =
N N H 4.4 Hz, 2H), 7.57 (d, J = 8.8 Hz, 4-Chloro-3-((7,8-dihydro-6H- 1H) 7.74 (s, 1H), 7.87-7.89 (m, pyrimido[5,4-b][1,4]oxazin-4- 4H), 8.02 (dd, Ji = 2.4 Hz, J2 =
yl)oxy)-N-(4-(4-methylpiperazin- 8.8 Hz, 1H), 8.12 (s, 1H), 10.49 1-y1)-3- (s, 1H); ESI-MS (m/z) 549 (trifluoromethyl)phenyl)benzamid (M+H)+.
e 10. 01 H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O W N i& CF3 C27 6 2.75-2.82 (m, 8H), 3.51-3.52 NXI ID) N
(br s, 2H), 4.20 (t, J = 4.0 Hz, ,NH Method A 2H), 7.53 (d, J = 8.8 Hz, 1H), N N 7.69-7.80 (m, 3H), 7.87-7.89 (m, H
4-Chloro-3-((7,8-dihydro-6H- 2H), 8.03 (dd, Ji = 2.4 Hz, J2 =
pyrimido[5,4-b][1,4]oxazin-4- 8.4 Hz, 2H), 8.10 (s, 1H), 10.48 yl)oxy)-N-(4-(pip erazin-1 -y1)-3 - (s, 1H); ESI-MS (m/z) 535 (trifluoromethyl)phenyl)benzamid (M+H)+.
e 11. CI H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 2.83 (t, J = 4.4 Hz, 4H), 3.52 (br NO N
s, 2H), 3.70 (t, J = 4.0 Hz, 4H), jc) W
0 Method A 4.20 (t, J = 4.0 Hz, 2H), 7.61 ( d, N N J = 8.8 Hz, 1H), 7.69 (s, 1H), H
4-Chloro-3-((7,8-dihydro-6H- 7.75-7.80 (m, 2H), 7.88-7.90 (m, pyrimido[5,4-b][1,4]oxazin-4- 2H), 8.05 ( dd, Ji = 2.4 Hz, J2 =
yl)oxy)-N-(4-morpholino-3- 8.8 Hz, 1H), 8.14 (s, 1H), 10.50 (trifluoromethyl)phenyl)benzamid (s, 1H); ESI-MS (m/z) 536 e (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method 12. CI a H Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) O N = r-rir'''. C28 0.97 (t, J = 7.2 Hz, 3H), 2.26-0 0 N.,9 2.51 (m, 10H), 3.41 (s, 2H), 3.52 Nx ) Method A (d, J = 6.8 Hz, 2H), 4.20 (t, J =
Nr N H 8.4 Hz, 2H), 7.26 ( d, J = 8.4 Hz, 4-Chloro-3-((7,8-dihydro-6H- 2H), 7.68-7.79 (m, 5H), 7.85 (s, pyrimido[5,4-b][1,4]oxazin-4- 2H), 10.28 (s, 1H); ESI-MS (m/z) yl)oxy)-N-(4-((4-ethylpiperazin-1- 509 (M+H)+.
yl)methyl)phenyl)benzamide

13. CI a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O N = CI r======.,. C29 0.97 (t, J = 6.8 Hz, 3H), 2.29-j:c) 0 N 2.51 (m, 10H), 3.51 (s, 4H), 4.20 N ) Method A (t, J = 4.4 Hz, 2H), 7.43 (d, J =
Nr N H 8.8 Hz, 1H), 7.66-7.74 (m, 2H), 4-Chloro-N-(3-chloro-4((4- 7.76-7.80 (m, 3H), 7.86-7.93 (m, ethylpiperazin-1- 2H), 10.41 (s, 1H); ESI-MS (m/z) yl)methyl)pheny1)-3-47,8- 543 (M+H)+.
dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

14. CI a H
Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N C7 6 0.97 (t, J = 7.2 Hz, 3H), 2.28-0 0 1\1 0 0 N r) 2.35 (m, 13H), 3.32 (br s, 2H), A
N ' ) Method A 3.52 (br s, 2H), 4.20 (t, J = 4.0 N N H Hz, 2H), 7.16 (d, J = 8.0 Hz, 4-Chloro-3-((7,8-dihydro-6H- 1H), 7.53-7.79 (m, 4H), 7.85 (s, pyrimido[5,4-b][1,4]oxazin-4- 1H), 7.86-7.87 (m, 2H), 10.19 (s, yl)oxy)-N-(4-((4-ethylpiperazin-1- 1H).
yl)methyl)-3-methylphenyl)benzamide

15. ci a H
Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 6 2.22 (s, 3H), 2.46 (t, J = 4.8 ID Hz, 4H), 3.21 (t, J=
4.8 Hz, 4H), = I ) N
Method A 3.51-3.52 (br s, 2H), 4.20 (t, J =
ON 4.2 Hz, 2H), 6.96 (s, 1H), 7.60 (s, H C
N) 2H), 7.64 (s, 1H), 7.69-7.77 (m, I 4-Chloro-3-((7,8-dihydro-6H-1H), 7.82 (s, 1H), 7.86-7.89 (m, pyrimido[5,4-b][1,4]oxazin-4-2H), 10.38 (s, 1H); ESI-MS (m/z) yl)oxy)-N-(3-(4-methylpiperazin-549 (M+H)+.
1-y1)-5 -(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

16. c1 A
H Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) CF3 3-bromo- 6 3.51-3.52 (br s, 2H), 4.21 (t, J
5- = 4.0 Hz, 2H), 7.69 (s, 2H), 7.77-Nj: C;1 ) Br (trifluoro 7.80 (m, 2H), 7.78-7.90(m, 2H), N N H
methyl)an 8.19 (s, 1H), 8.34 (s, 1H), 10.67 N-(3-Bromo-5- iline (s, 1H); ESI-MS (m/z) 531 (trifluoromethyl)pheny1)-4-chloro- (M+2H)+.
3-((7,8-dihydro-6H-pyrimido[5,4- Method A
b][1,4]oxazin-4-yl)oxy)benzamide

17. CI al H Al, Bl, lli NMR (400 MHz, DMSO-d6) N CF3 0 C44 6 0.99 (t, J = 7.2 Hz, 3H), 2.22-0 r1\1 2.50 (m, 6H), 3.09-4.36 (m, 6H), Method A 4.21 (br s, 2H), 7.45 (d, J = 8.8 N N H Hz, 1H), 7.68 (s, 1H), 7.79 (br s, 4-Chloro-3-((7,8-dihydro-6H- 2H), 7.89-7.91 (m, 2H), 8.12 (d, pyrimido[5,4-b][1,4]oxazin-4- J =
8.0 Hz, 1H), 8.26 (s, 1H), yl)oxy)-N-(4-(4-ethylpiperazine-1- 10.67 (s, 1H); ESI-MS (m/z) 591 carbonyl)-3- (M) (trifluoromethyl)phenyl)benzamid e

18. ci al H 0 Al, Bl, lli NMR (400 MHz, DMSO-d6) N CF3 .1L C8 6 1.99 (s, 3H), 2.33 (s, 2H), 2.39 0 0 r'N
N (s, 2H), 3.33-3.44 (m, 4H), 3.52 er) Method A (s, 2H), 3.60 (s, 2H), 4.20 (s, N N H 2H), 7.69-7.88 (m, 4H), 7.90 (s, N-(4-((4-Acetylpip erazin-1- 2H), 8.05 (d, J = 8.4 Hz, 1H), yl)methyl)-3- 8.18 (s, 1H), 10.56 (s, 1H); ESI-(trifluoromethyl)pheny1)-4-chloro- MS (m/z) 591 (M+H)+
3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

19. CI Ai Al, Bl, lli NMR (400 MHz, DMSO-d6) H
N

0 Br ...... C30 6 0.98 (t, J = 6.8 Hz, 3H), 2.27-40 r.N..., 1,1,0, 0 N,) 2.51 (m, 10H), 3.49-4.52 (m, j Method A 4H), 4.20 (t, J = 4.4 Hz, 2H), N N H
7.42 (d, J = 8.4 Hz, 1H), 7.69-N-(3-Bromo-4-((4-ethylpiperazin- 7.88 (m, 6H), 8.10 (s, 1H), 10.40 1-yl)methyl)pheny1)-4-chloro-3- (s, 1H).
((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

20. CI al Al, Bl, 'HNMR (400 MHz, DMSO-d6) H

O N
I C16 6 2.23 (s, 6H), 2.65 (t, J = 5.6 Hz, 2H), 3.51 (m, 2H), 4.16-4.20 0 S(21'N Method B (m, 4H), 7.31 (d, J= 9.6 Hz, 1H), N N H
7.69 (s, 1H), 7.75 (d, J = 8.4 Hz, 4-Chloro-3-((7,8-dihydro-6H- 1H), 7.81 (s, 1H), 7.86-7.88 (m, pyrimido[5,4-b][1,4]oxazin-4- 2H), 7.98 (d, J = 9.6 Hz, 1H), No. Intermed Analytical Data Structure and Name iates and Method yl)oxy)-N-(4-(2- 8.06 (br s, 1H), 10.40 (s, 1H);
(dimethylamino)ethoxy)-3- ESI-MS (m/z) 538 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

21. CI Al, Bl, lli NMR (400 MHz, DMSO-d6) H

6 2.18 (s, 6H), 2.35-2.50 (m, 0 WI N.,......."... ..-- 2H), 3.29-3.52 (m, 4H), 4.21 (m, N NJ:CI
I ) 0 I Method B 2H), 7.51 (d, J = 8.4 Hz, 1H), N N H
7.69-7.91 (m, 5H), 8.08 (d, J =
4-(4-Chloro-3-((7,8-dihydro-6H- 8.4 Hz, 1H), 8.21 (s, 1H), 8.38 pyrimido[5,4-b][1,4]oxazin-4- (m, 1H), 10.65 (s, 1H); ESI-MS
yl)oxy)benzamido)-N-(2- (m/z) 565 (M+H)+.
(dimethylamino)ethyl)-2-(trifluoromethyl)benzamide

22. CI Al, Bl, lli NMR (400 MHz, DMSO-d6) H

6 3.51-3.52 (br s, 2H), 4.20 (t, J
u3 0 WI so (trifluoro = 4.0 Hz, 2H), 7.47 (d, J = 7.6 N
I ) methyl)an Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), N N iline 7.69 (s, 1H), 7.88-7.99 (m, 4H), H
4-Chloro-3-((7,8-dihydro-6H- 8.04 (d, J = 8.4 Hz, 1H), 8.21 (s, pyrimido[5,4-b][1,4]oxazin-4- Method B 1H), 10.46 (s, 1H); ESI-MS (m/z) yl)oxy)-N-(3- 451 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

23. CI Al, Bl, lli NMR (400 MHz, DMSO-d6) H
O W N i CFr.N. C17 6 0.97 (t, J = 7.2 Hz, 3H), 1.66-O 0=
1.68 (m, 2H), 1.90-1.91 (m, 2H), N:
I ) IW 0 Method B 2.27-2.35 (m, 4H), 2.50-2.58 (m, N N H
2H), 3.52 (br s, 2H), 4.20 (t, J =
4-Chloro-3-((7,8-dihydro-6H- 3.6 Hz, 2H), 4.59 (m, 1H), 7.32 pyrimido[5,4-b][1,4]oxazin-4- (d, J
= 6.9 Hz, 1H), 7.69-7.88 yl)oxy)-N-(4-((l-ethylpiperidin-4- (m, 5H), 7.95 (d, J = 9.6 Hz, 1H), yl)oxy)-3- 8.06 (s, 1H), 10.38 (s, 1H); ESI-(trifluoromethyl)phenyl)benzamid MS (m/z) 578 (M+H)+.
e

24. CI Al, Bl, lli NMR (400 MHz, DMSO-d6) H
N u3 C20 6 1.04 (t, J = 7.2 Hz, 3H), 2.38 0 wi io (q, J= 7.2 Hz, 2H), 2.50-2.56 (br NC
I ) N Method B s, 4H), 3.21 (t, J = 4.4 Hz, 4H), N N CN) H
3.51-3.52 (br s, 2H), 4.20 (t, J =
4.0 Hz, 2H), 6.96 (s, 2H), 7.60 (s, 1H), 7.64 (s, 2H), 7.75-7.80 (m, 4-Chloro-3-((7,8-dihydro-6H- 2H), 7.87-7.89 (m, 2H); ESI-MS
pyrimido[5,4-b][1,4]oxazin-4- (m/z) 563 (M+H)+.
yl)oxy)-N-(3-(4-ethylpiperazin-1-y1)-5-No. Intermed Analytical Data Structure and Name iates and Method (trifluoromethyl)phenyl)benzamid e

25. a H Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) N u3 C18 6 1.0 (s, 6H), 2.50-2.59 (m, 4H), , N j : ) 0 3.20 (m, 4H), 3.51 (br s, 3H), N Method B 4.20 (s, 2H), 6.94 (s, 1H), 7.59-N N C ) 7.87 (m, 7H), 10.37 (s, 1H); ESI-H
r) MS (m/z) 577 (M+H)+.
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-isopropylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

26. ci am H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O WI N 0 cFrN C9 6 0.84 (t, J = 7.2 Hz, 3H), 1.40-Njo, 0 N) 1.42 (m, 2H), 2.21 (t J = 7.2 Hz, 1 j Method B 4H), 2.49-2.50 (m, 6H), 3.51-N N 3.56 (m, 4H), 4.19-4.21 (m, 2H), H
4-Chloro-3-((7,8-dihydro-6H- 7.69-7.77 (m, 4H), 7.77-7.87 (m, pyrimido[5,4-b][1,4]oxazin-4- 2H), 8.07 (d, J = 11.2 Hz, 1H), yl)oxy)-N-(4-((4-propylpiperazin- 8.17 (s, 1H), 10.54 (s, 1H); ESI-1-yl)methyl)-3- MS (m/z) 591 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

27. Ck Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N 40 cF3 C21 6 0.88 (t, J = 7.2 Hz, 3H), 1.45-1.50 (m, 2H), 2.28 (t, J= 7.6 Hz, Nts: 1 Oj 0 N
Method B 2H), 3.16-3.22 (m, 8H), 3.51-N N C ) 3.52 (br s, 2H), 4.20 (t, J = 4.0 H
N Hz, 2H), 6.95 (s, 1H), 7.59 (s, H 2H), 7.64 (s, 1H), 7.69-7.80 (m, 2H), 7.86-7.89 (m, 2H), 10.37 (s, 4-Chloro-3-((7,8-dihydro-6H- 1H); ESI-MS (m/z) 577 (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-propylpiperazin-1-y1)-5 -(trifluoromethyl) phenyl)benzamide

28. ci Ai u3 Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H

6 0.084-0.12 (m, 2H), 0.46-0.50 O wi 40 (m, 2H), 0.84-0.88 (m, 1H), 1 j N Method B 2.22-2.4 (m, 2H), 2.49-2.58 (m, NN ( ) 4H), 3.21-3.39 (m, 4H), 3.51-H
3.52 (m, 2H), 4.20 (t, J= 4.4 Hz, N
2H), 6.96 (s, 1H), 7.59-7.77 (m, 3H), 7.81-7.89 (m, 4H), 10.38 (s, No. Intermed Analytical Data Structure and Name iates and Method 4-Chloro-N-(3-(4- 1H); ESI-MS (m/z) 589 (M+H)+.
(cyclopropylmethyl)piperazin-l-y1)-5-(trifluoromethyl)pheny1)-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-y1)oxy)benzamide

29. CI Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O Wi N 0 0F3 C10 6 0.97 (t, J = 7.2 Hz, 3H), 2.27-NS(:' 2.51 (m, 10H), 3.34-3.37 (m, I ) Method B 1H), 3.39-3.53 (m, 3H), 4.21 (q, NN N J
= 4.4 Hz, 2H), 7.36 (s, 1H), H
7.69 (s, 1H), 7.75-7.80 (m, 2H), 4-Chloro-3-((7,8-dihydro-6H- 7.89-7.91 (m, 2H), 7.98 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4- 8.16 (s, 1H), 10.57 (s, 1H); ESI-yl)oxy)-N-(3-((4-ethylpiperazin-1- MS (m/z) 577 (M+H)+.
yl)methyl)-5-(trifluoromethyl)phenyl)benzamid e

30. 01 H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N C35 6 1.45 (q, J = 2.8 Hz, 2H), 1.85 0 0 u3 0 N: l rN, (d, J
= 12.0 Hz, 2H), 2.50-2.51 Method B (m, 7H), 2.78 (t, J = 11.6 Hz, N N
24.2(b1r(s, t 23H.7)8, (3m.5, 21-11)3.5, J2H=)4,.03.11z75-, H
2H), 6.94 (s, 1H), 7.60 (d, J =
4-Chloro-3-((7,8-dihydro-6H- 10.4 Hz, 2H), 7.69-7.89 (m, 5H), pyrimido[5,4-b][1,4]oxazin-4- 10.35 (s, 1H); ESI-MS (m/z) 577 yl)oxy)-N-(3-(4- (M+H)+.
(dimethylamino)piperidin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

31. a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 6 2.16 (s, 6H), 2.39 (t, J = 6.8 I ) N:

N Hz, 2H), 2.95 (s, 3H), 3.44-3.51 Method B (m, 4H), 4.20 (t, J = 4.4 Hz, 2H), 1\1 = H
7.39 (s, 1H), 7.47 (s, 1H), 7.69 I (s, 1H), 7.74-7.76 (m, 1H), 7.81 4-Chloro-3-((7,8-dihydro-6H- (s, 1H), 7.87 (s, 1H), 7.88 (s, pyrimido[5,4-b][1,4]oxazin-4- 2H), 10.34 (s, 1H); ESI-MS (m/z) yl)oxy)-N-(3-((2- 551 (M+H)+.
(dimethylamino)ethyl)(methyl)am ino)-5-(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

32. ci Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) 40 , CN 2-(3- 6 1.69 (s, 6H), 3.51-3.52 (m, aminophe 2H), 4.20 (t, J = 4.4 Hz, 2H), ny1)-2- 7.25-7.27 (m, 1H), 7.42 (t, J =
1\1 N methylpro 8.0 Hz, 1H), 7.69-7.82 (m, 4H), H panenitril 7.88-7.93 (m, 3H), 10.42 (s, 1H);
4-Chloro-N-(3-(2-cyanopropan-2- e ESI-MS (m/z) 449 (M)+.
yl)pheny1)-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4- Method B
yl)oxy)benzamide

33. a Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N C36 6 1.47-1.50 (m, 2H), 1.76-1.79 0 NO CN (m, 2H), 3.51-3.52 (br s, 2H), J, 0 L I j Method B 4.21(t, J = 4.0 Hz, 2H), 7.01 (dd, 1\1N H ii = 1.2 Hz, J2 =
7.2 Hz, 1H), 4-Chloro-N-(3-(1- 7.57 (s, 1H), 7.75 (s, 1H), 7.76-cyanocyclopropyl)pheny1)-3- 7.88 (m, 4H), 7.89-7.90 (br s, ((7,8-dihydro-6H-pyrimido[5,4- 2H), 10.44 (s, 1H); ESI-MS (m/z) b][1,4]oxazin-4-yl)oxy)benzamide 448 (M+H)+.

34. CI a H
Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N io cF3 C39 6 2.84 (t, J= 4.8 Hz, 4H),3.12 (t, J = 4.8 Hz, 4H), 3.52 (br s, 2H), ,C ) N
N O Method B 4.21 (t, J = 4.0 Hz, 2H), 6.94 (s, I
N N 1H), 7.59 (s, 2H), 7.63-7.89 (m, H C ) N 5H), 10.36 (s, 1H); ESI-MS (m/z) H 535 (M+H)+.
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(piperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

35. a Al H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 0 N * CF3 C23 6 0.93 (t, J = 6.4 Hz, 3H), 1.216-txc) o 1.26 (m, 2H), 1.55-1.57 (br s, ) Method B 1H), 1.70 (d, J = 11.2 Hz, 2H), H 2.75 (dt, J1 =
2.0 Hz, J2 = 12.4 Hz, 2H), 3.51-3.52 (m, 2H), 7.73 4-Chloro-3-((7,8-dihydro-6H- (d, J
= 12.4 Hz, 2H), 4.21 (t, J =
pyrimido[5,4-b][1,4]oxazin-4- 4.0 Hz, 2H), 6.93 (s, 1H), 7.59-yl)oxy)-N-(3-(4-methylpiperidin- 7.61 (m, 2H), 7.76 (s, 1H), 7.81-1-y1)-5 - 7.77 (m, 1H), 7.87 (s, 1H), 7.88-(trifluoromethyl)phenyl)benzamid 7.89 (m, 2H), 10.34 (s, 1H); ESI-e MS (m/z) 548 (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method

36. CI al Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N io cF3 C40 6 1.47-1.56 (m, 2H), 1.72 (d, J =

11.2 Hz, 2H), 2.50-2.72 (m, 3H), N ,CO Method B 3.03 (d, J = 11.6 Hz, 2H), 3.52 I ) N N (br s, 2H), 4.21 (t, J = 4.0 Hz, H
N 2H), 7.31 (s, 1H), 7.69-7.94 (m, H 6H), 8.07 (s, 1H), 10.52 (s, 1H);
4-Chloro-3-((7,8-dihydro-6H- ESI-MS (m/z) 534 (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(piperidin-4-y1)-5-(trifluoromethyl)phenyl)benzamid e

37. a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 0 WI N iio CF3 C41 6 1.34-1.67 (m, 2H), 1.77-1.80 0 (m, 2H), 1.98 (t, J
= 10.0 Hz, Method B 2H), 2.20 (s, 3H), 2.50-2.58 (m, N N
H 1H), 2.87 (d, J =
11.2 Hz, 2H), N 3.51-3.52 (br s, 2H), 4.21 (t, J =

4-Chloro-3-((7,8-dihydro-6H- 4.0 Hz, 2H), 7.33 (s, 1H), 7.69-pyrimido[5,4-b][1,4]oxazin-4- 7.93 (m, 6H), 8.08 (s, 1H), 10.52 yl)oxy)-N-(3-(1-methylpiperidin- (s, 1H); ESI-MS (m/z) 548 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

38. a Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N 0 gip io c3 C37 6 2.13-2.29 (m, 1H), 3.33-3.66 (m, 7H), 4.21 (t, J = 4.0 Hz, 2H), N N Method B 5.41-5.54 (m, 1H), 6.56 (s, 1H), NI ) c )1\1 H 7.28 (s, 1H), 7.51 (s, 1H), 7.77 \--F (s, 1H), 7.87-7.90 (m, 4H), 10.37 (S)-4-chloro-3-((7,8-dihydro-6H- (s, 1H); ESI-MS (m/z) 538 pyrimido[5,4-b][1,4]oxazin-4- (M+H)+.
yl)oxy)-N-(3-(3-fluoropyrrolidin-1-y1)-5 -(trifluoromethyl)phenyl)benzamid e

39. CI al Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N cF3 C42 6 3.18-3.19 (br s, 4H), 3.51-3.52 0 WI so (m, 2H), 3.84 (br s, 4H), 4.21 (t, Method B J = 4.0 Hz, 2H), 7.10 (s, 1H), 1 j N
N N H ( ) 7.62 (s, 1H), 7.69-7.89 (m, 6H), s, 10.41 (s, 1H); ESI-MS (m/z) 584 dro (M+H)+.
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(1,1-dioxidothiomorpholino)-5-No. Intermed Analytical Data Structure and Name iates and Method (trifluoromethyl)phenyl)benzamid e

40. a Al, Bl, '1-1 NMR (400 MHz, DMSO-d6) H
N 0 gip 0 c3 C11 6 2.18 (s, 6H), 3.47-3.51 (m, ,C

4H), 4.21 (t, J = 4.4 Hz, 2H), N
I ) Method B 7.36 (s, 1H), 7.69 (s, 1H), 7.75-N N 1\1 H I
7.80 (m, 2H), 7.89-7.91 (m, 2H), 4-Chloro-3-((7,8-dihydro-6H- 8.01 (s, 1H), 8.15 (s, 1H), 10.56 pyrimido[5,4-b][1,4]oxazin-4- (s, 1H); ESI-MS (m/z) 508 yl)oxy)-N-(3- (M+H)+.
((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)benzamid e

41. CI Al, Bl, 11-1 NMR (400 MHz, DMSO-d6) H
N 2-(3- 6 3.51-3.52 (m, 2H), 4.07 (s, 0 w 0 CN

aminophe 2H), 4.21 (br s, 2H), 7.09 (d, J =
N
I ) nyl)aceto 7.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, N N nitrile 1H), 7.69-7.89 (m, 5H), 7.90 (s, H
4-Chloro-N-(3- 2H), 10.40 (s, 1H); ESI-MS (m/z) (cyanomethyl)pheny1)-347,8- Method D 422 (M+H)+.
dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

42. CI F F Al, Bl, 11-1 NMR (400 MHz, DMSO-d6) H
N C45 6 3.51 (br s, 2H), 4.20-4.21 (br s, 2H), 7.55 (d, J = 7.6 Hz, 1H), N l I ) Method E 7.67 (d, J = 10.8 Hz, 2H), 7.79-N
H N 7.80 (br s, 2H), 7.89-7.91 (br s, 4-Chloro-N-(3- 2H), 8.10 (d, J = 8.8 Hz, 1H), (cyanodifluoromethyl)pheny1)-3- 8.29 (s, 1H), 10.52 (s, 1H); ESI-((7,8-dihydro-6H-pyrimido[5,4- MS (m/z) 458 (M+H)+.
b][1,4]oxazin-4-yl)oxy)benzamide

43. a Al, Bl, 11-1 NMR (400 MHz, DMSO-d6) H
N

cF3 C38 6 2.20-2.30 (m, 1H), 3.34-3.63 0 w 0 (m, 7H), 4.21 (t, J = 3.6 Hz, 2H), N l Method B 5.40-5.54 (br s, 1H), 6.56 (s, 1H), N N
H \__/ 7.28 (s, 1H), 7.51 (s, 1H), 7.81 'F (s, 1H), 7.87-7.89 (s, 4H), 10.37 (R)-4-Chloro-3-((7,8-dihydro-6H- (s, 1H); ESI-MS (m/z) 538 pyrimido[5,4-b][1,4]oxazin-4- (M+H)+.
yl)oxy)-N-(3-(3-fluoropyrrolidin-1-y1)-5 -(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

44. CI Ai H Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) O N io c3 C12 6 1.27-1.29 (m, 1H), 1.75-1.84 N (:) (m, 1H), 1.87-1.91 (m, 1H), 2.08 I ) N Method B (s, 6H), 2.33-2.75 (m, 4H), 3.50 H c NN (br s, 2H), 3.70 (q, J = 6.8 Hz, N¨ 2H), 4.20 (t, J = 4.0 Hz, 2H), / 7.68-7.70 (m, 2H), 7.75-7.90 (m, 4-Chloro-3-((7,8-dihydro-6H- 2H), 8.01 (br s, 2H), 8.03 (d, J =
pyrimido[5,4-b][1,4]oxazin-4- 6.6 Hz, 1H), 8.16 (s, 1H), 10.54 yl)oxy)-N-(4-((3- (s, 1H); ESI-MS (m/z) 577 (dimethylamino)pyrrolidin-1- (M+H)+.
yl)methyl)-3-(trifluoromethyl)phenyl)benzamid e

45. c1 Ai H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N u3 C13 6 1.25-1.29 (m, 1H), 1.62-1.65 N-'(-) 40 (m, 1H), 1.84-1.88 (m, 1H), 2.08 I ) N Method B (s, 6H), 2.33 (t, J = 6.8 Hz, 1H), NN
H c ) 2.45-2.76 (m, 3H), 3.52 (br s, 2H), 3.66 (q, J = 14.4 Hz, 2H), \ 4.20 (d, J = 4.0 Hz, 2H), 7.69-(S)-4-Chloro-3-((7,8-dihydro-6H- 7.75 (m, 3H), 7.77 (s, 1H), 7.88-pyrimido[5,4-b][1,4]oxazin-4- 7.90 (m, 2H), 8.03 (d, J = 8.4 Hz, yl)oxy)-N-(4-((3- 1H), 8.16 (s, 1H), 10.54 (s, 1H);
(dimethylamino)pyrrolidin-1- ESI-MS (m/z) 577 (M+H)+.
yl)methyl)-3-(trifluoromethyl)phenyl)benzamid e

46. CI A H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 6 1.25-1.29 (m, 1H), 1.63-1.66 NCI
(m, 1H), 1.76-1.89 (m, 1H), 2.10 1 ) N Method B (s, 6H), 2.35 (t, J = 6.8 Hz, 1H), NN 2.46-2.76 (m, 3H), 3.37 (br s, H c ) .1 R) N¨
2H), 3.66 (q, J = 14.4 Hz, 2H), / 4.20 (t, J = 10.4 Hz, 2H), 7.69-(R)-4-Chloro-3-((7,8-dihydro-6H- 7.80 (m, 4H), 7.88-7.90 (br s, pyrimido[5,4-b][1,4]oxazin-4- 2H), 8.03 (d, J = 8.0 Hz, 1H), yl)oxy)-N-(4-((3- 8.16 (s, 1H), 10.54 (s, 1H); ESI-(dimethylamino)pyrrolidin-1- MS (m/z) 577 (M+H)+.
yl)methyl)-3-(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

47. CI Ai H Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) O WI N is u3 C31 6 1.46-1.52 (m, 1H),1.92-1.99 N- (m, 1H), 2.14-2.25 (m, 4H), 2.51 d 1 ) N (s, 3H), 2.67-2.71 (m, 1H), 3.01-H C
N N Method 3.09 (m, 1H), 3.63-3.67 (br s, ) .1 R) B' 2H), 3.68-3.72 (br s, 2H), 4.20 (t, NH
/ J = 4.0 Hz, 2H), 7.69-7.90 (m, (R)-4-Chloro-3-((7,8-dihydro-6H- 7H), 8.02 (q, J = 8.4 Hz, 1H), pyrimido[5,4-b][1,4]oxazin-4- 8.16 (s, 1H), 10.54 (s, 1H); ESI-yl)oxy)-N-(4-((3- MS (m/z) 563 (M)+.
(methylamino)pyrrolidin-l-yl)methyl)-3-(trifluoromethyl)phenyl)benzamid e

48. a A
H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O Wj N i& CF3 C32 6 1.54-1.55 (m, 1H),1.98-2.01 Nj: ) 0 (m, 1H), 2.26 (s, 3H), 2.36-2.46 N N N
(m, 1H), 2.46-2.58 (m, 3H), 2.69 H (s) Method (t, J=
9.6 Hz, 1H), 3.36-3.39 (br 'ClH B' s, 1H), 3.52 (s, 2H), 3.69 (s, 2H), /
(S)-4-Chloro-3-((7,8-dihydro-6H- 4.20 (t, J = 4.0 Hz, 2H), 7.69 (s, pyrimido[5,4-b][1,4]oxazin-4- 1H), 7.73-7.90 (m, 5H), 8.04 (d, yl)oxy)-N-(4-((3- J =
8.4 Hz, 1H), 8.16 (s, 1H), (methylamino)pyrrolidin-1- 10.55 (s, 1H); ESI-MS (m/z) 563 yl)methyl)-3- (M)t (trifluoromethyl)phenyl)benzamid e

49. a Ai H F Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N 2-fluoro- 6 3.51 (br s, 2H), 4.20 (t, J = 4.0 0 WI so u3 NJõ0, 0 3- Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 1 j (trifluoro 7.66-7.94 (m, 7H), 10.48 (s, 1H);
N N H methyl)an ESI-MS (m/z) 469 (M+H)+.
4-Chloro-3-((7,8-dihydro-6H- iline pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(2-fluoro-3- Method B
(trifluoromethyl)phenyl)benzamid e

50. ci Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N 4-amino- 6 3.51-3.52 (br s, 2H), 4.20 (t, J
0 WI Ail CF3 0 0 2- = 4.4 Hz, 2H), 7.69 (s, 1H), 7.80-ON (trifluoro 7.91 (m, 4H), 8.26 (d, J = 1.6 Hz, N N H
methyl)be 1H), 8.28 (d, J = 2.0 Hz, 1H), 4-Chloro-N-(4-cyano-3-nzonitrile 8.42 (s, 1H), 10.54 (s, 1H); ESI-(trifluoromethyl)pheny1)-347,8- MS (m/z) 476 (M+H)+.
dihydro-6H-pyrimido[5,4- Method B
b][1,4]oxazin-4-yl)oxy)benzamide No. Intermed Analytical Data Structure and Name iates and Method

51. CI H Al, Bl, lli NMR (400 MHz, DMSO-d6) 6 3.51 (br s, 2H), 4.20 (t, J = 4.0 IW
(trifluoro Hz, 2H), 7.69-7.79 (m, 5H), r s-e 1 3 methyl)an 7.88-7.90 (br s, 2H), 7.99 (d, J =
N N iline 8.4 Hz, 2H), 10.62 (s, 1H); ESI-H
4-Chloro-3-((7,8-dihydro-6H- MS (m/z) 451 (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4- Method B
yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzamid e

52. 01 H Al, Bl, lli NMR (400 MHz, DMSO-d6) O W N,,CF3 C51 6 2.61 (d, J = 1.2 Hz, 3H), 3.51-J c(: 1 3.52 (br s, 2H), 4.20 (t, J = 4.4 ,) 0 Ni*-Hz, 2H), 7.69 (s, 1H), 7.77-7.91 N N Method B (m, 4H), 8.52 (d, J = 2.4 Hz, 1H), H
4-Chloro-3-((7,8-dihydro-6H- 9.06 (d, J = 2.0 Hz, 1H), 10.74 pyrimido[5,4-b][1,4]oxazin-4- (s, 1H); ESI-MS (m/z) 466 yl)oxy)-N-(6-methyl-5- (M+H)+.
(trifluoromethyl)pyridin-3-yl)benzamide

53. a A Al, Bl, lli NMR (400 MHz, DMSO-d6) H
N r CF3 3-amino- 6 3.51 (br s, 2H), 4.20 (t, J = 4.0 O WI
1W 5- Hz, 2H), 7.69 (s, 1H), 7.88-7.90 N 1,) NN) CN (trifluoro (m, 4H), 8.09 (s, 1H), 8.43 (s, methyl)be 1H), 8.48 (s, 1H), 10.84 (s, 1H);
H nzonitrile ESI-MS (m/z) 476 (M+H)+.
4-Chloro-N-(3-cyano-5-(trifluoromethyl)pheny1)-347,8- Method B
dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

54. a al Al, Bl, lli NMR (400 MHz, DMSO-d6) H

6 3.51 (br s, 2H), 3.83 (s, 3H), O WI
methoxy- 4.20 (t, J = 4.0 Hz, 2H), 7.00 (s, 5- 1H), 7.69-7.90 (m, 7H), 10.56 (s, = I ) OMe (trifluoro 1H); ESI-MS (m/z) 481 (M+H)+.
NN
H methyl)an 4-Chloro-3-((7,8-dihydro-6H- iline pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-methoxy-5-(trifluoromethyl)phenyl)benzamid Method B
e

55. a 0 H Al, Bl, 'HNMR (400 MHz, DMSO-d6) 3-fluoro- 6 3.51-3.52 (br s, 2H), 4.20 (t, J
O N is c3 5- = 4.0 Hz, 2H), 7.43 (d, J = 8.8 (trifluoro Hz, 1H), 7.69 (s, 1H), 7.77-7.90 = I ) F
methyl)an (m, 4H), 8.0-8.02 (br s, 2H), NN
H iline 10.75 (s, 1H); ESI-MS (m/z) 469 No. Intermed Analytical Data Structure and Name iates and Method 4-Chloro-3-((7,8-dihydro-6H- (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4- Method B
yl)oxy)-N-(3-fluoro-5-(trifluoromethyl)phenyl)benzamid e

56. CI Ai H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N 3- 6 3.51 (br s, 2H), 4.20 (br s, 2H), O w is u3 methoxy- 6.79 (s, 1H), 7.60 (br s, 2H), NC) 5-7.69-7.88 (m, 5H), 10.31 (s, 1H), 1 ) OH
(trifluoro 10.45 (s, 1H); ESI-MS (m/z) 467 NN
H methyl)an (M+H)+.
4-Chloro-3-((7,8-dihydro-6H- iline pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-hydroxy-5- Method F
(trifluoromethyl)phenyl)benzamid e

57. CI Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N 2- 6 3.51 (br s, 2H), 3.91 (s, 3H), O WI dli CF3 methoxy- 4.20 (t, J = 4.0 Hz, 2H), 7.29 (d, 5- J =
8.4 Hz, 1H), 7.59 (dd, Ji =
= 1 ) I
NN
(trifluoro 1.6 Hz, .1-2 = 8.4 Hz, 1H), 7.70-H
methyl)an 7.87 (m, 5H), 8.06 (s, 1H), 9.86 4-Chloro-3-((7,8-dihydro-6H- iline (s, 1H); ESI-MS (m/z) 548 pyrimido[5,4-b][1,4]oxazin-4- (M+H)+.
yl)oxy)-N-(2-methoxy-5- Method B
(trifluoromethyl)phenyl)benzamid e

58. ci Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O WI N 0 u3 C26 6 3.18 (t, J = 4.4 Hz, 4H), 3.51-0 0 3.52 (br s, 2H), 3.75 (t, J = 4.4 N: l I ) N Method B Hz, 4H), 4.20 (t, J = 4.0 Hz, 2H), N N H ( D
6.99 (s, 1H), 7.62 (s, 2H), 7.67-0 7.89 (m, 6H), 10.48 (s, 1H); ESI-4-Chloro-3-((7,8-dihydro-6H- MS (m/z) 536 (M+H)t pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-Morpholino-5-(trifluoromethyl)phenyl)benzamid e

59, a Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O WI N io u3 C60 6 1.83-1.85 (m, 1H), 2.21 (s, 0 6H), 2.49-2.51 (m, 1H), 3.06 (m, 1 j N
H C Method B 1H), 3.28-3.52 (m, 6H), 4.20 (t, J
NN = 4.4 Hz, 2H), 6.53 (s, 1H), 7.22 IR) N-(s, 1H), 7.48 (s, 1H), 7.69-7.90 / (m, 5H), 10.34 (s, 1H); ESI-MS
(R)-4-Chloro-3-((7,8-dihydro-6H- (m/z) 563 (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-No. Intermed Analytical Data Structure and Name iates and Method yl)oxy)-N-(3-(3-(dimethylamino)pyrrolidin-l-y1)-(trifluoromethyl)phenyl)benzamid e Al, Bl,

60. a 0 H
o N CF C61 1I-1 NMR (400 MHz, DMSO-d6) 1.80-1.82 (m, 1H), 2.20 (s, I\J N
N(s) Method B 6H), 2.79-2.82 (m, 1H), 3.06 (t, J
H c = 8.4 Hz, 1H), 3.26-3.51 (m, N¨ 6H), 4.20 (br s, 2H), 6.53 (s, 1H), /
(S)-4-Chloro-3-((7,8-dihydro-6H- 7.22 (s, 1H), 7.48 (s, 1H), 7.69 pyrimido[5,4-b][1,4]oxazin-4- (s, 1H), 7.74-7.88 (m, 4H), 10.33 yl)oxy)-N-(3-(3- (s, 1H); ESI-MS (m/z) 563 (dimethylamino)pyrrolidin-l-y1)- (M+H)+.

(trifluoromethyl)phenyl)benzamid e

61. CI 0 Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H

N% N r& CF3 C46 6 2.02-2.11 (m, 4H), 3.43-3.51 INI
(m, 4H), 3.52 (br s, 2H), 4.20 (t, C IW
1 ) Method B J = 4.0 Hz, 2H), 7.05 (s, 1H), NN 7.65-7.75 (m, 3H), 7.75-7.80 (m, H
2H), 7.87-7.89 (br s, 2H), 10.39 F F (s, 1H); ESI-MS (m/z) 570 4-Chloro-N-(3-(4,4- (M+H)+.
difluoropiperidin-l-y1)-5-(trifluoromethyl)pheny1)-347,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-y1)oxy)benzamide

62. CI 0 Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H

6 3.17 (d, J = 5.2 Hz, 3H), 3.33-Nc,o, o r 3.51 (m, 4H), 4.09 (d, J = 10.4 1 j N Method B Hz, 1H), 4.20 (s, 2H), 4.42 (m, NN
H ( ? 1H), 5.0 (s, 1H), 6.48 (s, 1H), ,f R) OH 7.22 (s, 1H), 7.46 (s, 1H), 7.69-(R)-4-Chloro-3-((7,8-dihydro-6H- 7.88 (s, 3H), 7.89 (s, 2H), 10.33 pyrimido[5,4-b][1,4]oxazin-4- (s, 1H); ESI-MS (m/z) 536 yl)oxy)-N-(3-(3- (M+H)+.
hydroxypyrrolidin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

63. ci & Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) H
O N s CF3 C52 6 1.73 (br s, 1H), 2.12 (m, 2H), 0 0 3.11 (br s, 2H), 3.25 (br s, 2H), Nxi j N 11 rN) Method 3.54-3.60 (m, 2H),3.76 (br s, B' 2H), 4.21 (s, 3H), 6.78 (s, 1H), \-NH 7.49 (s, 1H), 7.58 (s, 1H), 7.73-HCI 7.77 (br s, 2H), 7.91-8.0 (br s, N-(3-(1,4-Diazepan-l-y1)-5-2H), 9.21 (br s, 2H), 10.33 (s, (trifluoromethyl)pheny1)-4-chloro-1H) ESI-MS (m/z) 549 (M+H)+.
3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide hydrochloride

64. CI 40 H
Example 1I-1 NMR (400 MHz, DMSO-d6) N 0 CF N JCUCN 7 6 2.36-2.41 (m, 4H), 3.46-3.51 o n N,.) (dihydroc (m, 6H), 3.61 (br s, 2H), 4.04 (s, NCI
L I j hloride 2H), 4.20 (t, J =
4.0 Hz, 2H), '1\IN
H salt) 7.69 (s, 1H), 7.74-7.81 (m, 3H), 4-Chloro-N-(4-((4-(2-7.88-7.90 (br s, 2H), 8.05 (d, J =
cyanoacetyl)piperazin-1-8.0 Hz, 1H), 8.18 (s, 1H), 10.57 yl)methyl)-3- Method K (s, 1H); ESI-MS (m/z) 616 (trifluoromethyl)pheny1)-347,8- (M+H)+.
dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

65. a a Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O N s CF3 C55 6 1.96 (d, J = 10.4 Hz, 1H), 2.15 (d, J = 10.0 Hz, 1H), 3.17-3.25 NC)l I ) N Method (m, 2H), 3.37-3.39 (m, 1H), 3.42 NN (5)rõ B' (br s, 2H), 3.62 (d, J = 10.4 Hz, H
Ie(S) 1H), 4.0-4.21 (m, 3H), 4.46 (s, H HCI 1H), 4.67 (s, 1H), 6.71 (s, 1H), N-(3-41S,4S)-2,5- 7.53 (s, 1H), 7.56 (s, 1H), 7.13-diazabicyclo[2.2.1]heptan-2-y1)-5- 7.92 (m, 5H), 8.89-8.98 (m, 1H), (trifluoromethyl)pheny1)-4-chloro- 10.48 (s, 1H); ESI-MS (m/z) 616 3-((7,8-dihydro-6H-pyrimido[5,4- (M+H)+.
b][1,4]oxazin-4-yl)oxy)benzamide hydrochloride

66. ci &
H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 6 0.36 (br s, 2H), 0.44-0.45 (m, N 2H), 1.66 (br s, 1H), 2.68 (br s, I-31 j N Method B 4H), 3.18 (br s, 4H), 3.52 (br s, NN H C ) 2H), 4.21 (t, J = 8.4 Hz, 2H), N 6.55 (s, 1H), 7.59-7.88 (m, 7H), A 10.37 (s, 1H); ESI-MS (m/z) 575 4-Chloro-N-(3-(4- (M+H)+.
cyclopropylpiperazin-l-y1)-5-(trifluoromethyl)pheny1)-347,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-y1)oxy)benzamide No. Intermed Analytical Data Structure and Name iates and Method

67. CI AI Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) H

6 3.52 (br s, 2H), 4.21 (d, J= 8.4 IW
c,0 0 Hz, 2H), 5.82 (d, J = 11.2 Hz, N 1 ) NN) 0NH Method B 1H), 6.29-6.33 (m, 1H), 6.43-6.49 (m, 1H), 7.70 (s, 1H), 7.61-H % 7.63 (m, 6H), 8.45 (s, 1H), 10.53 N-(3-Acrylamido-5- (s, 1H), 10.62 (s, 1H); ESI-MS
(trifluoromethyl)pheny1)-4-chloro- (m/z) 520 (M+H)+.
3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

68. CI Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O N io u3 C59 6 2.42-2.51 (m, 4H), 3.25 (d, J =
N Method B 4.4 Hz, 4H), 3.33-3.52 (m, 3H), IC;1 ) N 4.21 (t, J = 4.0 Hz, 2H), 4.48 (t, J
NN = 6.0 Hz, 2H), 4.58 (t, J = 6.4 H C
N) Hz, 2H), 6.97 (s, 1H), 7.60 (s, 6 1H), 7.65 (s, 1H), 7.69-7.89 (m, 0 5H), 10.38 (s, 1H); ESI-MS (m/z) 4-Chloro-3-((7,8-dihydro-6H- 591 (M+H)t pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-(oxetan-3-yl)piperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

69. CI Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O N 40 c3 C56 6 1.92-1.94 (m, 1H), 1.95-2.04 = ,c) 0 (m, 1H), 3.11 (d, J = 10.4 Hz, 1 ) N Method B 2H), 3.17-3.52 (m, 4H), 4.21 (t, J
NN = 4.4 Hz, 2H), 4.42 (s, 1H), 5.0 H ( (S) OH (s, 1H), 6.49 (s, 1H), 7.22 (s, (S)-4-Chloro-3-((7,8-dihydro-6H- 1H), 7.46 (s, 1H), 7.74-7.89 (m, pyrimido[5,4-b][1,4]oxazin-4- 5H), 10.33 (s, 1H); ESI-MS (m/z) yl)oxy)-N-(3-(3- 536 (M+H)+.
hydroxypyrrolidin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

70. Cl Ai Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N 40 u3 C62 6 1.17 (s, 6H), 3.03-3.06 (m, N-1:3 1H), 3.52 (br s, 2H), 4.01 (br s, L.
I ) Method 2H), 4.21 (br s, 2H), 7.60 (s, 1H), NN NH B' 7.69 (s, 1H), 7.77-7.81 (m, 2H), H 7.92 (br s, 2H), 8.11-8.17 (m, 4-Chloro-3-((7,8-dihydro-6H- 2H), 10.65 (s, 1H); ESI-MS (m/z) pyrimido[5,4-b][1,4]oxazin-4- 522 (M+H)+.
yl)oxy)-N-(3-((isopropylamino)methyl)-5-(trifluoromethyl)phenyl)benzamid No. Intermed Analytical Data Structure and Name iates and Method e

71. CI
H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 6 1.32 (d, J = 5.2 Hz, 3H), 2.90 0 (t, J
= 11.2 Hz, 1H), 3.10-3.16 N Method (m, 2H), 3.36-3.40 (m, 3H), N N
H 4..õ B' 3.54-3.57 (m, 2H), 3.77-3.92 (m, H Hci 1H), 4.23 (br s, 2H), 7.09 (s, 1H), (S)-4-Chloro-3-((7,8-dihydro-6H- 7.71-7.77 (m, 4H), 7.92-7.95 (m, pyrimido[5,4-b][1,4]oxazin-4- 3H), 9.42-9.47 (br s, 1H), 9.66-yl)oxy)-N-(3-(3-methylpiperazin- 9.67 (br s, 1H), 10.58 (s, 1H);
1-y1)-5- ESI-MS (m/z) 549 (M+H)+.
(trifluoromethyl)phenyl)benzamid e hydrochloride

72. a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) O WI N = CF3 C54 6 1.31 (d, J= 6.0 Hz, 3H), 2.83-2.89 (m, 1H), 3.08-3.10 (m, 2H), NC)) 0 Method 3.36-3.40 (m, 3H), 3.51-3.54 (m, , N N N
H 4R B' 3H), 3.78-3.88 (m, 1H), 4.21 (t, J
N
H HCI = 4.0 Hz, 2H), 7.70-7.78 (m, (R)-4-Chloro-3-((7,8-dihydro-6H- 4H), 7.90-7.93 (m, 3H), 9.17-pyrimido[5,4-b][1,4]oxazin-4- 9.19 (m, 1H), 9.43-9.46 (m, 1H), yl)oxy)-N-(3-(3-methylpiperazin- 10.51 (s, 1H); ESI-MS (m/z) 549 1-y1)-5- (M+H)+..
(trifluoromethyl)phenyl)benzamid e hydrochloride

73. CI al Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N CF3 C58 6 2.61 (m, 4H), 3.20-3.24 (m, ir 7H), 3.52 (br s, 2H), 4.20 (t, J =
Method B 4.4 Hz, 2H), 6.98 (s, 1H), 7.60 (s, )\J N ( D

H 1H), 7.65 (s, 2H), 7.69-7.80 (m, N 2H), 7.87-7.89 (br s, 2H), 10.38 (s, 1H); ESI-MS (m/z) 573 4-Chloro-3-((7,8-dihydro-6H- (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-(prop-2-yn-1-y1)piperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

74. ci Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) W FN1 1" CF3 C48 6 1.79-1.92 (m, 2H), 1.99-2.04 (m, 2H), 3.22-3.26 (m, 2H), I ) N Method B 3.34-3.43 (m, 2H), 3.51-3.52 (m, NN ,, 2H), 4.20 (t, J = 8.4 Hz, 2H), H
Y 4.80-4.96 (m, 1H), 7.00 (s, 1H), F 7.63 (d, J = 8.4 Hz, 2H), 7.69-4-Chloro-3-((7,8-dihydro-6H- 7.89 (m, 5H), 10.37 (s, 1H); ESI-No. Intermed Analytical Data Structure and Name iates and Method pyrimido[5,4-b][1,4]oxazin-4- MS (m/z) 552 (M+H)t yl)oxy)-N-(3-(4-fluoropiperidin-1-y1)-5-(trifluoromethyl)phenyl)benzamid e

75. a a Al, Bl, 1H NMR (400 MHz, DMSO-d6) H
O WI N r cF3 C57 6 1.90-1.99 (m, 2H), 2.26 (s, .,(:) 0 r 3H), 2.45 (t, J = 5.2 Hz, 2H), y 1 1 method B 2.62 (t, J= 4.4 Hz, 2H), 3.46 (t, J
NI12 rN
¨N ) = 6.0 Hz, 2H), 3.52-3.55 (m, 4H), 4.20 (t, J = 3.6 Hz, 2H), \
\ 6.67 (s, 1H), 7.38 (s, 1H), 7.47 4-Chloro-3-((7,8-dihydro-6H- (s, 1H), 7.69 (s, 1H), 7.75 (d, J =
pyrimido[5,4-b][1,4]oxazin-4- 8.8 Hz, 1H), 7.81 (s, 1H), 7.87-yl)oxy)-N-(3-(4-methy1-1,4- 7.88 (m, 2H), 10.31 (s, 1H); ESI-diazepan-l-y1)-5- MS (m/z) 563 (M+H)+..
(trifluoromethyl)phenyl)benzamid e

76. a gam A2 1H NMR
(400 MHz, DMSO-d6) H
N 0 CF3 , Bl, C19 6 2.23 (br s, 3H), 2.40-2.51 (br s, NO 0 4H), 3.18-3.21 (br s, 4H), 4.85 (s, I N Method 2H), 6.97 (s, 1H), 7.60-7.97 (m, NN 0 H G' 5H), 8.10 (s, 1H), 10.41 (s, 1H), C
N) 11.80 (s, 1H); ESI-MS (m/z) 563 I
4-Chloro-N-(3-(4- (M+H)+.
methylpiperazin-l-y1)-5-(trifluoromethyl)pheny1)-347-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

77. a abh A2, Bl, 1H NMR (400 MHz, DMSO-d6) H
O VI N 0 CFp.N Cl 6 0.98 (t, J = 7.2 Hz, 3H), 2.28-0 N) 2.50 (m, 10H), 3.56 (s, 2H), 4.84 NN 0 Method J (s, 2H), 7.72 (d, J = 8.4 Hz, 1H), ¨
H 7.82 (d, J = 8.0 Hz, 1H), 7.94-4-Chloro-N-(4-((4-ethylpiperazin- 8.04 (m, 3H), 8.09 (s, 1H), 8.18 1-yl)methyl)-3- (s, 1H), 10.59 (s, 1H), 11.80 (s, (trifluoromethyl)pheny1)-347- 1H); ESI-MS (m/z) 591 (M+H)+.
oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

78. ci al H A3, 1H NMR
(400 MHz, DMSO-d6) O N 40, cFril. Bl, Cl 6 0.98 (t, J = 7.2 Hz, 3H), 1.35 N%y N, (d, J
= 6.0 Hz, 3H), 2.28-2.33 .).7s) Method B (m, 10H), 3.16-3.34 (m, 1H), N N H 3.56 (br s, 3H), 4.17 (t, J = 6.0 No. Intermed Analytical Data Structure and Name iates and Method (S)-4-Chloro-N-(4-((4- Hz, 1H), 7.69-7.87 (m, 4H), ethylpiperazin-1-yl)methyl)-3- 7.87-7.90 (m, 2H), 8.03 (d, J =
(trifluoromethyl)pheny1)-3-46- 8.8 Hz, 1H), 8.17 (s, 1H), 10.54 methyl-7,8-dihydro-6H- (s, 1H).
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

79, ci a H A3, 'H NMR
(400 MHz, DMSO-d6) 0 W N = CF3 Bl, C19 6 1.35 (d, J = 6.0 Hz, 3H), 2.23 0 (s, 3H), 2.45-2.50 (m, 4H), 3.15-Nc0),õts) N
Method B 3.22 (m, 5H), 3.53-3.57 (m, 1H), N N CNI) 4.17 (t, J = 6.0 Hz, 1H), 6.96 (s, H
1H), 7.60-7.69 (m, 3H), 7.75-(S)-4-Chloro-3-46-methyl-7,8- 7.86 (m, 2H), 7.87-7.89 (m, 2H), dihydro-6H-pyrimido[5,4- 10.36 (s, 1H); ESI-MS (m/z) 563 b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- (M+H)+.
methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

80. ci am H AS, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N Cl 6 0.98 (t, J = 7.2 Hz, 3H), 1.19 0 0 N,) (d, J
= 6.4 Hz, 3H), 2.33-2.51 NILX (Rlip Method A (m, 10H), 3.56 (s, 2H), 3.69-3.78 H (m, 2H), 4.25-4.28 (m, 1H), (R)-4-Chloro-N-(4-((4- 7.71-7.77 (m, 3H), 7.88-7.89 (br ethylpiperazin-1-yl)methyl)-3- s, 3H), 8.03 (d, J = 8.8 Hz, 1H), (trifluoromethyl)pheny1)-3-47- 8.17 (s, 1H), 10.54 (s, 1H); ESI-methy1-7,8-dihydro-6H- MS (m/z) 591 (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

81. CI H A6, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N Cl 6 0.98 (t, J = 7.2 Hz, 3H), 1.19 NOj 0 N I ''', N...-I , (d, J
= 6.4 Hz, 3H), 2.31-2.51 L :NS) Method A (m, 10H), 3.56 (s, 2H), 3.69-3.78 H (m, 2H), 4.26 (dd, Ji = 2.4 Hz, .1-2 (S)-4-Chloro-N-(4-((4- = 10.4 Hz, 1H), 7.71-7.77 (m, ethylpiperazin-1-yl)methyl)-3- 3H), 7.88-7.89 (br s, 3H), 8.03 (trifluoromethyl)pheny1)-3-47- (d, J
= 8.8 Hz, 1H), 8.17 (s, 1H), methyl-7,8-dihydro-6H- 10.55 (s, 1H); ESI-MS (m/z) 591 pyrimido[5,4-b][1,4]oxazin-4- (M+H)+.
yl)oxy)benzamide

82. ci H A4, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N cF N.--, Cl 6 0.98 (t, J = 6.8 Hz, 3H), 1.24 0 r 0 VII' N....) (s, 6H), 2.27-2.51 (m, 10H), 3.56 = I
Method A (s, 2H), 3.89 (s, 2H), 7.72 (s, N'N' 1H), 7.77 (d, J = 8.0 Hz, 2H), H
4-Chloro-3-47,7-dimethy1-7,8- 7.88-7.99 (m, 3H), 8.03 (dd, Ji =

No. Intermed Analytical Data Structure and Name iates and Method dihydro-6H-pyrimido[5,4- 2.0 Hz, J2 = 8.8 Hz, 1H), 8.17 (s, b][1,4]oxazin-4-yl)oxy)-N-(4-44- 1H), 10.55 (s, 1H); ESI-MS (m/z) ethylpiperazin-l-yl)methyl)-3- 605 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

83. CI H A4, Bl, 1I-1 NMR (400 MHz, DMSO-d6) o N io u3 C19 6 1.24 (s, 6H), 2.22 (s, 3H), 2.45-,II0 0 2.51 (m, 4H), 3.21 (t, J= 4.8 Hz, N
N Method A 4H), 3.89 (s, 2H), 6.96 (s, 1H), N r\ C j 7.60 (s, 1H), 7.64 (s, 1H), 7.76 N
I (d, J
= 8.4 Hz, 2H), 7.87-7.90 4-Chloro-3-47,7-dimethy1-7,8- (m, 3H), 10.38 (s, 1H); ESI-MS
dihydro-6H-pyrimido[5,4- (m/z) 577 (M)+.
b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

84. I. Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) O CFr.N C2 ..
6 2.15 (s, 3H), 2.18 (s, 3H), 2.49-Ni.L,0 0 1W N,.) 2.51 (m, 8H), 3.33 (br s, 4H), Method A 4.20 (t, J = 4.0 Hz, 2H), 7.46 (d, N1\1) H J =
8.0 Hz, 1H), 7.67-7.71 (m, 3-((7,8-Dihydro-6H-pyrimido[5,4- 4H), 7.80 (dd, ./i = 1.6 Hz, J2 =
b][1,4]oxazin-4-yl)oxy)-4-methyl- 7.6 Hz, 1H), 8.04 (dd, ./i = 2.0 N-(4-((4-methylpiperazin-1- Hz, J2 = 8.4 Hz, 1H), 8.18 (s, yl)methyl)-3- 1H), 10.41 (s, 1H); ESI-MS (m/z) (trifluoromethyl)phenyl)benzamid 543 (M+H)+.
e

85. 140 H Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) O N io c3 C20 ..
6 1.03 (t, J = 7.2 Hz, 3H), 2.18 Nj1:3 0 (s, 3H), 2.37 (q, J = 7.2 Hz, 2H), I j N 2.50-2.55 (br s 4H), 3.20-3.25 (br NN
H C ) Method B s,4H), 3.51-3.52 (br s, 2H), 4.20 N (t, J = 4.0 Hz, 2H), 6.93 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.61-3-((7,8-Dihydro-6H-pyrimido[5,4- 7.71 (m, 5H), 7.79 (d, J= 8.0 Hz, b][1,4]oxazin-4-yl)oxy)-N-(3-(4- 1H), 10.25 (s, 1H); ESI-MS (m/z) ethylpiperazin-l-y1)-5- 543 (M+H)+.
(trifluoromethyl)pheny1)-4-methylbenzamide

86. Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) H
J'' 0 N io ur N C3 6 0.95 (d, J= 6.8 Hz, 6H), 2.18 N,) (s, 3H), 2.38-2.50 (m, 9H), 3.50-N ='(:) 0 Method A 3.54 (m, 4H), 4.19 (t, J = 4.0 Hz, NI\J) 2H), 7.46 (d, J = 8.4 Hz, 1H), H 7.67-7.78 (m, 4H), 7.79 (d, J =
3-((7,8-Dihydro-6H-pyrimido[5,4-6.0 Hz, 1H), 8.03 (d, J = 8.8 Hz, No. Intermed Analytical Data Structure and Name iates and Method b] [1,4]oxazin-4-yl)oxy)-N-(4-44- 1H), 8.18 (s, 1H), 10.41 (s, 1H);
isopropylpiperazin-l-yl)methyl)- ESI-MS (m/z) 571 (M+H)+.
3-(trifluoromethyl)pheny1)-4-methylbenzamide

87. 1. Al, B3, 1H NMR (400 MHz, DMSO-d6) O 401 cF3 C19 6 2.22 (s, 6H), 2.46 (t, J = 4.8 0 Hz, 4H), 3.21 (t, J = 4.8 Hz, 4H), N Method A 3.50-3.51 (br s, 2H), 4.20 (t, J =
NN CN) H 4.0 Hz, 2H), 6.94 (s, 1H),7.46 (d, I J =
8.0 Hz, 1H), 7.62 (s, 1H), 3-((7,8-Dihydro-6H-pyrimido[5,4- 7.67-7.77 (m, 3H), 7.78 (s, 1H), b][1,4]oxazin-4-yl)oxy)-4-methyl- 7.80 (d, J = 2.0 Hz, 1H), 10.24 N-(3 -(4-methylpiperazin-l-y1)-5 - (s, 1H); ESI-MS (m/z) 529 (trifluoromethyl)phenyl)benzamid (M+H)+.
e

88. 40 cF3 Al, B3, 1H NMR (400 MHz, DMSO-d6) 6 1.01 (d, J = 6.8 Hz, 5H), 2.18 N CCI (s, 3H), 2.49-2.58 (m, 4H), 2.67-I ,( ) N Method B 2.70 (m, 1H), 3.19 (t, J = 4.8 Hz, N N C ) 4H), 3.50-3.51 (br s, 2H), 4.20 (t, H
N J = 4.0 Hz, 2H), 6.92 (s, 1H),7.46 (d, J = 8.0 Hz, 1H), 3-((7,8-Dihydro-6H-pyrimido[5,4- 7.61-7.78 (m, 6H), 7.80 (d, J =
b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- 2.0 Hz, 1H), 10.24 (s, 1H); ESI-isopropylpiperazin-l-y1)-5- MS (m/z) 557 (M+H)+.
(trifluoromethyl)pheny1)-4-methylbenzamide

89. 0 H Al, B3, 1H NMR (400 MHz, DMSO-d6) O N 0 cF3 C21 6 0.88 (t, J = 7.6 Hz, 3H), 1.45-0 0 1.50 (m, 2H), 2.18 (s, 3H), 2.28 N ' j N (t, J = 7.6 Hz, 2H), 3.19-3.20 (br N N H C ) s, 4H), 2.50 (br s, 4H), 3.50-3.51 N Method B (br s, 2H), 4.20 (t, J = 4.0 Hz, H 2H), 6.93 (s, 1H),7.46 (d, J = 8.0 3-((7,8-Dihydro-6H-pyrimido[5,4- Hz, 1H), 7.61 (s, 1H), 7.68 (s, b][1,4]oxazin-4-yl)oxy)-4-methyl- 2H), 7.78-7.80 (m, 3H), 10.25 (s, N-(3-(4-propylpiperazin-l-y1)-5- 1H); ESI-MS (m/z) 557 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

90. 0 H Al, B3, 1H NMR (400 MHz, DMSO-d6) O N 0 cF3 C22 6 0.10-0.12 (m, 2H), 0.46-0.51 0 (m, 2H), 0.87 (m, 1H), 2.18 (s, L 1 j N Method B 3H), 2.23 (d, J = 6.4 Hz, 2H), 1\1N
H C ) 2.49-2.59 (m, 4H), 3.21-3.28 (m, N 4H), 3.50-3.51 (m, 2H), 4.20 (t, J
= 4.4 Hz, 2H), 6.94 (s, 1H), 7.46 No. Intermed Analytical Data Structure and Name iates and Method N-(3-(4- (d, J=
8.0 Hz, 1H), 7.61 (s, 1H), (Cyclopropylmethyl)piperazin-1- 7.67-7.71 (m, 4H), 7.78 (dd, J1 =
y1)-5-(trifluoromethyl)pheny1)-3- 1.6 Hz, .12 = 7.6 Hz, 1H), 10.25 ((7,8-dihydro-6H-pyrimido[5,4- (s, 1H); ESI-MS (m/z) 569 b] [1,4]oxazin-4-yl)oxy)-4- (M+H)+.
methylbenzamide

91. e Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) l ki cF3 C10 6 0.97 (t, J = 7.2 Hz, 3H), 2.18 NC) o IW (s, 3H), 2.27-2.51 (m, 10H), 1 ) Method B 3.50-3.53 (m, 4H), 4.20 (t, J =
NN N
4.4 Hz, 2H), 7.34 (s, 1H), 7.46 H N
(d, J = 8.0 Hz, 1H), 7.73 (s, 3H), 3-((7,8-Dihydro-6H-pyrimido[5,4- 7.80 (d, J = 6.4 Hz, 1H), 8.00 (s, b] [1,4]oxazin-4-yl)oxy)-N-(3-44- 1H), 8.17 (s, 1H), 10.46 (s, 1H);
ethylpiperazin-l-yl)methyl)-5- ESI-MS (m/z) 557 (M+H)+.
(trifluoromethyl)pheny1)-4-methylbenzamide

92. 40 a Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) 6 2.19 (s, 3H), 3.50-3.51 (br s, NC) cF3 (trifluoro 2H), 4.20 (t, J = 4.0 Hz, 2H), 1 ) methyl)an 7.47 (d, J= 8.0 Hz, 1H), 7.79 (d, NN iline J = 2.0 Hz, 3H), 7.81 (d, J = 2.0 H
3-((7,8-Dihydro-6H-pyrimido[5,4- Hz, 3H), 8.00 (d, J = 8.4 Hz, b][1,4]oxazin-4-yl)oxy)-4-methyl- Method B 2H), 10.49 (s, 1H); ESI-MS (m/z) N-(4- 431 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

93. 0Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) IR"
o cF3 C26 6 2.51 (s, 3H), 3.18 (t, J = 4.8 Hz, 4H), 3.51 (br s, 2H), 3.75 (t, N Method B J = 4.4 Hz, 4H), 4.20 (t, J = 4.0 N N Co) H Hz, 2H), 6.97 (s, 1H), 7.46 (d, J
3-((7,8-Dihydro-6H-pyrimido[5,4- = 8.0 Hz, 1H), 7.63-7.78 (m, b][1,4]oxazin-4-yl)oxy)-4-methyl- 5H), 7.79 (dd, J1 = 1.6 Hz, .12 =
N-(3-morpholino-5- 8.0 Hz, 1H), 10.28 (s, 1H); ESI-(trifluoromethyl)phenyl)benzamid MS (m/z) 516 (M+H)+.
e

94. Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) 40 CF3 C60 6 1.79-1.85 (m, 1H), 2.13 (s, NICI 0 9H), 2.78-2.82 (m, 1H), 3.06 (t, J
I j N Method B = 8.4 Hz, 1H), 3.24-3.51 (m, H C .f R) 1\1"NI 6H), 4.20 (t, J = 4.4 Hz, 2H), N¨ 6.51 (s, 1H), 7.24 (s, 1H), 7.45 / (d, J
= 8.0 Hz, 1H), 7.50 (s, 1H), (R)-3-((7,8-Dihydro-6H-7.72 (s, 3H), 7.79 (dd, J1 = 1.6 pyrimido[5,4-b][1,4]oxazin-4-Hz, J2 = 8.0 Hz, 1H), 10.21 (s, yl)oxy)-N-(3-(3-1H); ESI-MS (m/z) 543 (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method (dimethylamino)pyrrolidin-l-y1)-5-(trifluoromethyl)pheny1)-4-methylbenzamide

95. I. H A2, B3, 1H NMR (400 MHz, DMSO-d6) O N CFrN Cl 1.13 (br s, 3H), 2.19 (s, 3H), i\jj,0, 0 IW N,) 2.50-2.80 (m, 10H), 3.63 (br s, Method J' 2H), 4.84 (s, 2H),7.52 (d, J = 8.0 NN-0 Hz, 1H), 7.72 (d, J = 8.4 Hz, H
N-(4-((4-Ethylpiperazin-1- 1H), 7.76 (s, 1H), 7.85 (d, J= 1.6 yl)methyl)-3- Hz, 1H), 8.07-8.08 (br s, 2H), (trifluoromethyl)pheny1)-4- 8.20 (s, 1H), 10.48 (s, 1H), 11.75 methyl-3-47-oxo-7,8-dihydro-6H- (s, 1H); ESI-MS (m/z) 571 pyrimido[5,4-b][1,4]oxazin-4- (M+H)+.
yl)oxy)benzamide

96. 0 A3, B3, 1H NMR (400 MHz, DMSO-d6) , oFrN, Cl 0.98 (t, J = 6.8 Hz, 3H), 1.35 (t, J

0 0 r N,) = 6.4 Hz, 3H), 2.18 (s, 3H), 2.23-L= XI (S) Method B 2.55 (m, 10H), 3.15-3.20 (m, N N 1H), 3.52-3.56 (m, 3H), 4.17 (t, J
H
(S)-N-(4-((4-Ethylpiperazin-1- = 6.4 Hz, 1H), 7.46 (d, J = 8.0 yl)methyl)-3- Hz, 1H), 7.67-7.71 (m, 4H), 7.79 (trifluoromethyl)pheny1)-4- (d, J
= 8.4 Hz, 1H), 8.04 (d, J =
methyl-3-46-methyl-7,8-dihydro- 8.4 Hz, 1H), 8.18 (s, 1H), 10.41 6H-pyrimido[5,4-b][1,4]oxazin-4- (s, 1H); ESI-MS (m/z) 571 yl)oxy)benzamide (M+H)+.

97. ci & H Al, 4-1H NMR (400 MHz, DMSO-d6) HN N 0 cFrN chloro-3- 6 0.98 (t, J = 7.2 Hz, 3H), 2.30-o N,) nitrobenz 2.34 (m, 10H), 3.48 (s, 2H), 3.56 = I ) oic acid, (s, 2H), 4.23 (t, J = 8.0 Hz, 2H), NN Cl 7.31 (s, 1H), 7.65-7.72 (m, 4H), H
4-Chloro-3-((7,8-dihydro-6H- 7.81 (s, 1H), 8.02 (d, J = 8.4 Hz, pyrimido[5,4-b][1,4]oxazin-4- Method C 1H), 8.20 (s, H), 8.80 (s, 1H), yl)amino)-N-(4-((4- 10.46 (s, 1H); ESI-MS (m/z) 576 ethylpiperazin-l-yl)methyl)-3- (M+H)+.
(trifluoromethyl)phenyl)benzamid e

98. el H Al, B14, 1H NMR (400 MHz, DMSO-d6) S N 0 oFrN, Cl 0.98 (t, J= 7.2 Hz, 3H), 2.31 (s, NO 0 N1,) 3H), 2.45-2.51 (m, 10H), 3.56 (s, I ) Method B 3H), 3.60 (s, 2H), 4.23 (t, J = 4.0 NN Hz, 2H), 7.54 (d, J = 8.0 Hz, H
3-((7,8-Dihydro-6H-pyrimido[5,4- 1H), 7.69-7.74 (m, 3H), 7.98 (dd, b][1,4]oxazin-4-yl)thio)-N-(4-((4- Ji =
2.0 Hz, .12 = 8.0 Hz, 1H), ethylpiperazin-l-yl)methyl)-3- 8.05 (dd, Ji = 1.6 Hz, .12 = 8.8 (trifluoromethyl)pheny1)-4- Hz, 1H), 8.13 (s, 1H), 8.19 (s, methylbenzamide 1H), 10.49 (s, 1H); ESI-MS (m/z) No. Intermed Analytical Data Structure and Name iates and Method 573 (M+H)+.

99. A7, B3, 1H NMR (400 MHz, DMSO-d6) S

H Cl 0.99 (t, J = 6.8 Hz, 3H), 2.32 (s, O N t CFn\j..
3H), 2.40-2.51 (m, 10H), 3.39 0 0 IW N,) I j Method B (m, 2H), 3.56 (s, 2H), 4.12 (t, J=
1\1N 4.0 Hz, 2H), 5.96 (d, J = 5.6 Hz, H 1H), 6.84 (s, 1H), 7.47-7.50 (m, 3-((3,4-Dihydro-2H-pyrido[3,2-3H), 7.69 (d, J = 8.8 Hz, 1H), b] [1,4]oxazin-8-yl)oxy)-N-(4-44-7.77 (dd, ./i = 2.0 Hz, .12 = 7.6 ethylpiperazin-1-yl)methyl)-3-Hz, 1H), 8.01 (d, J = 8.4 Hz, (trifluoromethyl)pheny1)-4- 1H), 8.17 (s, 1H), 10.43 (s, 1H);
methylbenzamide ESI-MS (m/z) 556 (M+H)+.

100. A7, B3, 1H NMR (400 MHz, DMSO-d6) cF3 C10 0.98 (t, J = 7.2 Hz, 3H), 2.32 (s, 3H), 2.45-2.51 (m, 10H), 3.38-3.43 (m, 2H), 3.53 (s, 2H), 4.12 N N N' Method B (t, J = 4.0 Hz, 2H), 5.97 (d, J =
H .,N, 5.6 Hz, 1H), 6.83 (s, 1H), 7.34 (s, 3-((3,4-Dihydro-2H-pyrido[3,2- 1H), 7.47-7.52 (m, 3H), 7.78 (dd, b] [1,4]oxazin-8-yl)oxy)-N-(3-((4-./i = 1.6 Hz, .12 = 7.6 Hz, 1H), ethylpiperazin-1-yl)methyl)-5-7.97 (s, 1H), 8.14 (s, 1H), 10.45 (trifluoromethyl)pheny1)-4-(s, 1H); ESI-MS (m/z) 556 methylbenzamide (M+H)+.

101. 0 H
A7, B3, 1H NMR (400 MHz, DMSO-d6) C20 1.04 (t, J= 7.2 Hz, 3H), 2.27 (s, a:0) 0 3H), 2.45-2.57 (m, 10H), 3.20-N Method B 3.29 (br s, 2H), 4.12 (t, J = 4.0 N N c)H Hz, 2H), 5.97 (d, J = 2.0 Hz, K 1H), 6.84 (s, 2H), 7.47-7.49 (m, 3-((3,4-Dihydro-2H-pyrido[3,2- 3H), 7.62 (d, J = 9.6 Hz, 2H), b] [1,4]oxazin-8-yl)oxy)-N-(3-(4- 7.76 (dd, ./i = 2.0 Hz, .12 = 8.0 ethylpiperazin-1-y1)-5- Hz, 1H), 10.26 (s, 1H); ESI-MS
(trifluoromethyl)pheny1)-4- (m/z) 542 (M+H)+.
methylbenzamide

102. A7, B3, 1H NMR (400 MHz, DMSO-d6) C17 0.99 (t, J = 7.2 Hz, 3H), 1.65-140 H CF 1.67 (m, 2H), 1.89-1.93 (m, 2H), O N la ny' Method B 2.31 (s, 3H), 2.45-2.58 (m, 6H), on 0 iw (:).
3.43 (br s, 2H), 4.12 (t, J = 4.0 N N Hz, 2H), 4.58 (m, 1H), 5.96 (d, J
H
3-((3,4-Dihydro-2H-pyrido[3,2- = 9.6 Hz, 1H), 6.84 (s, 1H), 7.30 b] [1,4]oxazin-8-yl)oxy)-N-(4-41- (d, J
= 9.6 Hz, 1H), 7.47-7.48 ethylpiperidin-4-yl)oxy)-3- (m, 3H), 7.75 (dd, ./i = 1.6 Hz, .12 (trifluoromethyl)pheny1)-4-= 8.0 Hz, 1H), 7.93 (dd, ./1 = 2.0 methylbenzamide Hz, J2 = 8.8 Hzõ 1H), 8.05 (s, 1H), 10.27 (s, 1H); ESI-MS (m/z) 557 (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method

103. a H
A7, B3, 1I-1 NMR (400 MHz, DMSO-d6) 0 N 0 cF3 C19 2.22 (s, 3H), 2.49-2.51 (m, 8H), 1 0 3.20 (t, J = 4.8 Hz, 3H), 3.42-10) N Method B 3.43 (m, 2H), 4.12 (t, J = 4.0 Hz, N
H CN) 2H), 5.97 (d, J = 5.6 Hz, 1H), I 6.83 (s, 1H), 6.93 (s, 1H), 7.47-3-((3,4-Dihydro-2H-pyrido[3,2- 7.49 (m, 3H), 7.62 (s, 2H), 7.76 b][1,4]oxazin-8-yl)oxy)-4-methyl- (dd, Ji = 1.6 Hz, .12 = 8.0 Hz, N-(3-(4-methylpiperazin-1-y1)-5- 1H), 10.25 (s, 1H); ESI-MS (m/z) (trifluoromethyl)phenyl)benzamid 528 (M+H)+.
e

104. a H
A8, 1I-1 NMR (400 MHz, DMSO-d6) 0 N cFrN B3, Cl 0.98 (t, J = 7.2 Hz, 3H), 2.26 (s, cp, 0 r 11,) 3H), 2.35-2.51 (m, 10H), 3.56 (s, I Method J' 2H), 4.70 (s, 2H), 6.38 (d, J = 5.6 il 'i\l'ip H Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), N-(4-((4-Ethylpiperazin-1- 7.64-7.85 (m, 4H), 8.01 (dd, ./1 =
yl)methyl)-3- 1.6 Hz, .12 = 8.0 Hz, 1H), 8.17 (s, (trifluoromethyl)pheny1)-4- 1H), 10.45 (s, 1H), 11.36 (s, 1H);
methyl-3-43-oxo-3,4-dihydro-2H- ESI-MS (m/z) 570 (M+H)+.
pyrido[3,2-b][1,4]oxazin-8-yl)oxy)benzamide

105. CI H
A9, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 0 7 N CFrN Cl 6 0.97 (t, J = 6.8 Hz, 3H), 2.29-Ntn0 IW 1\1) 2.65 (m, 12H), 3.56 (br s, 4H), I Method G 7.71 (d, J = 8.4 Hz, 1H), 7.77 (t, N N J =
8.8 Hz, 1H), 7.90-8.07 (m, H
4-Chloro-N-(4-((4-ethylpiperazin-4H), 8.17 (s, 1H), 8.62 (s, 1H), 1-yl)methyl)-3-10.57 (s, 1H); ESI-MS (m/z) 589 +
(trifluoromethyl)pheny1)-34 (M+H).

oxo-5,6,7,8-tetrahydropyrido[2,3 -d] pyrimidin-4-yl)oxy)benzamide

106. CI a H
Example 1I-1 NMR (400 MHz, DMSO-d6) N cFr.N 105-Step 6 1.09 (t, J = 6.8 Hz, 3H), 1.83-N 0 IW N.) 2 1.86 (m, 2H), 2.42-2.55 (m, I 10H), 2.71 (t, J = 6.0 Hz, 2H), N1\1 Method H 3.34-3.39 (m, 2H), 3.58 (s, H
4-Chloro-N-(4-((4-ethylpiperazin-2H),7.51 (s, 1H), 7.70-7.91 (m, 1-yl)methyl)-3- 5H), 8.04 (d, J = 8.0 Hz, 1H), (trifluoromethyl)pheny1)-3- 8.18 (s, 1H), 10.56 (s, 1H).
((5,6,7,8-tetrahydropyrido[2,3 -d] pyrimidin-4-yl)oxy)benzamide No. Intermed Analytical Data Structure and Name iates and Method

107. ci 0 H
Example 'I-1 NMR (400 MHz, DMSO-d6) N 0 cFN 105 6 1.01 (t, J = 6.8 Hz, 3H), 2.41-/N 0 N,) 2.55 (m, 10H), 3.30-3.40 (m, 1 Step 1- 4H), 3.58 (br s, 2H), 4.98 (d, J =
IVN Method H 4.4 Hz, 1H), 5.20 (s, 1H), 7.71-H
4-Chloro-N-(4-((4-ethylpiperazin- 7.77 (m, 3H), 7.89-7.94 (m, 3H), 1-yl)methyl)-3- 8.03 (d, J= 2.0 Hz, 1H), 8.17 (s, (trifluoromethyl)pheny1)-345- 1H), 10.61 (s, 1H); ESI-MS (m/z) hydroxy-5,6,7,8- 591 (M+H)+.
tetrahydropyrido[2,3-d]pyrimidin-4-yl)oxy)benzamide

108. 0 H
Example 1I-1 NMR (400 MHz, DMSO-d6) O N io CF/..N, 105-Step 6 1.23 (m, 3H), 1.84-1.86 (m, Nr' 0 2 2H), 2.15 (s, 3H), 2.45-2.55 (m, N N
10H), 2.71 (t, J = 6.0 Hz, 3H), H Method G 3.58 (br s, 3H), 7.42-7.71 (m, N-(4-((4-Ethylpiperazin-1- and 4H), 7.79 (d, J = 7.6 Hz, 2H), yl)methyl)-3- Method H 8.06 (d, J= 8.4 Hz, 1H), 8.19 (s, (trifluoromethyl)pheny1)-4- 1H), 10.44 (s, 1H); ESI-MS (m/z) methyl-34(5,6,7,8- 555 (M+H)+.
tetrahydropyrido[2,3-d]pyrimidin-4-yl)oxy)benzamide

109. I Al, B9, 1I-1 NMR (400 MHz, DMSO-d6) 0 cFv Cl 6 0.98 (t, J = 7.2 Hz, 3H), 2.29-0 0 .NI 2.39 (m, 10H), 3.50 (br s, 4H), 0 ri,) Method B 3.81 (s, 3H), 4.18 (t, J= 4.0 Hz, = 1 j 2H), 7.27 (d, J = 8.8 Hz, 1H), NN
H 7.64 (s, 3H), 7.69 (d, J = 8.8 Hz, 3-((7,8-Dihydro-6H-pyrimido[5,4- 1H), 7.98 (dd, J1 = 2.0 Hz, .1-2 =
b] [1,4]oxazin-4-yl)oxy)-N-(4-44- 8.4 Hz, 1H), 7.89 (dd, J1 = 2.0 ethylpiperazin-l-yl)methyl)-3- Hz, J2 = 8.4 Hz, 1H), 8.19 (s, (trifluoromethyl)pheny1)-4- 1H), 10.33 (s, 1H); ESI-MS (m/z) methoxybenzamide 573 (M+H)+.

110. cF3 Al, B10, 1I-1 NMR (400 MHz, DMSO-d6) 0 H Cl 6 1.01 (br s, 3H), 2.45-2.51 (m, 0 N 401 CFK=i\(= 10H), 3.33-3.59 (m, 4H), 4.19 (t, o ri,) Method B J = 4.4 Hz, 2H), 7.73-7.81 (m, = 1 ) 4H), 8.02-8.06 (m, 2H), 8.16-V.N 8.17 (m, 2H), 10.70 (s, 1H); ESI-H
3-((7,8-Dihydro-6H-pyrimido[5,4- MS (m/z) 611 (M+H)+.
b] [1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)pheny1)-5-(trifluoromethyl)benzamide No. Intermed Analytical Data Structure and Name iates and Method

111. Al, B6, 1I-1 NMR (400 MHz, DMSO-d6) 011 Cl 6 1.09 (t, J = 7.2 Hz, 3H),1.23-O 0Fri,i, 1.30 (m, 3H), 2.14 (s, 3H), 2.45-,orINI 0 LW N,.) I ) N Nr Method B 2.51 (m, 7H), 3.50 (br s, 2H), 3.56 (s, 2H), 4.19 (t, J = 4.0 Hz, H
3-((7,8-Dihydro-6H-pyrimido[5,4- 2H), 7.18 (dd, Ji = 3.2 Hz, J2 =
b] [1,4]oxazin-4-yl)oxy)-N-(4-44- 6.0 Hz, 1H), 7.33-7.35 (m, 2H), ethylpiperazin-l-yl)methyl)-3-7.67-7.71 (m, 3H), 7.95 (d, J =
(trifluoromethyl)pheny1)-2-8.0 Hz, 1H), 8.20 (s, 1H), 10.73 methylbenzamide (s, 1H); ESI-MS (m/z) 557 (M+H)+.

112. F3C 0 H Al, B13, 1I-1 NMR (400 MHz, DMSO-d6) O N 0 CFrN\ Cl 6 0.98 (t, J = 6.8 Hz, 3H), 2.30-),0 2.51 (m, 10H), 3.28-3.57 (m, N' i ) Method B 4H), 4.19 (t, J = 10.4 Hz, 2H), NN H 7.73 (s, 2H), 7.84-7.87 (m, 2H), 3-((7,8-Dihydro-6H-pyrimido[5,4- 7.98-9\8.03 (m, 3H), 8.16 (s, b] [1,4]oxazin-4-yl)oxy)-N-(4-44- 1H), 10.67 (s, 1H); ESI-MS (m/z) ethylpiperazin-l-yl)methyl)-3- 611 (M+H)+.
(trifluoromethyl)pheny1)-4-(trifluoromethyl)benzamide

113. ci Al, B8, 1I-1 NMR (400 MHz, DMSO-d6) Sii 0F Cl 6 0.98 ( t, J = 7.2 Hz, 3H), 1.0-O 0 , 1.23 (m, 2H), 2.29-2.49 (m, 8H), NO N,) Method B 3.48-3.49 (br s, 2H), 3.56 (s, 2H), I ) NN 4.16 (t, J = 4.4 Hz, 2H), 7.27 H (dd, J1 = 4.0 Hz, J2 = 8.4 Hz, 2-Chloro-5-((7,8-dihydro-6H-1H), 7.38 (d, J = 2.8 Hz, 1H), pyrimido[5,4-b][1,4]oxazin-4-7.71 (d, J = 8.4 Hz, 1H), 7.88 (d, yl)oxy)-N-(4-((4-ethylpiperazin-1-J = 2.0 Hz, 2H), 7.91 (s, 1H), yl)methyl)-3-8.15 (d, J= 2.0 Hz, 1H), 9.05 (s, (trifluoromethyl)phenyl)benzamid 1H), 10.86 (s, 1H); ESI-MS (m/z) e 577 (M+H)+.

114. a H Al, B7, 1I-1 NMR (400 MHz, DMSO-d6) O N CF Cl 6 0.98 ( t, J = 6.8 Hz, 3H), 1.23 OLI\i 0 =NO (br s, 2H), 2.16 (s, 3H), 2.31-2.51 L I j NI\r Method B (m, 8H), 3.56-3.57 (br s, 4H), H 4.21 (t, J = 4.0 Hz, 2H), 7.43 (d, 4-Chloro-3-((7,8-dihydro-6H- J =
8.0 Hz, 1H), 7.53 (d, J = 8.0 pyrimido[5,4-b][1,4]oxazin-4- Hz, 1H), 7.70-7.74 (m, 3H), 7.94 yl)oxy)-N-(4-((4-ethylpiperazin-1- (d, J
= 8.4 Hz, 1H), 8.18 (s, 1H), yl)methyl)-3- 10.77 (s, 1H); ESI-MS (m/z) 591 (trifluoromethyl)pheny1)-2- (M+H)+.
methylbenzamide No. Intermed Analytical Data Structure and Name iates and Method

115. F H Al, B11, NMR
(400 MHz, DMSO-d6) O N Cl ..
6 0.99 ( t, J = 7.2 Hz, 3H), 2.40-2.51 (m, 9H), 3.33-3.39 (m, 1H), NO
Method B 3.47-3.50 (m, 2H), 3.57 (s, 2H), NN 4.17 (t, J = 4.4 Hz, 2H), 7.34-H
5-((7,8-Dihydro-6H-pyrimido[5,4- 7.42 (m, 3H), 7.70-7.75 (m, 3H), b] [1,4]oxazin-4-yl)oxy)-N-(4-((4- 7.92 (t, J = 8.8 Hz, 1H), 8.15 (s, ethylpiperazin-l-yl)methyl)-3- 1H), 10.75 (s, 1H); ESI-MS (m/z) (trifluoromethyl)pheny1)-2- 561 (M+H)+.
fluorobenzamide

116. CI Al, B5, NMR
(400 MHz, DMSO-d6) H Cl 6 0.98 ( t, J = 5.1 Hz, 3H), 3.29-O N
CFnr\j.. 3.39 (m, 10H), 3.50-3.56 (m, 0 4H), 4.17 (br s, 2H), 7.54 (s, 1H), Method B 7-71-8.01 (s, 6H), 8.17 (s, 1H), NN 10.63(s, 1H); ESI-MS (m/z) 577 3-Chloro-5-((7,8-dihydro-6H- (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-y1)methyl)-3-(trifluoromethyl)phenyl)benzamid

117. ci 0 Al, 5- NMR
(400 MHz, DMSO-d6) VI 0 N AN 1. amino-2- 6 0.98 ( t, J= 7.2 Hz, 3H), 2.31-NX k.,F3 0) H H
chlorophe 2.51 (m, 10H), 3.50-3.52 (m, nol, Cl 4H), 4.19 (t, J = 4.4 Hz, 2H), N N
7.25 (dd, J, = 2.4 Hz, .1-2 = 8.8 1-(4-Chloro-3-((7,8-dihydro-6H- Method I Hz, 1H), 7.42 (d, J = 8.8 Hz, pyrimido[5,4-b][1,4]oxazin-4- 2H), 7.48-7.93 (m, 4H), 7.93 (s, yl)oxy)pheny1)-3-(4((4- 1H), 9.02 (s, 1H), 9.08 (s, 1H);
ethylpiperazin-l-yl)methyl)-3- ESI-MS (m/z) 592 (M)+.
(trifluoromethyl)phenyl)urea

118. CI 40 0 Al, 5- NMR
(400 MHz, DMSO-d6) O N
amino-2- 6 1.09 ( t, J = 5.6 Hz, 3H), 2.50-H chlorophe 2.77 (m, 10H), 3.50 (br s, 2H), ) nol, C15 3.82 (br s, 2H), 4.19 (t, J = 8.4 NN Hz, 2H), 7.55 (t, J = 8.8 Hz, 1H), N-(4-Chloro-3-((7,8-dihydro-6H- Method B 7.65-7.95 (m, 5H), 8.15-8.27 (m, pyrimido[5,4-b][1,4]oxazin-4- 2H), 10.64 (s, 1H); ESI-MS (m/z) yl)oxy)pheny1)-444- 577 (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)benzamide No. Intermed Analytical Data Structure and Name iates and Method

119. CI al H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 6 1.17 (d, J = 6.4 Hz, 6H), 2.33 c, 0 0 (t, J
= 11.6 Hz, 2H), 3.62-3.65 1 ) N Method J (br s, 2H), 3.68-3.72 (m, 4H), Nil (R?. J(S) (Step 1 4.20 (t, J = 4.0 Hz, 2H), 7.02 (s, and 2) 1H), 7.57 (s, 1H), 7.68-7.90 (m, 4-Chloro-3-((7,8-dihydro-6H- 6H), 10.39 (s, 1H); ESI-MS (m/z) pyrimido[5,4-b][1,4]oxazin-4- 564 (M+H)+.
yl)oxy)-N-(3-((2R,6S)-2,6-dimethylmorpholino)-5-(trifluoromethyl)phenyl)benzamid e

120. CI al A6, 1H NMR (400 MHz, DMSO-d6) H
N 0 cF3 Bl, C19 6 1.18 (d, J = 6.4 Hz, 3H), 2.27 (s, 3H), 2.47-2.51 (m, 4H), 3.22 N Method A (br s, 4H), 3.69-3.78 (m, 2H), (s)j,, N El ", C j 4.25-4.28 (m, 1H), 6.97 (s, 1H), 7.61 (s, 1H), 7.64 (s, 1H), 7.71-N
I 7.77 (m, 2H), 7.87-7.89 (m, 3H), (S)-4-Chloro-3-((7-methyl-7,8- 10.38 (s, 1H); ESI-MS (m/z) 563 dihydro-6H-pyrimido[5,4- (M+H)+.
b] [1,4]oxazin-4-yl)oxy)-N-(344-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

121. CI Ai AS, 1H NMR (400 MHz, DMSO-d6) H

cF3 Bl, C19 6 1.18 (d, J = 6.8 Hz, 3H), 2.24 0 0 (s, 3H), 2.47-2.51 (m, 4H), 3.21-NIX(R...., N Method A 3.22 (m, 4H), 3.69-3.78 (m, 2H), H CN) 4.24-4.28 (m, 1H), 6.97 (s, 1H), I 7.60 (s, 1H), 7.64 (s, 1H), 7.71-(R)-4-Chloro-3-((7-methyl-7,8- 7.77 (m, 2H), 7.87-7.89 (m, 3H), dihydro-6H-pyrimido[5,4- 10.38 (s, 1H); ESI-MS (m/z) 563 b][1 ,4]o x a zin- 4 -y 1)o xy)-N - (3 - (4 - (M+H)+.
methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

122. CI a, H A10 1H NMR
(400 MHz, DMSO-d6) Bl, C19 6 1.35 (d, J = 6.4 Hz, 3H), 2.23 mo .P r (s, 2H), 2.46-2.51 (m, 4H), 3.18-IL I (R)) N Method B 3.21 (m, 5H), 3.53-3.57 (m, 2H), NN CN) 4.15-4.19 (m, 1H), 6.96 (s, 1H), H

7.60 (s, 1H), 7.64 (s, 1H), 7.75-(R)-4-Chloro-3-((6-methyl-7,8- 7.79 (m, 2H), 7.86-7.89 (m, 3H), dihydro-6H-pyrimido[5,4- 10.37 (s, 1H); ESI-MS (m/z) 563 b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- (M+H)+.
methylpiperazin-l-y1)-5-No. Intermed Analytical Data Structure and Name iates and Method (trifluoromethyl)phenyl)benzamid e

123. Ci al A10, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
N 40 cF3,,,,,....... Cl 6 0.98 (t, J = 7.2 Hz, 3H), 1.35 0 0 Ij f\ I
(d, J = 6.4 Hz, 3H), 2.28-2.50 (m N:ci ((pia` Method B , 9H), 3.16-3.21 (m, 2H), 3.34-N N 3.56 (m, 3H), 4.17 (t, J = 6.0 Hz, H
(R)-4-Chloro-N-(4-((4-1H), 7.69-7.79 (m, 4H), 7.88-ethylpiperazin-1-yl)methyl)-3-7.90 (m, 2H), 8.03 (d, J= 8.0 Hz, (trifluoromethyl)pheny1)-3-46-1H), 8.77 (s, 1H), 10.54 (s, 1H);
methy1-7,8-dihydro-6H-ESI-MS (m/z) 591 (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

124. a Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H

6 1.04 (d, J = 6.4 Hz, 3H), 1.24 (s, 1H), 2.65-3.0 (m, 3H), 3.22-NJC N Method 3.34 (m, 3H), 3.52 (br s, 2H), N N
H C (Id. B ' 3.93 (m, 1H), 4.20 (br s, 2H), N H 6.87 (s, 1H), 7.54 (s, 1H), 7.59 (S)-4-Chloro-3-((7,8-dihydro-6H- (s, 1H), 7.69 (s, 1H), 7.76 (d, J
pyrimido[5,4-b][1,4]oxazin-4- = 8.8 Hz, 1H), 7.81 (s, 1H), 7.87 yl)oxy)-N-(3-(2-methylpiperazin- (s, 2H),10.35 (s, 1H); ESI-MS
1-y1)-5- (m/z) 549 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

125. a Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H

6 1.04 (d, J= 6.4 Hz, 3H), 2.50-3.17 (m, 5H), 3.17-3.25 (m, 2H), Method 3.52 (br s, 2H), 3.93 (br s, 1H), N N C

H (I) B' 4.20 (t, J = 4.4 Hz, 2H), 6.87 (s, N H 1H), 7.53 (s, 1H),7.59 (s, 1H), (R)-4-Chloro-3-((7,8-dihydro-6H- 7.51-7.76 (br s, 1H), 7.69 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4- 7.77 (s, 1H), 7.81-7.88 (m, 2H), yl)oxy)-N-(3-(2-methylpiperazin- 10.35 (s, 1H); ESI-MS (m/z) 549 1-y1)-5- (M+H)+.
(trifluoromethyl)phenyl)benzamid e

126. CI a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N u3 C74 6 3.51-3.52 (m, 2H), 3.80-3.82 0 so (m, 2H), 3.99-4.01 (m, 2H), 4.20 r\X 0 N (m, 1H), 4.25 (s, 3H), 7.60 (s, N X ) Method J 1H), 7.69 (s, 1H), 7.77-7.82 (m, 0 (Step 1 2H), 7.89-7.91 (m, 2H), 8.12 (d, 4-Chloro-3-((7,8-dihydro-6H- and 2) J= 9.6 Hz, 2H), 10.67 (s, 1H);
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-oxomorpholino)-No. Intermed Analytical Data Structure and Name iates and Method (trifluoromethyl)phenyl)benzamid e

127. cl a H Al, Bl, 1H NMR (400 MHz, DMSO-d6) N 0 c3 C71 6 1.78 (d, J = 9.2 Hz, 1H), 1.88 0 (d, J
= 9.6 Hz, 1H), 2.25 (s, 3H), t'Cj' (0) s () N Method B 2.42-2.51 (m, 1H), 2.82 (d, J =
N
N C' H 9.6 Hz, 2H), 3.18 (d, J= 8.8 Hz, N (s) 2H), 3.51-3.52 (m, 2H), 4.20 (t, J

4-Chloro-3-((7,8-dihydro-6H- = 4.0 Hz, 2H), 4.32 (s, 1H), 6.57 pyrimido[5,4-b][1,4]oxazin-4- (s, 1H), 7.23 (s, 1H), 7.46 (s, yl)oxy)-N-(3-((1S,4S)-5-methyl- 1H), 7.69 (s, 1H), 7.86-7.88 (m, 2,5-diazabicyclo[2.2.1]heptan-2- 4H), 10.33 (s, 1H); ESI-MS (m/z) 561 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

128. CI a H Al, Bl, 1H NMR (400 MHz, DMSO-d6) 6 1.08 (d, J = 5.6 Hz, 3H), 1.25 (br s, 3H), 2.25 (br s, 3H), 2.84-NCJCO) a N Method B 2.86 (m, 2H), 3.51-3.60 (m, 4H), N N
H C (R144. 4.20 (t, J = 3.6 Hz, 2H), 6.99 (s, N 1H), 7.58 (s, 1H), 7.65-7.81 (m, I
(R)-4-Chloro-3-((7,8-dihydro-6H- 2H), 7.87-7.89 (m, 4H), 10.38 (s, pyrimido[5,4-b][1,4]oxazin-4- 1H);
ESI-MS (m/z) 563 (M+H)+.
yl)oxy)-N-(3-(3,4-dimethylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

129. cl a H Al, Bl, 1H NMR (400 MHz, DMSO-d6) 6 1.06 (d, J = 6.0 Hz, 3H), 1.24 0 Wj , N j: oj 0 (s, 3H), 2.22 (s, 3H), 2.82-2.85 N Method B (m, 2H), 3.51-3.60 (m, 4H), 4.21 N N
H C (s) (t, J = 4.0 Hz, 2H), 6.98 (s, 1H), 7.57 (s, 1H), 7.57-7.77 (m, 2H), I
(S)-4-Chloro-3-((7,8-dihydro-6H- 7.87-7.89 (m, 4H), 10.37 (s, 1H);
pyrimido[5,4-b][1,4]oxazin-4- ESI-MS (m/z) 563 (M+H)+.
yl)oxy)-N-(3-(3,4-dimethylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

130. a H A7, B3, 1H NMR (400 MHz, DMSO-d6) 0 N I* CF3 C26 6 2.27 (s, 3H), 3.16-3.18 (m, 4H), 3.42-3.44 (m, 2H), 3.74-CY)) N Method B 3.76 (m, 4H), 4.12 (t, J = 4.0 Hz, N N ( ) 2H), 5.97 (d, J = 5.6 Hz, 1H), H
0 6.85 (s, 1H), 6.96 (s, 1H), 7.48-No. Intermed Analytical Data Structure and Name iates and Method 3-((3,4-Dihydro-2H-pyrido[3,2- 7.50 (m, 3H), 7.64 (d, J = 9.6 Hz, b][1,4]oxazin-8-yl)oxy)-4-methyl- 2H), 7.77 (dd, Ji = 1.6 Hz, J2 =
N-(3-morpholino-5- 7.6 Hz, 1H), 10.29 (s, 1H); ESI-(trifluoromethyl)phenyl)benzamid MS (m/z) 515 (M+H)+.
e

131. a H
A7, B3, 1H NMR (400 MHz, DMSO-d6) 0 N 0 CF3 C61 6 1.81-2.27 (m, 9H), 2.84 (m, ,exNoN) 0 I
(N 1H), 3.07 (t, J = 8.4 Hz, 1H), Method B 3.23-3.50 (m, 7H), 4.12(t, J= 4.0 H \ i(S) Hz, 2H), 5.96 (d, J = 5.6 Hz, N¨ 1H), 6.51 (s, 1H), 6.84 (s, 1H), /
(S)-3-((3,4-Dihydro-2H- 7.23 (s, 1H), 7.47-7.50 (m, 4H), pyrido[3,2-b][1,4]oxazin-8- 7.77 (dd, Ji = 1.6 Hz, J2 = 8.0 yl)oxy)-N-(3-(3- Hz, 1H), 10.22 (s, 1H); ESI-MS
(dimethylamino)pyrrolidin-l-y1)- (m/z) 542 (M+H)+.
5-(trifluoromethyl)pheny1)-4-methylbenzamide

132. CF3 Al, 5- 1H NMR (400 MHz, DMSO-d6) ci a 0 6 amino-2- 6 1.76 (m, 3H), 2.48-2.51 (m, O NN I\1 chlorophe 4H), 3.149 (br s, 4H), 3.50 (br s, N o H H LN, nol, C19 2H), 4.19 (t, J = 4.0 Hz, 2H), NkN) 6.83 (s, 1H), 7.21-7.26 (m, 3H), H Method I 7.42 (t, J = 8.4 Hz, 1H), 7.49 (d, 1-(4-Chloro-3-((7,8-dihydro-6H- J =
2.4 Hz, 1H), 7.68 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4- 7.73 (s, 1H), 8.99 (s, 1H), 9.04 yl)oxy)pheny1)-3-(3-(4- (s, 1H); ESI-MS (m/z) 564 methylpiperazin-l-y1)-5- (M+H)+.
(trifluoromethyl)phenyl)urea

133. a Ai H Al, Bl, 1H NMR (400 MHz, DMSO-d6) 6 1.07 (t, J = 6.0 Hz, 3H), 2.02 0 0 (m, 1H), 2.21 (br s, 3H), 2.68-NO ',CI j N Method B 3.03 (m, 4H), 3.52 (br s, 3H), N N
H C (s 4.05-4.07 (m, 1H), 4.20 (t, J =
N1 4.4 Hz, 2H), 6.90 (s, 1H), 7.56-(S)-4-Chloro-3-((7,8-dihydro-6H- 7.81 (m, 3H), 7.87-7.89 (m, 4H), pyrimido[5,4-b][1,4]oxazin-4- 10.36 (s, 1H); ESI-MS (m/z) 563 yl)oxy)-N-(3-(2,4- (M+H)t dimethylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

134. CI a H Al, Bl, 1H NMR (400 MHz, DMSO-d6) 6 1.07 (t, J= 6.8 Hz, 3H), 2.02 (t, 0 0 J =
8.8 Hz, 1H), 2.20 (s, 3H), NO ',CI ) Method B 2.70 (d, J = 11.6 Hz, 2H), 2.84 N N C (RD
H (d, J
= 11.2 Hz, 1H), 2.99 (t, J=
N 8.4 Hz, 1H), 3.51-3.52 (m, 2H), I

No. Intermed Analytical Data Structure and Name iates and Method (R)-4-Chloro-3-((7,8-dihydro-6H- 4.05 (m, 1H), 4.20 (t, J = 4.8 Hz, pyrimido[5,4-b][1,4]oxazin-4- 2H), 6.89 (s, 1H), 7.558 (s, 2H), yl)oxy)-N-(3-(2,4- 7.60 (s, 1H), 7.69-7.81 (m, 1H), dimethylpiperazin-l-y1)-5- 7.86-7.89 (m, 4H), 10.35 (s, 1H);
(trifluoromethyl)phenyl)benzamid ESI-MS (m/z) 563 (M+H)+.
e

135. CI H Al, Bl, 1H NMR (400 MHz, DMSO-d6) N cF3 C66 6 2.29 (s, 3H), 3.01 (t, J = 5.6 0 0 Hz, 2H), 3.51-3.52 (br s, 2H), N tC
L I ) 1\1 N 0,,,..n 3.75 (t, J = 6.0 Hz, 2H), 4.21 (t, J
H \-- .N1 , = 4.0 Hz, 2H), 4.80-4.86 (m, 4-Chloro-3-((7,8-dihydro-6H-Method B 1H), 6.88 (s, 1H), 7.60 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4-7.69 (s, 1H), 7.76-7.89 (m, 5H), yl)oxy)-N-(3-((1-methylazetidin-10.53 (s, 1H).
3-yl)oxy)-5-(trifluoromethyl)phenyl)benzamid e

136. al H AS, 1H NMR
(400 MHz, DMSO-d6) N u 0 40 3 B3, C19 6 1.18 (d, J = 6.0 Hz, 3H), 2.18 0 0 (s, 3H), 2.23 (s, 3H), 2.46-2.51 NA N N (R
N Method A (m, 4H), 3.21 (t, J= 4.4 Hz, 4H), A=0' H C ) 3.73-3.77 (m, 2H), 4.25 (dd, J1 =
NI 2.4 Hz, J2 = 10.4 Hz, 1H), 6.94 (R)-4-Methyl-3-((7-methyl-7,8- (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), dihydro-6H-pyrimido[5,4- 7.62 (s, 1H), 7.67-7.69 (m, 3H), b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- 7.78 (dd, J1 = 4.0 Hz, .1-2 = 10.0 methylpiperazin-l-y1)-5- Hz, 2H), 10.25 (s, 1H); ESI-MS
(trifluoromethyl)phenyl)benzamid (m/z) 543 (M+H)+.
e

137. al H A4, B3, 1H NMR (400 MHz, DMSO-d6) N u 0 so 3 C19 6 1.24 (s, 6H), 2.19 (s, 3H), 2.22 N:0 0 (s, 3H), 2.45-2.51 (m, 4H), 3.21 NX N
N Method A (t, J = 4.4 Hz, 4H), 3.88 (s, 2H), H CN) 6.94 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.67-7.70 (m, I
3((7,7-Dimethy1-7,8-dihydro-6H- 3H), 7.78-7.80 (m, 2H), 10.25 (s, pyrimido[5,4-b][1,4]oxazin-4- 1H); ESI-MS (m/z) 557 (M+H)+.
yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

138. ci H Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) N C64 6 3.50-3.52 (br s, 2H), 3.89 (s, cF

0 3H), 4.21 (t, J = 4.0 Hz, 2H), Method B 7.66 (s, 1H), 7.70 (s, 1H), 7.71-N
H N-N N v / 7.82 (m, 2H), 7.90-7.92 (br s, / 2H), 8.01 (s, 1H), 8.20 (s, 1H), 4-Chloro-3-((7,8-dihydro-6H- 8.27 (s, 2H), 10.58 (s, 1H); ESI-pyrimido[5,4-b][1,4]oxazin-4- MS (m/z) 531 (M+H)+.
yl)oxy)-N-(3-(1-methy1-1H-pyrazol-4-y1)-5-(trifluoromethyl)phenyl)benzamid e

139. H H Al, 4- 1I-1 NMR (400 MHz, DMSO-d6) Ai NN 0 CF3 aminophe 6 2.24 (s, 3H), 2.47-2.51 (m, 0 nol, C19 4H), 3.19-3.20 (m, 4H), 3.47-CN 3.48 (br s, 2H), 4.16 (t, J = 4.4 N ) Method I Hz, 2H), 6.82 (s, 1H), 7.02 (d, J
N N
H I = 8.8 Hz, 2H), 7.22 (s, 1H), 7.28 1-(4-((7,8-Dihydro-6H- (s, 1H), 7.44 (t, J = 8.8 Hz, 2H), pyrimido[5,4-b][1,4]oxazin-4- 7.64 (s, 1H), 7.69 (s, 1H), 8.75 yl)oxy)pheny1)-3-(3-(4- (s, 1H), 8.88 (s, 1H); ESI-MS
methylpiperazin-l-y1)-5- (m/z) 530 (M+H)+.
(trifluoromethyl)phenyl)urea

140. CI a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N CF3 C77 6 1.63-1.64 (m, 1H), 1.89-1.99 onIr (m, 1H), 2.09 (s, 6H), 2.30-2.33 o /
Method B (m, 1H), 2.46-2.74 (m, 4H), 1\1 N 1;1--,,N
H 1...j \ 3.68-3.72 (m, 3H), 4.01 (t, J =
(R)-4-Chloro-3-((7,8-dihydro-6H- 7.2 Hz, 1H), 4.21 (t, J = 4.4Hz, pyrimido[5,4-b][1,4]oxazin-4- 2H), 7.37 (s, 1H), 7.69 (s, 1H), yl)oxy)-N-(3-((3- 7.75-7.91 (m, 4H), 7.99 (s, 1H), (dimethylamino)pyrrolidin-1- 8.14 (s, 1H), 10.57 (s, 1H).
yl)methyl)-5-(trifluoromethyl)phenyl)benzamid e

141. CI 0 H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) 0 N CF3 C78 6 1.87-1.89 (m, 1H), 1.91-1.99 0 I. (m, 1H), 2.11 (s, 6H), 2.31 (t, J=
Method B 6.8 Hz, 1H), 2.56-2.76 (m, 4H), N N H NILyiNi \ 3.52-3.69 (m, 3H), 3.6-3.72 (m, (S)-4-Chloro-3-((7,8-dihydro-6H- 1H), 4.21 (t, J = 4.0 Hz, 2H), pyrimido[5,4-b][1,4]oxazin-4- 7.37 (s, 1H), 7.69 (s, 1H), 7.75-yl)oxy)-N-(3-((3- 7.90 (m, 4H), 7.99 (s, 1H), 8.14 (dimethylamino)pyrrolidin-1- (s, 1H), 10.56 (s, 1H).
yl)methyl)-5-(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

142. CI H A15, 'I-1 NMR (400 MHz, DMSO-d6) N o CF3 Bl, C19 6 1.55 (d, J = 6.8 Hz, 3H), 2.50-0 0 IW 2.51 (m, 3H), 2.76 (m, 4H), 3.33 N:INX y N
(m, 4H), 5.02 (q, J = 6.8 Hz, 1H), H j Method 7.08 (s, 1H), 7.84-8.0 (m, 4H), N G' 8.09 (d, J= 2.0 Hz, 1H), 8.01 (s, (R)-4-Chloro-3-46-methyl-7-oxo- 1H), 8.11 (s, 1H), 11.79 (s, 1H);
7,8-dihydro-6H-pyrimido[5,4- ESI-MS (m/z) 577 (M+H)+.
b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

143. CI H All, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N

cF3 C19 6 0.98 (t, J = 7.6 Hz, 3H), 1.55-o 0 0 1.59 (m, 2H), 2.23 (s, 3H), 2.46 N (t, J
= 4.8 Hz, 4H), 3.21 (t, J =
1\1 N H C ) Method A 4.4 Hz, 4H), 3.50 (br s, 1H), N

I 3.94-3.96 (m, 1H), 4.21 (t, J =
(R)-4-Chloro-3-47-ethyl-7,8- 8.0 Hz, 1H), 6.96 (s, 1H), 7.60 (s, dihydro-6H-pyrimido[5,4- 1H), 7.64 (s, 1H), 7.71 (s, 1H), b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- 7.76 (d, J = 9.2 Hz, 1H), 7.95 (m, methylpiperazin-l-y1)-5- 2H), 8.0 (s, 1H), 10.37 (s, 1H);
(trifluoromethyl)phenyl)benzamid ESI-MS (m/z) 577 (M+H)+.
e

144. All, B3, 1I-1 NMR (400 MHz, DMSO-d6) 0 H CF3 C19 6 0.97 (t, J = 7.6 Hz, 3H), 1.53-o N 0 1.61 (m, 2H), 2.18 (s, 3H), 2.23 0 o NIL (R),,,... N
(s, 3H), 2.46 (t, J = 4.8 Hz, 4H), NN N H CN) Method A 3.21 (t, J = 4.4 Hz, 4H), 3.48-3.49 (br s, 1H), 3.91-3.95 (m, I 1H), 4.20 (dd, Ji = 2.8 Hz, .12 =
(R)-3-47-Ethy1-7,8-dihydro-6H-10.8 Hz, 1H), 6.94 (s, 1H), 7.46 pyrimido[5,4-b][1,4]oxazin-4-(d, J = 8.0 Hz, 1H), 7.62 (s, 1H), yl)oxy)-4-methyl-N-(3-(4-7.67-7.69 (br s, 3H), 7.79 (dd, Ji methylpiperazin-l-y1)-5-= 2.0 Hz, .12 = 8.0 Hz, 1H), 7.87 (trifluoromethyl)phenyl)benzamid (s, 1H), 10.25 (s, 1H); ESI-MS
e (m/z) 557 (M+H)+.

145. Cl Al2, 1I-1 NMR (400 MHz, DMSO-d6) H
o N 0 c3 Bl, C19 6 0.98 (t, J = 7.2 Hz, 3H), 1.54-o 0 1.61 (m, 2H), 2.24 (s, 3H), 2.48-N)1' (s N ." ) N 2.51 (m, 4H), 3.21-3.22 (br s, C
H
N ) Method A 4H), 3.49-3.50 (m, 1H), 3.92-I N 3.96 (m, 1H), 4.20-4.23 (m, 1H), (S)-4-Chloro-3((7-ethy1-7,8- 6.97 (s, 1H), 7.60 (s, 1H), 7.64 dihydro-6H-pyrimido[5,4- (s, 1H), 7.71-7.77 (m, 2H), 7.86-b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- 7.94 (m, 2H), 7.95 (s, 1H), 10.37 No. Intermed Analytical Data Structure and Name iates and Method methylpiperazin-l-y1)-5- (s, 1H); ESI-MS (m/z) 577 (M)+.
(trifluoromethyl)phenyl)benzamid e

146. a H Al2, lli NMR (400 MHz, DMSO-d6) B3, C19 6 0.98 (t, J = 7.2 Hz, 3H), 1.51-e 10 0 0 1.63 (m, 2H), 2.18 (s, 3H), 2.23 ( s) (s, 3H), 2.47-2.51 (m, 4H), 3.21 H
CN) Method A (t, J= 4.4 Hz, 4H), 3.48-3.49 (m, N 1H), 3.91-3.95(m, 1H), 4.21 (dd, I
(S)-3((7-Ethy1-7,8-dihydro-6H- Ji =
2.8 Hz, .12 = 10.8 Hz, 1H), pyrimido[5,4-b][1,4]oxazin-4- 6.94 (s, 1H), 7.46 (d, J = 8.4 Hz, yl)oxy)-4-methyl-N-(3-(4- 1H), 7.62-7.78 (m, 4H), 7.80 (d, methylpiperazin-1-y1)-5- J =
1.6 Hz, 1H), 7.87 (s, 1H), (trifluoromethyl)phenyl)benzamid 10.25 (s, 1H); ESI-MS (m/z) 557 e (M+H)+.

147. F VrI-1 N
VI oo Ir Al, 4-'HNMR (400 MHz, DMSO-d6) AI
amino-2- 6 1.45 ( br s, 4H), 3.49 (br s, 2H), fluorophe 4.17 (t, J = 4.0 Hz, 2H), 7.12-NIIX ) nol, C68 7.23 (m, 3H), 7.37 (d, J = 8.8 Hz, NI N 1H), 7.62-7.75 (m, 5H), 10.03 (s, H
N-(4-((7,8-Dihydro-6H-Method 1H), 10.25 (s, 1H); ESI-MS (m/z) +
pyrimido[5,4-b][1,4]oxazin-4-M 468 (M+H).
yl)oxy)-3-fluoropheny1)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

148. a H Al, Bl, lli NMR (400 MHz, DMSO-d6) N r CF3 C67 6 1.70-1.72 (m, 2H), 1.87-1.90 0o IW (m, 2H), 2.08 (s, 3H), 2.19 (t, J =
1\11 \-- N) a 8.0 Hz, 2H), 2.46-2.51 (m, 2H), H Method B 3.51 (br s, 2H), 4.20 (t, J = 4.0 NI Hz, 2H), 4.650 (br s, 1H), 7.33 4-Chloro-3-((7,8-dihydro-6H- (d, J
= 8.8 Hz, 1H), 7.53 (d, J =
pyrimido[5,4-b][1,4]oxazin-4- 7.2 Hz, 1H), 7.70 (s, 1H),7.78-yl)oxy)-N-(2-((l-methylpiperidin- 7.85 (m, 4H), 8.09 (s, 1H), 9.71 4-yl)oxy)-5- (s, 1H); ESI-MS (m/z) 564 (trifluoromethyl)phenyl)benzamid (M+H)+.
e

149. a H A16, lli NMR (400 MHz, DMSO-d6) Bl, C19 6 1.45 (d, J = 6.4 Hz, 3H), 2.22 - 0 0 (s, 3H), 2.46-2.51 (m, 4H), 3.21 NCX (sjr 4, J=
4.4 Hz, 4H), 4.74 (m, 1H), N INIO CN) 6.96 (s, 1H), 7.60 (s, 1H), 7.65 N Method (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), (S)-4-Chloro-3-46-methyl-7-oxo- G' 7.90 (dd, Ji = 2.0 Hz, .12 = 8.4 7,8-dihydro-6H-pyrimido[5,4- Hz, 1H), 7.92-7.96 (m, 3H), b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- 10.48 (s, 1H).

No. Intermed Analytical Data Structure and Name iates and Method methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid

150. a Ai A17, NMR (400 MHz, DMSO-d6) N CF3 Bl, C19 6 1.54 (s, 6H), 2.29 (br s, 4H), N:iC 2.50-2.51 (brs , 3H), 3.24 (br s, C:t9 4H), 6.99 (s, 1H), 7.62 (s, 1H), 7.65 (s, 1H), 7.82 (d, J = 8.4 Hz, Method 1H), 7.94 (dd, J, = 2.0 Hz, J2 =
4-Chloro-3((6,6-dimethy1-7-oxo- G' 8.4 Hz, 1H), 8.01 (s, 1H), 8.13 7,8-dihydro-6H-pyrimido[5,4- (s, 1H), 10.43 (s, 1H), 11.79 (s, b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- 1H); ESI-MS (m/z)591(M+H)+.
methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid

151. H H
Al, 4- 1I-1 NMR (400 MHz, DMSO-d6) NN cFrNJ
aminophe 6 0.98 (t, J = 7.2 Hz, 3H), 2.29-0 1W N,) 0 WI nol, Cl 2.51 (m, 10H), 3.48-3.52 (m , 4H), 4.16 (t, J = 4.0 Hz, 2H), N:Cin N N Method I 7.02 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.45-7.64 (m, 1-(4-((7,8-Dihydro-6H- 3H), 7.69 (s, 1H), 7.8 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4- 9.08 (br s, 1H), 9.32 (br s, 1H);
yl)oxy)pheny1)-3-(444- ESI-MS (m/z)558(M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)urea

152. cF3 Al, B12, NMR (400 MHz, DMSO-d6) 40 C19 6 2.24 (s, 3H), 2.48-2.51 ( br s, CI Ai 4H), 3.22 (t, J = 4.8 Hz, 4H), 3.51 (t, J = 4.0 Hz, 2H), 4.20 (t, J
WI
NLC0) Method B = 4.0 Hz, 2H), 6.97 (s, 1H), 7.43 N (d, J = 8.4 Hz, 1H), 7.62-7.66 (m, 3H), 7.83 (br s, 1H), 7.93 3-Chloro-4-((7,8-dihydro-6H- (dd, J, = 2.0 Hz, J2 = 8.4 Hz, pyrimido[5,4-b][1,4]oxazin-4- 1H), 8.15 (s, 1H), 10.42 (s, 1H).
yl)oxy)-N-(3-(4-methylpiperazin-1-y1)-5 (trifluoromethyl)phenyl)benzamid

153. Al, B12, NMR (400 MHz, DMSO-d6) CI N CF
Cl 6 0.99 (t, J = 6.8 Hz, 3H), 1.99-Ai _ 3 2.33 (m, 2H), 2.40-2.51 (m, 7H), 0 WI Method B 3.51 (t, J = 4.0 Hz, 3H), 3.58 (s, 2H), 4.20 (t, J = 4.0 Hz, 2H), 1 ) 7.43 (d, J = 8.4 Hz, 1H), 7.70 (s, NN
2H), 7.72-8.05 (m, 2H), 8.16-3-Chloro-4-((7,8-dihydro-6H- 8.20 (m, 3H), 10.59 (s, 1H).

No. Intermed Analytical Data Structure and Name iates and Method pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-y1)methyl)-3-(trifluoromethyl)phenyl)benzamid e

154. H H
N N j Al, 4- 1H NMR (400 MHz, DMSO-d6) Al isr amino-2- 6 0.98 (t, J = 6.8 Hz, 3H), 2.06 o WI tW CF N kl,) methylph (s, 3H), 2.28-2.51 (m, 9H), 3.48-j' enol, Cl 3.52 (m, 5H), 4.17 (t, J= 4.0 Hz, NIC
N N H 2H), 6.92 (d, J = 8.8 Hz, 1H), 1-(4-((7,8-Dihydro-6H- Method I 7.24 (dd, ./i = 2.4 Hz, J2 = 8.4 pyrimido[5,4-b][1,4]oxazin-4- Hz, 1H), 7.37 (d, J = 2.4 Hz, yl)oxy)-3-methylpheny1)-3-(4-44- 1H), 7.54-7.64 (m, 4H), 7.99 (s, ethylpiperazin-l-yl)methyl)-3- 1H), 8.74 (s, 1H), 9.04 (s, 1H);
(trifluoromethyl)phenyl)urea ESI-MS (m/z) 572 (M+H)+.

155. a H
A7, B3, 1H NMR (400 MHz, DMSO-d6) 0 N I. CF3 C59 6 2.27 (s, 3H), 2.42-2.51 (m, I j N 3H), 3.16-3.23 (m, 4H), 3.45-3.47 (m, 4H), 4.11-4.12 (m, 2H), *1\IN
H (N) Method B 4.80 (d, J = 6.0 Hz, 2H), 4.57 (d, J = 6.4 Hz, 2H), 5.96 (d, J = 5.6 6 Hz, 1H), 6.84 (s, 1H), 6.94 (s, 0 1H), 7.48 (d, J = 5.6 Hz, 3H), 3-((3,4-Dihydro-2H-pyrido[3,2- 7.62 (d, J = 10.0 Hz, 2H), 7.76 b][1,4]oxazin-8-yl)oxy)-4-methyl- (dd, ./1 = 1.2 Hz, J2 = 7.6 Hz, N-(3 -(4-(oxetan-3 -yl)piperazin-1- 1H), 10.27 (s, 1H); ESI-MS (m/z) 570 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

156. H H
Al, 4- 1H NMR (400 MHz, DMSO-d6) Y 1.1 amino-2- 6 2.05 (s, 3H), 2.22 (s, 3H), 2.45 methylph (br s, 4H), 3.19 (br s, 4H), 3.49 CN enol, C19 (br s, 2H), 4.17 (t, J = 4.0 Hz, N) 2H),6.81 (s, 1H), 6.92 (d, J = 8.4 N N
H I Hz, 1H), 7.21-7.28 (m, 3H), 7.37 1-(4-((7,8-Dihydro-6H- Method I (s, 1H), 7.60 (s, 2H), 8.69 (s, pyrimido[5,4-b][1,4]oxazin-4- 1H), 8.89 (s, 1H); ESI-MS (m/z) yl)oxy)-3-methylpheny1)-3-(3-(4- 544 (M+H)+.
methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)urea

157. H H
CF J Al, 4-1H NMR (400 MHz, DMSO-d6) CI N N An y Allik r"..N
0 ir N,) amino-2- 6 0.98 (t, J
= 7.2 Hz, 3H), 2.28-W

chlorophe 2.51 (m, 10H), 3.49-3.53 (m, 0 11: j nol, Cl 4H), 4.18 (br s, 2H), 7.18 (d, J =
1\1 8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, N N
H Method I 1H), 7.58-7.69 (m, 4H), 7.78 (s, 1-(3-Chloro-4-((7,8-dihydro-6H- 1H), 7.97 (s, 1H), 9.02 (s, 1H), No. Intermed Analytical Data Structure and Name iates and Method pyrimido[5,4-b][1,4]oxazin-4- 9.16 (s, 1H); ESI-MS (m/z) 592 yl)oxy)pheny1)-3-(444- (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)urea

158. H H Al, 4- 11-1 NMR (400 MHz, DMSO-d6) ci N N u3 40 'or 40 amino-2- 6 2.22 (s, 3H), 2.45 (t, J = 4.4 O chlorophe Hz, 4H), 3.19 (t, J = 4.4 Hz, 4H), N:X1 a) CN) nol, C19 3.49-3.50 (m, 2H), 4.18 (t, J =
N N N 4.0 Hz, 2H), 6.83 (s, 1H), 7.16-H I 7.32 (m, 4H), 7.65-7.69 (m, 2H), 1-(3-Chloro-4-((7,8-dihydro-6H- Method I 7.78 (s, 1H), 9.05 (br s, 2H);
pyrimido[5,4-b][1,4]oxazin-4- ESI-MS (m/z) 564 (M+H)+.
yl)oxy)pheny1)-3-(3-(4-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)urea

159. CI al Al, Bl, 11-1 NMR (400 MHz, DMSO-d6) H
N

CF C19 6 2.4 (s, 3H), 2.50-2.51 (m, 4H), O W is 3.12 (s, 3H), 3.20-3.23 (br s, 4H), 3.59 (t, J = 4.4 Hz, 2H), 4.28 (t, J
I ) N
N N Method L =
4.4 Hz, 2H), 6.97 (s, 1H), 7.63 I C ) N (d, J = 13.6 Hz, 2H), 7.75-7.79 I (m, 2H), 7.86-7.89 (m, 2H), 4-Chloro-3-((8-methyl-7,8- 10.38 (s, 1H); ESI-MS (m/z) 563 dihydro-6H-pyrimido[5,4- (M+H)+.
b] [1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

160. CI al Al, Bl, 11-1 NMR (400 MHz, DMSO-d6) H
N 0 c3 C65 6 3.51-3.52 (br, 2H), 4.21 (t, J =

4.0 Hz, 2H), 7.70 (s, 2H), 7.71-N:1 c j Method 7.93 (m, 5H), 8.04 (s, 2H), 8.20 N N N B' (s, 1H), 10.58 (s, 1H), 13.13(br s, H %
N-NH 1H) ; ESI-MS (m/z)517(M+H)+.
N-(3-(1H-Pyrazol-4-y1)-5-(trifluoromethyl)pheny1)-4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

161. CI A13, 11-1 NMR (400 MHz, DMSO-d6) H
O WI N 0 CF3 Bl, 6 (t, J = 6.8 Hz, 6H), r\i,(0, 0 C19 1.90 (m, 1H), 2.24 (s, 3H), 2.50-N
1 (R) 2.51 (m, 4H), 3.22 (br s, 4H), N N-y CN) H 4.12 (br s, 3H), 6.97 (s, 1H), 7.61 I Method A (s, 1H), 7.64 (s, 1H), 7.71 (s, (R)-4-Chloro-3-((7-isopropyl-7,8- 1H), 7.75-7.77 (m, 1H), 7.87-dihydro-6H-pyrimido[5,4- 7.88 (m, 2H), 8.0 (s, 1H), 10.38 b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- (s, 1H); ESI-MS (m/z) 591 (M)+.

No. Intermed Analytical Data Structure and Name iates and Method methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

162. CI A14, 1H NMR
(400 MHz, DMSO-d6) H
O WI N 0 CF3 Bl, 6 (t, J = 7.2 Hz, 6H), Nj,, 0(s ). 0 C19 1.85-1.87 (m, 1H), 2.23 (s, 3H), 2.46-2.50 (m, 4H), 3.21 (t, J =
N H õr cN) 4.8 Hz, 4H), 4.12 (br s, 3H), 6.97 N Method A (s, 2H), 7.60 (s, 2H), 7.64 (s, (S)-4-Chloro-3-((7-isopropyl-7,8- 1H), 7.75 (s, 1H), 7.87-7.88 (m, dihydro-6H-pyrimido[5,4- 1H), 8.0 (br s, 1H), 10.38 (s, 1H);
b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- APCI-MS (m/z) 591 (M)t methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

163. CI ai H AS, 1H NMR
(400 MHz, DMSO-d6) O W N io c3 Bl, C81 6 1.06-1.09 (m, 3H), 1.18 (d, J =
N,,, 0 0 6.0 Hz, 3H), 1.26 (d, J = 6.0 Hz, (R),,. N Method A 3H), 2.34 (m, 2H), 2.46-2.67 (m, N N CN) 8H), 3.34-3.56 (m, 2H), 3.70-H
3.78 (m, 1H), 4.27(t, J = 9.6 Hz, 1H), 7.71 (s, 1H), 7.76-7.79 (m, 4-Chloro-N-(4-(1-(4- 1H), 7.89 (br s, 4H), 8.07 (d, J =
ethylpiperazin-1-yl)ethyl)-3- 11.2 Hz, 1H), 8.51 (s, 1H), 10.57 (trifluoromethyl)pheny1)-3 - (((R)- (s, 1H); ESI-MS (m/z) 605 7-methyl-7,8-dihydro-6H- (M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

164. CI ai Al, Bl, 1H NMR (400 MHz, DMSO-d6) H

6 3.52 (br s, 2H), 4.21 (t, J = 4.4 Hz, 2H), 7.70 (s, 1H), 7.79-7.88 NC) I ) (m, 3H), 7.91-8.01 (m, 6H), 8.30 N N Method B (s, 1H), 8.41 (s, 1H), 10.71 (s, H
1H); ESI-MS (m/z) 552 (M+H)+.
CN
4-Chloro-N-(4'-cyano-5-(trifluoromethy1)41,1'-bipheny1]-3-y1)-347,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

165. CI al Al, Bl, 1H NMR (400 MHz, DMSO-d6) H

6 3.52 (br s, 2H), 4.21 (br s, 2H), 7.70-7.93 (m, 8H), 8.08 (d, J =
NC;ll L I ) Method B 8.0 Hz, 1H), 8.28 (d, J = 11.2 Hz, N N
H 2H), 8.38 (s, 1H), 10.69 (s, 1H);
CN ESI-MS (m/z) 552 (M+H)+.
4-Chloro-N-(3'-cyano-5-No. Intermed Analytical Data Structure and Name iates and Method (trifluoromethyl)-[1,1'-bipheny1]-3-y1)-347,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-y1)oxy)benzamide

166. a a H te rt-Butyl 1H NMR (400 MHz, DMSO-d6) N

cF3 (3-chloro- 6 2.23 (s, 3H), 2.46 (br s, 4H), 0 is 2- 2.93 (s, 3H), 3.21 (br s, 4H), 4.57 0.N.-tN N
formylphe (s, 2H), 6.15 (d, J= 5.6 Hz, 1H), H CN) nyl)carba 6.97 (s, 1H), 7.61 (d, J = 12.0 mate, Hz, 2H), 7.88-7.89 (m, 1H), I Bl, C19 7.96-7.98 (m, 3H), 9.8 (s, 1H), 4-Chloro-3-43-methy1-2-oxo-10.41 (s, 1H); ESI-MS (m/z) 575 1,2,3,4-tetrahydropyrido[2,3-(M+H)+.
d]pyrimidin-5 -yl)oxy)-N-(3 - (4-Method N
methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

167. CI 0 All, 1H NMR
(400 MHz, DMSO-d6) H
N
Bl, Cl 6 0.96 (t, J=
O CFrNi.
NO 0 I, N,) 6.0 Hz, 6H), 1.54-1.61 (m, 2H), Method A 2.28-2.39 (m, 10H), 3.49-3.50 1 (R) NN (m, 1H), 3.56 (s, 2H), 3.92-3.96 H
(R)-4-Chloro-3-47-ethyl-7,8-(m, 1H), 4.22 (dd, J1 = 2.8 Hz, = 10.8 Hz, 1H), 7.71 (s, 1H), dihydro-6H-pyrimido[5,4-7.72-7.96 (m, 5H), 8.03 (dd, ./1 =
b] [1,4]oxazin-4-yl)oxy)-N-(4-((4-1.6 Hz, J2 = 8.4 Hz, 1H), 8.17 (trifluoromethyl)phenyl)benzamid ethylpiperazin-l-yl)methyl)-3-(d, J = 2.0 Hz, 1H), 10.54 (s, 1H); ESI-MS (m/z) 605 (M+H)+.
e

168. CI al Al, Bl, 1H NMR (400 MHz, DMSO-d6) H
O N io cF3 C82 6 1.09 (t, J = 7.6 Hz, 3H), 2.36 (q, J= 7.2 Hz, 2H), 3.51-3.52 (br õ,j,o, 0 NO
1 j HNO Method B s, 2H), 4.21 (t, J = 4.4 Hz, 2H), NN 7.69 (s, 1H), 7.75-7.91 (m, 6H), H
8.37 (s, 1H), 10.27 (s, 1H), 10.95 4-Chloro-3-((7,8-dihydro-6H- (s, 1H); ESI-MS (m/z) 522 pyrimido[5,4-b][1,4]oxazin-4- (M+H)t yl)oxy)-N-(3-propionamido-5-(trifluoromethyl)phenyl)benzamid e

169. a H Al, B3, 1H NMR (400 MHz, DMSO-d6) O N s CF3 3-(4-6 2.16 (s, 3H), 2.18 (s, 3H), 3.49 i\i O methyl- (s, 2H), 4.18 (m, 2H), 7.43-7.51 j-'N
1 j 1H- (m, 2H), 7.63-7.74 (m, 4H), 7.80 NN
H N?
imidazol- (dd, J= 7.9, 1.8 Hz, 1H), 8.12 (s, N-1-y1)-5- 1H), 8.19 (s, 1H), ), 8.26 (d, J =
3((7,8-Dihydro-6H-pyrimido[5,4- (trifluoro 2.1 Hz, 1H), 10.58 (s, 1H);
b][1,4]oxazin-4-yl)oxy)-4-methyl- methyl)an LCMS: ESI 511 (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method N-(3-(4-methy1-1H-imidazol-1- iline y1)-5-(trifluoromethyl)phenyl)benzamid Method A
e or B

170. CI Al, Bl, 'I-1 NMR (400 MHz, DMSO-d6) H 3-(4- 6 2.15 (s, 3H), 3.49 (s, 2H), 4.18 methyl- (t, J
= 4.4 Hz, 2H), 7.43 (s, 2H), 1 ) 1H- 7.65 (m, 2H), 7.75 (s, 1H), 7.83¨
N
H N
imidazol- 7.94 (m, 2H), 8.05 (m, 2H), N
N¨\ 1-y1)-5- 8.13 (s, 1H), 10.74 (br, 1H);
4-Chloro-3-((7,8-dihydro-6H- (trifluoro LCMS: ESI (M+H)+ 531, 533.
pyrimido[5,4-b][1,4]oxazin-4- methyl)an yl)oxy)-N-(3-(4-methyl-1H- iline imidazol-1-y1)-5-(trifluoromethyl)phenyl)benzamid Method A
or B
e

171. a H Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) N r CF3 2-fluoro- 6 2.17 (s, 3H), 10.29 (s, 1H), 5- 3.48 (m, 2H), 4.17 (m, 2H), 4.17 NC:1 0 F W
1 j (trifluoro (m, 2H), 7.45 (d, J = 7.9 N N H
methyl)an Hz, 1H), 7.54 (t, J= 9.4 Hz, 1H), 3-((7,8-Dihydro-6H-pyrimido[5,4- iline 7.60-7.71 (m, 4H), 7.77 (dd, J =
b][1,4]oxazin-4-yl)oxy)-N-(2- 7.9, 1.8 Hz, 1H), 7.96-8.06 (m, fluoro-5-(trifluoromethyl)pheny1)- Method A 1H); LCMS: ESI (M+H)+ 459.
4-methylbenzamide or B

172. a Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) H
N 0 WO ..õ1. CF3 2-fluoro- 6 3.49 (s, 2H);
5- 4.18 (t, J = 4.3 Hz, 2H), 7.52 (t, J
i\jc,o, 0 F IW
I j (trifluoro = 9.4 Hz, 1H), 7.62 (s, 1H), 7.67 N N H
methyl)an (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 4-Chloro-3-((7,8-dihydro-6H- iline 7.77 (s, 1H), 7.82-7.91 (m, 2H), pyrimido[5,4-b][1,4]oxazin-4- 8.07 (d, J = 6.8 Hz, 1H), 10.44 yl)oxy)-N-(2-fluoro-5- Method A (s, 1H).
(trifluoromethyl)phenyl)benzamid or B
e

173. Al, B3, 1H NMR (400 MHz, 0 0 CFrN,I.- Cl D20) 6 1.34 (t, J = 7.4 Hz, 1\j*c,0 0 N 3H), 2.22 (s, 3H), 3.29 (q, J = 7.4 Method A Hz, 2H), 3.10-3.80 (m, 8H), 3.68 1 j N N or B
(br s, 2H), 4.28 (br s, 2H), 4.35 H (br s, 2H), 7.52 (d, J = 8.0 Hz, 3-((7,8-Dihydro-6H-pyrimido[5,4- 1H), 7.61 (s, 1H), 7.74 (d, J = 6.3 b][1,4]oxazin-4-yl)oxy)-N-(4-44-Hz, 2H), 7.75 (d, J = 8.0 Hz, ethylpiperazin-l-yl)methyl)-3-1H), 7.87 (d, J = 8.0 Hz, 1H), (trifluoromethyl)pheny1)-4-8.01 (s, 1H); LCMS: ESI
methylbenzamide (M+H)+ 557.

No. Intermed Analytical Data Structure and Name iates and Method

174. CI A, Al, Bl, lliNMR (400 MHz, D20) 6 1.34 C1 (t, J
= 7.5 Hz, 3H), 3.33 (q, J =
O WI N CFrN, 0 7.5 Hz, 2H), 3.40-3.80 (m, 8H), Method A 3.66 (t, J= 4.1 Hz, 2H), 4.32 (t, J
) NN = 4.1 Hz, 2H), 4.55 (s, 2H), 7.70 (d, J = 6.5 Hz, 2H), 7.75-7.82 4-Chloro-3-((7,8-dihydro-6H- (m, 4H), 7.84 (d, J = 7.8 Hz, 1H), pyrimido[5,4-b][1,4]oxazin-4- 8.02 (s, 1H); LCMS: ESI
yl)oxy)-N-(4-((4-ethylpiperazin-1- (M+H)+ 577.
yl)methyl)-3-(trifluoromethyl)phenyl)benzamid

175. CI Step 2- 1I-1 NMR (400 MHz, DMSO-d6) O WI N cF3 A7, 6 2.41 (t, J = 4.4 Hz, 4H), 3.23 (t, 0= Bl, C59 J = 4.4 Hz, 4H), 3.43-3.47 (m, 3H), 4.10 (t, J = 3.6 Hz, 2H), NN (N) Method 0 4.47 (t, J = 6.0 Hz, 2H), 4.57 (t, J
= 6.8 Hz, 2H), 6.10 (d, J = 5.6 Hz, 1H), 6.96 (s, 2H), 7.53 (d, J
0 = 5.6 Hz, 1H), 7.60 ( br s, 3H), 4-Chloro-3-((3,4-dihydro-2H- 7.77-7.84 (m, 2H), 10.39 (s, 1H);
pyrido[3,2-b][1,4]oxazin-8- ESI-MS (m/z) 590 (M+H)+.
yl)oxy)-N-(3-(4-(oxetan-3-yl)piperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid

176. CI Ai Step 1- NMR
(400 MHz, DMSO-d6) O WI N cF3 A7, 6 2.27 (s, 3H), 2.44-2.47 (br s, Bl, C19 4H), 3.19-3.21 (br s, 4H), 3.43 C ) (br s, 2H), 4.10 (t, J = 4.0 Hz, N N (N) Method 0 2H), 6.10 (d, J = 5.6 Hz, 1H), 6.96 (s, 2H), 7.53 (d, J = 5.6 Hz, 4-Chloro-3-((3,4-dihydro-2H-1H), 7.59 (s, 3H), 7.78-7.85 (m, pyrido[3,2-b][1,4]oxazin-8-2H), 10.38 (s, 1H); ESI-MS (m/z) 548 (M+H)+.
yl)oxy)-N-(3-(4-methylpiperazin-1-y1)-5 -(trifluoromethyl)phenyl)benzamid

177. H H Al, 4-1I-1 NMR (400 MHz, DMSO-d6) ci NN c3 = amino-2- 6 3.49 (br s, 2H), 4.18 (br s, 2H), chlorophe 7.19 (d, J= 8.8 Hz, 1H), 7.32 (d, N' nol, 3- J =
8.4 Hz, 2H), 7.52 (t, J = 8.0 (trifluoro Hz, 1H), 7.60 (d, J = 8.0 Hz, N N
methyl)an 1H), 7.66-7.68 (m, 2H), 7.78 (s, 1-(3-Chloro-4-((7,8-dihydro-6H- iline 1H), 8.01 (s, 1H), 9.0 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4- 9.15 (s, 1H); ESI-MS (m/z) 466 yl)oxy)pheny1)-3-(3- Method I (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method (trifluoromethyl)phenyl)urea

178. H H Al, 3- lli NMR (400 MHz, DMSO-d6) (trifluoro 6 3.48 (t, J= 4.4 Hz, 2H), 4.16 (t, 0 Wj methyl)an J = 4.4 Hz, 2H), 7.02-7.04 (m, NA' iline, 4- 2H), 7.31 (d, J = 8.8 Hz, 1H), ) aminophe 7.44-7.46 (m, 2H), 7.51 (t, J =
N N
H nylbenzyl 7.6 Hz, 1H), 7.58 (d, J= 8.8 Hz, 1-(4-((7,8-Dihydro-6H-carbonate 1H), 7.64 (s, 1H), 7.69 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4- 8.32 (s, 1H), 8.18 (s, 1H), 9.05 yl)oxy)pheny1)-3-(3- Method I' (s, 1H); ESI-MS (m/z) 432 (trifluoromethyl)phenyl)urea (M+H)+.

179. H H
Al, 4- lli NMR (400 MHz, DMSO-d6) 0 NN 40, cF3 aminophe 6 3.47-3.48 (br s, 2H), 4.16 (t, J
O ON nol, 4-= 8.8 Hz, 2H), 7.05 (d, J = 8.8 N:CXI0j amino-2- Hz, 2H), 7.47 (d, J = 9.2 Hz, (trifluoro 2H), 7.66 (s, 2H), 7.78 (d, J = 7.2 N N
H
methyl)be Hz, 1H), 8.04 (d, J = 8.4 Hz, 1-(4-Cyano-3-nzonitrile 1H), 8.22 (s, 1H), 9.08 (s, 1H), (trifluoromethyl)pheny1)-3-(4- 9.63 (s, 1H); ESI-MS (m/z) 457 ((7,8-dihydro-6H-pyrimido[5,4- Method I (M+H)+.
b] [1,4]oxazin-4-yl)oxy)phenyl)urea

180. CI Ai Al, Bl, 'H NMR
(400 MHz, DMSO-d6) H
N C83 6 1.81 (s, 6H), 3.52 (br s, 2H), O WI so cF3 4.21 (t, J = 4.0 Hz, 2H), 7.69 (s, NAC)) 0 ON Method D 1H), 7.78-7.89 (m, 3H), 7.90-N
H N 7.92 (m, 2H), 8.13 (dd, ./1 = 2.0 4-Chloro-N-(4-(2-cyanopropan-2-Hz, J2 = 8.8 Hz, 1H), 8.31 (s, 1H), 10.67 (s, 1H); ESI-MS (m/z) y1)-3-(trifluoromethyl)pheny1)-3-518 (M+H)+.
((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

181. ci A18, Bl, 'HNMR (400 MHz, DMSO-d6) H
oW NOCF3 3-6 2.42-2.44 (m, 6H), 3.59-3.61 N,10 (trifluoro (m, 4H), 3.81-3.83 (m, 1H), c 0 N J. N
methyl)an 4.09-4.19 (m, 2H), 7.48 (d, J =
iline 7.6 Hz, 1H), 7.61 (t, J = 8.0 Hz, H N 1H), 7.72-7.91 (m, 5H), 8.04 (d, ( ) Method A J= 8.0 Hz, Hz, 1H), 8.21 (s, 1H), (R)-4-Chloro-3-((7- 10.60 (s, 1H); ESI-MS (m/z) 550 (morpholinomethyl)-7,8-dihydro- (M+H)+.
6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

182. H H
Al, 4- 'll NMR (400 MHz, DMSO-d6) N N CN
40 X 40 aminophe 6 3.4 (br s, 2H), 4.16 (br s, 2H), 0 nol, 3- 7.01 (d, J =
8.0 Hz, 2H), 7.51 (d, N:N CX10) CF3 amino-5- J = 8.8 Hz, 2H), 7.69 (s, 2H), (trifluoro 7.78 (s, 1H), 8.12 (s, 1H), 8.23 N
H
methyl)be (s, 1H), 10.27 (br s, 2H); ESI-MS
1-(3 -Cyano-5 - nzonitrile (m/z) 457 (M+H)+.
(trifluoromethyl)pheny1)-3-(4-((7,8-dihydro-6H-pyrimido[5,4- Method I
b] [1,4]oxazin-4-yl)oxy)phenyl)urea

183. H H
AS, lli NMR (400 MHz, DMSO-d6) ci N N CF
4-amino- 6 0.85 (t, J = 6.4 Hz, 1H), 0.97 (t, WI Yo 01 0 2- J = 6.8 Hz, 3H), 1.17-1.28 (m, chlorophe 3H), 2.27-2.38 (m, 8H), 3.52 (br (N) nol, Cl s, 2H), 3.66-3.74 (m, 3H), 4.23 N N
H
(d, J = 9.2 Hz, 1H), 7.18 (t, J =
(R)-1-(3-Chloro-4-47-methyl-7,8- Method I 8.4 Hz, 1H), 7.31 (t, J = 9.2 Hz, dihydro-6H-pyrimido[5,4- 1H), 7.57-7.67 (m, 3H), 7.77 (s, b][1,4]oxazin-4-yl)oxy)pheny1)-3- 2H), 7.96 (s, 1H), 9.04 (s, 1H), (4-((4-ethylpip erazin-1- 9.18 (s, 1H); ESI-MS (m/z) 606 yl)methyl)-3- (M+H)+.
(trifluoromethyl)phenyl)urea

184. F H H
Al, 4- lli NMR (400 MHz, DMSO-d6) N N CF3 amino-3- 6 2.23 (s, 3H), 2.47 (br s, 4H), W Yo 0 fluorophe 3.16-3.20 (m, 4H), 3.48 (br s, N nol, C19 2H), 4.10-4.17 (m, 2H), 6.84 (s, CN) 1H), 6.91 (d, J = 9.2 Hz, 1H), N N
H I Method I 7.12-7.18 (m, 2H), 7.27 (s, 1H), 1-(4-((7,8-Dihydro-6H- 7.72 (s, 2H), 7.99 (t, J = 9.2 Hz, pyrimido[5,4-b][1,4]oxazin-4- 1H), 8.55 (s, 1H), 9.26 (s, 1H);
yl)oxy)-2-fluoropheny1)-3-(3-(4- ESI-MS (m/z) 548 (M+H)+.
methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)urea

185. CF3 Al, lli NMR (400 MHz, DMSO-d6) 0 0 methyl 4- 6 2.30 (s, 3H), 2.50-25.51 (br s, hydroxyb 4H), 3.25 (br s, 4H), 3.50 (d, J =
1.1 N N
c.,N, enzoate, 2.8 Hz, 2H), 4.17 (t, J = 4.4 Hz, C19 2H), 6.96 (s, 1H), 7.25 (d, J = 8.8 N:CiCo) Hz, 2H), 7.67 (d, J = 9.6 Hz, N N H 2H), 7.81 (s, 2H), 7.99 (d, J= 8.8 4-((7,8-Dihydro-6H-pyrimido[5,4- Method B Hz, 2H),10.33 (s, 1H); ESI-MS
b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- (m/z) 515 (M+H)t methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

186. cF3 Al, 1t1 NMR (400 MHz, DMSO-d6) methyl 4- 6 1.0 (t, J = 6.8 Hz, 3H), 2.41-hydroxyb 2.51 (m, 10H), 3.49-3.50 (br s, OP ri enzoate, 4H), 4.17 (t, J = 4.4 Hz, 2H), NOCl 7.25 (d, J = 8.8 Hz, 2H), 7.21 (d, I ) J =
8.4 Hz, 3H), 7.99 (d, J = 4.8 N N Method B Hz, 3H), 8.22 (s, 1H), 10.49 (s, H
4-((7,8-Dihydro-6H-pyrimido[5,4- 1H); ESI-MS (m/z) 543 (M)+.
b] [1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)b enzamid e

187. H H A7, 1H NMR (400 MHz, DMSO-d6) Al NN I. CF3 4- 6 2.23 (s, 3H), 2.44-2.49 (m, o aminophe 2H), 3.17-3.21 (m, 4H), 3.39-nol, C19 3.43 (m, 4H), 4.08-4.12 (m, 2H), 1 ) (NJ 6.01 (d, J = 5.6 Hz, 1H), 6.76-N N
H I Method I 6.83 (m, 2H), 6.97 (d, J = 8.8 Hz, 1-(4-((3,4-Dihydro-2H- 2H), 7.20-7.29 (m, 2H), 7.42-pyrido[3,2-b][1,4]oxazin-8- 7.49 (m, 3H), 8.76 (s, 1H), 8.87 yl)oxy)pheny1)-3-(3-(4- (s, 1H); ESI-MS (m/z) 529 methylpiperazin-l-y1)-5- (M+H)+.
(trifluoromethyl)phenyl)urea

188. H H A7, 1H NMR (400 MHz, DMSO-d6) Al Ny N 0 CF3 4- 6 0.98 (t, J = 7.2 Hz, 3H), 2.30-aminophe 2.40 (m, 10H), 3.17 (d, J = 5.2 c,lo I j N
) nol, Cl Hz, 1H), 3.39-3.44 (m, 2H), 3.53 C
(s, 2H), 4.09-4.11 (m, 2H), 6.01 1\1 N N Method I (d, J = 4.4 Hz, 1H), 6.76 (s, 1H), H
6.97 (d, J = 8.8 Hz, 2H), 7.46 1-(4-((3,4-Dihydro-2H-(dd, Ji =1.6 Hz, ./i = 7.2 Hz, 2H), pyrido[3,2-b][1,4]oxazin-8- 7.56 (d, J = 8.4 Hz, 1H), 7.62 (d, yl)oxy)pheny1)-3-(4((4- J =
8.4 Hz, 1H), 7.97 (d, J = 2.0 ethylpiperazin-l-yl)methyl)-3- Hz, 1H), 8.77 (s, 1H), 8.98 (s, (trifluoromethyl)phenyl)urea 1H); ESI-MS (m/z) 557 (M+H)+.

189. CI Ai Al, Bl, 1H NMR (400 MHz, DMSO-d6) H
O N 0 cF3 C84 6 2.28 (s, 6H), 3.11 (s, 2H), 3.51-3.52 (m, 2H), 4.20 (t, J= 4.4 Hz, N c,1:2 0 I ) HN,0 2H), 7.76 (d, J = 8.8 Hz, 1H), N N
H L Method B 7.81-7.83 (m, 3H), 7.88-7.90 (m, 1\1 3H), 8.46 (s, 1H), 10.15 (s, 1H), I 10.60 (s, 1H); ESI-MS (m/z) 551 4-Chloro-3-((7,8-dihydro-6H-(M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(2-(dimethylamino)acetamido)-5-(trifluoromethyl)phenyl)benzamid No. Intermed Analytical Data Structure and Name iates and Method e

190. CI Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H

6 0.84 (d, J = 6.0 Hz, 6H), 2.23-0 0 2.26 (m, 1H), 3.11-3.40 (m, 5H), )):
N ' j HN TO 3.51-3.52 (br s, 2H), 4.21 (t, J =
N N
6 4.0 Hz, 2H), 7.69-7.90 (m, 6H), 8.40 (s, 1H), 10.30 (s, 1H), 10.59 H
Method B
N (s, 1H); ESI-MS (m/z) 591 (M+H)+.
N-(3-(4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamido)-5-(trifluoromethyl)pheny1)-1-isopropylazetidine-3-carboxamide

191. a A19, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O N 0 CF3 Cl 6 0.98 (t, J = 7.2 Hz, 3H), 2.30-Nj):0 0 2.51 (m, 10H), 3.33-3.60 (m, I N)=''OH (N) Method A 5H), 4.12-4.21 (m, 2H), 5.06-N
5.08 (m, 1H), 7.71-7.90 (m, 6H), H
) 8.01-8.04 (m, 1H), 8.17 (s, 1H), 10.54 (s, 1H); ESI-MS (m/z) 607 (S)-4-Chloro-N-(4-((4- (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)pheny1)-3-47-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

192. a H Al, B2, 1I-1 NMR (400 MHz, DMSO-d6) 6 2.24 (s, 3H), 2.50 (br s, 4H), 3.21 (br s, 4H), 3.50 (br s, 2H), I ) N Method B 4.18 (t, J = 4.0 Hz, 2H), 6.96 (s, N N
H CN) 1H), 7.36 (dd, ./i =1.6 Hz, J1 =
I 7.2 Hz, 1H), 7.56 (d, J =
8.0 Hz, 3-((7,8-Dihydro-6H-pyrimido[5,4- 1H), 7.63-7.74 (m, 4H), 7.78-b] [1,4]oxazin-4-yl)oxy)-N-(3-(4- 7.82 (m, 2H), 10.34 (s, 1H);
methylpiperazin-l-y1)-5- ESI-MS (m/z) 515 (M+H)+.
(trifluoromethyl)phenyl)benzamid e

193. CI Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O N I* CF3 C88 6 3.52 (br s, 2H), 4.21 (t, J = 4.4 Hz, 2H), 7.59-7.60 (m, 2H), NO
I ) Method B 7.78-7.80 (m, 3H), 7.89-7.91 (m, N N I I
3H), 8.24 (s, 1H), 8.35 (s, 1H), H
8.67 (d, J = 5.6 Hz, 2H), 10.70 I (s, 1H); ESI-MS (m/z) 552 N (M+H)+.
4-Chloro-3-((7,8-dihydro-6H-No. Intermed Analytical Data Structure and Name iates and Method pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(pyridin-4-ylethyny1)-5-(trifluoromethyl)phenyl)benzamid e

194. F H H
Al, 4- 1I-1 NMR (400 MHz, DMSO-d6) N N CF3 amino-3- 6 0.98 (t, J = 7.2 Hz, 3H), 2.28-0 WI Yo 110 fluorophe 2.33 (m, 10H), 3.48 (br s, 4H), N ' Cll N nol, Cl 4.16 (t, J = 4.0 Hz, 2H), 6.91 (d, )): ) ( ) J =
9.2 Hz, 1H), 7.14 (dd, Ji =2.8 N N N Method I Hz, J, = 12.0 Hz, 1H), 7.54 (d, J
H
= 8.8 Hz, 1H), 7.64 (d, J = 8.4 1-(4-((7,8-Dihydro-6H-Hz, 1H), 7.72 (s, 2H), 7.98-8.03 pyrimido[5,4-b][1,4]oxazin-4-(m, 2H), 8.56 (s, 1H), 9.33 (s, yl)oxy)-2-fluoropheny1)-3-(444-1H); ESI-MS (m/z) 576 (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyOurea

195. CI al A, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
0 WI N 0 CF3 C86 6 2.11 (s, 6H), 3.16-3.22 (m, NO 1H), 3.51-3.52 (br s, 2H), 3.61 (t, c, 0 I j N J =
5.2 Hz, 2H), 3.96 (t, J = 7.2 N N H Hz, 2H), 4.20 (t, J = 4.4 Hz, 2H), ? Method B 6.43 (s, 1H), 7.16 (s, 1H), 7.48 (s, 1H), 7.69 (s, 1H), 7.75 (d, J =
4-Chloro-3-((7,8-dihydro-6H-8.8 Hz, 1H), 7.86 (s, 1H), 7.88-pyrimido[5,4-b][1,4]oxazin-4-7.93 (m, 2H), 10.34 (s, 1H);
yl)oxy)-N-(3-(3-ESI-MS (m/z) 549 (M+H)+.
(dimethylamino)azetidin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

196. CI H Step 2-1I-1 NMR (400 MHz, DMSO-d6) N 0 CF3 A7, 6 0.98 (t, J = 6.8 Hz, 3H), 2.27-Bl, Cl 2.38 (m, 10H), 3.43 (br s, 2H), I ) N 3.55 (s, 2H), 4.12 (d, J = 4.8 Hz, I\JN
H C ) Method 0 2H), 6.10 (d, J = 5.2 Hz, 1H), N 6.95 (s, 1H), 7.53 (d, J = 5.6 Hz, 2H), 7.61 (s, 1H), 7.70 (d, J = 8.4 4-Chloro-3-((3,4-dihydro-2H- Hz, 1H), 7.82-7.85 (m, 1H), 7.99 pyrido[3,2-b][1,4]oxazin-8- (d, J=
8.8 Hz, 1H), 8.15 (s, 1H), yl)oxy)-N-(4-((4-ethylpiperazin-1- 10.55 (s, 1H) ;ESI-MS (m/z) 576 yl)methyl)-3- (M+H)+.
(trifluoromethyl)phenyl)benzamid e No. Intermed Analytical Data Structure and Name iates and Method

197. H H Al, 4- 1t1 NMR (400 MHz, DMSO-d6) N N
40 'or 40 aminophe 6 1.24 (t, J = 6.4 Hz, 3H), 3.17-O nylbenzyl 3.41 (m, 6H), 3.51 (m, 2H), 3.57-N
carbonate, 3.69 (m, 4H), 4.18-4.19 (br s, r ) ) L N ) C28 2H), 4.33 (br s, 2H), 7.04 (d, J =
N N
H
7.2 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1-(4-((7,8-Dihydro-6H- Method I' 2H), 7.51-7.56 (m, 4H), 7.82 (m, pyrimido[5,4-b][1,4]oxazin-4- 2H), 9.29-9.51 (m, 2H); ESI-MS
yl)oxy)pheny1)-3-(444- (m/z) 490 (M+H)+.
ethylpiperazin-l-yl)methyl)phenyl)urea

198. CI H H Al, 4- 1H NMR
(400 MHz, DMSO-d6) Ai NN

amino-3- 6 0.98 (t, J = 7.2 Hz, 3H), 2.29-chlorophe 2.39 (m, 10H), 3.49 (br s, 4H), 0 N nol, Cl 4.16 (t, J = 4.4 Hz, 2H), 7.08 (dd, 1\1CX
I ) (N) Ji =
2.40 Hz, .1-2 = 8.8 Hz, 1H), N N
Method I 7.31 (s, 1H), 7.56 (d, J= 8.4 Hz, H
C
1H),7.64 (d, J = 8.4 Hz, 1H), 1-(2-Chloro-4-((7,8-dihydro-6H-7.73 (s, 2H), 7.99 (s, 1H), 8.05 pyrimido[5,4-b][1,4]oxazin-4-(dd, J = 8.8 Hz, 1H), 8.40 (s, yl)oxy)pheny1)-3-(444-1H), 9.70 (s, 1H); ESI-MS (m/z) ethylpiperazin-l-yl)methyl)-3-592 (M+H)+.
(trifluoromethyl)phenyl)urea

199. H H
A7, 1H NMR (400 MHz, DMSO-d6) NN 40 is 0 4- 6 0.98 (t, J = 7.2 Hz, 3H), 2.30-aminophe 2.40 (m, 10H), 3.35-3.45 (m, X ,0 N
CN ) nol, C28 5H), 4.10 (s, 2H), 6.00 (d, J = 5.6 Hz, 1H), 6.75 (s, 1H), 6.97 (d, J
N N
H
C = 8.4 Hz, 2H), 7.18 (d, J = 8.0 1-(4-((3,4-Dihydro-2H- Hz, 2H), 7.39 (d, J= 8.0 Hz, 2H), pyrido[3,2-b][1,4]oxazin-8- 7.43-7.47 (m, 2H), 8.65 (s, 1H), yl)oxy)pheny1)-3-(4((4- 8.69 (s, 1H); ESI-MS (m/z) 489 ethylpiperazin-1- (M+H)+.
yl)methyl)phenyl)urea

200. a H
Al, B3, 1H NMR (400 MHz, DMSO-d6) 6 2.19 (s, 3H), 3.581 (br s, 2H), 0 4.20 (t, J = 4.0 Hz, 2H), 6.72 (d, Method B J = 16.0 Hz, 1H), 7.23 (s, 1H), NN /
H 7.45-7.49 (m, 2H), 7.69-7.72 (m, H2N 0 5H), 7.82 (d, J = 2.0 Hz, 1H), (E)-N-(3 -(3 -Amino-3 -oxoprop-1- 8.16 (s, 1H), 8.34 (s, 1H), 10.54 en-1-y1)-5- (s, 1H); ESI-MS (m/z) 500 (trifluoromethyl)pheny1)-347,8- (M+H)+.
dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide No. Intermed Analytical Data Structure and Name iates and Method

201. a H Al, B3, lli NMR (400 MHz, DMSO-d6) 6 2.19 (s, 3H), 3.51 (s, 2H), 4.20 N:CXI0j 0 (s, 2H), 7.49 (d, J = 6.8 Hz, 1H), Method B 7.64-7.73 (m, 4H), 7.80-7.81 (m, H 2H), 8.26 (s, 2H), 8.34 (s, 1H), 0 NH2 10.59 (s, 1H); ESI-MS (m/z) 498 N-(3 -(3 -Amino-3 -oxoprop-1-yn-1- (M+H)+.
y1)-5-(trifluoromethyl)pheny1)-3-47,8-dihydro-6H-pyrimido[5,4-b] [1,4]oxazin-4-yl)oxy)-4-methylbenzamide

202. H H
A20, 4- lli NMR (400 MHz, DMSO-d6) aminophe 6 1.02 (m, 3H), 1.24 (br s, 2H), 0 nol, Cl 1.90 (br s, 2H), 2.50 (br s, 5H), rL re/C1) CN N
) 3.34-3.41 (m, 5H), 3.54 (s, 2H), Method I 3.99 (t, J = 5.2 Hz, 2H), 6.16 (d, NI\I
H
) 1-(4-((4- J = 5.6 Hz, 2H), 6.98 (d, J
= 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, Ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)pheny1)-3-(4-2H), 7.59-7.63 (m, 3H), 7.97 (s, 1H), 8.84 (s, 1H), 9.05 (s, 1H);
((2,3,4,5-tetrahydropyrido[3,2-ESI-MS (m/z) 571 (M+H)+.
b][1,4]oxazepin-9-yl)oxy)phenyl)urea

203. H H
A21, lli NMR (400 MHz, DMSO-d6) NCn14N N CF3 11 C)r 1.1 benzyl (4- 6 1.01 (t, J = 7.2 Hz, 3H), 2.42 0 hydroxyp (br s, 10H), 3.33 (br s, 2H), 3.54 O N
henyl)car (br s, 2H), 4.04 (d, J = 8.0 Hz, 1 ) (N) bamate, 2H), 6.91 (d, J =
9.2 Hz, 2H), N N
H
Cl 7.41 (d, J= 9.2 Hz, 2H), 7.57 (d, 1-(4-((7-Cyano-3,4-dihydro-2H- J =
8.4 Hz, 1H), 7.62 (d, J = 8.4 pyrido[3,2-b][1,4]oxazin-8- Method P Hz, 1H), 7.96 (s, 1H), 8.10 (s, yl)oxy)pheny1)-3-(4((4- 2H), 8.79 (s, 1H), 9.04 (s, 1H);
ethylpiperazin-l-yl)methyl)-3- ESI-MS (m/z) 582 (M+H)+.
(trifluoromethyl)phenyl)urea

204. a H
Al, B3, lli NMR (400 MHz, DMSO-d6) 6 2.19 (s, 3H), 3.51 (br s, 2H), NOc, 0 4.20 (t, J = 4.0 Hz, 2H), 6.60 (d, 1 j Method B J = 16.8 Hz, 1H), 7.48 (d, J = 8.0 N N /
H CN Hz, 1H), 7.68-7.83 (m, 6H), 8.25 (E)-N-(3-(2-Cyanoviny1)-5- (d, J
= 14.8 Hz, 2H), 10.59 (s, (trifluoromethyl)pheny1)-347,8- 1H); ESI-MS (m/z) 482 (M+H)+.
dihydro-6H-pyrimido[5,4-b] [1,4]oxazin-4-yl)oxy)-4-methylbenzamide No. Intermed Analytical Data Structure and Name iates and Method

205. H H
Al, 4- 'I-1 NMR (400 MHz, DMSO-d6) aminophe 6 1.25 (t, J = 7.2 Hz, 3H), 3.17-VI Yo 1101 nylbenzyl 3.68 (m, 13H), 4.18 (t, J = 4.0 N' C:Il HCI N
carbonate, Hz, 2H), 4.45 (m, 2H), 7.05 (d, J
) C10 = 8.8 Hz, 2H), 7.47 (d, J = 9.2 N N
H Hz, 2H), 7.81 (d, J = 6.4 Hz, 1-(4-((7,8-Dihydro-6H- Method I' 2H), 8.09 (s, 2H), 9.61 (s, 1H), pyrimido[5,4-b][1,4]oxazin-4- 9.82 (s, 1H), 11.50 (br s, 1H);
yl)oxy)pheny1)-3-(344- ESI-MS (m/z) 558 (M+H)+.
ethylpiperazin-l-yl)methyl)-5-(trifluoromethyl)phenyl)urea hydrochloride

206. AS, 4- 1I-1 NMR (400 MHz, DMSO-d6) H H

aminophe 6 1.06 (s, 3H), 1.17 (d, J = 6.4 VI Yo 40 nylbenzyl Hz, 6H), 2.50-2.51 (m, 8H), 3.56 O carbonate (br s, 2H), 3.65-3.73 (m, 2H), NO N
I ) ,Cl 4.22 (dd, J1 = 2.4 Hz, J2 = 7.2 CN
NN Hz, 2H), 7.45 (dd, J1 = 2.4 Hz, H
Method I' J2 = 6.8 Hz, 2H), 7.60-7.63 (m, (R) - 1-(4-((4-Ethylpip erazin-1- 2H), 7.72 (d, J = 6.0 Hz, 2H), yl)methyl)-3- 7.07 (s, 1H), 8.90 (s, 1H), 9.15 (trifluoromethyl)pheny1)-3-(4-47- (s, 1H); ESI-MS (m/z) 572 methyl-7,8-dihydro-6H- (M+H)+.
pyrimido [5 ,4-b] [1,4]oxazin-4-yl)oxy)phenyl)urea

207. a Example 1I-1 NMR (400 MHz, DMSO-d6) H
ow Ns cF3 163 6 0.85-1.24 (m, 9H), 2.28-2.34 No 0 cH3 (br s, 6H), 3.51 (br s, 3H), 3.70-1 N Chiral 3.76 (m, 3H), 4.27 (d, J = 10.8 NN ( ) separation Hz, 2H), 7.71 (d, J = 3.6 Hz, H
N 3H), 7.78 (t, J = 3.6 Hz, 2H), ) 7.89 (br s, 1H), 8.06 (d, J = 9.2 4-Chloro-N-(4-(1-(4- Hz, 1H), 8.15 (s, 1H), 10.55 (s, ethylpiperazin-l-yl)ethyl)-3- 1H);
ESI-MS (m/z) 605 (M)+;
(trifluoromethyl)pheny1)-3 -(((R)- chiral purity: 98.45%.
7-methy1-7,8-dihydro-6H-pyrimido [5 ,4-b] [1,4]oxazin-4-yl)oxy)benzamide (Isomer I) No. Intermed Analytical Data Structure and Name iates and Method

208. Example 11-1 NMR (400 MHz, DMSO-d6) ci Ai H 163 6 1.18-1.30 (m, 9H), 2.30-2.50 N I* CF3 (m, 6H), 3.51-3.65 (m, 3H), 0 cH3 Chiral 3.69-3.78 (m, 3H), 4.26 (d, J =

separation 8.0 Hz, 2H), 7.71-7.79 (m, 3H), N N H CN) 7.89-7.90 (m, 3H), 8.08 (d, J =
8.0 Hz, 1H), 8.15 (s, 1H), 10.57 ) (s, 1H); ESI-MS (m/z) 605 (M)+;
4-Chloro-N-(4-(1-(4- chiral purity: 99.48%.
ethylpip erazin-l-yl)ethyl)-3-(trifluoromethyl)pheny1)-3 -(((R)-7-methy1-7,8-dihydro-6H-pyrimido [5 ,4-b] [1,4]oxazin-4-yl)oxy)benzamide (Isomer II)

209. ON
A7, 1H NMR (400 MHz, DMSO-d6) * benzyl (4- 6 1.29 (s, 9H), 3.40 (br s, 2H), hydroxyp 4.09 (t, J = 4.4 Hz, 2H), 6.00 (d, H H
N N N
henyl)car J = 5.6 Hz, 1H), 6.41 (s, 1H), 0 lr 1 IN
bamate, 6.76 (s, 1H), 6.95 (d, J = 9.2 Hz, C91 2H), 7.40 (d, J = 9.2 Hz, 1H), 1 ) 7.46 (d, J = 5.6 Hz, 2H), 7.80 (d, N N Method I" J = 8.8 Hz, 2H), 7.99 (d, J = 8.8 H
1 -(3-(tert-Buty1)-1-(4-Hz, 2H), 8.55 (s, 1H), 9.06 (s, +
cyanopheny1)-1H-pyrazol-5 -y1)-3 - 1H); ESI-MS (m/z) 510 (M+H).
(4-43,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazin-8-yl)oxy)phenyl)urea

210. H H AS, 4- 1H NMR (400 MHz, DMSO-d6) ci a NYN -(----- amino-2- 6 1.17 (d, J = 6.4 Hz, 3H), 1.13 0 chlorophe (s, 9H), 3.67-6.74 (m, 2H), 4.25 R
N Cj( nol, 5- (dd, Ji = 2.4 Hz, J2 = 10.0 Hz, (tert- 1H), 6.51 (s, 1H), 7.20 (d, J =
N N
H
butyl)isox 8.8 Hz, 1H), 7.29 (dd, J1 = 2.4 (R)-1-(5-(tert-Butypisoxazol-3- azol-3- Hz, J2 = 8.8 Hz, 1H), 7.67 (s, y1)-3-(3-chloro-44(7-methyl-7,8- amine 1H), 7.79 (s, 2H), 9.02 (s, 1H), dihydro-6H-pyrimido[5,4- Method I 9.63 (s, 1H); ESI-MS (m/z) 459 b] [1,4]oxazin-4- (M+H)+.
yl)oxy)phenyl)urea

211. H H
A7, 1H NMR (400 MHz, DMSO-d6) laNYN ----(-- benzyl (4- 6 1.29 (s, 9H), 3.39-3.42 (m, hydroxyp 2H), 4.10 (t, J = 4.0 Hz, 2H), C,0 henyl)car 6.03 (d, J = 5.6 Hz, 1H), 6.49 (s, 1 j bamate, 1H), 6.78 (s, 1H), 6.96-6.99 (m, N N
H 5-(tert- 2H), 7.43-7.47 (m, 3H), 8.81 (s, 1-(5-(tert-Butyl)isoxazol-3-y1)-3-butyl)isox 1H), 9.49 (s, 1H); ESI-MS (m/z) (4-((3 ,4-dihydro-2H-pyrido [3,2- azol-3- 410 (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method b] [1,4]oxazin-8- amine yl)oxy)phenyl)urea Method I"

212. H H A26, 1H NMR
(400 MHz, DMSO-d6) benzyl (4- 6 1.17 (t, J = 7.2 Hz, 3H), 3.13-O W
hydroxyp 4.0 (m, 16H), 4.26 (t, J = 4.0 Hz, N henyl)car 2H), 6.89 (m, 1H), 7.0 (d, J = 8.8 cj) N bamate, Hz, 2H), 7.42 (s, 1H), 7.45-7.47 . HCI
HN) Cl (m, 2H), 7.65 (d, J= 9.6 Hz, 1H), , >
1-(4-((3,4-Dihydro-2H- 7.87 (m, 1H), 8.03 (br s, 1H), pyrido[3,2-b][1,4]oxazin-7- 9.57-9.61 (m, 1H), 10.03 (br s, yl)oxy)pheny1)-3-(4((4- Method I" 1H); ESI-MS (m/z) 557 (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)urea

213. 0 H
A7, B3, 1H NMR (400 MHz, DMSO-d6) 0 N,ci...¶_ 5-(tert- 6 1.31 (s, 9H), 2.27 (s, 3H), 3.42 ),o 0 N-0 I ) butyl)isox (br s, 2H), 4.10 (t, J = 4.0 Hz, azol-3- 2H), 6.02 (d, J = 5.6 Hz, 1H), *NI N
H amine 6.69 (s, 1H), 6.84 (s, 1H), 7.45 N-(5-(tert-Butyl)isoxazol-3-y1)-3- (d, J
= 8.0 Hz, 1H), 7.50 (d, J =
((3,4-dihydro-2H-pyrido[3,2- Method B 5.6 Hz, 2H), 7.78 (dd, J1 = 1.6 b] [1,4]oxazin-8-yl)oxy)-4- Hz, J2 = 7.6 Hz, 1H), 11.32 (s, methylbenzamide 1H); ESI-MS (m/z) 409 (M+H)+.

214. CI a A22, Bl, 1H NMR (400 MHz, DMSO-d6) H
O N CF3 Cl 6 0.86 (t, J = 6.4 Hz, 3H), 2.28-N j10) 0 1 1\1).'() N 2.51 (m, 10H), 3.33 (d, J = 6.8 Method A Hz, 3H), 3.40-3.47 (m, 2H), 3.56 H ci) (s, 2H), 3.79-3.81 (br s, 1H), 4.14 ) (t, J= 3.6 Hz, 2H), 7.70-7.78 (m, 3H), 7.88-8.02 (m, 2H), 8.08 (d, (R)-4-Chloro-N-(4-((4- J =
11.6 Hz, 2H), 8.17 (s, 1H), ethylpiperazin-1-yl)methyl)-3- 10.55 (s, 1H); ESI-MS (m/z) 621 (trifluoromethyl)pheny1)-3-47- (M+H)+.
(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

215. CI Ai A23, Bl, 1H NMR (400 MHz, DMSO-d6) H
O WI N 0 CF3 Cl 6 0.98 (t, J = 7.2 Hz, 3H), 2.22 (s, 6H), 2.27-2.51 (m, 12 H), Method A 3.56 (s, 2H), 3.74-3.75 (br s, 1H), I
NN'I\I (NJ
4.08 (dd, J1 = 4.8 Hz, J2 = 11.2 H
N Hz, 1H), 4.14-4.18 (m, 1H), ) 7.70-7.78 (m, 4H), 7.88-7.90 (m, (R)-4-Chloro-3-((7- 2H), 8.02 (dd, J1 = 1.6 Hz, .1-2 =
((dimethylamino)methyl)-7,8- 12.0 Hz, 1H), 8.17 (s, 1H), 10.55 dihydro-6H-pyrimido[5,4- (s, 1H); ESI-MS (m/z) 634 b] [1,4]oxazin-4-yl)oxy)-N-(4-((4- (M+H)+.

No. Intermed Analytical Data Structure and Name iates and Method ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)benzamid e

216. H H
A5 , 4- 1H NMR (400 MHz, DMSO-d6) y amino-2- 6 1.17 (d, J = 6.0 Hz, 3H), 1.24 F Ai NN 0 CF3 fluorophe (br s, 3H), 2.50-2.61 (m, 10H), 0 N nol, Cl 3.56-3.75 (m, 4H), 4.23 (d, J =
N'CX, 1 (R C ) 8.0 Hz, 1H), 7.12-7.22 (m, 2H), N N N
H Method I 7.57-7.68 (m, 4H), 7.77 (s, 1H), (R)-1-(4-((4-Ethylpiperazin-1- 7.95 (s, 1H), 9.42 (s, 1H), 9.50 yl)methyl)-3- (s, 1H); ESI-MS (m/z) 590 (trifluoromethyl)pheny1)-3-(3- (M+H)+.
fluoro-447-methy1-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea

217. F H H
A20, 1H NMR (400 MHz, DMSO-d6) w benzy1 (2- 6 0.98 (t, J = 7.2 Hz, 3H), 1.90 AI NN s CF3 0 fluoro-4- (br s, 2H), 2.30-2.38 (m, 10H), ((C)) N
c) hydroxyp 3.23 (s, 2H), 3.53 (s, 2H), 3.97 (t, henyl)car J = 5.6 Hz, 2H), 6.22 (s, 1H), N N
H > bamate, 6.27 (d, J = 5.2 Hz, 1H), 6.82 (d, 1-(4-((4-Ethylpiperazin-1- Cl J =
9.2 Hz, 1H),7.05 (dd, J1= 2.8 yl)methyl)-3- Hz, J2 = 12.0 Hz, 1H), 7.53 (d, J
(trifluoromethyl)pheny1)-3-(2- Method I" = 8.0 Hz, 1H), 7.63-7.65 (m, fluoro-4-((2,3,4,5- 2H), 7.98-8.04 (m, 2H), 8.53 (s, tetrahydropyrido[3,2- 1H), 9.30 (s, 1H); ESI-MS (m/z) b] [1,4]oxazepin-9- 589 (M+H)+.
yl)oxy)phenyl)urea

218. jib ON
A7, B3, 1H NMR (400 MHz, DMSO-d6) C92 6 1.30 (s, 9H), 2.26 (s, 3H), 3.40 140N N (br s, 2H), 4.08 (br s, 2H), 6.0 (d, 0 1 11) 0 ,N
Method D J = 5.6 Hz, 1H), 6.44 (s, 1H), c N N
6.86 (s, 1H), 7.32 (s, 1H), 7.44-H 7.49 (m, 2H), 7.63-7.65 (m, 2H), N-(3-(tert-Butyl)-1-(3- 7.78 (d, J = 6.8 Hz, 1H), 7.84 (d, cyanopheny1)-1H-pyrazol-5-y1)-3- J =
7.6 Hz, 1H), 7.95 (s, 1H), ((3,4-dihydro-2H-pyrido[3,2- 10.39 (s, 1H); ESI-MS (m/z) 509 b] [1,4]oxazin-8-yl)oxy)-4- (M+H)+.
methylbenzamide

219. ON
A7, B3, 1H NMR (400 MHz, DMSO-d6) 410 C91 6 1.30 (s, 9H), 2.51 (s, 3H), 3.41 Method D (br s, 2H), 4.09 (br s, 2H), 6.02 0 N (d, J = 4.8 Hz, 1H), 6.47 (s, 1H), 0 1 iN 6.86 (s, 1H), 7.34 (s, 1H), 7.46 1 j (d, J
= 8.0 Hz, 1H), 7.51 (d, J =
N'N H 5.6 Hz, 1H), 7.64 (d, J = 6.4 Hz, No. Intermed Analytical Data Structure and Name iates and Method N-(3-(tert-Butyl)-1-(4- 1H), 7.72 (d, J = 8.0 Hz, 2H), cyanopheny1)-1H-pyrazo1-5-y1)-3- 7.91 (d, J = 8.4 Hz, 2H), 10.45 ((3,4-dihydro-2H-pyrido[3,2- (s, 1H); ESI-MS (m/z) 509 b][1,4]oxazin-8-yl)oxy)-4- (M+H)+.
methylbenzamide

220. CI H
A5 , Bl, 1I-1 NMR (400 MHz, DMSO-d6) N 3-(4- 6 1.18 (d, J = 6.4 Hz, 3H), 2.22 Ntc0 0 IW methylpip (s, 3H), 2.45 (br s, 4H), 3.11 (br I N erazin-1- s, 4H), 3.69-3.77 (m, 2H), 4.25 N N CN) yl)aniline (d, J= 10.0 Hz, 1H), 6.71 (d, J =
H
8.4 Hz, 1H), 7.16 (t, J = 8.0 Hz, I
1H), 7.24 (d, J = 7.6 Hz, 1H), (R)-4-Chloro-347-methy1-7,8-Method B 7.35 (s, 1H), 7.70-7.74 (m, 2H), dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-7.86 (d, J = 8.4 Hz, 3H), 10.12 methylpiperazin-1-(s, 1H); ESI-MS (m/z) 495 +
yl)phenyl)benzamide (M+H).

221. I
AS, Bl, 1I-1 NMR (400 MHz, DMSO-d6) rN
CI L ) C99 6 1.18 (d, J =
6.0 Hz, 3H), 2.15 la H N (s, 3H), 2.40 (br s, 4H), 2.92 (br N
0 Method B s, 4H), 3.69-3.77 (m, 2H), 4.26 N 0 VI (d, J
= 8.4 Hz, 1H), 7.37 (d, J =
L I rp VI 3 8.4 Hz, 1H), 7.51 (d, J=
8.8 Hz, 1\1N
H 1H), 7.73-7.85 (m, 4H), 7.91 (s, (R)-4-Chloro-3((7-methy1-7,8- 1H), 8.22 (s, 1H), 9.71 (s, 1H);
dihydro-6H-pyrimido[5,4- ESI-MS (m/z) 563 (M+H)+.
b][1,4]oxazin-4-yl)oxy)-N-(2-(4-methylpiperazin-l-y1)-5-(trifluoromethyl)phenyl)benzamid e

222. a H
Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) O N 40 cF3 C96 6 2.19 (s, 3H), 3.51-3.52 (br s, i\ijp0 2H), 4.10-4.12 (m, 2H), 4.21 (t, J
1 ) Method D = 4.0 Hz, 2H), 5.43 (t, J = 6.0 H Hz, 1H), 7.48 (d, J = 8.4 Hz, HO 2H), 7.7.3-7.79 (m, 3H), 7.81 (d, 3-((7,8-Dihydro-6H-pyrimido[5,4- J =
1.6 Hz, 1H), 8.19 (d, J = 8.0 b][1,4]oxazin-4-yl)oxy)-N-(3-(3- Hz, 2H), 10.51 (s, 1H); ESI-MS
hydroxyprop-1-yn-l-y1)-5- (m/z) 485 (M+H)+.
(trifluoromethyl)pheny1)-4-methylbenzamide

223. CI H H AS, 4- 1I-1 NMR (400 MHz, DMSO-d6) NNv amino-3- 6 0.41-0.43 (m, 2H), 0.64-Ø68 O chlorophe (m, 2H), 1.17 (d, J= 6.4 Hz, 3H), I

nylbenzyl 2.51-2.59 (m, 1H), 3.66-3.74 (m, I\&(Rcarbonate, 2H), 4.21 (dd, J1 = 2.8 Hz, J2 =
N N
H cycloprop 9.2 Hz, 1H), 7.03 (dd, J1 = 2.8 No. Intermed Analytical Data Structure and Name iates and Method (R)-1-(2-Chloro-4-47-methyl-7,8-anamine Hz, J2 = 9.2 Hz, 1H), 7.11 (d, J
dihydro-6H-pyrimido[5,4- = 2.8 Hz, 1H), 7.24 (d, J = 2.8 b][1,4]oxazin-4-yl)oxy)pheny1)-3- Hz, 1H), 7.73 (s, 1H), 7.79 (s, cyclopropylurea Method I' 1H), 7.87 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H); ESI-MS (m/z) 376 (M+H)+.

224. CI
A24 , Bl, 1H NMR (400 MHz, DMSO-d6) =N CF3 Cl 6 0.99 (t, J = 6.4 Hz, 3H), 2.33-0 IW 2.34 (m, 10H), 4.10 (br s, 4H), N N 4.21 (t, J= 4.40 Hz, 2H), 7.73 (d, CI
CrI) Method A J = 8.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.93 (s, 2H), 8.03 (d, J
4-Chloro-3-((2-chloro-7,8- = 8.4 Hz, 1H), 8.18 (s, 1H), 8.35 dihydro-6H-pyrimido[5,4- (s, 1H), 10.59 (s, 1H); ESI-MS
b][1,4]oxazin-4-yl)oxy)-N-(4-((4- (m/z) 611 (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)benzamid

225. H H A4, 4-1H NMR (400 MHz, DMSO-d6) aminophe 6 1.10 (t, J = 7.2 Hz, 3H), 1.23 W To 10 nylbenzy1 (s, 6H), 2.37-2.41 (m, 8H), 3.54 carbonate, (m, 4H), 3.84 (s, 2H), 7.05 (d, J
CNJ Cl = 8.8 Hz, 2H), 7.46 (d, J =
8.8 N
Hz, 2H), 7.59-7.64 (m, 2H), 1-(4((7,7-Dimethyl-7,8-dihydro- Method I' 7.72-7.74 (m, 2H), 7.98 (m, 1H), 6H-pyrimido[5,4-b][1,4]oxazin-4- 8.82 (s, 1H), 9.06 (s 1H); ESI-yl)oxy)pheny1)-3-(444- MS (m/z) 586 (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)urea

226. ON
A20, 1H NMR (400 MHz, DMSO-d6) H H 41Ik benzyl (2- 6 1.30 (s, 9H), 1.87-1.93 (m, fluoro-4- 2H), 3.17-3.25 (m, 2H), 3.98 (t, J
N N N
hydroxyp = 8.8 Hz, 2H), 6.15 (d, J = 5.6 =Is iN
henyl)car Hz, 2H), 6.40 (s, 1H), 6.96 (d, J
bamate, = 8.8 Hz, 2H), 7.42 (d, J = 9.2 C91 Hz, 2H), 7.64 (d, J = 9.2 Hz, N 2H), 8.02 (d, J = 8.8 Hz, 2H), Method R 8.55 (s, 1H), 9.13 (s, 1H); ESI-1 -(3-(tert-Buty1)-1-(4-+
cyanopheny1)-1H-pyrazol-5 -y1)-3 MS (m/z) 542 (M+H).
(2-fluoro-442,3,4,5-tetrahydropyrido[3,2-b] [1,4]oxazepin-9-yl)oxy)phenyl)urea No. Intermed Analytical Data Structure and Name iates and Method

227. ,ON A4, Bl, '1-1 NMR (400 MHz, DMSO-d6) CI Ai H C92 6 1.22 (s, 6H), 1.30 (s, 9H), 3.86 N N (s, 2H), 6.46 (s, 1H), 7.65-7.75 o 1 ,N
NICI o Method A (m, 6H), 7.82 (d, J= 5.2 Hz, 2H), 1 7.99 (s, 1H), 10.56 (s, 1H); ESI-N N\-MS (m/z) 558 (M+H) H +.
N-(3-(tert-Buty1)-1-(3-cyanopheny1)-1H-pyrazol-5-y1)-4-chloro-3-47,7-dimethy1-7,8-dihydro-6H-pyrimido[5,4-b.] [1,4]oxazin-4-yl)oxy) benzamide

228. H H A4, 4- 11-1 NMR (400 MHz, DMSO-d6) amino-2- 6 1.10 (t, J = 7.2 Hz, 3H), 1.23 VI Yo 40 o fluorophe (s, 6H), 2.50-2.52 (m, 10H), 3.58 N nol, Cl (s, 2H), 3.86 (s, 2H), 7.14-7.24 NCX:j I CN) (m, 2H), 7.58-7.72 (m, 4H), 7.79 N N
H
(s, 1H), 7.96 (s, 1H), 9.18 (s, 1-(4-47,7-Dimethy1-7,8-dihydro- Method I' 1H), 9.29 (s, 1H); ESI-MS (m/z) 6H-pyrimido[5,4-b][1,4]oxazin-4- 604 (M+H)+.
yl)oxy)-3-fluoropheny1)-3-(444-ethylpiperazin-1-y1)methyl)-3-(trifluoromethyl)phenyl)urea

229. H H
A4, 4- 11-1 NMR (400 MHz, DMSO-d6) ci a NYN -(--- amino-2- 6 1.23 (s, 6H), 1.31 (s, 9H), 3.87 0 ' chlorophe (s, 2H), 6.52 (s, 1H), 7.22 (d, J =
I
N,C nol, 5- 8.8 Hz, 1H), 7.30 (dd, Ji = 2.8 (tert- Hz, .1-2 = 9.2 Hz, 1H), 7.68 (s, N N\-H butyl)isox 1H), 7.79 (s, 2H), 8.99 (s, 1H), 1-(5-(tert-Butyl)isoxazol-3-y1)-3- azol-3- 9.63 (s, 1H); ESI-MS (m/z) 473 (3-chloro-447,7-dimethy1-7,8- amine (M+H)+.
dihydro-6H-pyrimido[5,4-b.] [1,4]oxazin-4- Method I
yl)oxy)phenyl)urea

230. CN
A4, 11-1 NMR (400 MHz, DMSO-d6) Nit C91 6 1.22 (s, 6H), 1.29 (s, 9H), 3.84 H H Method Q (s, 2H), 6.43 (s, 1H), 7.15 (d, CI N N N5 1H), 7.30 (d, 1H), 7.66-7.80 (m, 140 Y '17 0 , 5H), 7.99 (d, J = 7.2 Hz, 2H), 0 8.65 (s, 1H), 9.25 (s, 1H); ESI-NCN):N_ MS (m/z) 573 (M+H)+.
H
1 -(3 -(t e rt-Buty1)-1-(4-cyanopheny1)-1H-pyrazol-5-y1)-3-(3-chloro-4-47,7-dimethy1-7,8-dihydro-6H-pyrimido[5,4-b.] [1,4]oxazin-4-No. Intermed Analytical Data Structure and Name iates and Method yl)oxy)phenyl)urea

231. H H A4, 4- 1H NMR
(400 MHz, DMSO-d6) 140 X 1.1 amino-2- 6 0.99 (t, J = 7.2 Hz, 3H), 1.23 O chlorophe (s, 6H), 2.50-2.52 (m, 10H), 3.53 .j,,, o N
N
N CN) nol, Cl (s, 2H), 3.87 (s, 2H), 7.21 (d, J=
N \- 8.8 Hz, 1H), 7.31-7.34 (m, 1H), H
) Method I 7.60-7.78 (m, 3H), 7.79 (s, 2H), 1-(3-Chloro-4-47,7-dimethy1-7,8- 7.97 (s, 1H), 8.98 (s, 1H), 9.12 dihydro-6H-pyrimido [5,4- (s, 1H); ESI-MS (m/z) 620 b][1,4]oxazin-4-yl)oxy)pheny1)-3- (M+H)+.
(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

232. H H
A4, 1H NMR (400 MHz, DMSO-d6) 4-amino- 6 0.87 (s, 3H), 1.27 (s, 6H), 2.05 VI Yo 1101 0 2- (s, 3H), 2.39 (m, 10H), 3.53 (s, N
methylph 2H), 3.84 (s, 2H), 6.94 (d, J = 6.8 N:C) I CN) enyl Hz, 1H), 7.36 (d, J = 2.0 Hz, N N
H
benzylcar 1H), 7.57 (s, 1H), 7.60-7.67 (m, 1-(4-47,7-Dimethy1-7,8-dihydro- bonate , 4H), 7.97 (s, 1H), 8.71 (s, 1H), 6H-pyrimido[5,4-b][1,4]oxazin-4- Cl 9.02 (s, 1H); ESI-MS (m/z) 600 yl)oxy)-3-methylpheny1)-3-(4-44- (M+H)+.
ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)urea Method I'

233. * ON
A4 , C92 1H NMR (400 MHz, DMSO-d6) H H 6 1.10 (s, 6H), 1.25 (s, 9H), 3.84 oi 00NN N Method Q (s, 2H), 6.42 (s, 1H), 7.18-7.23 11 I...5Nv..
0 ' (m, 2H), 7.50-7.80 (m, 6H), 7.76 NO (s, 1H), 8.61 (s, 1H), 9.22 (s, 1 1H); ESI-MS (m/z) 573 (M+H)+.

H
1-(3-(tert-Buty1)-1-(3-cyanopheny1)-1H-pyrazol-5 -y1)-3 -(3-chloro-4-47,7-dimethy1-7,8-dihydro-6H-pyrimido [5,4-b.] [1,4]oxazin-4-yl)oxy)phenyl)urea

234. a H Al, B3, 1H NMR (400 MHz, DMSO-d6) N s SO2Me 0 C94 6 2.18 (s, 3H), 3.30 (s, 3H), 3.50 (br s, 2H), 4.19 (t, J = 3.6 Hz, 1 j Method B 2H), 7.46 (d, J = 6.4 Hz, 1H), NN
H 7.63-7.70 (m, 5H), 7.80 (s, 1H), 3 -((7,8-Dihydro-6H-pyrimido [5,4- 8.13 (s, 1H), 8.39 (s, 1H), 10.52 b][1,4]oxazin-4-yl)oxy)-4-methyl- (s, 1H); ESI-MS (m/z) 441 N-(3- (M+H)+.
(methylsulfonyl)phenyl)benzamid No. Intermed Analytical Data Structure and Name iates and Method e

235. a H A4 , B3, 1I-1 NMR (400 MHz, DMSO-d6) O N 0 cF3 Cl 6 0.97 (d, J= 6.0 Hz, 3H), 1.24 ,,,cx0v (s, 6H), 2.18-2.32 (m, 11H), 3.34 IL I N Method A (s, 2H), 3.55 (m, 2H). 3.88 (s, N N H CN) 2H), 7.46 (d, J = 6.8 Hz, 2H), 7.68-8.04 (m, 5H), 8.18 (s, 1H), ) 10.42 (s, 1H); ESI-MS (m/z) 585 347,7-Dimethy1-7,8-dihydro-6H-(M+H)+.
pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-y1)methyl)-3-(trifluoromethyl)pheny1)-4-methylbenzamide

236. * CN
A7, C92 1I-1 NMR (400 MHz, DMSO-d6) H H 6 1.29 (s, 9H), 3.41 (br s, 2H), N N N Method Q 4.10 (t, J = 4.0 Hz, 2H), 6.01 (d, (:
00 )r) , ,N
J = 6.0 Hz, 1H), 6.40 (s, 1H), CY) 6.85 (s, 1H), 6.95 (d, J = 8.8 Hz, ) 2H), 7.40 (d, J = 8.8 Hz, 2H), IV N 7.46 (d, J = 6.0 Hz, 1H), 7.73 (t, H
1 - (3 - (t e rt -Buty1)-1-(3- J =
8.0 Hz, 1H), 7.86 (d, J = 8.0 cyanopheny1)-1H-pyrazol-5-y1)-3- Hz, 1H), 7.91 (d, J = 8.4 Hz, (4-((3,4-dihydro-2H-pyrido[3,2- 1H), 8.03 (s, 1H), 8.52 (s, 1H), b] [1,4]oxazin-8- 9.06 (s, 1H); ESI-MS (m/z) 510 yl)oxy)phenyl)urea (M+H)+.

237. so H
Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) 0 0 C93 6 1.48 (s, 6H), 2.18 (s, 3H), 3.51 0 0 (br s, 2H), 4.20 (t, J = 4.0 Hz, N OH
N)X j Method D 2H), 5.58 (s, 1H), 7.41 (s, 1H), N N I I
H 7.48 (d, J = 8.0 Hz, 1H), 7.68 (s, OH 2H), 7.73 (s, 1H), 7.80 (dd, ./1 =
3-((7,8-Dihydro-6H-pyrimido[5,4- 1.6 Hz, .1-2 = 8.0 Hz, 1H), 8.17 (s, b] [1,4]oxazin-4-yl)oxy)-N-(3-(3- 2H), 10.48 (s, 1H); ESI-MS (m/z) hydroxy-3-methylbut-l-yn-l-y1)- 513 (M+H)+.
5-(trifluoromethyl)pheny1)-4-methylbenzamide

238. 0 H Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) N CHF2 C97 6 2.18 (s, 3H), 3.50 (br s, 2H), N (3' 4.19 (t, J = 3.6 Hz, 2H), 6.95-I ) Method B 7.10 (m, 1H), 7.45 (d, J = 6.0 Hz, NN
H 3H), 7.49-7.67 (m, 2H), 7.71-N-(3-(Difluoromethyl)pheny1)-3- 7.78 (m, 2H), 7.79 (d, J= 5.2 Hz, ((7,8-dihydro-6H-pyrimido[5,4- 1H), 8.05 (s, 1H), 10.36 (s, 1H);
b] [1,4]oxazin-4-yl)oxy)-4- ESI-MS (m/z) 413 (M+H)+.
methylbenzamide No. Intermed Analytical Data Structure and Name iates and Method

239. NH2 A20, NMR (400 MHz, DMSO-d6) 0 benzyl (2- 6 1.28 (s, 9H), 1.87-1.90 (br s, F H H fluoro-4- 2H), 3.21-3.23 (br s, 2H), 3.21-N N N
IN
hydroxyp 3.23 (br s, 2H), 3.95 (t, J = 4.8 henyl)car Hz, 2H), 6.19-6.25 (m, 2H), 6.40 ,0 bamate, (s, 2H), 6.80 (s, 1H), 7.0 (d, J =
C92 10.0 Hz, 1H), 7.62-7.63 (m, 4H), 1\1 N
7.90-7.95 (br s, 1H), 8.0-8.01 (m, 3-(3-(tert-Butyl)-5-(3-(2-fluoro-4- 1H), 8.85 (s, 1H); ESI-MS (m/z) 42,3,4,5-tetrahydropyrido[3,2- Method R 560 (M+H)+.
b][1,4]oxazepin-9-yl)oxy)phenyOureido)-1H-pyrazol-1-y1)benzamide

240. CI &.1 AS , Bl, NMR (400 MHz, DMSO-d6) 5-(tert- 6 1.18 (d, J = 6.0 Hz, 3H), 1.32 0 0 N butyl)isox (s, 9H), 3.69-3.77 (m, 2H), 4.26 azol-3- (d, J=
8.4 Hz, 1H), 6.71 (s, 1H), N N amine 7.71-7.75 (br s, 2H), 7.91 (s, 3H), (R)-N-(5-(tert-Butyl)isoxazol-3- 11.45 (s, 1H); ESI-MS (m/z) 444 y1)-4-chloro-3-47-methyl-7,8- (M+H)+.
Method B
dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

241. Al, B3, NMR
(400 MHz, DMSO-d6) N SO2Et C98 6 1.12 (t, J = 7.6 Hz, 3H), 2.19 ) Method B (s, 3H), 3.28 (q, J = 7.2 Hz, 2H), 3.58 (s, 2H), 4.20 (s, 2H), 7.47 N N
(d, J = 8.0 Hz, 1H), 7.59-7.72 3-((7,8-Dihydro-6H-pyrimido[5,4- (m, 5H), 7.82 (d, J = 7.6 Hz, 1H), b][1,4]oxazin-4-yl)oxy)-N-(3- 8.15 (d, J = 7.6 Hz, 1H), 8.36 (s, (ethylsulfonyl)pheny1)-4- 1H), 10.54 (s, 1H); ESI-MS (m/z) methylbenzamide 455 (M+H)+.

242. a Al, B3, NMR
(400 MHz, DMSO-d6) O N cF3 C95 6 2.51 (s, 3H), 3.36 (s, 3H), 3.51 Nk,0, 0 (s, 2H), 4.20 (t, J = 3.6 Hz, 2H), 1 j Method D 4.43 (s, 2H), 7.48 (d, J = 8.0 Hz, N N
1H), 7.54 (s, 1H), 7.72 (s, 3H), '0 7.80 (d, J= 8.0 Hz, 1H), 8.21 (s, 3-((7,8-Dihydro-6H-pyrimido[5,4- 2H), 10.52 (s, 1H); ESI-MS (m/z) b][1,4]oxazin-4-yl)oxy)-N-(3-(3- 499 (M+H)+.
methoxyprop-1-yn-l-y1)-5-(trifluoromethyl)pheny1)-4-methylbenzamide No. Intermed Analytical Data Structure and Name iates and Method

243. H H
A7, C94 1I-1 NMR (400 MHz, DMSO-d6) N N SO2Me 6 3.20 (s, 3H), 3.39 (s, 2H), 4.13 0 Yo I I 0 I
0 Method Q (s, 2H), 6.06 (d, J = 5.2 Hz, 1H), ?IC') (Boc 7.01 (d, J = 8.0 Hz, 3H), 7.48-deprotecti 7.58 (m, 5H), 7.67 (d, J= 7.2 Hz, N N
H on done 1H), 8.16 (s, 1H), 8.91 (s, 1H), 1-(4-((3,4-Dihydro-2H- using 9.20 (s, 1H); ESI-MS (m/z) 441 pyrido[3,2-b][1,4]oxazin-8- hydrochlo (M+H)+.
yl)oxy)pheny1)-3-(3- ric acid) (methylsulfonyl)phenyl)urea

244. a H
F F Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) 6 2.19 (s, 3H), 3.51 (br s, 2H), N (3' 0 3.79-3.88 (m, 2H), 4.20 (s, 2H), I ) Method D 5.65 (t, J = 5.6 Hz, 1H), 7.24 (d, 1\1N1 H J =
7.6 Hz, 1H), 7.45-7.46 (m, N-(3-(1,1-Difluoro-2- 2H), 7.68-7.71 (m, 3H), 7.80 (d, hydroxyethyl)pheny1)-3-47,8- J =
8.0 Hz, 1H), 7.93 (d, J = 8.0 dihydro-6H-pyrimido[5,4- Hz, 1H), 7.97 (s, 1H), 10.33 (s, b] [1,4]oxazin-4-yl)oxy)-4- 1H);
ESI-MS (m/z) 443 (M+H)+.
methylbenzamide

245. a H Al, B3, 1I-1 NMR (400 MHz, DMSO-d6) O N 0 cF3 C101 6 2.19 (s, 3H), 3.83 (br s, 2H), Ni 0 0 4.20 (br s, 2H), 7.49 (d, J = 8.0 l Hz, 1H), 7.68-7.74 (m, 2H), 7.80 N N ) 11 H Method D (d, J = 7.6 Hz, 2H), 7.99 (s, 1H), ON 8.38 (s, 1H), 8.49 (s, 1H), 10.68 N-(3-(Cyanoethyny1)-5-(s, 1H); ESI-MS (m/z) 480 (trifluoromethyl)pheny1)-3#7,8- (M+H)+.
dihydro-6H-pyrimido[5,4-b] [1,4]oxazin-4-yl)oxy)-4-methylbenzamide

246. H H
A7, C98 1I-1 NMR (400 MHz, DMSO-d6) N N SO2Et 6 1.09-1.13 (m, 3H), 3.25-3.44 VI Yo 1101 0 Method Q (m, 4H), 4.13 (s, 2H), 6.07 (d, J
) , 0 (Boc = 3.2 Hz, 1H), 6.99 (d, J = 7.2 deprotecti Hz, 3H), 7.48-7.58 (m, 5H), 7.67 N N
H on done (d, J
= 7.2 Hz, 1H), 8.13 (s, 1H), 1-(4-((3,4-Dihydro-2H- using 8.91 (d, J = 5.2 Hz, 1H), 9.22 (d, pyrido[3,2-b][1,4]oxazin-8-hydrochlo J = 6.0 Hz, 1H); ESI-MS (m/z) yl)oxy)pheny1)-3-(3- ric acid) 455 (M+H)+.
(ethylsulfonyl)phenyl)urea

247. CI Al, Bl, 1I-1 NMR (400 MHz, DMSO-d6) H
O WI N 0 c3 C102 6 1.40 (d, J = 6.8 Hz, 3H), 3.51-N j(31 0 3.52 (br s, 2H), 4.20 (t, J = 4.4 L I j Method D Hz, 2H), 4.61-4.64 (m, 1H), 5.56 N N I I
(d, J = 5.2 Hz, 1H), 7.46 (s, 1H), H
HO 7.69 (s, 1H), 7.78-7.90 (m, 4H), No. Intermed Analytical Data Structure and Name iates and Method 4-Chloro-3-((7,8-dihydro-6H- 8.16 (s, 2H), 10.62 (s, 1H); ESI-pyrimido[5,4-b][1,4]oxazin-4- MS (m/z) 519 (M+H)+.
yl)oxy)-N-(3-(3-hydroxybut-1-yn-1-y1)-5-(trifluoromethyl)phenyl)benzamid e

248. A7, 3- 1H NMR (400 MHz, DMSO-d6) H H
aminoben 6 3.46 (br s, 2H), 4.15 (br s, 2H), N N
WI To 0 so2NH2 zenesulfo 6.08 (d, J= 5.2 Hz, 1H), 7.02 (d, 0 namide J =
6.8 Hz, 2H), 7.16 (br s, 1H), X0 Method Q 7.41-7.57 (m, 8H), 8.07 (s, 1H), j N N (Boc 8.91 (s, 1H), 9.14 (s, 1H); ESI-H deprotecti MS (m/z) 442 (M+H)+.
3-(3-(4-((3,4-Dihydro-2H- on done pyrido[3,2-b][1,4]oxazin-8- using yl)oxy)phenyl)ureido)benzenesulf hydrochlo onamide ric acid)

249. ci A4 , Bl, 1H NMR (400 MHz, DMSO-d6) H
WI N, 5-(tert- 6 1.23 (s, 6H), 1.31 (s, 9H), 3.88 butyl)isox (s, 2H), 6.70 (s, 1H), 7.0-7.50 (br I )7 azol-3- s, 1H), 7.74-7.74 (m, 2H), 7.88-N N amine 7.91 (m, 3H);
ESI-MS (m/z) 458 H
N-(5-(tert-Butyl)isoxazol-3-y1)-4- Method B (M+H)+.
chloro-3-47,7-dimethy1-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide

250. A4, 1H NMR (400 MHz, DMSO-d6) ci 0 N N N 3-(tert- 6 1.22 (m, 15H), 3.61 (s, 3H), I. A I N buty0-1- 3.86 (s, 2H), 6.06 (s, 1H), 7.19 N ,H H aH3 methyl- (br s, 1H), 7.31 (br s, 1H), 7.68 *L 1H- (s, 1H), 7.80-7.90 (m, 3H), 7.06-N N pyrazol-5- 7.10 (m, 1H); ESI-MS (m/z) 486 H
1-(3-(tert-Buty1)-1-methy1-1H- amine (M+H)+.
pyrazol-5-y1)-3-(4-chloro-3-47,7- Method Q
dimethy1-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea

251. ci Al, Bl, 1H NMR (400 MHz, DMSO-d6) =H
N 0 SO2Me C104 6 0.98 (t, J = 6.8 Hz, 3H), 2.33-2.50 (m, 10H), 3.47 (s, 3H), 3.51 Method B (br s, 2H), 3.81 (s, 2H), 4.21 (br N
N N C N) H t, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.75-7.80 (m, 2H), 7.90-7.91 (m, 2H), 8.13 (dd, ./1 =
4-Chloro-3-((7,8-dihydro-6H- 1.6 Hz, .1-2 = 8.0 Hz, 1H), 8.44 (s, No. Intermed Analytical Data Structure and Name iates and Method pyrimido[5,4-b][1,4]oxazin-4- 1H), 10.66 (s, 1H); ESI-MS (m/z) yl)oxy)-N-(4-((4-ethylpiperazin-1- 587 (M+H)+.
yl)methyl)-3-(methylsulfonyl)phenyl)benzamid

252. CN
A20, 4- 1I-1 NMR (400 MHz, DMSO-d6) amino-3- 6 1.28 (s, 9H), 1.87-1.90 (m, H
N N
fluorophe 2H), 3.21-3.25 (m, 2H), 3.95 (t, J
ytt 0 nol, C92 = 5.6 Hz, 2H), 6.21 (t, J = 3.6 Hz, 1H), 6.26 (d, J = 5.2 Hz, e(c)) 1H), 6.42 (s, 1H), 6.80 (dd, J, =
N N Method I 1.6 Hz, .1-2 = 8.8 Hz, 1H), 7.02 1-(3-(tert-Butyl)-1-(3-(dd, J, = 2.8 Hz, J2 = 12.0 Hz, cyanopheny1)-1H-pyrazol-5-y1)-3-1H), 7.64 (d, J = 5.2 Hz, 1H), (2-fluoro-442,3,4,5- 7.74 (t, J = 8.0 Hz, 1H), 7.87 (d, tetrahydropyrido[3,2-J = 8.0 Hz, 1H), 7.91-7.96 (m, b][1,4]oxazepin-9- 2H), 8.05 (s, 1H), 8.89-8.93 (m, yl)oxy)phenyl)urea 2H); ESI-MS (m/z) 542 (M+H)+.

253. A4, NMR (400 MHz, DMSO-d6) B3, C103 6 1.24 (s, 6H), 1.38 (d, J = 6.4 NI*1,0 0 Hz, 3H), 2.19 (s, 3H), 3.88 (s, 2H), 4.60-4.63 (m, 1H), 5.52 (d, NN
OH Method D J = 5.2 Hz, 1H), 7.48 (d, J = 8.4 3((7,7-Dimethy1-7,8-dihydro-6H- Hz, 1H), 7.63 (d, J = 8.8 Hz, pyrimido[5,4-b][1,4]oxazin-4- 1H), 7.68-7.70 (m, 2H), 7.78-yl)oxy)-N-(4-(3-hydroxybut-1-yn- 7.81 (m, 2H), 8.09 (d, J = 3.0 Hz, 1-y1)-3-(trifluoromethyl)pheny1)- 1H), 8.25 (s, 1H), 10.56 (s, 1H);
4-methylbenzamide ESI-MS (m/z)527(M+H)+.

254. * ON A4, NMR
(400 MHz, DMSO-d6) H H C92 6 1.21 (s, 6H), 1.29 (s, 9H), 3.82 N N N (s, 2H), 6.41 (s, 1H), 7.62 (d, J =
x IN
Method Q 6.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.70-7.76 (m, 3H), 7.90-7.93 (m, 2H), 8.04 (t, J= 1.6 Hz, NT 1H), 8.52 (s, 1H), 9.04 (s, 1H);
1-(3-(tert-Butyl)-1-(3- ESI-MS (m/z) 539 (M+H)+.
cyanopheny1)-1H-pyrazol-5-y1)-3-(4-47,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea

255. A20, B3, NMR
(400 MHz, DMSO-d6) 0 N cF3 C19 6 1.23-1.35 (m, 5H), 1.91-1.95 c,0 (m, 2H), 2.21-2.27 (m, 4H), 2.46 Method B (s, 3H), 3.20 (s, 3H), 3.31-3.65 1\1 N
C (m, 2H), 4.00-4.02 (m, 2H), 6.66 (d, J= 5.6 Hz, 1H), 6.94 (s, 1H), No. Intermed Analytical Data Structure and Name iates and Method 4-Methyl-N-(3-(4- 7.55 (d, J = 8.0 Hz, 2H), 7.60-methylpiperazin-1-y1)-5- 7.65 (m, 2H), 7.84 (d, J = 7.2 Hz, (trifluoromethyl)pheny1)-3- 1H), 8.04 (d, J = 5.2 Hz, 1H), ((2,3,4,5-tetrahydropyrido[3,2- 10.28 (s, 1H); ESI-MS (m/z) 542 b] [1,4]oxazepin-9- (M+H)+.
yl)oxy)benzamide

256. A4, B3, 1H NMR (400 MHz, DMSO-d6) 1401 id cF3 C105 6 1.24 (s, 6H), 2.19 (s, 3H), 2.59 O (t, J = 6.8 Hz, 2H), 3.59 (q, J =
N'Cx ` IW
I
Method D 6.8 Hz, 2H), 3.88 (s, 2H), 4.91 (t, OH
N N7 J = 5.6 Hz, 1H), 7.47 (d, J = 8.0 H
Hz, 1H), 7.62 (d, J = 8.4 Hz, 347,7-Dimethy1-7,8-dihydro-6H-1H), 7.69 (d, J = 4.8 Hz, 2H), pyrimido[5,4-b][1,4]oxazin-4-7.76-7.82 (m, 2H), 8.07 (d, J =
yl)oxy)-N-(4-(4-hydroxybut-l-yn-8.8 Hz, 1H), 88.23 (d, J = 1.6 Hz, 1-y1)-3 -(trifluoromethyl)pheny1)-4-methylbenzamide 1H), 10.53 (s, 1H); ESI-MS
(m/z) 527 (M+H)+.

257. a H A4, 1H NMR
(400 MHz, DMSO-d6) O N so SO2Me B3, C106 6 1.24 (s, 6H), 2.19 (s, 3H), 2.24 N0 0 (s, 3H), 2.48-2.52 (m, 4H), 3.17-I N Method D 2.25 (m, 7H), 3.88 (s, 2H), 7.14 N N CN) H (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.69-7.73 (m, 3H), 7.78-7.84 (m, I
3((7,7-Dimethy1-7,8-dihydro-6H- 3H), 10.31 (s, 1H); ESI-MS (m/z) pyrimido[5,4-b][1,4]oxazin-4- 567 (M+H)+.
yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-l-y1)-5-(methylsulfonyl)phenyl)benzamid e

258. H H
A7, 1H NMR (400 MHz, DMSO-d6) =4-y I*
6 2.23 (s, 3H), 2.44-2.52 (m, N N SO2Me aminophe 4H), 3.16-3.23 (m, 6H), 3.37-X _0 j N
CN) nol, C106 3.42 (m, 5H), 4.10 (t, J = 4.8 Hz, N N
1H), 6.01 (d, J = 5.6 Hz, 1H), H I Method I 6.76 (s, 1H), 6.95-7.03 (m, 3H), 1-(4-((3,4-Dihydro-2H- 7.32 (s, 1H), 7.41-7.48 (m, 3H), pyrido[3,2-b][1,4]oxazin-8- 8.74 (s, 1H), 8.93 (s, 1H); ESI-yl)oxy)pheny1)-3-(3-(4- MS (m/z) 539 (M+H)+.
methylpiperazin-l-y1)-5-(methylsulfonyl)phenyl)urea

259. H H A7, 4-1H NMR (400 MHz, DMSO-d6) Ai NyN to SO2Me aminophe 6 0.99 (t, J = 7.2 Hz, 3H), 2.22-0 nol, C104 2.49 (m, 10H), 3.37 (q, J = 7.2 N
C N) Hz, 2H), 3.46 (s, 3H), 3.78 (s, Method I 2H), 4.10 (t, J = 4.0 Hz, 2H), N N H 6.02 (d, J= 5.6 Hz, 1H), 6.76 (s, ) 1H), 6.98 (d, J = 9.2 Hz, 2H), No. Intermed Analytical Data Structure and Name iates and Method 1-(4-((3,4-Dihydro-2H- 7.40-7.49 (m, 4H), 7.70 (dd, J1 =
pyrido[3,2-b][1,4]oxazin-8- 2.4, J2= 8.4 Hz, 1H), 8.17 (d, J =
yl)oxy)pheny1)-3-(4((4- 2.0 Hz, 1H), 8.75 (s, 1H), 9.14 (s, ethylpiperazin-1-yl)methyl)-3- 1H); ESI-MS (m/z) 567 (M+H)+.
(methylsulfonyl)phenyl)urea

260. CI A4, Bl, 1I-1 =

NMR (400 MHz, DMSO-d6) H
N C81 6 0.98 (t, J = 6.8 Hz, 3H), 1.24 N):0 0 WI 0 cF3 , 0 cH3 (s, 6H), 2.27-2.51 (m, 10H), 3.56 ) N N N
(N) Method A (s, 2H), 3.89 (s, 2H), 7.72 (s, Chiral 1H), 7.77 (d, J = 8.0 Hz, 2H), H
separation 7.88-7.99 (m, 3H), 8.03 (dd, J1 =
) 2.0 Hz, .12 = 8.8 Hz, 1H), 8.17 (s, 4-Chloro-3-47,7-dimethy1-7,8- 1H), 10.55 (s, 1H); ESI-MS (m/z) dihydro-6H-pyrimido[5,4- 605 (M+H)+.
b][1,4]oxazin-4-yl)oxy)-N-(4-(1-(4-ethylpiperazin-l-y1)ethyl)-3-(trifluoromethyl)phenyl)benzamid e

261. CI A4, Bl, 1I-1 =

NMR (400 MHz, DMSO-d6) H
OWI N.CF3 C81 6 0.98 (t, J = 6.8 Hz, 3H), 1.24 INIc,o, 0 cH3 (s, 6H), 2.27-2.51 (m, 10H), 3.56 1 j< N Method A (s, 2H), 3.89 (s, 2H), 7.72 (s, NN CN) Chiral 1H), 7.77 (d, J = 8.0 Hz, 2H), H
separation 7.88-7.99 (m, 3H), 8.03 (dd, J1 =
) 2.0 Hz, .12 = 8.8 Hz, 1H), 8.17 (s, 4-Chloro-3-47,7-dimethy1-7,8- 1H), 10.55 (s, 1H); ESI-MS (m/z) dihydro-6H-pyrimido[5,4- 605 (M+H)t b][1,4]oxazin-4-yl)oxy)-N-(4-(1-(4-ethylpiperazin-l-y1)ethyl)-3-(trifluoromethyl)phenyl)benzamid e

262. A4, Bl, 1I-1 NMR (400 MHz, DMSO-d6) ci d 0.96 (t, J = 7.2 Hz, 3H), 1.22-1.25 (m, 9H), 2.20-2.34 (m, 8H), N c), 0 ScH3 Method A 3.46-3.51 (m, 3H), 3.89 (s, 2H), 1 k N 7.71 (s, 1H), 7.74-7.80 (m, 2H), NN H CN ) 7.86-7.91 (m, 3H), 8.02-8.06 (m, 1H), 8.14 (d, J = 2.4 Hz, 1H), ) 10.54 (s, 1H); ESI-MS (m/z) 619 4-Chloro-3-47,7-dimethy1-7,8-(M+H)+.
dihydro-6H-pyrimido[5,4-b] [1,4]oxazin-4-yl)oxy)-N-(4-(1-(4-ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)benzamid e (Racemic) PHARMACOLOGICAL ACTIVITY
This is a one step binding assay based on the binding and displacement of the labeled tracer where compound addition is followed by addition of the anti-GST tagged europium (Eu) as the donor and Alexa Fluor labelled tracer as the acceptor.
Simultaneous binding of both the tracer and GST-antibody to the kinase domain of HPK1 results in a high degree of FRET (fluorescence resonance energy transfer) from the anti-GST tagged europium (Eu) fluorophore to the Alexa Fluor 647 fluorophore on the kinase tracer and this signal is reduced in presence of the inhibitor that can be measured.
Test compounds or reference compounds such as Sunitinib were dissolved in dimethylsulfoxide (DMSO) to prepare 10.0 mM stock solutions and diluted to the desired concentration. The final concentration of DMSO in the reaction was 3% (v/v).
The assay mixture was prepared by mixing 6nM of the Eu-Anti-GST Antibody and 15nM MAP4K-enzyme in the Kinase buffer containing 50mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM
EGTA, 0.01% Brij-35 with or without the desired concentration of the compound.
The reaction was incubated on ice for 15mins. The pre-incubation step was terminated by addition of the 30nM Kinase Tracer 222 into the reaction mixture. After shaking for 5 min the reaction was further incubated for 1 hour at room temperature and this was kept and read at 4 C on an ARTEMIS reader as per the kit instructions (Thermo). The inhibition of test compound was calculated based on the FRET ratio of 665 / 615. The activity was calculated as a percent of control reaction. IC50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.
The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 26. Percentage inhibition at concentrations of 1.0 ILLM and 10.0 ILLM are given in the table along with IC50 (nM) details for selected examples.
The ICso (nM) values are set forth in Table 26 wherein "A" refers to an ICso value of less than 50 nM, "B" refers to ICso value in range of 50.01 to 100.0 nM, "C"
refers to ICso values more than 100.01 to 500 nM and "D" refers to ICso values more than 500 nM.
Table 26:
% Inhibition at IC50 value Sr. no. Compound No.
1 uM 10 MM (nM) 1. Example 1 53.13 70.95 2. Example 2 6L76 78.75 3. Example 3 68.47 4. Example 4 72.67 78.09 C

% Inhibition at IC50 value Sr. no. Compound No.
1 pM 10 pM (nM) 5. Example 5 33.21 47.41 -6. Example 6 33.33 57.59 -7. Example 7 66.26 72.1 D
8. Example 8 18.8 66.8 D
9. Example 9 36.71 58.38 -10. Example 10 28.23 62.99 -11. Example 11 60.05 59.56 D
12. Example 12 14.1 4.4 -13. Example 13 35.6 67.1 D
14. Example 14 17.8 42.4 D
15. Example 15 69.5 78.7 C
16. Example 16 21.2 20.6 -17. Example 17 21.8 70 D
18. Example 18 14.5 40.5 -19. Example 19 38.53 68.87 D
20. Example 20 2.7 30.2 -21. Example 21 16.9 55.27 D
22. Example 22 23.53 64.92 D
23. Example 23 56 70.1 D
24. Example 24 57.24 84.42 D
25. Example 25 40.01 81.32 D
26. Example 26 70.66 87.25 C
27. Example 27 49.07 77.88 D
28. Example 28 37.96 64.08 D
29. Example 29 33.41 69.51 D
30. Example 30 35.3 74.9 D
31. Example 31 41.66 73.12 D
32. Example 32 17.47 71.32 D
33. Example 33 8.97 65.23 D
34. Example 34 46.96 77.43 D
35. Example 35 5.34 10.79 -36. Example 36 36.69 66.31 D
37. Example 37 36.87 65.59 D
38. Example 38 10.94 10.37 -39. Example 39 37.42 68.78 D
40. Example 40 24.77 65.08 D
41. Example 41 9.31 40.69 -42. Example 42 9.08 2.28 -% Inhibition at IC50 value Sr. no. Compound No.
1 pM 10 pM (nM) 43. Example 43 32.96 5.15 -44. Example 44 48.2 77.9 D
45. Example 45 34.1 75.9 D
46. Example 46 56.68 85.26 D
47. Example 47 43.65 72.8 D
48. Example 48 37.25 53.68 D
49. Example 49 15A4 34.98 -50. Example 50 9.5 3.9 -51. Example 51 0 19.84 -52. Example 52 17.81 67.33 D
53. Example 53 54.92 52.04 D
54. Example 54 24.44 38.07 D
55. Example 55 21.99 67.76 D
56. Example 56 31.8 83.85 D
57. Example 57 10.61 30.02 -58. Example 58 53.52 21.58 D
59. Example 59 24.08 66.02 D
60. Example 60 47.98 75.2 D
61. Example 61 35.07 42.95 D
62. Example 62 24.71 67.35 D
63. Example 63 44.7 79.5 D
64. Example 64 41.76 71.6 D
65. Example 65 51.9 76.53 D
66. Example 66 48.78 63.97 D
67. Example 67 62.28 84.47 D
68. Example 68 62.5 84.42 D
69. Example 69 41.19 76.6 D
70. Example 70 43.79 79.6 D
71. Example 71 32.37 73.02 D
72. Example 72 40.12 73.38 D
73. Example 73 42.94 14.64 D
74. Example 74 32.11 17.20 D
75. Example 75 49.16 75.14 D
76. Example 76 53.25 77.82 D
77. Example 77 69.82 82.63 D
78. Example 78 76.4 86.3 D
79. Example 79 55.2 80.8 D
80. Example 80 81.39 84.78 A

% Inhibition at IC50 value Sr. no. Compound No.
1 pM 10 pM (nM) 81. Example 81 77.83 77.31 B
82. Example 82 84.2 85.2 A
83. Example 83 63.73 29.77 C
84. Example 84 58.9 78.1 D
85. Example 85 49.65 76.31 D
86. Example 86 49.8 78 D
87. Example 87 65 80 C
88. Example 88 20.34 69.98 D
89. Example 89 34.91 70.3 D
90. Example 90 31.48 71.86 D
91. Example 91 8.08 40.76 -92. Example 92 0 31.48 -93. Example 93 50.82 18.14 D
94. Example 94 20.34 51.33 D
95. Example 95 58.57 80.37 D
96. Example 96 68.63 88.18 C
97. Example 97 5.6 76 D
98. Example 98 34.4 72.5 D
99. Example 99 75.94 80.67 C
100. Example 100 35.47 69.93 D
101. Example 101 47.52 75.18 D
102. Example 102 73.73 85.52 C
103. Example 103 61 79.9 D
104. Example 104 68.32 82.95 C
105. Example 105 44.1 77.8 D
106. Example 106 68.28 79.05 C
107. Example 107 19.96 61.1 D
108. Example 108 62.83 68.35 D
109. Example 109 11.61 48.97 D
110. Example 110 1.82 38.89 -111. Example 111 4.24 26.9 -112. Example 112 35.08 76.48 D
113. Example 113 7.32 18.27 -114. Example 114 24.76 63.45 D
115. Example 115 30.79 63.74 D
116. Example 116 24.82 55.72 D
117. Example 117 68.8 86.6 D
118. Example 118 5.56 21.19 -% Inhibition at IC50 value Sr. no. Compound No.
1 pM 10 pM (nM) 119. Example 119 16.96 64.21 D
120. Example 120 69.88 33.44 C
121. Example 121 72.32 47.1 C
122. Example 122 68.5 84.28 C
123. Example 123 77.94 88.52 C
124. Example 124 37.6 77.54 D
125. Example 125 13.1 58.05 D
126. Example 126 19.14 56.79 D
127. Example 127 51.5 81.31 D
128. Example 128 35.59 75.33 D
129. Example 129 22.62 75.02 D
130. Example 130 58.41 77.74 D
131. Example 131 59.69 77.59 D
132. Example 132 2.76 19.96 -133. Example 133 42.99 74.42 D
134. Example 134 4.57 60.59 D
135. Example 135 23.26 70.69 D
136. Example 136 58.43 79.18 D
137. Example 137 52.62 ppt D
138. Example 138 49.09 81.44 D
139. Example 139 55.4 78.93 D
140. Example 140 34.55 68.28 D
141. Example 141 38.67 74.26 D
142. Example 142 45.46 ppt D
143. Example 143 55.9 81.2 D
144. Example 144 52.6 70.5 D
145. Example 145 65.8 82.6 C
146. Example 146 59.9 81.8 D
147. Example 147 2.9 29.2 D
148. Example 148 16.1 23.9 -149. Example 149 50.9 78.4 D
150. Example 150 39.7 66.1 D
151. Example 151 81.6 88.4 C
152. Example 152 2.6 25.3 D
153. Example 153 21.9 45.5 D
154. Example 154 87.3 88.7 C
155. Example 155 71.2 ppt C
156. Example 156 29.57 81.52 D

% Inhibition at IC50 value Sr. no. Compound No.
1 pM 10 pM (nM) 157. Example 157 81.5 83.04 B
158. Example 158 27.89 82.15 D
159. Example 159 9.12 31.9 -160. Example 160 33.12 ppt D
161. Example 161 36.3 83.12 D
162. Example 162 53.39 84.28 D
163. Example 163 80.21 85.83 B
164. Example 164 40.25 ppt -165. Example 165 0 ppt -166. Example 166 36.05 ppt -167. Example 167 85.06 88.47 B
168. Example 168 36.73 80.81 D
169. Example 169 12.51 27.14 -170. Example 170 20.06 32.35 -171. Example 171 9.71 9.18 -172. Example 172 13.92 19.34 -173. Example 173 64.87 74.86 D
174. Example 174 71.14 72.8 C
175. Example 175 61.3 43.34 D
176. Example 176 58.99 82.66 D
177. Example 177 29.34 76.34 D
178. Example 178 22.6 69.27 D
179. Example 179 38.74 83.38 D
180. Example 180 31.59 68.17 D
181. Example 181 12.17 45.63 D
182. Example 182 23.13 78.33 D
183. Example 183 89.24 86.1 A
184. Example 184 34.25 77.07 D
185. Example 185 0.23 1.68 -186. Example 186 3.18 0 -187. Example 187 42.7 78.2 D
188. Example 188 83.9 81.4 A
189. Example 189 28.04 64.65 D
190. Example 190 15.19 59.03 D
191. Example 191 74.76 84.18 C
192. Example 192 2.06 16.41 D
193. Example 193 0.05 6.15 -194. Example 194 84.23 85.32 B

% Inhibition at IC50 value Sr. no. Compound No.
1 pM 10 pM (nM) 195. Example 195 55.56 83.59 D
196. Example 196 80.62 85.73 C
197. Example 197 0 34.89 D
198. Example 198 80.17 83.16 B
199. Example 199 2.95 61.89 D
200. Example 200 35.42 83.32 D
201. Example 201 29.54 66.36 D
202. Example 202 87.83 87.57 A
203. Example 203 32.34 76.3 D
204. Example 204 30.75 54.15 D
205. Example 205 0 38.18 D
206. Example 206 75.93 74.6 B
207. Example 207 88.2 86.32 A
208. Example 208 11.88 74.06 D
209. Example 209 78.23 87.05 C
210. Example 210 76.66 90.18 C
211. Example 211 71.03 90.78 C
212. Example 212 63.57 89.35 C
213. Example 213 71.56 80.6 C
214. Example 214 85.85 93.25 B
215. Example 215 46.68 84.15 D
216. Example 216 86.76 89.77 B
217. Example 217 86.87 88.31 A
218. Example 218 62.7 85.64 D
219. Example 219 32.66 75.29 D
220. Example 220 0 15.85 D
221. Example 221 30.35 71.36 D
222. Example 222 52.09 ppt D
223. Example 223 0 29.98 -224. Example 224 1.14 54.61 D
225. Example 225 83.78 88.31 A
226. Example 226 85.77 88.27 A
227. Example 227 64.83 82.36 C
228. Example 228 84.54 87.6 A
229. Example 229 85.18 84.82 C
230. Example 230 85 87.16 B
231. Example 231 88.34 81.52 A
232. Example 232 84.18 86.82 A

% Inhibition at IC50 value Sr. no. Compound No.
1 pM 10 pM (nM) 233. Example 233 79.07 83.61 A
234. Example 234 19.03 51.95 D
235. Example 235 79 86.5 C
236. Example 236 86.73 88.02 B
237. Example 237 42.78 77.72 D
238. Example 238 0 33.03 D
239. Example 239 87.31 88.65 A
240. Example 240 78.57 86.3 C
241. Example 241 4 13.4 -242. Example 242 31.88 42.35 -243. Example 243 43.09 73.18 D
244. Example 244 0.623 17.31 -245. Example 245 22.94 16.97 -246. Example 246 45.39 77.93 D
247. Example 247 44.20 , 94.21 D
248. Example 248 33.96 81.92 D
249. Example 249 47.38 62.97 D
250. Example 250 71.89 79.55 C
251. Example 251 3.24 39.98 D
252. Example 252 86.49 85.32 A
253. Example 253 49.74 D
254. Example 254 74.61 80.32 C
255. Example 255 40.22 53.24 D
256. Example 256 48.07 -D
257. Example 257 22.12 53.42 D
258. Example 258 46.90 79.11 D
259. Example 259 55.00 84.44 D
(-): Not determined.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I) stereoisomer, diastereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, wherein A is selected from CH and N;
D is selected from CR1R2 and CO;
E is selected from (CR3R4)m, NR1 and CO;
F is selected from O, CH2, CHOH and CO;
each occurrence of R5 is selected from hydrogen, halogen, cyano, hydroxyl and 8alkyl;
R7 is selected from hydrogen and C1-8alkyl;
each occurrence of R6 is selected from halogen, cyano, hydroxyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, C1-8alkoxyC1-8alkyl, C3-6cycloalkyl and 6cycloalkylC1-8alkyl;
R1, R2, R3 and R4 which may be same or different, are each independently selected from hydrogen, amine, C1-8alkyl, C3-6cycloalkyl, haloC1-8alkyl, hydroxyC1-8alkyl, C3-6cycloalkylC1-8alkyl, C1-8alkoxy, 3-15 membered heterocyclyl, C1-8alkyl3-15 membered heterocyclyl and CR a R b NR a R b;
R a and R b, which may be the same or different, are each independently selected from hydrogen and C1-8alkyl;
Z is selected from O, NH and S;

L is selected from x and y represents point of attachment;
Ring Q is selected from each occurrence of R8 is selected from halogen, cyano, cyanoC1-8alkyl, cyanohaloC1-8alkyl, cyanoC3-6cycloalkyl, C1-8alkyl, haloC1-8alkyl, hydroxyC1-8alkyl, hydroxyC1-8haloalkyl, and -SO2R1;
each occurrence of R9 is selected from halogen, cyano, hydroxyl, C1-8alkyl, haloC1- 8alkyl, hydroxyC1-8alkyl, C1-8alkoxy, R10 is selected from halogen, hydroxyl, cyano, C1-8alkyl, haloC1-8alkyl, C3-6cycloalkyl and C6-14aryl; wherein C6-14aryl is optionally substituted with one or more substituents selected from halogen, hydroxyl, cyano, amide or C1-8alkyl;
'm' is 1 or 2;
'n' is 0, 1 or 2;
`p' is 0 or 1;
'q' is 0 or 1; and T is 1 or 2.

2. The compound according to claim 1, wherein A is CH.

3. The compound according to claim 1, wherein A is N.

4. The compound according to claim 1, wherein D is CR1R2 or CO.

5. The compound according to claim 1, wherein E is (CR3R4)m, NR1 or CO.

6. The compound according to claim 1, wherein F is O, CH2, CHOH or CO.

7. The compound according to claim 1 to 6, wherein R5 is hydrogen, chloro or cyano.

8. The compound according to claim 1 to 6, wherein R7is hydrogen or methyl.

9. The compound according to any of claims, wherein R3 is hydrogen or methyl.

10. The compound according to any of claims, wherein Wis hydrogen or methyl.

11. The compound according to any of claims, wherein 'm' is 1 or 2.

12. The compound according to claim 1, wherein Z is O.

13. The compound according to claim 1, wherein Z is NH.

14. The compound according to claim 1, wherein Z is S.

15. The compound according to claim 1, wherein R6 is chloro, fluoro, methyl, trifluoromethyl or methoxy.

16. The compound according to claim 1 or 12, wherein 'n' is 0, 1 or 2.

17. The compound according to claim 1, wherein L is

18. The compound according to claim 1, wherein L is

19. The compound according to claim 1, wherein L is

20. The compound according to claim 1, wherein L is

21. The compound according to claim 1, wherein Ring Q is

22. The compound according to any of claims, wherein R8 is chloro, bromo, cyano, cyanomethyl, cyanoisopropyl, cyanodifluoromethyl, cyanocyclopropane, methyl, trifluoromethyl, difluoromethyl, hydroxyl difluoromethyl or -SO2R1.

23. The compound according to any of claims, wherein R1 is hydrogen, methyl, ethyl or amine.

24. The compound according to any of claims, wherein R2 is hydrogen, methyl, ethyl, isopropyl, hydroxyl methyl, methoxymethyl, 3-15 membered heterocyclylC1-8alkyl or CR a R b NR a R b.

25. The compound according to any of claims, wherein R a and R b are hydrogen or methyl.

26. The compound according to any of claims, wherein D is CH2, CH-CH3, CH- CH3, C(CH3)2, CH-CH(CH3)2, CH-CH2OH, CH-CH2-O-CH3, , N(CH3)2 Or CO.

27. The compound according to any of claims, wherein R9 is fluoro, bromo, cyano, hydroxyl, methyl, trifluoromethyl, methoxy,

28. The compound according to any of claims, wherein R10 is methyl, trifluoromethyl or C6-14aryl.

29. The compound according to any of claims, wherein 't' is 2.

30. The compound according to any of claims, wherein 'p' is 0 or 1.

31. The compound according to any of claims, wherein 'q' is 0 or 1.

32. The compound according to any of claims, wherein A is CH or N;
D is CH2, CH-CH3, CH-CH2-CH3, C(CH3)2, CH-CH(CH3)2, CH-CH2OH, CH-CH2-O- CH3, , CH-CH2-N(CH3)2, CO or cycloalkyl;

E is CH2, CH-CH3, C(CH3)2, (CH2)2, N-CH3 or CO;
F is O, CH2, CHOH or CO;
R5 is hydrogen, chloro or cyano;
R7 is hydrogen or methyl;
Z is O, NH or S;
R6 is chloro, fluoro, methyl, trifluoromethyl or methoxy;
L is Ring Q is 'm' is 1 or 2; and 'n' is 0, 1 or 2.

33. A compound selected from 3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-fluorobenzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-isopropylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-methylpiperidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(morpholinomethyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(42-(dimethylamino)ethyl)(methyl)amino)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-morpholino-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)benzamide;
4-Chloro-N-(3-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-3-((7,8-dihydro-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-methylphenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
N-(3-Bromo-5-(trifluoromethyl)phenyl)-4-chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(4-ethylpiperazine-1-carbonyl)-3-(trifluoromethyl)phenyl)benzamide;
N-(4-((4-Acetylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;

N-(3-Bromo-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-4-chloro-3-((7,8-dihydro-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(2-(dimethylamino)ethoxy)-3-(trifluoromethyl)phenyl)benzamide;
4-(4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamido)-N-(2-(dimethylamino)ethyl)-2-(trifluoromethyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((1-ethylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-ethylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-isopropylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-propylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-propylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-N-(3-(4-(cyclopropylmethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-(dimethylamino)piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-N-(3-(2-cyanopropan-2-yl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-N-(3-(1-cyanocyclopropyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(piperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

4-Chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(piperidin-4-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(1-methylpiperidin-4-yl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-fluoropyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(1,1-dioxidothiomorpholino)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-N-(3-(cyanomethyl)phenyl)-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-N-(3-(cyanodifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(R)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-fluoropyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((3-(methylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((3-(methylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)benzamide;

4-Chloro-N-(3-cyano-5-(trifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-methoxy-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-fluoro-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-hydroxy-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(2-methoxy-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-Morpholino-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-N-(3-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(R)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
N-(3-(1,4-Diazepan-1-yl)-5-(trifluoromethyl)phenyl)-4-chloro-3-((7,8-dihydro-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide hydrochloride;
4-Chloro-N-(4-((4-(2-cyanoacetyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
N-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)phenyl)-4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide hydrochloride;
4-Chloro-N-(3-(4-cyclopropylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
N-(3-Acrylamido-5-(trifluoromethyl)phenyl)-4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-(oxetan-3-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((isopropylamino)methyl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide hydrochloride;
(R)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide hydrochloride;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-(prop-yn-1-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methyl-1,4-diazepan-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-((7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(S)-4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(S)-4-Chloro-3-((6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(S)-4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-ethylpiperazin-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-isopropylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;

3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-isopropylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(4-propylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
N-(3-(4-(Cyclopropylmethyl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(4-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-morpholino-5-(trifluoromethyl)phenyl)benzamide;
(R)-3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
N-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-((7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(S)-N-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-((6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)amino)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)thio)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(4-((4-ethylpiperazin-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(3-((4-ethylpiperazin-yl)methyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(3-(4-ethylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(4-((1-ethylpiperidin-yl)oxy)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

N-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-43-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)benzamide;
4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3((5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)oxy)benzamide;
4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)oxy)benzamide;
4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((5-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)oxy)benzamide;
N-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methyl-3-((5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)oxy)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methoxybenzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-methylbenzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-(trifluoromethyl)benzamide;
2-Chloro-5-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-methylbenzamide;
5-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-fluorobenzamide;
3-Chloro-5-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
1-(4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
N-(4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((2R,6S)-2,6-dimethylmorpholino)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-34(7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

(R)-4-Chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-((6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(2-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-oxomorpholino)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((1S,4S)-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3,4-dimethylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3,4-dimethylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-4-methyl-N-(3-morpholino-5-(trifluoromethyl)phenyl)benzamide;
(S)-3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(3-(3-(dimethylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
1-(4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)urea;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(2,4-dimethylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(2,4-dimethylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((1-methylazetidin-3-yl)oxy)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Methyl-3-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
3-((7,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)benzamide;
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)urea;
(R)-4-Chloro-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(34(3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-46-methyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-47-ethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-3-47-Ethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-34(7-ethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-3-47-Ethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
N-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(2-((1-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-34(6-methyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-46,6-dimethyl-7-oxo-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
3-Chloro-4-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
3-Chloro-4-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-3-methylphenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
3-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-4-methyl-N-(3-(4-(oxetan-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-3-methylphenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)urea;
1-(3-Chloro-4-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
1-(3-Chloro-4-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)urea;
4-Chloro-3-((8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
N-(3-(1H-Pyrazol-4-yl)-5-(trifluoromethyl)phenyl)-4-chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(R)-4-Chloro-3-((7-isopropyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(S)-4-Chloro-3-((7-isopropyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-N-(4-(1-(4-ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)-3-(4R)-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-N-(4'-cyano-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-3-47,8-dihydro-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-N-(3'-cyano-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-3-47,8-dihydro-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
4-Chloro-3-43-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
(R)-4-Chloro-3-((7-ethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-propionamido-5-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide;

3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(2-fluoro-5-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(3-(4-(oxetan-yl)piperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
1-(3-Chloro-4-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea;
1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(4-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
4-Chloro-N-(4-(2-cyanopropan-2-yl)-3-(trifluoromethyl)phenyl)-3-((7,8-dihydro-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(R)-4-Chloro-3-((7-(morpholinomethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamide;
1-(3-Cyano-5-(trifluoromethyl)phenyl)-3-(4-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
(R)-1-(3-Chloro-4-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-2-fluorophenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)urea;
4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)urea;

1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(2-(dimethylamino)acetamido)-5-(trifluoromethyl)phenyl)benzamide;
N-(3-(4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamido)-5-(trifluoromethyl)phenyl)-1-isopropylazetidine-3-carboxamide;
(S)-4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(hydroxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(pyridin-ylethynyl)-5-(trifluoromethyl)phenyl)benzamide;
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-2-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-(dimethylamino)azetidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
4-Chloro-3-((3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)urea;
1-(2-Chloro-4-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)urea;
(E)-N-(3-(3-Amino-3-oxoprop-1-en-1-yl)-5-(trifluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide;
N-(3-(3-Amino-3-oxoprop-1-yn-1-yl)-5-(trifluoromethyl)phenyl)-3-47,8-dihydro-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide;
1-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-42,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)phenyl)urea;
1-(4-((7-Cyano-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
(E)-N-(3-(2-Cyanovinyl)-5-(trifluoromethyl)phenyl)-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide;

1-(4-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(3-((4-ethylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)urea hydrochloride;
(R)-1-(4-((4-Ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-47-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
4-Chloro-N-(4-(1-(4-ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)-34(R)-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide (Isomer I);
4-Chloro-N-(4-(1-(4-ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)-34(R)-7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide (Isomer II);
1-(3-(tert-Butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(4-43,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)urea;
(R)-1-(5-(tert-Butypisoxazol-3-yl)-3-(3-chloro-447-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
1-(5-(tert-Butyl)isoxazol-3-yl)-3-(4-43,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-yl)oxy)phenyl)urea;
1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
N-(5-(tert-Butyl)isoxazol-3-yl)-343,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-4-methylbenzamide;
(R)-4-Chloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(methoxymethyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
(R)-4-Chloro-3-((7-((dimethylamino)methyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
(R)-1-(4-((4-Ethylpiperazin-l-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-47-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
1-(4-((4-Ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-42,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)phenyl)urea;
N-(3-(tert-Butyl)-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-((3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-4-methylbenzamide;
N-(3-(tert-Butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-((3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)-4-methylbenzamide;
(R)-4-Chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(4-methylpiperazin-1-yl)phenyl)benzamide;

(R)-4-Chloro-3-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(2-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-hydroxyprop-1-yn-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
(R)-1-(2-Chloro-4-((7-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-cyclopropylurea;
4-Chloro-3-((2-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;
1-(4-((7,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
1-(3-(tert-Butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-((2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)phenyl)urea;
N-(3-(tert-Butyl)-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-4-chloro-3-47,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
1-(4-((7,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-3-fluorophenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
1-(5-(tert-Butyl)isoxazol-3-yl)-3-(3-chloro-44(7,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
1-(3-(tert-Butyl)-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-chloro-4-47,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
1-(3-Chloro-4-((7,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
1-(4-((7,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-3-methylphenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea;
1-(3-(tert-Butyl)-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-chloro-4-47,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(methylsulfonyl)phenyl)benzamide;
3-((7,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
1-(3-(tert-Butyl)-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(4-43,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)urea;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;

N-(3-(Difluoromethyl)phenyl)-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide;
3-(3-(tert-Butyl)-5-(3-(2-fluoro-442,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)phenyl)ureido)-1H-pyrazol-1-yl)benzamide;
(R)-N-(5-(tert-Butypisoxazol-3-yl)-4-chloro-347-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(ethylsulfonyl)phenyl)-4-methylbenzamide;
3-((7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-methoxyprop-1-yn-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;
1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(3-(methylsulfonyl)phenyl)urea;
N-(3-(1,1-Difluoro-2-hydroxyethyl)phenyl)-347,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide;
N-(3-(Cyanoethynyl)-5-(trifluoromethyl)phenyl)-3-47,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methylbenzamide;
1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(3-(ethylsulfonyl)phenyl)urea;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(3-(3-hydroxybut-1-yn-1-yl)-5-(trifluoromethyl)phenyl)benzamide;
3-(3-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl ureido) benzenesulfonamide;
N-(5-(tert-Butyl)isoxazol-3-yl)-4-chloro-347,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)benzamide;
1-(3-(tert-Butyl)-1-methyl-1H-pyrazol-5-yl)-3-(4-chloro-3-47,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;
4-Chloro-3-((7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(methylsulfonyl)phenyl)benzamide;
1-(3-(tert-Butyl)-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-442,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)phenyl)urea;
347,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(3-hydroxybut-1-yn-1-yl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
1-(3-(tert-Butyl)-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(447,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)phenyl)urea;

4-Methyl-N-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-3-((2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-9-yl)oxy)benzamide;
3-((7,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(4-hydroxybut-1-yn-1-yl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide;
3-((7,7-Dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-4-methyl-N-(3-(4-methylpiperazin-1-yl)-5-(methylsulfonyl)phenyl)benzamide;
1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(3-(4-methylpiperazin-1-yl)-5-(methylsulfonyl)phenyl)urea;
1-(4-((3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-8-yl)oxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(methylsulfonyl)phenyl)urea;
4-Chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(1-(4-ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)benzamide (Isomer I);
4-Chloro-3-((7,7-dimethyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)oxy)-N-(4-(1-(4-ethylpiperazin-1-yl)ethyl)-3-(trifluoromethyl)phenyl)benzamide (Isomer II) and pharmaceutically acceptable salt thereof

34. A compound of formula or a pharmaceutically acceptable salt thereof.

35. A compound of formula or a pharmaceutically acceptable salt thereof.

36. A compound of formula or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 and a pharmaceutically acceptable excipient.

38. The pharmaceutical composition according to claim 37, wherein the pharmaceutically acceptable excipient is a carrier or diluent.

39. A method of treating a MAP4K1 (HPK1) mediated disease, disorder, syndrome, or condition in a subject comprising administering an effective amount of a compound according to any one of claims 1 to 36.

40. The method according to claim 39, wherein the disease, disorder, syndrome or condition is autoimmune, neurodegenerative, neurological, inflammatory, hyperproliferative, and cardiovascular diseases.

41. The method according to claim 39, wherein the disease, disorder, syndrome or condition is selected from the group consisting of Parkinson's disease, Alzheimer's disease, stroke and associated memory loss, arthritis, allergies, asthma, diabetes, insulin-resistant diabetes, liver ischemia, reperfusion injury, hearing loss or deafness, neural tube birth defects, obesity, chronic myelogenous leukemia (CML), oxidative damage to liver and kidney, melanomas, thyroid cancers, adenocarcinoma, breast cancer, central nervous system cancers such as glioblastomas, astrocytomas and ependymomas, colorectal cancer, squamous cell carcinomas, small and non-small cell lung cancers, ovarian cancer, endometrial cancer, pancreatic cancer, prostate cancer, sarcoma and skin cancers.

42. The method according to claim 39, wherein the disease, disorder, syndrome or condition is cancer.