U.S. patent application number 14/913336 was filed with the patent office on 2017-02-23 for certain chemical entities, compositions, and methods.
The applicant listed for this patent is NEUPHARMA, INC.. Invention is credited to Xiangping QIAN, Yong-Liang ZHU.
Application Number | 20170050936 14/913336 |
Document ID | / |
Family ID | 52484273 |
Filed Date | 2017-02-23 |
United States Patent
Application |
20170050936 |
Kind Code |
A1 |
QIAN; Xiangping ; et
al. |
February 23, 2017 |
CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS
Abstract
Chemical entities that are effective as kinase inhibitors,
pharmaceutical compositions and methods of treatment are disclosed.
The chemical entities disclosed specifically inhibit signal
transduction and cellular proliferation by modulating the activity
of protein kinases to regulate and modulate abnormal or
inappropriate cell proliferation, differentiation, or metabolism.
The compounds include a pyrido[3,2-d]pyrimidine scaffold
substituted with aromatic and heteroaromatic moieties.
Inventors: |
QIAN; Xiangping; (Foster
City, CA) ; ZHU; Yong-Liang; (Fremont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NEUPHARMA, INC. |
Foster City |
CA |
US |
|
|
Family ID: |
52484273 |
Appl. No.: |
14/913336 |
Filed: |
August 22, 2014 |
PCT Filed: |
August 22, 2014 |
PCT NO: |
PCT/US14/52409 |
371 Date: |
February 19, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
61869596 |
Aug 23, 2013 |
|
|
|
61900283 |
Nov 5, 2013 |
|
|
|
62000946 |
May 20, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/02 20180101;
A61K 31/517 20130101; A61K 31/5377 20130101; A61P 43/00 20180101;
C07D 401/04 20130101; C12Q 2600/158 20130101; C07D 405/12 20130101;
C12Q 1/6886 20130101; C07C 57/145 20130101; C07D 401/12 20130101;
C07D 403/04 20130101; C07D 401/14 20130101; C12Q 2600/156 20130101;
G01N 33/57484 20130101; A61K 45/06 20130101; C07D 403/12 20130101;
C07D 471/04 20130101; A61K 31/553 20130101; A61P 35/00 20180101;
C07D 239/84 20130101; C07D 413/12 20130101; A61K 31/517 20130101;
A61K 2300/00 20130101; A61K 31/5377 20130101; A61K 2300/00
20130101 |
International
Class: |
C07D 239/84 20060101
C07D239/84; A61K 31/5377 20060101 A61K031/5377; A61K 31/517
20060101 A61K031/517; C07D 401/04 20060101 C07D401/04; C07C 57/145
20060101 C07C057/145; C07D 401/14 20060101 C07D401/14; C07D 401/12
20060101 C07D401/12; C07D 413/12 20060101 C07D413/12; C07D 403/12
20060101 C07D403/12; C07D 405/12 20060101 C07D405/12; A61K 45/06
20060101 A61K045/06; C07D 471/04 20060101 C07D471/04 |
Claims
1. A compound of Formula I: ##STR00362## or a pharmaceutically
acceptable salt thereof, wherein: X.sub.3 is C--R.sub.12 or N;
X.sub.4 is C--R.sub.13 or N; X.sub.5 is C--R.sub.14 or N; n is 0,
1, 2, 3, 4, or 5; m is 0, 1, 2, 3, 4, or 5; ##STR00363## is aryl or
heteroaryl; ##STR00364## is aryl, heteroaryl, or heterocycloalkyl;
R.sub.6, R.sub.12, R.sub.13, R.sub.14, and each Z are independently
hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, oxo,
sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy,
optionally substituted cycloalkyloxy, optionally substituted
aryloxy, optionally substituted heteroaryloxy, optionally
substituted heterocycloalkyloxy, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl; and each Q is independently
hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, oxo,
sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy,
optionally substituted cycloalkyloxy, optionally substituted
aryloxy, optionally substituted heteroaryloxy, optionally
substituted heterocycloalkyloxy, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl,
optionally substituted carbamimidoyl, or E; wherein E is an
electrophilic group capable of forming a covalent bond with a
nucleophile.
2. The compound or pharmaceutically acceptable salt of claim 1,
wherein ##STR00365## is selected from the group consisting of:
pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, furazanyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole,
1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazolyl, dithiazolyl,
tetrazolyl, pyridinyl, pyranyl, thiopyranyl, diazinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazinyl, and
phenyl; and ##STR00366## is selected from the group consisting of:
piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,
pyrrolidinyl, tetrahydrofuranyl, diazepanyl, azetidinyl, oxetanyl,
oxiranyl, aziridinyl, pyrrolyl, furanyl, thienyl, imidazolyl,
pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, furazanyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazolyl,
dithiazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, diazinyl,
pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl,
dithiinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
tetrazinyl, and phenyl.
3. (canceled)
4. The compound or pharmaceutically acceptable salt of claim 2,
wherein ##STR00367## is phenyl or pyridinyl.
5. (canceled)
6. The compound or pharmaceutically acceptable salt of claim 2,
wherein ##STR00368## is phenyl or pyridinyl.
7. The compound or pharmaceutically acceptable salt of claim 2,
wherein ##STR00369## is selected from the group consisting of:
piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,
pyrrolidinyl, tetrahydrofuranyl, diazepanyl, azetidinyl, oxetanyl,
oxiranyl, and aziridinyl.
8. (canceled)
9. (canceled)
10. The compound or pharmaceutically acceptable salt of claim 1,
wherein m is 1, 2, or 3; and at least one Q is E.
11. The compound or pharmaceutically acceptable salt of claim 1,
wherein n is 1 and Z is optionally substituted
heterocycloalkyl.
12. The compound or pharmaceutically acceptable salt of claim 11,
wherein Z is optionally substituted piperazinyl.
13. (canceled)
14. The compound or pharmaceutically acceptable salt of claim 1,
wherein ##STR00370## X.sub.1 is C--R.sub.2 or N; and R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently hydrogen,
cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl,
sulfonyl, optionally substituted alkoxy, optionally substituted
cycloalkyloxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, optionally substituted
heterocycloalkyloxy, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocycloalkyl,
optionally substituted amino, optionally substituted acyl,
optionally substituted alkoxycarbonyl, optionally substituted
aminocarbonyl, optionally substituted aminosulfonyl, or optionally
substituted carbamimidoyl.
15. The compound or pharmaceutically acceptable salt of claim 1,
wherein ##STR00371## X.sub.2 is C--R.sub.11 or N; and R.sub.11,
R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are independently hydrogen,
cyano, halo, hydroxy, azido, nitro, carboxy, oxo, sulfinyl,
sulfanyl, sulfonyl, optionally substituted alkoxy, optionally
substituted cycloalkyloxy, optionally substituted aryloxy,
optionally substituted heteroaryloxy, optionally substituted
heterocycloalkyloxy, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocycloalkyl,
optionally substituted amino, optionally substituted acyl,
optionally substituted alkoxycarbonyl, optionally substituted
aminocarbonyl, optionally substituted aminosulfonyl, optionally
substituted carbamimidoyl, or E; wherein E is an electrophilic
group capable of forming a covalent bond with a nucleophile.
16. The compound of claim 1, having the structure of Formula Ia:
##STR00372## or a pharmaceutically acceptable salt thereof,
wherein: X.sub.1 is C--R.sub.2 or N; X.sub.2 is C--R.sub.11 or N;
X.sub.3 is C--R.sub.12 or N; X.sub.4 is C--R.sub.13 or N; X.sub.5
is C--R.sub.14 or N; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl; and R.sub.8, R.sub.9, and
R.sub.10 are independently hydrogen, cyano, halo, hydroxy, azido,
nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally
substituted alkoxy, optionally substituted cycloalkyloxy,
optionally substituted aryloxy, optionally substituted
heteroaryloxy, optionally substituted heterocycloalkyloxy,
optionally substituted alkyl, optionally substituted cycloalkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted heterocycloalkyl, optionally substituted
amino, optionally substituted acyl, optionally substituted
alkoxycarbonyl, optionally substituted aminocarbonyl, optionally
substituted aminosulfonyl, optionally substituted carbamimidoyl, or
E; wherein E is an electrophilic group capable of forming a
covalent bond with a nucleophile.
17. The compound or pharmaceutically acceptable salt of claim 16,
wherein R.sub.1 is hydrogen, cyano, halo, hydroxy, --CONH.sub.2,
optionally substituted alkoxy, or optionally substituted
cycloalkyloxy.
18. (canceled)
19. The compound or pharmaceutically acceptable salt of claim 16,
wherein R.sub.2, R.sub.3, and R.sub.4 are independently hydrogen,
cyano, halo, hydroxy, carboxy, optionally substituted alkoxy,
optionally substituted lower alkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, or
optionally substituted aminocarbonyl.
20. (canceled)
21. The compound or pharmaceutically acceptable salt of claim 19,
wherein R.sub.2 and R.sub.4 are hydrogen, and R.sub.3 is optionally
substituted morpholinyl, optionally substituted piperazinyl,
optionally substituted pyrrolidinyl, optionally substituted
piperidinyl, optionally substituted azetidinyl, or optionally
substituted amino.
22. (canceled)
23. The compound or pharmaceutically acceptable salt of claim 19,
wherein R.sub.2 and R.sub.3 are hydrogen, and R.sub.4 is optionally
substituted morpholinyl, optionally substituted piperazinyl,
optionally substituted pyrrolidinyl, optionally substituted
piperidinyl, optionally substituted azetidinyl, or optionally
substituted amino.
24. The compound or pharmaceutically acceptable salt of claim 16,
wherein R.sub.5 is hydrogen, halo, cyano, optionally substituted
alkoxy, or optionally substituted alkyl.
25. (canceled)
26. The compound or pharmaceutically acceptable salt of claim 1,
wherein R.sub.6 is hydrogen or optionally substituted amino.
27. (canceled)
28. The compound or pharmaceutically acceptable salt of claim 16,
wherein R.sub.7 and R.sub.11 are independently hydrogen, cyano,
optionally substituted lower alkyl, halo, or methoxy.
29. (canceled)
30. The compound or pharmaceutically acceptable salt of claim 16,
wherein R.sub.8, R.sub.9, and R.sub.10 are independently hydrogen,
cyano, halo, hydroxy, carboxy, optionally substituted alkoxy,
optionally substituted cycloalkyloxy, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted amino, optionally substituted acyl,
optionally substituted alkoxycarbonyl, optionally substituted
aminocarbonyl, or E; wherein E is an electrophilic group capable of
forming a covalent bond with a nucleophile.
31. The compound or pharmaceutically acceptable salt of claim 30,
wherein at least one of R.sub.8, R.sub.9, and R.sub.10 is halo or
optionally substituted amino.
32. (canceled)
33. (canceled)
34. The compound or pharmaceutically acceptable salt of claim 30,
wherein at least one of R.sub.8, R.sub.9, and R.sub.10 is E, where
E is an electrophilic group capable of forming a covalent bond with
a cysteine residue of a protein.
35. The compound or pharmaceutically acceptable salt of claim 30,
wherein at least one of R.sub.8, R.sub.9, and R.sub.10 is E; and
wherein E is selected from ##STR00373##
36. The compound or pharmaceutically acceptable salt of claim 35,
wherein E is ##STR00374##
37. (canceled)
38. The compound or pharmaceutically acceptable salt of claim 1,
wherein m is 1, 2, 3, 4, or 5; at least one Q is E; and E is an
electrophilic group capable of forming a covalent bond with a
cysteine residue of a protein.
39. The compound or pharmaceutically acceptable salt of claim 38,
wherein E is selected from ##STR00375##
40. The compound or pharmaceutically acceptable salt of claim 39,
wherein E is ##STR00376##
41. (canceled)
42. The compound or pharmaceutically acceptable salt of claim 1,
wherein R.sub.12 is hydrogen, halo, cyano, --CONH.sub.2,
--NHCOCH.sub.3, or optionally substituted lower alkyl.
43. (canceled)
44. The compound or pharmaceutically acceptable salt of claim 1,
wherein R.sub.13 and R.sub.14 are independently hydrogen, cyano,
optionally substituted lower alkyl, halo, or methoxy.
45. (canceled)
46. The compound or pharmaceutically acceptable salt of claim 1,
wherein at least one of X.sub.3, X.sub.4, and X.sub.5 is N.
47. The compound or pharmaceutically acceptable salt of claim 1,
wherein X.sub.3 is N, X.sub.4 is C--R.sub.13, and X.sub.5 is
C--R.sub.14.
48. The compound or pharmaceutically acceptable salt of claim 1,
wherein X.sub.3 is C--R.sub.12, X.sub.4 is N, and X.sub.5 is
C--R.sub.14.
49. The compound or pharmaceutically acceptable salt of claim 1,
wherein X.sub.3 is C--R.sub.12, X.sub.4 is C--R.sub.13, and X.sub.5
is N.
50-74. (canceled)
75. A compound or pharmaceutically acceptable salt thereof, wherein
the compound is chosen from the group consisting of:
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)phen-
yl) acetamide,
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)phen-
yl) acetamide,
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl) acetamide,
8-(2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[4,3-d]pyrimidine-2-amine,
8-(2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,2-d]pyrimidine-2-amine,
8-(2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidine-2-amine,
8-(5-chloro-2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin--
2-amine,
8-(3-chlorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2-
-amine,
8-(3-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2--
amine,
8-(2,6-difluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-
-2-amine,
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)-
pyrido[3,4-d]pyrimidin-2-amine,
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-morpholinophenyl)pyri-
do [3,4-d]pyrimidin-2-amine,
8-(3-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrim-
idin-2-amine,
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]-
pyrimidin-2-amine,
8-(4-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrim-
idin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]-
pyrimidin-2-amine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,-
4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-morpholinophenyl)pyri-
do [3,4-d]pyrimidin-2-amine,
8-phenyl-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine,
8-(2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-a-
mine,
8-(2-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidi-
n-2-amine,
8-(2,6-difluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d-
]pyrimidin-2-amine,
8-(5-chloro-2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyri-
midin-2-amine,
8-(3-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-a-
mine,
8-(3-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidi-
n-2-amine,
N-(4-fluoro-3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]-
pyrimidin-8-yl)phenyl)acetamide,
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyr-
ido[3,4-d]pyrimidin-2-amine,
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-(piperazin-1-yl)pheny-
l)pyrido[3,4-d]pyrimidin-2-amine,
8-(3-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d-
]pyrimidin-2-amine,
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[-
3,4-d]pyrimidin-2-amine,
8-(4-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d-
]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[-
3,4-d]pyrimidin-2-amine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyr-
ido[3,4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-(piperazin-1-yl)pheny-
l)pyrido[3,4-d]pyrimidin-2-amine,
N1-(1-(2-fluoroethyl)azetidin-3-yl)-N4-(8-(2-fluorophenyl)pyrido[3,4-d]py-
rimidin-2-yl)benzene-1,4-diamine,
N1-(1-(2-fluoroethyl)azetidin-3-yl)-N4-(8-(3-(2-morpholinoethoxy)phenyl)p-
yrido[3,4-d]pyrimidin-2-yl)benzene-1,4-diamine,
N1-(8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)pyrido[3,4-d]pyrimidin-2-yl)-
-N4-(1-(2-fluoroethyl)azetidin-3-yl)benzene-1,4-diamine,
N1-(8-(5-chloro-2-fluorophenyl)pyrido[3,4-d]pyrimidin-2-yl)-N4-(1-(2-fluo-
roethyl)azetidin-3-yl)benzene-1,4-diamine,
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acr-
ylamide,
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)acrylamide,
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)phenyl)acr-
ylamide,
N-(3-(2-((4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)ph-
enyl)acrylamide,
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-
-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidin-8-
-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)phenyl)acrylamide,
N-(3-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)acrylamide, N-(3-(2-((4-(azetidin-3-ylamino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide, tert-butyl
3-((4-((8-(3-acrylamidophenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)am-
ino)azetidine-1-carboxylate,
N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
2-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[4,-
3-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(piperidin-4-ylamino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acrylamide,
(R)--N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(R)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(R)--N-(3-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(R)--N-(3-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((4(3-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyri-
midin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)-
phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)-
phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]p-
yrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]p-
yrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino-
)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido[-
3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-y-
l)phenyl)acetamide,
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-y-
l)phenyl)acetamide,
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acetamide,
8-(2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidin-2-a-
mine,
8-(2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,2-d]pyrimidi-
n-2-amine,
8-(2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyr-
imidin-2-amine,
8-(5-chloro-2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyri-
midin-2-amine,
8-(3-chlorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(3-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(2,6-difluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyr-
ido [3,4-d]pyrimidin-2-amine,
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-morpholinopyridin-3-y-
l)pyrido[3,4-d]pyrimidin-2-amine,
8-(3-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(4-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyr-
ido [3,4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-morpholinopyridin-3-y-
l)pyrido [3,4-d]pyrimidin-2-amine,
8-phenyl-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido
[3,4-d]pyrimidin-2-amine,
8-(2-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimid-
in-2-amine,
8-(2-chlorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimid-
in-2-amine,
8-(2,6-difluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyr-
imidin-2-amine,
8-(5-chloro-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4--
d]pyrimidin-2-amine,
8-(3-chlorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimid-
in-2-amine,
8-(3-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimid-
in-2-amine,
N-(4-fluoro-3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyri-
midin-8-yl)phenyl)acetamide,
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3--
yl)pyrido [3,4-d]pyrimidin-2-amine,
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyrid-
in-3-yl)pyrido [3,4-d]pyrimidin-2-amine,
8-(3-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido-
[3,4-d]pyrimidin-2-amine,
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)p-
yrido [3,4-d]pyrimidin-2-amine,
8-(4-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido-
[3,4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)p-
yrido [3,4-d]pyrimidin-2-amine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3--
yl)pyrido [3,4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyrid-
in-3-yl)pyrido[3,4-d]pyrimidin-2-amine,
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(2-fluorophenyl)pyrido[3,4-d]py-
rimidin-2-yl)pyridine 2,5-diamine,
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(3-(2-morpholinoethoxy)phenyl)p-
yrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine,
N5-(8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)pyrido[3,4-d]pyrimidin-2-yl)-
-N2-(1-(2-fluoroethyl)azetidin-3-yl)pyridine-2,5-diamine,
N5-(8-(5-chloro-2-fluorophenyl)pyrido[3,4-d]pyrimidin-2-yl)-N2-(1-(2-fluo-
roethyl)azetidin-3-yl)pyridine-2,5-diamine,
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)acrylamide,
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acrylamide,
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-yl)phen-
yl)acrylamide,
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-yl)phen-
yl)acrylamide,
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrim-
idin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrim-
idin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acrylamide,
N-(3-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)phenyl)acrylamide,
N-(3-(2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)phenyl)acrylamide, tert-butyl
3-((5-((8-(3-acrylamidophenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-2-
-yl)amino)azetidine-1-carboxylate,
N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,2-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[4,3-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)phenyl)acrylamide,
N-(3-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)phenyl)acrylamide,
(R)--N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(R)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(R)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide,
(R)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide,
(S)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-
-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-
-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,2-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4-
,3-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)py-
rido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxypyridin-3-yl-
)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((2-methoxy-6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino-
)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido[-
3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)acrylamide,
N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide,
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)pyridin-4--
yl)acrylamide,
N-(2-(2-((4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)pyridin-4--
yl)acrylamide,
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-
-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidin-8-
-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide,
N-(2-(2-((4-(azetidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide,
N-(2-(2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide, tert-butyl
3-((4-((8-(4-acrylamidopyridin-2-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)phe-
nyl)amino)azetidine-1-carboxylate,
N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
2-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[4,-
3-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-(piperidin-4-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl-
)pyridin-4-yl)acrylamide,
N-(2-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido[3,4-d]pyri-
midin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-y-
l)pyridin-4-yl)acetamide,
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-y-
l)pyridin-4-yl)acetamide,
N-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-2-ami-
ne,
N-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,2-d]pyrimidin-2--
amine,
N-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-
-2-amine,
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3--
yl)pyrido[3,4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)p-
yrido[3,4-d]pyrimidin-2-amine,
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)pyrido-
[3,4-d]pyrimidin-2-amine,
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)p-
yrido [3,4-d]pyrimidin-2-amine,
N-(6-(piperazin-1-yl)pyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-
-2-amine,
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyri-
midin-8-yl)pyridin-4-yl)acetamide,
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)-
pyrido[3,4-d]pyrimidin-2-amine,
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin--
3-yl)pyrido[3,4-d]pyrimidin-2-amine,
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)-
pyrido[3,4-d]pyrimidin-2-amine,
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin--
3-yl)pyrido[3,4-d]pyrimidin-2-amine,
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(4-(2-morpholinoethoxy)pyridin--
2-yl)pyrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine,
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-
-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-
-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,2-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4-
,3-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)py-
rido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxypyridin-3-yl-
)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((2-methoxy-6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide,
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)acrylamide,
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide,
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide,
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)pyridin-4-yl)acrylamide, tert-butyl
3-((5-((8-(4-acrylamidopyridin-2-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyr-
idin-2-yl)amino)azetidine-1-carboxylate,
N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,2-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[4,3-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(R)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(S)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,2-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[4,3-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)a-
mino)pyrido [3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)ami-
no)pyrido [3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)pro-
piolamide,
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)phenyl)propiolamide,
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)propiolamide,
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)phenyl)propiolamide,
(E)-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl-
)but-2-enamide,
(Z)--N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pheny-
l)but-2-enamide,
(Z)-3-fluoro-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)phenyl)but-2-enamide,
(E)-3-fluoro-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)phenyl)but-2-enamide,
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)met-
hacrylamide,
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)eth-
enesulfonamide,
(E)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)phenyl)but-2-enamide,
(Z)--N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)but-2-enamide,
(Z)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)but-2-enamide,
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)methacrylamide,
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)ethenesulfonamide,
3,3-difluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)acrylamide,
3-methyl-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[3,2-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[4,3-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin--
3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amin-
o)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3--
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)propiolamide,
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)propiolamide,
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)propiolamide,
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)propiolamide,
(E)-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
pyridin-4-yl)but-2-enamide,
(Z)--N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl-
)pyridin-4-yl)but-2-enamide,
(Z)-3-fluoro-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)but-2-enamide,
(E)-3-fluoro-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)but-2-enamide,
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)methacrylamide,
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)ethenesulfonamide,
(E)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(Z)--N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]-
pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(Z)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)methacrylamide,
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)ethene sulfonamide,
3,3-difluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
3-methyl-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-morpholinophenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,2-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[4,3-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido
[3,4-d]pyrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)a-
mino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)ami-
no)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)propiolamide,
N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)propiolamide,
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)propiolamide,
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)pyridin-4-yl)propiolamide,
(E)-N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridi-
n-4-yl)but-2-enamide,
(Z)--N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrid-
in-4-yl)but-2-enamide,
(Z)-3-fluoro-N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)pyridin-4-yl)but-2-enamide,
(E)-3-fluoro-N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)pyridin-4-yl)but-2-enamide,
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)methacrylamide,
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)ethenesulfonamide,
(E)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)pyridin-4-yl)but-2-enamide,
(Z)--N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)but-2-enamide,
(Z)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide,
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)methacrylamide,
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)ethenesulfonamide,
3,3-difluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
3-methyl-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]py-
rimidin-8-yl)pyridin-4-yl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[3,2-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[4,3-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin--
3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amin-
o)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-4-(dimethylamino)-N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3--
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)propiolamide,
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)propiolamide,
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)propiolamide,
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)phenyl)propiolamide,
(E)-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
phenyl)but-2-enamide,
(Z)--N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl-
)phenyl)but-2-enamide,
(Z)-3-fluoro-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)but-2-enamide,
(E)-3-fluoro-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)but-2-enamide,
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)methacrylamide,
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)ethenesulfonamide,
(E)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)but-2-enamide,
(Z)--N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]-
pyrimidin-8-yl)phenyl)but-2-enamide,
(Z)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
(E)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)methacrylamide,
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)ethenesulfonamide,
3,3-difluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
3-methyl-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)phenyl)but-2-enamide,
8-(2-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidine-2-
,4-diamine,
8-(5-chloro-2-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyr-
imidine-2,4-diamine,
8-(5-chloro-2-fluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-
-d]pyrimidine-2,4-diamine,
8-(3-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidine-2-
,4-diamine,
8-(2,6-difluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidi-
ne-2,4-diamine,
8-(2,6-difluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]py-
rimidine-2,4-diamine,
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)py-
rido[3,4-d]pyrimidine-2,4-diamine,
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(6-morpholinopyridin-3--
yl)pyrido[3,4-d]pyrimidine-2,4-diamine,
8-(3-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)pyrido
diamine,
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N2-(6-morpholinopyridin-3--
yl)pyrido[3,4-d]pyrimidine-2,4-diamine,
8-(4-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4--
d]pyrimidine-2,4-diamine,
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)pyrido-
[3,4-d]pyrimidine-2,4-diamine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)py-
rido [3,4-d]pyrimidine-2,4-diamine,
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(6-morpholinopyridin-3--
yl)pyrido[3,4-d]pyrimidine-2,4-diamine,
8-(2-fluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimi-
dine-2,4-diamine,
N2-(6-(piperazin-1-yl)pyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidi-
ne-2,4-diamine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(6-(piperazin-1-yl)pyridin-3-
-yl)pyrido[3,4-d]pyrimidine-2,4-diamine,
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido[3,4--
d]pyrimidine-2,4-diamine,
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido-
[3,4-d]pyrimidine-2,4-diamine,
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido[3,4--
d]pyrimidine-2,4-diamine,
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido-
[3,4-d]pyrimidine-2,4-diamine,
N2-(4-(piperazin-1-yl)phenyl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidine-2,4-
-diamine,
8-(2-fluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-
e-2,4-diamine,
8-(5-chloro-2-fluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-
e-2,4-diamine,
8-(3-fluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidine-2,4-dia-
mine,
8-(2,6-difluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-
e-2,4-diamine,
8-(5-chloro-2-fluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyr-
imidine-2,4-diamine,
8-(2,6-difluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidi-
ne-2,4-diamine,
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3-
,4-d]pyrimidine-2,4-diamine,
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(4-(piperazin-1-yl)phenyl)py-
rido[3,4-d]pyrimidine-2,4-diamine,
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-morpholinophenyl)pyr-
ido [3,4-d]pyrimidine-2,4-diamine,
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-(piperazin-1-yl)phen-
yl)pyrido[3,4-d]pyrimidine-2,4-diamine,
8-(3-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyri-
midine-2,4-diamine,
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d-
]pyrimidine-2,4-diamine,
8-(4-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyri-
midine-2,4-diamine,
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d-
]pyrimidine-2,4-diamine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3-
,4-d]pyrimidine-2,4-amine,
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-morpholinophenyl)pyr-
ido[3,4-d]pyrimidine-2,4-diamine,
8-(2-fluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidine-2-
,4-diamine,
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(4-(piperazin-1-yl)phenyl)py-
rido[3,4-d]pyrimidine-2,4-diamine,
(E)-N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)-4-(dimethylamino)but-2-enamide,
N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)ph-
enyl)acrylamide,
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)acrylamide,
(E)-N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide,
N-(3-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(E)-N-(3-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)ami-
no)pyrido[3,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide,
N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)ph-
enyl)propiolamide,
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)propiolamide,
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)ethenesulfonamide,
(E)-N-(2-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)-4-(dimethylamino)but-2-enamide,
N-(2-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)py-
ridin-4-yl)acrylamide,
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide,
(E)-N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide,
N-(2-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(E)-N-(2-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)ami-
no)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamid-
e,
N-(2-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
pyridin-4-yl)propiolamide,
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)propiolamide,
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)ethenesulfonamide,
(E)-N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)phenyl)-4-(dimethylamino)but-2-enamide,
N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)acrylamide,
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(2-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide,
(E)-N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido-
[3,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide,
N-(3-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)a-
mino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
(E)-N-(3-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3--
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamid-
e,
N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)phenyl)propiolamide,
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)propiolamide,
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)ethenesulfonamide,
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-
-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrido[4,3-d]p-
yrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrido[3,2-d]p-
yrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)pyrido[3,4-d]-
pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide,
N-(3-(2-((4-(2,3-difluoro-4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)py-
rido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide, and
N-(3-(2-((4-(2,3-difluoro-4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide.
76. A pharmaceutically acceptable salt of the compound of claim
1.
77-79. (canceled)
80. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and the compound or pharmaceutically acceptable
salt of claim 1.
81. The pharmaceutical composition of claim 80, wherein the
composition is formulated in a form chosen from the group
consisting of tablets, capsules, powders, liquids, suspensions,
suppositories, and aerosols.
82. A packaged pharmaceutical composition comprising the
pharmaceutical composition of claim 80 and instructions for using
the composition to treat a subject suffering from cancer.
83. A method of treating cancer in a subject which comprises
administering to a subject in need thereof a therapeutically
effective amount of the compound or pharmaceutically acceptable
salt of claim 1.
84. The method of claim 83, wherein the cancer is colon carcinoma,
pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma,
chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma,
endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,
synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,
adenocarcinoma, sweat gland carcinoma, thyroid cancer, sebaceous
gland carcinoma, papillary carcinoma, papillary adenocarcinomas,
cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma,
renal cell carcinoma, hepatoma, bile duct carcinoma,
choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor,
cervical cancer, testicular tumor, lung carcinoma, small cell lung
carcinoma, non-small cell lung cancer, bladder carcinoma,
epithelial carcinoma, glioma, astrocytoma, medulloblastoma,
craniopharyngioma, ependymoma, pinealoma, hemangioblastoma,
acoustic neuroma, oligodendroglioma, meningioma, melanoma,
neuroblastoma, retinoblastoma, leukemia, acute lymphocytic leukemia
and acute myelocytic leukemia (myeloblastic, promyelocytic,
myelomonocytic, monocytic and erythroleukemia); chronic leukemia
(chronic myelocytic (granulocytic) leukemia and chronic lymphocytic
leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and
non-Hodgkin's disease), multiple myeloma, Waldenstrom's
macroglobulinemia, or heavy chain disease.
85. (canceled)
86. A method of treating a disorder mediated by EGFR in a subject
in need thereof, comprising administering to the subject a
therapeutically effective amount of the compound or
pharmaceutically acceptable salt of claim 1.
87. A method of treating a cancer in a subject in need thereof,
comprising: a) determining the presence or absence of and EGFR
mutation in a biological sample isolated from the subject; and b)
if an EGFR mutation or double mutations are determined to be
present in the subject, administering to the subject a
therapeutically effective amount of the compound or
pharmaceutically acceptable salt of claim 1.
88. (canceled)
89. The method of claim 87, wherein the EGFR mutation is del
E746-A750, del E747-E749/A750P, del E747-S752/P753S, del
E747-T751/Sins/A750P, del S752-1759, G719S, G719C, L861Q, L858R,
T790M, or L858R/T790M.
90-94. (canceled)
95. The method of claim 87, wherein the cancer is colon carcinoma,
pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma,
chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma,
endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,
synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,
adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,
papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,
medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,
hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal
carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung
carcinoma, small cell lung carcinoma, non-small cell lung cancer,
bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,
medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,
melanoma, neuroblastoma, retinoblastoma, leukemia, acute
lymphocytic leukemia and acute myelocytic leukemia (myeloblastic,
promyelocytic, myelomonocytic, monocytic and erythroleukemia);
chronic leukemia (chronic myelocytic (granulocytic) leukemia and
chronic lymphocytic leukemia); and polycythemia vera, lymphoma
(Hodgkin's disease and non-Hodgkin's disease), multiple myeloma,
Waldenstrom's macroglobulinemia, or heavy chain disease.
96. (canceled)
97. The method of claim 86, further comprising administering an
additional anti-cancer and/or cytotoxic agent.
Description
CROSS-REFERENCE
[0001] This application claims the benefit of priority to U.S.
Provisional Application No. 61/869,596, filed on Aug. 23, 2013,
U.S. Provisional Application No. 61/900,283, filed on Nov. 5, 2013;
and U.S. Provisional Application No. 62/000,946, filed May 20,
2014, which applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] There are at least 400 enzymes identified as protein
kinases. These enzymes catalyze the phosphorylation of target
protein substrates. The phosphorylation is usually a transfer
reaction of a phosphate group from ATP to the protein substrate.
The specific structure in the target substrate to which the
phosphate is transferred is a tyrosine, serine or threonine
residue. Since these amino acid residues are the target structures
for the phosphoryl transfer, these protein kinase enzymes are
commonly referred to as tyrosine kinases or serine/threonine
kinases.
[0003] The phosphorylation reactions, and counteracting phosphatase
reactions, at the tyrosine, serine and threonine residues are
involved in countless cellular processes that underlie responses to
diverse intracellular signals (typically mediated through cellular
receptors), regulation of cellular functions, and activation or
deactivation of cellular processes. A cascade of protein kinases
often participate in intracellular signal transduction and are
necessary for the realization of these cellular processes. Because
of their ubiquity in these processes, the protein kinases can be
found as an integral part of the plasma membrane or as cytoplasmic
enzymes or localized in the nucleus, often as components of enzyme
complexes. In many instances, these protein kinases are an
essential element of enzyme and structural protein complexes that
determine where and when a cellular process occurs within a
cell.
[0004] The identification of effective small compounds which
specifically inhibit signal transduction and cellular proliferation
by modulating the activity of tyrosine and serine/threonine kinases
to regulate and modulate abnormal or inappropriate cell
proliferation, differentiation, or metabolism is therefore
desirable. In particular, the identification of compounds that
specifically inhibit the function of a kinase which is essential
for processes leading to cancer would be beneficial.
SUMMARY OF THE INVENTION
[0005] In one aspect, the present disclosure provides a compound of
Formula I
##STR00001##
[0006] or a pharmaceutically acceptable salt thereof, wherein
[0007] X.sub.3 is C--R.sub.12, or N;
[0008] X.sub.4 is C--R.sub.13, or N;
[0009] X.sub.5 is C--R.sub.14, or N;
[0010] n is 0, 1, 2, 3, 4, or 5;
[0011] m is 0, 1, 2, 3, 4, or 5;
##STR00002##
is aryl or heteroaryl;
##STR00003##
is aryl, heteroaryl, or heterocycloalkyl;
[0012] R.sub.6, R.sub.12, R.sub.13, R.sub.14, and each Z is
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, oxo, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl;
[0013] each Q is independently hydrogen, cyano, halo, hydroxy,
azido, nitro, carboxy, oxo, sulfinyl, sulfanyl, sulfonyl,
optionally substituted alkoxy, optionally substituted
cycloalkyloxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, optionally substituted
heterocycloalkyloxy, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocycloalkyl,
optionally substituted amino, optionally substituted acyl,
optionally substituted alkoxycarbonyl, optionally substituted
aminocarbonyl, optionally substituted aminosulfonyl, optionally
substituted carbamimidoyl, or E; wherein E is an electrophilic
group capable of forming a covalent bond with a nucleophile.
[0014] In some embodiments,
##STR00004##
is selected from the group consisting of: pyrrolyl, furanyl,
thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furazanyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazole, 1,2,5-oxadiazole,
1,3,4-oxadiazole, thiadiazolyl, dithiazolyl, tetrazolyl, pyridinyl,
pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazinyl, and
phenyl; and
##STR00005##
is selected from the group consisting of: piperazinyl, morpholinyl,
piperidinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl,
diazepanyl, azetidinyl, oxetanyl, oxiranyl, aziridinyl, pyrrolyl,
furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
furazanyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole, 1,2,5-oxadiazole,
1,3,4-oxadiazole, thiadiazolyl, dithiazolyl, tetrazolyl, pyridinyl,
pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazinyl, and
phenyl. For example
##STR00006##
is selected from the group consisting of: phenyl, pyridinyl,
pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,
isoxazolyl, and thienyl. For example,
##STR00007##
is selected from the group consisting of: phenyl, pyridinyl,
pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,
isoxazolyl, and thienyl. In some embodiments,
##STR00008##
is phenyl or pyridinyl. In other embodiments,
##STR00009##
is phenyl or pyridinyl. In some embodiments,
##STR00010##
is selected from the group consisting of: piperazinyl, morpholinyl,
piperidinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl,
diazepanyl, azetidinyl, oxetanyl, oxiranyl, and aziridinyl. In some
embodiments,
##STR00011##
is selected from the group consisting of: piperazinyl, morpholinyl,
piperidinyl, pyrrolidinyl, tetrahydrofuranyl, and diazepanyl. In
some embodiments,
##STR00012##
is selected from the group consisting of: piperazinyl, morpholinyl,
piperidinyl, and pyrrolidinyl.
[0015] In some embodiments, m is 1, 2, or 3; and at least one Q is
E. In some embodiments, n is 1 and Z is an optionally substituted
heterocycloalkyl. In some embodiments, Z is optionally substituted
piperazinyl. For example, Z is methylpiperazinyl or
acetylpiperazinyl. In some embodiments, Z is amino optionally
substituted with optionally substituted heterocycloalkyl.
[0016] In another aspect, the present disclosure provides the
compound or pharmaceutically acceptable salt of Formula I
wherein
##STR00013##
[0017] X.sub.1 is C--R.sub.2, or N; and
[0018] R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl. Another embodiment of the
invention described wherein
##STR00014##
[0019] X.sub.2 is C--R.sub.11, or N; and
[0020] R.sub.11, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are
independently, hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, oxo, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl or E; wherein E is an
electrophilic group capable of forming a covalent bond with a
nucleophile.
[0021] In some embodiments, the compound of Formula I is a compound
of Formula Ia
##STR00015##
[0022] or a pharmaceutically acceptable salt thereof, wherein
[0023] X.sub.1 is C--R.sub.2, or N;
[0024] X.sub.2 is C--R.sub.n, or N;
[0025] X.sub.3 is C--R.sub.12, or N;
[0026] X.sub.4 is C--R.sub.13, or N;
[0027] X.sub.5 is C--R.sub.14, or N;
[0028] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl;
[0029] R.sub.8, R.sub.9, and R.sub.10 are independently hydrogen,
cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl,
sulfonyl, optionally substituted alkoxy, optionally substituted
cycloalkyloxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, optionally substituted
heterocycloalkyloxy, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocycloalkyl,
optionally substituted amino, optionally substituted acyl,
optionally substituted alkoxycarbonyl, optionally substituted
aminocarbonyl, optionally substituted aminosulfonyl, optionally
substituted carbamimidoyl, or E; wherein E can be an electrophilic
group capable of forming a covalent bond with a nucleophile. In
some embodiments, at least one of R.sub.8, R.sub.9, and R.sub.10 is
E. In some embodiments, R.sub.3 is amino optionally substituted
with optionally substituted heterocycloalkyl. In some embodiments,
R.sub.4 is amino optionally substituted with optionally substituted
heterocycloalkyl.
[0030] In some embodiments, the compound or pharmaceutically
acceptable salt has the Formula Ib:
##STR00016##
[0031] wherein:
[0032] X.sub.1 is N or C--R.sub.2;
[0033] each R.sub.1, R.sub.2, R.sub.4, or R.sub.5 is independently
H or halo;
[0034] R.sub.3 is optionally substituted heterocycloalkyl; and
[0035] E is an electrophilic group capable of forming a covalent
bond with a nucleophile.
[0036] For example, the compound or pharmaceutically acceptable
salt has the Formula Ib':
##STR00017##
[0037] In some embodiments, X.sub.1 is C--R.sub.2. In some
embodiments, R.sub.1 and R.sub.2 are independently hydrogen or
halo. In some embodiments, R.sub.1 and R.sub.2 are hydrogen. In
some embodiments, R.sub.1 is hydrogen and R.sub.2 is halo. In some
embodiments, R.sub.1 is hydrogen and R.sub.2 is fluoro. In some
embodiments, R.sub.1 is halo and R.sub.2 is hydrogen. In some
embodiments, R.sub.1 is fluoro and R.sub.2 is hydrogen. In some
embodiments, R.sub.1 and R.sub.2 are halo. In some embodiments,
R.sub.1 and R.sub.2 are fluoro.
[0038] In some embodiments, R.sub.3 is optionally substituted
morpholinyl, optionally substituted piperazinyl, optionally
substituted pyrrolidinyl, optionally substituted piperidinyl,
optionally substituted azetidinyl, or substituted amino. For
example, R.sub.3 is optionally substituted morpholinyl,
pyrrolidinyl, piperazinyl, or piperidinyl.
[0039] In some embodiments, R.sub.3 is piperazinyl, morpholinyl,
piperidinyl, or pyrrolidinyl, optionally substituted with
--R.sup.a, --OR.sup.b, optionally substituted amino (including
--NR.sup.cCOR.sup.b, --NR.sup.cCO.sub.2R.sup.a,
--NR.sup.cCONR.sup.bR.sup.c, --NR.sup.bC(NR.sup.c)NR.sup.bR.sup.c,
--NR.sup.bC(NCN)NR.sup.bR.sup.c, and --NR.sup.cSO.sub.2R.sup.a),
halo, cyano, azido, nitro, oxo (as a substituent for cycloalkyl or
heterocycloalkyl), optionally substituted acyl (such as
--COR.sup.b), optionally substituted alkoxycarbonyl (such as
--CO.sub.2R.sup.b), aminocarbonyl (such as --CONR.sup.bR.sup.c),
--OCOR.sup.b, --OCO.sub.2R.sup.a, --OCONR.sub.bR.sup.c,
--OP(.sup.O)(O.sup.Rb)OR.sup.c, sulfanyl (such as SR.sup.b),
sulfinyl (such as --SOR.sup.a) or sulfonyl (such as
--SO.sub.2R.sup.a and --SO.sub.2NR.sup.bR.sup.c),
where R.sup.a is optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, or optionally
substituted heteroaryl; R.sup.b is hydrogen, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl, optionally substituted
aryl, or optionally substituted heteroaryl; and R.sup.c is hydrogen
or optionally substituted C.sub.1-C.sub.4 alkyl; or R.sup.b and
R.sup.c, and the nitrogen to which they are attached, form an
optionally substituted heterocycloalkyl group; and where each
optionally substituted group is unsubstituted or independently
substituted with one or more, such as one, two, or three,
substituents independently chosen from C.sub.1-C.sub.4 alkyl, aryl,
heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4
alkyl-, C.sub.1-C.sub.4 haloalkyl, --OC.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH,
--OC.sub.1-C.sub.4 haloalkyl, halo, --OH, --NH.sub.2,
--C.sub.1-C.sub.4 alkyl-NH.sub.2, --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl),
--NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a
substituent for cycloalkyl or heterocycloalkyl), --CO.sub.2H,
--C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), and --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0040] In some embodiments, R.sub.3 is
##STR00018##
[0041] In some embodiments, R.sub.a is C.sub.1-C.sub.6 alkyl,
optionally substituted with C.sub.1-C.sub.4 alkyl, aryl,
heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4
alkyl-, C.sub.1-C.sub.4 haloalkyl, --OC.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH,
--OC.sub.1-C.sub.4 haloalkyl, halo, --OH, --NH.sub.2,
--C.sub.1-C.sub.4 alkyl-NH.sub.2, --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl),
--NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a
substituent for cycloalkyl or hetero cyclo alkyl), --CO.sub.2H,
--C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0042] In some embodiments, R.sub.a is C.sub.1-C.sub.6 alkyl,
optionally substituted with OH, halo, C.sub.1-C.sub.4 alkyl, or
--OC.sub.1-C.sub.4 alkyl. In some embodiments, R.sub.a is
--CH.sub.3, --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2OMe, --CH.sub.2C(CH.sub.3).sub.2OH, or
--CH.sub.2CH(CH.sub.3)OH.
[0043] In another aspect, the present disclosure provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound or pharmaceutically acceptable salt of any
one of compounds described herein. The pharmaceutical composition
may be formulated in a form which is a tablet, capsule, powder,
liquid, suspension, suppository, or aerosol. The pharmaceutical
composition may be packaged with instructions for using the
composition to treat a subject suffering from cancer.
[0044] In another aspect, the present disclosure provides a method
of treating cancer in a subject which comprises administering to a
subject in need thereof a therapeutically effective amount of a
compound or pharmaceutically acceptable salt of any one of the
compounds described herein. The cancer may be colon carcinoma,
pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma,
chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma,
endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,
synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,
rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,
adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,
papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,
medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,
hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal
carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung
carcinoma, small cell lung carcinoma, non-small cell lung cancer,
bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,
medulloblastoma, craniopharyngioma, ependymoma, pinealoma,
hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,
melanoma, neuroblastoma, retinoblastoma, leukemia, acute
lymphocytic leukemia and acute myelocytic leukemia (myeloblastic,
promyelocytic, myelomonocytic, monocytic and erythroleukemia);
chronic leukemia (chronic myelocytic (granulocytic) leukemia and
chronic lymphocytic leukemia); and polycythemia vera, lymphoma
(Hodgkin's disease and non-Hodgkin's disease), multiple myeloma,
Waldenstrom's macroglobulinemia, or heavy chain disease. In a
further embodiment, the cancer is melanoma, non-small cell lung
cancer, thyroid cancer, ovarian cancer, or colon cancer. The
melanoma may be unresectable or metastatic melanoma.
[0045] In another aspect, the present disclosure provides a method
of treating a disorder mediated by EGFR kinase or EGFR mutants in a
subject in need thereof, comprising administering to the subject a
therapeutically effective amount of a compound or pharmaceutically
acceptable salt of any one of the compounds described herein.
[0046] In another aspect, the present disclosure provides a method
of treating a disorder in a subject in need thereof, comprising: a)
determining the presence or absence of a EGFR mutation in a
biological sample isolated from the subject; and b) if a EGFR
mutation is determined to be present in the subject, administering
to the subject a therapeutically effective amount of a compound or
pharmaceutically acceptable salt of any one of the compounds
described herein.
[0047] Somatic activating mutations of the EGFR gene, increased
gene copy number and certain clinical and pathological features
have been found in certain types of cancer. The specific types of
activating mutations may be Exon 19 deletion (del E746-A750)
mutations, the single-point substitution mutation L858R in exon 21
and the point mutation T790M. A specific type of activating
mutation may also be the double mutations of L858R and T790M. In
some embodiments, determining the presence or absence of the EGFR
mutation comprises amplifying EGFR nucleic acid from a biological
sample and sequencing the amplified nucleic acid. In some other
embodiments, determining the presence or absence of the EGFR
mutation comprises detecting a mutant EGFR polypeptide in a
biological sample using a binding agent to a mutant EGFR
polypeptide. The binding agent may be an antibody. The biological
sample may be isolated from a tumor of the subject. In some
embodiments, determining the presence or absence of the both L858R
and T790M EGFR mutations comprises amplifying EGFR nucleic acid
from the biological sample and sequencing the amplified nucleic
acid, or detecting a double mutant EGFR polypeptide from the
biological sample.
[0048] In some embodiments, the disorder is cancer. The cancer may
be colon carcinoma, pancreatic cancer, breast cancer, ovarian
cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma,
liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma,
angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's
tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma,
basal cell carcinoma, adenocarcinoma, sweat gland carcinoma,
sebaceous gland carcinoma, papillary carcinoma, papillary
adenocarcinomas, cystadenocarcinoma, medullary carcinoma,
bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct
carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'
tumor, cervical cancer, testicular tumor, lung carcinoma, small
cell lung carcinoma, non-small cell lung cancer, bladder carcinoma,
epithelial carcinoma, glioma, astrocytoma, medulloblastoma,
craniopharyngioma, ependymoma, pinealoma, hemangioblastoma,
acoustic neuroma, oligodendroglioma, meningioma, melanoma,
neuroblastoma, retinoblastoma, leukemia, acute lymphocytic leukemia
and acute myelocytic leukemia (myeloblastic, promyelocytic,
myelomonocytic, monocytic and erythroleukemia); chronic leukemia
(chronic myelocytic (granulocytic) leukemia and chronic lymphocytic
leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and
non-Hodgkin's disease), multiple myeloma, Waldenstrom's
macroglobulinemia, or heavy chain disease. In a further embodiment,
the cancer is melanoma, non-small cell lung cancer, thyroid cancer,
ovarian cancer, or colon cancer. The melanoma may be unresectable
or metastatic melanoma.
[0049] The treatment method described herein may further comprise
administering an additional anti-cancer and/or cytotoxic agent.
INCORPORATION BY REFERENCE
[0050] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference in their
entireties to the same extent as if each individual publication,
patent, or patent application was specifically and individually
indicated to be incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
[0051] As used herein, the following words and phrases are
generally intended to have the meanings as set forth below, except
to the extent that the context in which they are used indicates
otherwise.
[0052] The following abbreviations and terms have the indicated
meanings throughout: [0053] AcOH=acetic acid [0054]
Boc=tert-butoxycarbonyl [0055] c-=cyclo [0056]
DCC=dicyclohexylcarbodiimide [0057] DIEA=N,N-diisopropylethylamine
[0058] DMAP=4-dimethylaminopyridine [0059]
EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide [0060]
eq=equivalent(s) [0061] Et=ethyl [0062] EtOAc or EA=ethyl acetate
[0063] EtOH=ethanol [0064] g=gram [0065] h or hr=hour [0066]
HBTU=O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0067] HOBt=hydroxybenzotriazole [0068]
HPLC=high pressure liquid chromatography [0069] i-=iso [0070] kg or
Kg=kilogram [0071] L or 1=liter [0072] LC/MS=LCMS=liquid
chromatography-mass spectrometry [0073] LRMS=low resolution mass
spectrometry [0074] m/z=mass-to-charge ratio [0075] Me=methyl
[0076] MeOH=methanol [0077] mg=milligram [0078] min=minute [0079]
mL=milliliter [0080] mmol=millimole [0081] n-=normal [0082]
NaOAc=sodium acetate [0083] PE=petroleum ether [0084] Ph=phenyl
[0085] Prep=preparative [0086] quant. quantitative [0087]
RP-HPLC=reverse phase-high pressure liquid chromatography [0088]
rt, r.t., or RT=room temperature [0089] s-=sec-=secondary [0090]
t-=tert-=tertiary [0091] THF=tetrahydrofuran [0092] TLC=thin layer
chromatography [0093] UV=ultraviolet
[0094] As used herein, when any variable occurs more than one time
in a chemical formula, its definition on each occurrence is
independent of its definition at every other occurrence.
[0095] As used herein, a dash ("-") that is not between two letters
or symbols is used to indicate a point of attachment for a
substituent. For example, --CONH.sub.2 is attached through the
carbon atom.
[0096] As used herein, "optional" or "optionally" is meant that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances wherein the event or
circumstance occurs and instances in which it does not. For
example, "optionally substituted alkyl" encompasses both "alkyl"
and "substituted alkyl" as defined below. It will be understood by
those skilled in the art, with respect to any group containing one
or more substituents, that such groups are not intended to
introduce any substitution or substitution patterns that are
sterically impractical, synthetically non-feasible and/or
inherently unstable.
[0097] As used herein, "alkyl" refers to straight chain and
branched chain having the indicated number of carbon atoms, usually
from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as
1 to 6 carbon atoms. For example C.sub.1-C.sub.6 alkyl encompasses
both straight and branched chain alkyl of from 1 to 6 carbon atoms.
When an alkyl residue having a specific number of carbons is named,
all branched and straight chain versions having that number of
carbons are intended to be encompassed; thus, for example, "butyl"
is meant to include n-butyl, sec-butyl, isobutyl and t-butyl;
"propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to
alkyl groups having one to six carbons. Examples of alkyl groups
include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,
tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,
3-hexyl, 3-methylpentyl, and the like. Alkylene is a subset of
alkyl, referring to the same residues as alkyl, but having two
points of attachment. Alkylene groups will usually have from 2 to
20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to
6 carbon atoms. For example, C.sub.0 alkylene indicates a covalent
bond and C.sub.1 alkylene is a methylene group.
[0098] As used herein, "alkenyl" refers to an unsaturated branched
or straight-chain alkyl group having at least one carbon-carbon
double bond derived by the removal of one molecule of hydrogen from
adjacent carbon atoms of the parent alkyl. The group may be in
either the cis or trans configuration about the double bond(s).
Typical alkenyl groups include, but are not limited to, ethenyl;
propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl
(allyl), prop-2-en-2-yl; butenyls such as but-1-en-1-yl,
but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,
but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl; and the like. In certain embodiments, an
alkenyl group has from 2 to 20 carbon atoms and in other
embodiments, from 2 to 6 carbon atoms. "Lower alkenyl" refers to
alkenyl groups having two to six carbons.
[0099] As used herein, "alkynyl" refers to an unsaturated branched
or straight-chain alkyl group having at least one carbon-carbon
triple bond derived by the removal of two molecules of hydrogen
from adjacent carbon atoms of the parent alkyl. Typical alkynyl
groups include, but are not limited to, ethynyl; propynyls such as
prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl,
but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certain embodiments,
an alkynyl group has from 2 to 20 carbon atoms and in other
embodiments, from 3 to 6 carbon atoms. "Lower alkynyl" refers to
alkynyl groups having two to six carbons.
[0100] As used herein, "cycloalkyl" refers to a non-aromatic
carbocyclic ring, usually having from 3 to 7 ring carbon atoms. The
ring may be saturated or have one or more carbon-carbon double
bonds. Examples of cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and
cyclohexenyl, as well as bridged and caged ring groups such as
norbornane.
[0101] As used herein, "alkoxy" refers to an alkyl group of the
indicated number of carbon atoms attached through an oxygen bridge
such as, for example, methoxy, ethoxy, propoxy, isopropoxy,
n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy,
isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy,
3-methylpentyloxy, and the like. Alkoxy groups will usually have
from 1 to 7 carbon atoms attached through the oxygen bridge. "Lower
alkoxy" refers to alkoxy groups having one to six carbons.
[0102] As used herein, "acyl" refers to the groups H--C(O)--;
(alkyl)-C(O)--; (cycloalkyl)-C(O)--; (aryl)-C(O)--;
(heteroaryl)-C(O)--; and (heterocycloalkyl)-C(O)--, wherein the
group is attached to the parent structure through the carbonyl
functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and
heterocycloalkyl are as described herein. Acyl groups have the
indicated number of carbon atoms, with the carbon of the keto group
being included in the numbered carbon atoms. For example a C.sub.2
acyl group is an acetyl group having the formula
CH.sub.3(C.dbd.O)--.
[0103] As used herein, "formyl" refers to the group --C(O)H.
[0104] As used herein, "alkoxycarbonyl" refers to a group of the
formula (alkoxy)(C.dbd.O)-- attached through the carbonyl carbon
wherein the alkoxy group has the indicated number of carbon atoms.
Thus a C.sub.1-C.sub.6 alkoxycarbonyl group is an alkoxy group
having from 1 to 6 carbon atoms attached through its oxygen to a
carbonyl linker.
[0105] As used herein, "azido" refers to the group --N.sub.3.
[0106] As used herein, "amino" refers to the group --NH.sub.2.
[0107] As used herein, "mono- and di-(alkyl)amino" refers to
secondary and tertiary alkyl amino groups, wherein the alkyl groups
are as defined above and have the indicated number of carbon atoms.
The point of attachment of the alkylamino group is on the nitrogen.
Examples of mono- and di-alkylamino groups include ethylamino,
dimethylamino, and methyl-propyl-amino.
[0108] As used herein, "aminocarbonyl" refers to the group
--CONR.sup.bR.sup.c, where
[0109] R.sup.b is H, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, or optionally substituted alkoxy; and
[0110] R.sup.c is hydrogen or optionally substituted
C.sub.1-C.sub.4 alkyl; or
[0111] R.sup.b and R.sup.c taken together with the nitrogen to
which they are bound, form an optionally substituted 4- to
8-membered nitrogen-containing heterocycloalkyl which optionally
includes 1 or 2 additional heteroatoms chosen from O, N, and S in
the heterocycloalkyl ring;
[0112] where each substituted group is independently substituted
with one or more substituents independently C.sub.1-C.sub.4 alkyl,
aryl, heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-,
heteroaryl-C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4 haloalkyl,
--OC.sub.1-C.sub.4 alkyl, --OC.sub.1-C.sub.4 alkylphenyl,
--C.sub.1-C.sub.4 alkyl-OH, --OC.sub.1-C.sub.4 haloalkyl, halo,
--OH, --NH.sub.2, --C.sub.1-C.sub.4 alkyl-NH.sub.2,
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl),
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkylphenyl), --NH(C.sub.1-C.sub.4
alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl,
heterocycloalkyl, or heteroaryl), --CO.sub.2H,
--C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0113] As used herein, "aryl" refers to: 6-membered carbocyclic
aromatic rings, for example, benzene; bicyclic ring systems wherein
at least one ring is carbocyclic and aromatic, for example,
naphthalene, indane, and tetralin; and tricyclic ring systems
wherein at least one ring is carbocyclic and aromatic, for example,
fluorene.
[0114] For example, aryl includes 6-membered carbocyclic aromatic
rings fused to a 4- to 8-membered heterocycloalkyl ring containing
1 or more heteroatoms chosen from N, O, and S. For such fused,
bicyclic ring systems wherein only one of the rings is a
carbocyclic aromatic ring, the point of attachment may be at the
carbocyclic aromatic ring or the heterocycloalkyl ring. Bivalent
radicals formed from substituted benzene derivatives and having the
free valences at ring atoms are named as substituted phenylene
radicals. Bivalent radicals derived from univalent polycyclic
hydrocarbon radicals whose names end in "-yl" by removal of one
hydrogen atom from the carbon atom with the free valence are named
by adding "-idene" to the name of the corresponding univalent
radical, e.g. a naphthyl group with two points of attachment is
termed naphthylidene. Aryl, however, does not encompass or overlap
in any way with heteroaryl, separately defined below. Hence, if one
or more carbocyclic aromatic rings is fused with a heterocycloalkyl
aromatic ring, the resulting ring system is heteroaryl, not aryl,
as defined herein.
[0115] As used herein, "aryloxy" refers to the group --O-aryl.
[0116] As used herein, "aralkyl" refers to the group
-alkyl-aryl.
[0117] As used herein, "carbamimidoyl" refers to the group
--C(.dbd.NH)--NH2.
[0118] As used herein, "substituted carbamimidoyl" refers to the
group --C(.dbd.NR.sup.e)--NR.sup.fR.sup.g where
[0119] R.sup.e is hydrogen, cyano, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, or optionally substituted
heterocycloalkyl; and
[0120] R.sup.f and R.sup.g are independently hydrogen optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, or optionally
substituted heterocycloalkyl,
[0121] provided that at least one of R.sup.e, R.sup.f, and R.sup.g
is not hydrogen and wherein substituted alkyl, cycloalkyl, aryl,
heterocycloalkyl, and heteroaryl refer respectively to alkyl,
cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or
more (such as up to 5, for example, up to 3) hydrogen atoms are
replaced by a substituent independently --R.sup.a, --OR.sup.b,
optionally substituted amino (including --NR.sup.cCOR.sup.b,
--NR.sup.cCO.sub.2R.sup.a, --NR.sup.cCONR.sup.bR.sup.c,
--NR.sup.bC(NR.sup.c)NR.sup.bR.sup.c, --NR)C(NCN)NR.sup.bR.sup.c,
and --NR.sup.cSO.sub.2R.sup.a), halo, cyano, nitro, oxo (as a
substituent for cycloalkyl, heterocycloalkyl, and heteroaryl),
optionally substituted acyl (such as --COO, optionally substituted
alkoxycarbonyl (such as --CO.sub.2R.sup.b), aminocarbonyl (such as
--CONR.sup.bR.sup.c), --OCOR.sup.b, --OCO.sub.2R.sup.a,
--OCONR.sup.bR.sup.c, --OP(O)(OR.sup.b)OR.sup.c, sulfanyl (such as
SR.sup.b), sulfinyl (such as --SOR.sup.a), or sulfonyl (such as
--SO.sub.2R.sup.a and --SO.sub.2NR)R.sup.c),
[0122] where R.sup.a is optionally substituted C1-C6 alkyl,
optionally substituted aryl, or optionally substituted
heteroaryl;
[0123] R.sup.b is H, optionally substituted C1-C6 alkyl, optionally
substituted aryl, or optionally substituted heteroaryl; and
[0124] R.sup.c is hydrogen or optionally substituted C1-C4 alkyl;
or
[0125] R.sup.b and R.sup.c, and the nitrogen to which they are
attached, form an optionally substituted heterocycloalkyl group;
and
[0126] where each optionally substituted group is unsubstituted or
independently substituted with one or more, such as one, two, or
three, substituents independently C.sub.1-C.sub.4 alkyl, aryl,
heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4
alkyl-, C.sub.1-C.sub.4 haloalkyl, --OC.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH,
--OC.sub.1-C.sub.4 haloalkyl, halo, --OH, --NH.sub.2,
--C.sub.1-C.sub.4 alkyl-NH.sub.2, --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl),
--NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a
substituent for cycloalkyl, heterocycloalkyl, or heteroaryl),
--CO.sub.2H, --C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 phenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl), --SO.sub.2
NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0127] As used herein, E refers to the electrophilic group capable
of forming a covalent bond with a nucleophile. In some embodiments,
compounds comprising E can undergo a spontaneous reaction with a
protein. In some embodiments, compounds comprising E can undergo a
spontaneous reaction with a protein to form a new covalent bond
under moderate reaction conditions. In some embodiments, compounds
comprising E can undergo a spontaneous reaction with a protein to
form a new covalent bond wherein the new covalent bond forms
between the compound and the nitrogen or sulfur of an amino acid
residue sidechain. Some non-limiting examples of the amino acid can
be lysine or cysteine, for example. In some embodiments, moderate
reaction conditions can be at a temperature below about 50.degree.
C., 45.degree. C., 40.degree. C., 39.degree. C., 38.degree. C.,
37.degree. C., 36.degree. C., 35.degree. C., 34.degree. C.,
33.degree. C., 30.degree. C., 27.degree. C., 25.degree. C.,
20.degree. C., or 5.degree. C. in an aqueous solution at a
concentration of protein and compound below about 1M for example.
In some embodiments, E is an electrophilic group capable of forming
a covalent bond with a cysteine residue of a protein. In some
embodiments, compounds comprising E are capable of forming a
covalent bond with a cysteine residue of a protein. Examples of E
include, but are not limited to, the following groups:
##STR00019## ##STR00020##
[0128] As used herein, "halo" refers to fluoro, chloro, bromo, and
iodo, and the term "halogen" includes fluorine, chlorine, bromine,
and iodine.
[0129] As used herein, "haloalkyl" refers to alkyl as defined above
having the specified number of carbon atoms, substituted with 1 or
more halogen atoms, up to the maximum allowable number of halogen
atoms. Examples of haloalkyl include, but are not limited to,
trifluoromethyl, difluoromethyl, 2-fluoro ethyl, and
penta-fluoroethyl.
[0130] As used herein, "heteroaryl" refers to:
[0131] 5- to 7-membered aromatic, monocyclic rings containing one
or more, for example, from 1 to 4, or in certain embodiments, from
1 to 3, heteroatoms chosen from N, O, and S, with the remaining
ring atoms being carbon;
[0132] bicyclic heterocycloalkyl rings containing one or more, for
example, from 1 to 4, or in certain embodiments, from 1 to 3,
heteroatoms chosen from N, O, and S, with the remaining ring atoms
being carbon and wherein at least one heteroatom is present in an
aromatic ring; and
[0133] tricyclic heterocycloalkyl rings containing one or more, for
example, from 1 to 5, or in certain embodiments, from 1 to 4,
heteroatoms chosen from N, O, and S, with the remaining ring atoms
being carbon and wherein at least one heteroatom is present in an
aromatic ring.
[0134] For example, heteroaryl includes a 5- to 7-membered
heterocycloalkyl, aromatic ring fused to a 4- to 8-membered
cycloalkyl or heterocycloalkyl ring. For such fused, bicyclic
heteroaryl ring systems wherein only one of the rings contains one
or more heteroatoms, the point of attachment may be at either ring.
When the total number of S and O atoms in the heteroaryl group
exceeds 1, those heteroatoms are not adjacent to one another. In
certain embodiments, the total number of S and O atoms in the
heteroaryl group is not more than 2. In certain embodiments, the
total number of S and O atoms in the aromatic heterocycle is not
more than 1. Examples of heteroaryl groups include, but are not
limited to, pyridyl, pyrazinyl, pyrimidinyl, pyrazolinyl,
imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,
tetrazolyl, thienyl, benzothiophenyl, furanyl, pyrrolyl,
benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl, triazolyl,
quinolinyl, quinoxalinyl, pyrazolyl, and
5,6,7,8-tetrahydroisoquinolinyl. Bivalent radicals derived from
univalent heteroaryl radicals whose names end in "-yl" by removal
of one hydrogen atom from the atom with the free valence are named
by adding "-idene" to the name of the corresponding univalent
radical, e.g. a pyridyl group with two points of attachment is a
pyridylidene. Heteroaryl does not encompass or overlap with aryl,
cycloalkyl, or heterocycloalkyl, as defined herein.
[0135] Substituted heteroaryl also includes ring systems
substituted with one or more oxide (--O.sup.-) substituents, such
as pyridinyl N-oxides.
[0136] As used herein, "heterocycloalkyl" refers to a single,
non-aromatic ring, usually with 3 to 8 ring atoms, containing at
least 2 carbon atoms in addition to 1-3 heteroatoms independently
chosen from oxygen, sulfur, and nitrogen, as well as combinations
comprising at least one of the foregoing heteroatoms. The ring may
be saturated or have one or more carbon-carbon double bonds.
Suitable heterocycloalkyl groups include but are not limited to,
for example, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl,
azetidinyl, diazepanyl, diazocanyl, pyrrolidinyl, morpholinyl,
piperidinyl, piperazinyl, imidazolidinyl, pyrazolidinyl,
dihydrofuranyl, and tetrahydrofuranyl. Substituted heterocycloalkyl
can also include ring systems substituted with one or more oxo
(.dbd.O) or oxide (--O.sup.-) substituents, such as piperidinyl
N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and
1,1-dioxo-1-thiomorpholinyl.
[0137] "Heterocycloalkyl" also includes bicyclic ring systems
wherein one non-aromatic ring, usually with 3 to 7 ring atoms,
contains at least 2 carbon atoms in addition to 1-3 heteroatoms
independently chosen from oxygen, sulfur, and nitrogen, as well as
combinations comprising at least one of the foregoing heteroatoms;
and the other ring, usually with 3 to 7 ring atoms, optionally
contains 1-3 heteratoms independently chosen from oxygen, sulfur,
and nitrogen and is not aromatic.
[0138] As used herein, "sulfanyl" refers to the groups:
--S-(optionally substituted (C.sub.1-C.sub.6)alkyl),
--S-(optionally substituted cycloalkyl), --S-(optionally
substituted aryl), --S-(optionally substituted heteroaryl), and
--S-(optionally substituted heterocycloalkyl). Hence, sulfanyl
includes the group C.sub.1-C.sub.6 alkylsulfanyl.
[0139] As used herein, "sulfinyl" refers to the groups:
--S(O)-(optionally substituted (C.sub.1-C.sub.6)alkyl),
--S(O)-(optionally substituted cycloalkyl), --S(O)-(optionally
substituted aryl), --S(O)-optionally substituted heteroaryl),
--S(O)-(optionally substituted heterocycloalkyl); and
--S(O)-(optionally substituted amino).
[0140] As used herein, "sulfonyl" refers to the groups:
--S(O.sub.2)-(optionally substituted (C.sub.1-C.sub.6)alkyl),
--S(O.sub.2)-(optionally substituted cycloalkyl),
--S(O.sub.2)-(optionally substituted aryl),
--S(O.sub.2)-(optionally substituted heteroaryl),
--S(O.sub.2)-(optionally substituted heterocycloalkyl), and
--S(O.sub.2)-(optionally substituted amino).
[0141] As used herein, "substituted" refers to any one or more
hydrogens on the designated atom or group is replaced with a
selection from the indicated group, provided that the designated
atom's normal valence is not exceeded. When a substituent is oxo
(i.e. .dbd.O) then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds or useful synthetic
intermediates. A stable compound or stable structure is meant to
imply a compound that is sufficiently robust to survive isolation
from a reaction mixture, and subsequent formulation as an agent
having at least practical utility. Unless otherwise specified,
substituents are named into the core structure. For example, it is
to be understood that when (cycloalkyl)alkyl is listed as a
possible substituent, the point of attachment of this substituent
to the core structure is in the alkyl portion.
[0142] As used herein, the terms "substituted" alkyl, cycloalkyl,
aryl, heterocycloalkyl, and heteroaryl, unless otherwise expressly
defined, refer respectively to alkyl, cycloalkyl, aryl,
heterocycloalkyl, and heteroaryl wherein one or more (such as up to
5, for example, up to 3) hydrogen atoms are replaced by a
substituent independently --R.sup.a, --OR.sup.b, optionally
substituted amino (including --NR.sup.cOR.sup.b,
--NR.sup.cCO.sub.2R.sup.a, --NR.sup.cCONR.sup.bR.sup.c,
--NR.sup.bC(NR.sup.c)NR.sup.bR.sup.c,
--NR.sup.bC(NCN)NR.sup.bR.sup.c, and --NR.sup.cSO.sub.2R.sup.a),
halo, cyano, azido, nitro, oxo (as a substituent for cycloalkyl or
heterocycloalkyl), optionally substituted acyl (such as
--COR.sup.b), optionally substituted alkoxycarbonyl (such as
--CO.sub.2R.sup.b), aminocarbonyl (such as --CONR.sup.bR.sup.c),
--OCOR.sup.b, --OCO.sub.2R.sup.a, --OCONR.sup.bR.sup.c,
--OP(.sup.O)(O.sup.Rb)OR.sup.c, sulfanyl (such as SR.sup.b),
sulfinyl (such as --SOR.sup.a) or sulfonyl (such as
--SO.sub.2R.sup.a and --SO.sub.2NR)R.sup.c),
[0143] where R.sup.a is optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, or optionally
substituted heteroaryl; R.sup.b is hydrogen, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl, optionally substituted
aryl, or optionally substituted heteroaryl; and
[0144] R.sup.c is hydrogen or optionally substituted
C.sub.1-C.sub.4 alkyl; or
[0145] R.sup.b and R.sup.c, and the nitrogen to which they are
attached, form an optionally substituted heterocycloalkyl group;
and
[0146] where each optionally substituted group is unsubstituted or
independently substituted with one or more, such as one, two, or
three, substituents independently C.sub.1-C.sub.4 alkyl, aryl,
heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4
alkyl-, C.sub.1-C.sub.4 haloalkyl, --OC.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH,
--OC.sub.1-C.sub.4 haloalkyl, halo, --OH, --NH.sub.2,
--C.sub.1-C.sub.4 alkyl-NH.sub.2, --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl),
--NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a
substituent for cycloalkyl or hetero cyclo alkyl), --CO.sub.2H,
--C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0147] As used herein, "substituted acyl" refers to the groups
(substituted alkyl)-C(O)--; (substituted cycloalkyl)-C(O)--;
(substituted aryl)-C(O)--; (substituted heteroaryl)-C(O)--; and
(substituted heterocycloalkyl)-C(O)--, wherein the group is
attached to the parent structure through the carbonyl functionality
and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and
heterocycloalkyl, refer respectively to alkyl, cycloalkyl, aryl,
heteroaryl, and heterocycloalkyl wherein one or more (such as up to
5, for example, up to 3) hydrogen atoms are replaced by a
substituent independently --R.sup.a, --OR.sup.b, optionally
substituted amino (including --NR.sup.cCOR.sup.b,
--NR.sup.cCO.sub.2R.sup.a, --NR.sup.cCONR.sup.bR.sup.c,
--NR.sup.bC(NR.sup.c)NR.sup.bR.sup.c,
--NR.sup.bC(NCN)NR.sup.bR.sup.c, and --NR.sup.cSO.sub.2R.sup.a),
halo, cyano, nitro, oxo (as a substituent for cycloalkyl or
heterocycloalkyl), optionally substituted acyl (such as
--COR.sup.b), optionally substituted alkoxycarbonyl (such as
--CO.sub.2R.sup.b), aminocarbonyl (such as --CONR.sup.bR.sup.c),
--OCOR.sup.b, --OCO.sub.2R.sup.a, --OCONR.sup.bR.sup.c,
--OP(O)(OR))OR.sup.c, sulfanyl (such as SR.sup.b), sulfinyl (such
as --SOR.sup.a), or sulfonyl (such as --SO.sub.2R.sup.a and
--SO.sub.2NR.sup.bR.sup.c),
[0148] where R.sup.a is optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, or optionally substituted
heteroaryl;
[0149] R.sup.b is H, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally
substituted heteroaryl; and
[0150] R.sup.c is hydrogen or optionally substituted
C.sub.1-C.sub.4 alkyl; or
[0151] R.sup.b and R.sup.c, and the nitrogen to which they are
attached, form an optionally substituted heterocycloalkyl group;
and
[0152] where each optionally substituted group is unsubstituted or
independently substituted with one or more, such as one, two, or
three, substituents independently C.sub.1-C.sub.4 alkyl, aryl,
heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4
alkyl-, C.sub.1-C.sub.4 haloalkyl, --OC.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH,
--OC.sub.1-C.sub.4 haloalkyl, halo, --OH, --NH.sub.2,
--C.sub.1-C.sub.4 alkyl-NH.sub.2, --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl),
--NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a
substituent for cycloalkyl or hetero cyclo alkyl), --CO.sub.2H,
--C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0153] As used herein, "substituted alkoxy" refers to alkoxy
wherein the alkyl constituent is substituted (i.e. --O-(substituted
alkyl)) wherein "substituted alkyl" refers to alkyl wherein one or
more (such as up to 5, for example, up to 3) hydrogen atoms are
replaced by a substituent independently
--R.sup.a, --OR.sup.b, optionally substituted amino (including
--NR.sup.cCOR.sup.b, --NR.sup.cCO.sub.2R.sup.a,
--NR.sup.cCONR.sup.bR.sup.c, --NR.sup.bC(NR.sup.c)NR.sup.bR.sup.c,
--NR.sup.bC(NCN)NR.sup.bR.sup.c, and --NR.sup.cSO.sub.2R.sup.a),
halo, cyano, nitro, oxo (as a substituent for cycloalkyl or
heterocycloalkyl), optionally substituted acyl (such as --COO,
optionally substituted alkoxycarbonyl (such as --CO.sub.2R.sup.b),
aminocarbonyl (such as --CONR.sup.bR.sup.c), --OCOR.sup.b,
--OCO.sub.2R.sup.a, --OCONR.sup.bR.sup.c,
--OP(O)(OR.sup.b)OR.sup.c, sulfanyl (such as SR.sup.b), sulfinyl
(such as --SOR.sup.a), and sulfonyl (such as --SO.sub.2R.sup.a and
--SO.sub.2NR.sup.bR.sup.c),
[0154] where R.sup.a is optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, or optionally substituted
heteroaryl;
[0155] R.sup.b is H, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally
substituted heteroaryl; and
[0156] R.sup.c is hydrogen or optionally substituted
C.sub.1-C.sub.4 alkyl; or
[0157] R.sup.b and R.sup.c, and the nitrogen to which they are
attached, form an optionally substituted heterocycloalkyl group;
and
[0158] where each optionally substituted group is unsubstituted or
independently substituted with one or more, such as one, two, or
three, substituents independently C.sub.1-C.sub.4 alkyl, aryl,
heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4
alkyl-, C.sub.1-C.sub.4 haloalkyl, --OC.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH,
--OC.sub.1-C.sub.4 haloalkyl, halo, --OH, --NH.sub.2,
--C.sub.1-C.sub.4 alkyl-NH.sub.2, --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl),
--NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a
substituent for cycloalkyl or hetero cyclo alkyl), --CO.sub.2H,
--C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0159] In some embodiments, a substituted alkoxy group is
"polyalkoxy" or --O-- (optionally substituted alkylene)-(optionally
substituted alkoxy), and includes groups such as
--OCH.sub.2CH.sub.2OCH.sub.3, and residues of glycol ethers such as
polyethyleneglycol, and --O(CH.sub.2CH.sub.2O).sub.xCH.sub.3, where
x is an integer of 2-20, such as 2-10, and for example, 2-5.
Another substituted alkoxy group is hydroxyalkoxy or
--OCH.sub.2(CH.sub.2).sub.yOH, where y is an integer of 1-10, such
as 1-4.
[0160] As used herein, "substituted alkoxycarbonyl" refers to the
group (substituted alkyl)-O--C(O)-- wherein the group is attached
to the parent structure through the carbonyl functionality and
wherein substituted refers to alkyl wherein one or more (such as up
to 5, for example, up to 3) hydrogen atoms are replaced by a
substituent independently --R.sup.a, --OR.sup.b, optionally
substituted amino (including --NR.sup.cCOR.sup.b,
--NR.sup.cCO.sub.2R.sup.a, --NR.sup.cCONR.sup.bR.sup.c,
--NR.sup.bC(NR.sup.c)NR.sup.bR.sup.c,
--NR.sup.bC(NCN)NR.sup.bR.sup.c, and --NR.sup.cSO.sub.2R.sup.a),
halo, cyano, nitro, oxo (as a substituent for cycloalkyl or
heterocycloalkyl), optionally substituted acyl (such as
--COR.sup.b) optionally substituted alkoxycarbonyl (such as
--CO.sub.2R.sup.b), aminocarbonyl (such as --CONR.sup.bR.sup.c),
--OCOR.sup.b, --OCO.sub.2R.sup.a, --OCONR.sup.bR.sup.c,
--OP(O)(OR.sup.b)OR.sup.c, sulfanyl (such as SR), sulfinyl (such as
--SOR.sup.a), and sulfonyl (such as --SO.sub.2R.sup.a and
--SO.sub.2NR.sup.bR.sup.c),
[0161] where R.sup.a is optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, or optionally substituted
heteroaryl;
[0162] R.sup.b is H, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally
substituted heteroaryl; and
[0163] R.sup.c is hydrogen or optionally substituted
C.sub.1-C.sub.4 alkyl; or
[0164] R.sup.b and R.sup.c, and the nitrogen to which they are
attached, form an optionally substituted heterocycloalkyl group;
and
[0165] where each optionally substituted group is unsubstituted or
independently substituted with one or more, such as one, two, or
three, substituents independently C.sub.1-C.sub.4 alkyl, aryl,
heteroaryl, aryl-C.sub.1-C.sub.4 alkyl-, heteroaryl-C.sub.1-C.sub.4
alkyl-, C.sub.1-C.sub.4 haloalkyl, --OC.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH,
--OC.sub.1-C.sub.4 haloalkyl, halo, --OH, --NH.sub.2,
--C.sub.1-C.sub.4 alkyl-NH.sub.2, --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --NH(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkylphenyl),
--NH(C.sub.1-C.sub.4 alkylphenyl), cyano, nitro, oxo (as a
substituent for cycloalkyl or hetero cyclo alkyl), --CO.sub.2H,
--C(O)OC.sub.1-C.sub.4 alkyl, --CON(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkyl), --CONH(C.sub.1-C.sub.4 alkyl),
--CONH.sub.2, --NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0166] As used herein, "substituted amino" refers to the group
--NHR.sup.d or --NR.sup.dR.sup.e wherein R.sup.d is hydroxyl,
formyl, optionally substituted alkoxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
acyl, optionally substituted carbamimidoyl, aminocarbonyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted heterocycloalkyl, optionally substituted
alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R.sup.e is
chosen from optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, or optionally substituted heterocycloalkyl, and wherein
substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and
heteroaryl refer respectively to alkyl, cycloalkyl, aryl,
heterocycloalkyl, and heteroaryl wherein one or more (such as up to
5, for example, up to 3) hydrogen atoms are replaced by a
substituent independently --R.sup.a, --OR'', optionally substituted
amino (including --NR.sup.cCOR.sup.b, --NR.sup.cCO.sub.2R.sup.a,
--NR.sup.cCONR.sup.bR.sup.c, --NR.sup.bC(NR.sup.c)NR.sup.bR.sup.c,
--NR.sup.bC(NCN)NR.sup.bR.sup.c, and --NR.sup.cSO.sub.2R.sup.a),
halo, cyano, nitro, oxo (as a substituent for cycloalkyl or
heterocycloalkyl), optionally substituted acyl (such as --COO,
optionally substituted alkoxycarbonyl (such as --CO.sub.2R.sup.b),
aminocarbonyl (such as --CONR.sup.bR.sup.c), --OCOR.sup.b,
--OCO.sub.2R.sup.a, --OCONR.sup.bR.sup.c,
--OP(O)(OR.sup.b)OR.sup.c, sulfanyl (such as SR.sup.b), sulfinyl
(such as --SOR.sup.a), or sulfonyl (such as --SO.sub.2R.sup.a and
--SO.sub.2NR.sup.bR.sup.c),
[0167] wherein R.sup.a is optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted aryl, or optionally substituted
heteroaryl;
[0168] R.sup.b is H, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, or optionally
substituted heteroaryl; and
[0169] R.sup.c is hydrogen or optionally substituted
C.sub.1-C.sub.4 alkyl; or R.sup.b and R.sup.c, and the nitrogen to
which they are attached, form an optionally substituted
heterocycloalkyl group; and wherein each optionally substituted
group is unsubstituted or independently substituted with one or
more, such as one, two, or three, substituents independently chosen
from C.sub.1-C.sub.4 alkyl, aryl, heteroaryl, aryl-C.sub.1-C.sub.4
alkyl-, heteroaryl-C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4
haloalkyl, --OC.sub.1-C.sub.4 alkyl, --OC.sub.1-C.sub.4
alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH, --OC.sub.1-C.sub.4
haloalkyl, halo, --OH, --NH.sub.2, --C.sub.1-C.sub.4
alkyl-NH.sub.2, --N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl),
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkylphenyl), --NH(C.sub.1-C.sub.4
alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or
hetero cyclo alkyl), --CO.sub.2H, --C(O)OC.sub.1-C.sub.4 alkyl,
--CON(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl),
--CONH(C.sub.1-C.sub.4 alkyl), --CONH.sub.2,
--NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4 haloalkyl);
and wherein optionally substituted acyl, optionally substituted
alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.
[0170] The term "substituted amino" also refers to N-oxides of the
groups --NHR.sup.d, and NR.sup.dR.sup.d each as described above.
N-oxides can be prepared by treatment of the corresponding amino
group with, for example, hydrogen peroxide or m-chloroperoxybenzoic
acid. The person skilled in the art is familiar with reaction
conditions for carrying out the N-oxidation.
[0171] Compounds described herein include, but are not limited to,
their optical isomers, racemates, and other mixtures thereof. In
those situations, the single enantiomers or diastereomers, i.e.,
optically active forms, can be obtained by asymmetric synthesis or
by resolution of the racemates. Resolution of the racemates can be
accomplished, for example, by conventional methods such as
crystallization in the presence of a resolving agent, or
chromatography, using, for example a chiral high-pressure liquid
chromatography (HPLC) column. In addition, compounds include Z- and
E-forms (or cis- and trans-forms) of compounds with carbon-carbon
double bonds. Where compounds described herein exist in various
tautomeric forms, the term "compound" is intended to include all
tautomeric forms of the compound.
[0172] Compounds of Formula I also include crystalline and
amorphous forms of those compounds, including, for example,
polymorphs, pseudopolymorphs, solvates (including hydrates),
unsolvated polymorphs (including anhydrates), conformational
polymorphs, and amorphous forms of the compounds, as well as
mixtures thereof "Crystalline form," "polymorph," and "novel form"
may be used interchangeably herein, and are meant to include all
crystalline and amorphous forms of the compound, including, for
example, polymorphs, pseudopolymorphs, solvates (including
hydrates), unsolvated polymorphs (including anhydrates),
conformational polymorphs, and amorphous forms, as well as mixtures
thereof, unless a particular crystalline or amorphous form is
referred to. Similarly, "pharmaceutically acceptable forms" of
compounds of Formula I also include crystalline and amorphous forms
of those compounds, including, for example, polymorphs,
pseudopolymorphs, solvates (including hydrates), unsolvated
polymorphs (including anhydrates), conformational polymorphs, and
amorphous forms of the pharmaceutically acceptable salts, as well
as mixtures thereof.
[0173] A "solvate" is formed by the interaction of a solvent and a
compound. The term "compound" is intended to include solvates of
compounds. Similarly, "pharmaceutically acceptable salts" includes
solvates of pharmaceutically acceptable salts. Suitable solvates
are pharmaceutically acceptable solvates, such as hydrates,
including monohydrates and hemi-hydrates.
[0174] Compounds of Formula I also include other pharmaceutically
acceptable forms of the recited compounds, including chelates,
non-covalent complexes, prodrugs, and mixtures thereof.
[0175] A "chelate" is formed by the coordination of a compound to a
metal ion at two (or more) points. The term "compound" is intended
to include chelates of compounds. Similarly, "pharmaceutically
acceptable salts" includes chelates of pharmaceutically acceptable
salts.
[0176] A "non-covalent complex" is formed by the interaction of a
compound and another molecule wherein a covalent bond is not formed
between the compound and the molecule. For example, complexation
can occur through van der Waals interactions, hydrogen bonding, and
electrostatic interactions (also called ionic bonding). Such
non-covalent complexes are included in the term "compound".
Similarly, pharmaceutically acceptable salts include "non-covalent
complexes" of pharmaceutically acceptable salts.
[0177] The term "hydrogen bond" refers to a form of association
between an electronegative atom (also known as a hydrogen bond
acceptor) and a hydrogen atom attached to a second, relatively
electronegative atom (also known as a hydrogen bond donor).
Suitable hydrogen bond donor and acceptors are well understood in
medicinal chemistry.
[0178] "Hydrogen bond acceptor" refers to a group comprising an
oxygen or nitrogen, such as an oxygen or nitrogen that is sp.sup.2
hybridized, an ether oxygen, or the oxygen of a sulfoxide or
N-oxide.
[0179] The term "hydrogen bond donor" refers to an oxygen,
nitrogen, or heteroaromatic carbon that bears a hydrogen. group
containing a ring nitrogen or a heteroaryl group containing a ring
nitrogen.
[0180] The compounds disclosed herein can be used in different
enriched isotopic forms, e.g., enriched in the content of .sup.2H,
.sup.3H, .sup.11C, .sup.13C and/or .sup.14C. In one particular
embodiment, the compound is deuterated at least one position. Such
deuterated forms can be made by the procedure described in U.S.
Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos.
5,846,514 and 6,334,997, deuteration can improve the efficacy and
increase the duration of action of drugs.
[0181] Deuterium substituted compounds can be synthesized using
various methods such as described in: Dean, Dennis C.; Editor.
Recent Advances in the Synthesis and Applications of Radiolabeled
Compounds for Drug Discovery and Development. [In: Curr., Pharm.
Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The
Synthesis of Radiolabeled Compounds via Organometallic
Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E.
Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem.,
1981, 64(1-2), 9-32.
[0182] "Pharmaceutically acceptable salts" include, but are not
limited to salts with inorganic acids, such as hydrochlorate,
carbonate, phosphate, hydrogenphosphate, diphosphate, hydrobromate,
sulfate, sulfinate, nitrate, and like salts; as well as salts with
an organic acid, such as malate, malonate, maleate, fumarate,
tartrate, succinate, citrate, acetate, lactate, gluconate,
methanesulfonate, Tris (hydroxymethyl-aminomethane),
p-toluenesulfonate, priopionate, 2-hydroxyethylsulfonate, benzoate,
salicylate, stearate, oxalate, pamoate, and alkanoate such as
acetate, HOOC--(CH.sub.2).sub.n--COOH where n is 0-4, and like
salts. Other salts include sulfate, methasulfonate, bromide,
trifluoracetate, picrate, sorbate, benzilate, salicilate, nitrate,
phthalate or morpholine. Pharmaceutically acceptable cations
include, but are not limited to sodium, potassium, calcium,
aluminum, lithium, and ammonium.
[0183] In addition, if the compounds described herein are obtained
as an acid addition salt, the free base can be obtained by
basifying a solution of the acid salt. Conversely, if the product
is a free base, an addition salt, particularly a pharmaceutically
acceptable addition salt, may be produced by dissolving the free
base in a suitable organic solvent and treating the solution with
an acid, in accordance with conventional procedures for preparing
acid addition salts from base compounds. Those skilled in the art
will recognize various synthetic methodologies that may be used to
prepare non-toxic pharmaceutically acceptable addition salts.
[0184] "Prodrugs" described herein include any compound that
becomes a compound of Formula I when administered to a subject,
e.g., upon metabolic processing of the prodrug. Similarly,
"pharmaceutically acceptable salts" includes "prodrugs" of
pharmaceutically acceptable salts. Examples of prodrugs include
derivatives of functional groups, such as a carboxylic acid group,
in the compounds of Formula I. Exemplary prodrugs of a carboxylic
acid group include, but are not limited to, carboxylic acid esters
such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and
aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl
esters such as ethyl ester, acyloxyalkyl esters such as
pivaloyloxymethyl (POM), glycosides, and ascorbic acid
derivatives.
[0185] Other exemplary prodrugs include amides of carboxylic acids.
Exemplary amide prodrugs include metabolically labile amides that
are formed, for example, with an amine and a carboxylic acid.
Exemplary amines include NH.sub.2, primary, and secondary amines
such as NHR.sup.x, and NR.sup.xR.sup.y, wherein R.sup.x is
hydrogen, (C.sub.1-C.sub.18)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.4)-alkyl-,
(C.sub.6-C.sub.14)-aryl which is unsubstituted or substituted by a
residue (C.sub.1-C.sub.2)-alkyl, (C.sub.1-C.sub.2)-alkoxy, fluoro,
or chloro; heteroaryl-,
(C.sub.6-C.sub.14)-aryl-(C.sub.1-C.sub.4)-alkyl where aryl is
unsubstituted or substituted by a residue (C.sub.1-C.sub.2)-alkyl,
(C.sub.1-C.sub.2)-alkoxy, fluoro, or chloro; or
heteroaryl-(C.sub.1-C.sub.4)-alkyl- and in which R.sup.y has the
meanings indicated for R.sup.x with the exception of hydrogen or
wherein R.sup.x and R.sup.y, together with the nitrogen to which
they are bound, form an optionally substituted 4- to 7-membered
heterocycloalkyl ring which optionally includes one or two
additional heteroatoms chosen from nitrogen, oxygen, and sulfur. A
discussion of prodrugs is provided in T. Higuchi and V. Stella,
Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers
in Drug Design, American Pharmaceutical Association and Pergamon
Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier,
1985.
[0186] As used herein, the terms "group", "radical" or "fragment"
are synonymous and are intended to indicate functional groups or
fragments of molecules attachable to a bond or other fragments of
molecules.
[0187] As used herein, the term "leaving group" refers to the
meaning conventionally associated with it in synthetic organic
chemistry, i.e., an atom or group displaceable under nucleophilic
displacement conditions. Examples of leaving groups include, but
are not limited to, dimethylhydroxylamino (e.g. Weinreb amide),
halogen, alkane- or arylsulfonyloxy, such as methanesulfonyloxy,
ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and
thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy,
isopropyloxy, acyloxy, and the like.
[0188] As used herein, the term "protective group" or "protecting
group" refers to a group which selectively blocks one reactive site
in a multifunctional compound such that a chemical reaction can be
carried out selectively at another unprotected reactive site in the
meaning conventionally associated with it in synthetic chemistry.
Certain processes of this invention rely upon the protective groups
to block certain reactive sites present in the reactants. Examples
of protecting groups can be found in Wuts et al., Green's
Protective Groups in Organic Synthesis, (J. Wiley, 4th ed.
2006).
[0189] As used herein, the term "deprotection" or "deprotecting"
refers to a process by which a protective group is removed after a
selective reaction is completed. Certain protective groups may be
preferred over others due to their convenience or relative ease of
removal. Without being limiting, deprotecting reagents for
protected amino or anilino group include strong acid such as
trifluoroacetic acid (TFA), concentrated HCl, H.sub.2SO.sub.4, or
HBr, and the like.
[0190] As used herein, "modulation" refers to a change in activity
as a direct or indirect response to the presence of a chemical
entity as described herein, relative to the activity of in the
absence of the chemical entity. The change may be an increase in
activity or a decrease in activity, and may be due to the direct
interaction of the compound with the a target or due to the
interaction of the compound with one or more other factors that in
turn affect the target's activity. For example, the presence of the
chemical entity may, for example, increase or decrease the target
activity by directly binding to the target, by causing (directly or
indirectly) another factor to increase or decrease the target
activity, or by (directly or indirectly) increasing or decreasing
the amount of target present in the cell or organism.
[0191] As used herein, "active agent" is used to indicate a
chemical entity which has biological activity. In certain
embodiments, an "active agent" is a compound having pharmaceutical
utility. For example an active agent may be an anti-cancer
therapeutic.
[0192] As used herein, "significant" refers to any detectable
change that is statistically significant in a standard parametric
test of statistical significance such as Student's T-test, where
p<0.05.
[0193] As used herein, a "pharmaceutically acceptable" component is
one that is suitable for use with humans and/or animals without
undue adverse side effects (such as toxicity, irritation, and
allergic response) commensurate with a reasonable benefit/risk
ratio.
[0194] As used herein, "therapeutically effective amount" of a
chemical entity described herein refers to an amount effective,
when administered to a human or non-human subject, to provide a
therapeutic benefit such as amelioration of symptoms, slowing of
disease progression, or prevention of disease.
[0195] "Treating" or "treatment" encompasses administration of at
least one compound of Formula I, or a pharmaceutically acceptable
salt thereof, to a mammalian subject, particularly a human subject,
in need of such an administration and includes (i) arresting the
development of clinical symptoms of the disease, such as cancer,
(ii) bringing about a regression in the clinical symptoms of the
disease, such as cancer, and/or (iii) prophylactic treatment for
preventing the onset of the disease, such as cancer.
[0196] As used herein, "cancer" refers to all types of cancer or
neoplasm or malignant tumors found in mammals, including carcinomas
and sarcomas. Examples of cancer are cancer of the brain, breast,
cervix, colon, head & neck, kidney, lung, non-small cell lung,
melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and
Medulloblastoma.
[0197] As used herein, "subject" refers to a mammal that has been
or will be the object of treatment, observation or experiment. The
methods described herein can be useful in both human therapy and
veterinary applications. In some embodiments, the subject is a
human.
[0198] The term "mammal" is intended to have its standard meaning,
and encompasses humans, dogs, cats, sheep, and cows, for
example.
[0199] As used herein, the term EGFR is used to refer the epidermal
growth factor receptor (EGFR), a receptor tyrosine kinase of the
ErbB family. The terms "EGFR", "Her1", "ErbB1" and the like are
used interchangeably to refer to the gene or protein product of the
gene.
A. Compounds
[0200] In one aspect, provided is a compound of Formula I
##STR00021##
[0201] or a pharmaceutically acceptable salt thereof, wherein
[0202] X.sub.3 is C--R.sub.12, or N;
[0203] X.sub.4 is C--R.sub.13, or N;
[0204] X.sub.5 is C--R.sub.14, or N;
[0205] n is 0, 1, 2, 3, 4, or 5;
[0206] m is 0, 1, 2, 3, 4, or 5;
##STR00022##
is aryl or heteroaryl;
##STR00023##
is aryl, heteroaryl, or heterocycloalkyl;
[0207] R.sub.6, R.sub.12, R.sub.13, R.sub.14, and each Z is
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, oxo, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryloxy, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted heterocycloalkyl, optionally
substituted amino, optionally substituted acyl, optionally
substituted alkoxycarbonyl, optionally substituted aminocarbonyl,
optionally substituted aminosulfonyl, or optionally substituted
carbamimidoyl;
[0208] each Q is independently hydrogen, cyano, halo, hydroxy,
azido, nitro, carboxy, oxo, sulfinyl, sulfanyl, sulfonyl,
optionally substituted alkoxy, optionally substituted
cycloalkyloxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, optionally substituted
heterocycloalkyloxy, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryloxy, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted heterocycloalkyl, optionally substituted amino,
optionally substituted acyl, optionally substituted alkoxycarbonyl,
optionally substituted aminocarbonyl, optionally substituted
aminosulfonyl, optionally substituted carbamimidoyl, or E; wherein
E is an electrophilic group capable of forming a covalent bond with
a nucleophile.
[0209] In some embodiments,
##STR00024##
and
##STR00025##
are each independently 5-membered aryl, 6-membered aryl, 5-membered
heteroaryl, or 6-membered heteroaryl.
[0210] In some embodiments,
##STR00026##
is 5-membered aryl, 6-membered aryl, 5-membered heteroaryl, or
6-membered heteroaryl; and
##STR00027##
independently 5-membered aryl, 6-membered aryl, 5-membered
heteroaryl, 6-membered heteroaryl, 5-membered heterocycloalkyl, or
6-membered heterocycloalkyl.
[0211] In some embodiments,
##STR00028##
is selected from the group consisting of: pyrrolyl, furanyl,
thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furazanyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazole, 1,2,5-oxadiazole,
1,3,4-oxadiazole, thiadiazolyl, dithiazolyl, tetrazolyl, pyridinyl,
pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazinyl, and
phenyl; and
##STR00029##
[0212] is selected from the group consisting of: piperazinyl,
morpholinyl, piperidinyl, thiomorpholinyl, pyrrolidinyl,
tetrahydrofuranyl, diazepanyl, azetidinyl, oxetanyl, oxiranyl,
aziridinyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl,
1,2,4-triazolyl, furazanyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole,
1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazolyl, dithiazolyl,
tetrazolyl, pyridinyl, pyranyl, thiopyranyl, diazinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl,
1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazinyl, and
phenyl.
[0213] In some embodiments,
##STR00030##
is selected from the group consisting of: phenyl, pyridinyl,
pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,
isoxazolyl, and thienyl.
[0214] In some embodiments,
##STR00031##
is selected from the group consisting of: phenyl, pyridinyl,
pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,
isoxazolyl, and thienyl. In some embodiments, m is 1, 2, or 3; and
at least one Q is E.
[0215] In some embodiments,
##STR00032##
is selected from the group consisting of: piperazinyl, morpholinyl,
piperidinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl,
diazepanyl, azetidinyl, oxetanyl, oxiranyl, aziridinyl. In some
embodiments,
##STR00033##
is selected from the group consisting of: piperazinyl, morpholinyl,
piperidinyl, pyrrolidinyl, and tetrahydrofuranyl, and diazepanyl.
In some embodiments,
##STR00034##
is selected from the group consisting of: piperazinyl, morpholinyl,
piperidinyl, and pyrrolidinyl. In some embodiments,
##STR00035##
is attached to the core via a carbon-carbon bond. In some
embodiments,
##STR00036##
is attached to the core via a carbon-nitrogen bond. In some
embodiments,
##STR00037##
is selected from the group consisting of:
##STR00038## ##STR00039##
wherein each W is independently selected from the group consisting
of hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, oxo,
sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy,
optionally substituted cycloalkyloxy, optionally substituted
aryloxy, optionally substituted heteroaryloxy, optionally
substituted heterocycloalkyloxy, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted aryloxy,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted heterocycloalkyl, optionally substituted
amino, optionally substituted acyl, optionally substituted
alkoxycarbonyl, optionally substituted aminocarbonyl, optionally
substituted aminosulfonyl, optionally substituted carbamimidoyl, or
E; wherein E is an electrophilic group capable of forming a
covalent bond with a nucleophile. In some embodiments, W is E;
wherein E is an electrophilic group capable of forming a covalent
bond with a nucleophile. In some embodiments, at least one W is E.
In some embodiments, W is selected from the group consisting of H,
optionally substituted alkyl, and
##STR00040##
In some embodiments, each W is selected from the group consisting
of H, C.sub.1-C.sub.4 alkyl, and
##STR00041##
[0216] In some embodiments, at least one Q is E; wherein E is an
electrophilic group capable of forming a covalent bond with a
cysteine residue of a protein. In some embodiments, E is selected
from
##STR00042##
[0217] For example, in some embodiments, E is
##STR00043##
In some embodiments, E is
##STR00044##
[0218] Another embodiment, provided is the compound or
pharmaceutically acceptable salt of Formula I wherein
##STR00045##
[0219] X.sub.1 is C--R.sub.2, or N; and
[0220] R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryloxy, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted heterocycloalkyl, optionally
substituted amino, optionally substituted acyl, optionally
substituted alkoxycarbonyl, optionally substituted aminocarbonyl,
optionally substituted aminosulfonyl, or optionally substituted
carbamimidoyl.
[0221] Another embodiment, provided is the compound or
pharmaceutically acceptable salt of Formula I wherein
##STR00046##
[0222] X.sub.1 is C--R.sub.2, or N; and
[0223] R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl.
[0224] Another embodiment of the invention described wherein
##STR00047##
[0225] X.sub.2 is C--R.sub.11, or N; and
[0226] R.sub.11, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are
independently, hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, oxo, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl or E; wherein E is an
electrophilic group capable of forming a covalent bond with a
nucleophile.
[0227] Another embodiment of the invention described wherein
##STR00048##
[0228] X.sub.2 is C--R.sub.11, or N; and
[0229] R.sub.11, R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are
independently, hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, oxo, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl or E; wherein E is an
electrophilic group capable of forming a covalent bond with a
nucleophile.
[0230] In some embodiments, the compound is of Formula Ia
##STR00049##
[0231] or a pharmaceutically acceptable salt thereof, wherein
[0232] X.sub.1 is C--R.sub.2, or N;
[0233] X.sub.2 is C--R.sub.11, or N;
[0234] X.sub.3 is C--R.sub.12, or N;
[0235] X.sub.4 is C--R.sub.13, or N;
[0236] X.sub.5 is C--R.sub.14, or N;
[0237] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are
independently hydrogen, cyano, halo, hydroxy, azido, nitro,
carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted
alkoxy, optionally substituted cycloalkyloxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycloalkyloxy, optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
heterocycloalkyl, optionally substituted amino, optionally
substituted acyl, optionally substituted alkoxycarbonyl, optionally
substituted aminocarbonyl, optionally substituted aminosulfonyl, or
optionally substituted carbamimidoyl;
[0238] R.sub.8, R.sub.9, and R.sub.10 are independently hydrogen,
cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl,
sulfonyl, optionally substituted alkoxy, optionally substituted
cycloalkyloxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, optionally substituted
heterocycloalkyloxy, optionally substituted alkyl, optionally
substituted cycloalkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted heterocycloalkyl,
optionally substituted amino, optionally substituted acyl,
optionally substituted alkoxycarbonyl, optionally substituted
aminocarbonyl, optionally substituted aminosulfonyl, optionally
substituted carbamimidoyl, or E; where E is an electrophilic group
capable of forming a covalent bond with a nucleophile. In some
embodiments, E is electrophilic group capable of forming a covalent
bond with a cysteine residue of a protein.
[0239] In some embodiments, the compound or pharmaceutically
acceptable salt has the Formula Ib:
##STR00050##
[0240] wherein:
[0241] X.sub.1 is N or C--R.sub.2;
[0242] each R.sub.1, R.sub.2, R.sub.4, or R.sub.5 is independently
H or halo;
[0243] R.sub.3 is optionally substituted heterocycloalkyl; and
[0244] E is an electrophilic group capable of forming a covalent
bond with a nucleophile.
[0245] In some embodiments, the compound or pharmaceutically
acceptable salt has the Formula Ib':
##STR00051##
[0246] In some embodiments, R.sub.1 is hydrogen, cyano, halo,
hydroxy, --CONH.sub.2, optionally substituted alkoxy, or optionally
substituted cycloalkyloxy. In some embodiments, R.sub.1 is
hydrogen, cyano, fluoro, chloro, hydroxy, hydroxymethyl,
--CONH.sub.2, or methoxy. In some embodiments, R.sub.1 is hydrogen,
cyano, fluoro, chloro, hydroxy, or methoxy. In some embodiments,
R.sub.1 is hydrogen. In some embodiments, R.sub.1 is methoxy. In
some embodiments, R.sub.1 is fluoro.
[0247] In some embodiments, R.sub.2, R.sub.3, and R.sub.4 are
independently hydrogen, cyano, halo, hydroxy, carboxy, optionally
substituted alkoxy, optionally substituted lower alkyl, optionally
substituted heterocycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted amino,
optionally substituted acyl, optionally substituted alkoxycarbonyl,
or optionally substituted aminocarbonyl.
[0248] In some embodiments, R.sub.2 is hydrogen. In some
embodiments, R.sub.2 is fluoro.
[0249] In some embodiments, R.sub.3 is hydrogen, optionally
substituted alkoxy, optionally substituted lower alkyl, optionally
substituted heterocycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, or optionally substituted amino.
In some embodiments, R.sub.3 is optionally substituted
heterocycloalkyl, or optionally substituted heteroaryl. In some
embodiments, R.sub.3 is optionally substituted morpholinyl,
optionally substituted piperazinyl, optionally substituted
pyrrolidinyl, optionally substituted piperidinyl, optionally
substituted imidazolidinyl, optionally substituted pyrazolidinyl,
optionally substituted azetidinyl, optionally substituted
1,4-diazepanyl, optionally substituted 1,4-diazocanyl, optionally
substituted pyranyl, optionally substituted imidazolyl, optionally
substituted pyrazolyl, or optionally substituted pyridyl. In some
embodiments, R.sub.3 is pyrrolidin-1-yl, morpholin-4-yl,
piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,
azetidin-1-yl, 1,4-diazepan-1-yl, or 1,4-diazocan-1-yl, each of
which is optionally substituted with one or two groups
independently hydroxyl, methoxy, amino, fluoro, oxo, or lower alkyl
optionally substituted with hydroxy, methoxy, fluoro or amino. In
some embodiments, R.sub.3 is pyrrolidin-2-yl, morpholin-2-yl,
piperidin-2-yl, piperazin-2-yl, 4-methylpiperazin-2-yl,
azetidin-2-yl, 1,4-diazepan-2-yl, 1,4-diazocan-2-yl,
pyrrolidin-3-yl, morpholin-3-yl, piperidin-3-yl, piperidin-4-yl,
piperazin-3-yl, azetidin-3-yl, 1,4-diazepan-3-yl, or
1-4,-diazocan-3-yl, each of which is optionally substituted with
one or two groups independently hydroxyl, methoxy, amino, fluoro,
oxo, or lower alkyl optionally substituted with hydroxy, methoxy,
fluoro or amino. In some embodiments, R.sub.3 is
2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2,3-dihydrofuranyl, or
2,5-dihydrofuranyl, piperidinyl N-oxide, morpholinyl-N-oxide,
1-oxo-1-thiomorpholinyl or 1,1-dioxo-1-thiomorpholinyl, each of
which is optionally substituted with one or two independent groups
consisting of hydroxyl, methoxy, amino, fluoro, oxo, or lower alkyl
optionally substituted with hydroxy, methoxy, fluoro or amino.
[0250] In some embodiments, R.sub.3 is
##STR00052##
wherein R.sup.a is C.sub.1-C.sub.6 alkyl, optionally substituted
with C.sub.1-C.sub.4 alkyl, aryl, heteroaryl, aryl-C.sub.1-C.sub.4
alkyl-, heteroaryl-C.sub.1-C.sub.4 alkyl-, C.sub.1-C.sub.4
haloalkyl, --OC.sub.1-C.sub.4 alkyl, --OC.sub.1-C.sub.4
alkylphenyl, --C.sub.1-C.sub.4 alkyl-OH, --OC.sub.1-C.sub.4
haloalkyl, halo, --OH, --NH.sub.2, --C.sub.1-C.sub.4
alkyl-NH.sub.2, --N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl),
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4
alkyl)(C.sub.1-C.sub.4 alkylphenyl), --NH(C.sub.1-C.sub.4
alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl or
heterocycloalkyl), --CO.sub.2H, --C(O)OC.sub.1-C.sub.4 alkyl,
--CON(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl),
--CONH(C.sub.1-C.sub.4 alkyl), --CONH.sub.2,
--NHC(O)(C.sub.1-C.sub.4 alkyl), --NHC(O)(phenyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(C.sub.1-C.sub.4 alkyl),
--N(C.sub.1-C.sub.4 alkyl)C(O)(phenyl), --C(O)C.sub.1-C.sub.4
alkyl, --C(O)C.sub.1-C.sub.4 alkylphenyl, --C(O)C.sub.1-C.sub.4
haloalkyl, --OC(O)C.sub.1-C.sub.4 alkyl, --SO.sub.2(C.sub.1-C.sub.4
alkyl), --SO.sub.2(phenyl), --SO.sub.2(C.sub.1-C.sub.4 haloalkyl),
--SO.sub.2NH.sub.2, --SO.sub.2NH(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH(phenyl), --NHSO.sub.2(C.sub.1-C.sub.4 alkyl),
--NHSO.sub.2(phenyl), or --NHSO.sub.2(C.sub.1-C.sub.4
haloalkyl).
[0251] In some embodiments, R.sup.a is C.sub.1-C.sub.6 alkyl,
optionally substituted with OH, halo, C.sub.1-C.sub.4 alkyl, or
--OC.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.a is
--CH.sub.3, --CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2OMe, --CH.sub.2C(CH.sub.3).sub.2OH, or
--CH.sub.2CH(CH.sub.3)OH.
[0252] In some embodiments, R.sub.4 is hydrogen, optionally
substituted alkoxy, optionally substituted lower alkyl, optionally
substituted heterocycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, or optionally substituted amino.
In some embodiments, R.sub.4 is hydrogen, optionally substituted
heterocycloalkyl, or optionally substituted heteroaryl. In some
embodiments, R.sub.4 is optionally substituted morpholinyl,
optionally substituted piperazinyl, optionally substituted
pyrrolidinyl, optionally substituted piperidinyl, optionally
substituted imidazolidinyl, optionally substituted pyrazolidinyl,
optionally substituted azetidinyl, optionally substituted
1,4-diazepanyl, optionally substituted 1,4-diazocanyl, optionally
substituted pyranyl, optionally substituted imidazolyl, optionally
substituted pyrazolyl, or optionally substituted pyridyl. In some
embodiments, R.sub.4 is pyrrolidin-1-yl, morpholin-4-yl,
piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,
azetidin-1-yl, 1,4-diazepan-1-yl, or 1,4-diazocan-1-yl, each of
which is optionally substituted with one or two groups
independently hydroxyl, amino, fluoro, oxo, or lower alkyl
optionally substituted with hydroxy, fluoro, or amino. In some
embodiments, R.sub.4 is pyrrolidin-2-yl, morpholin-2-yl,
piperidin-2-yl, piperazin-2-yl, 4-methylpiperazin-2-yl,
azetidin-2-yl, 1,4-diazepan-2-yl, 1,4-diazocan-2-yl,
pyrrolidin-3-yl, morpholin-3-yl, piperidin-3-yl, piperidin-4-yl,
piperazin-3-yl, azetidin-3-yl, 1,4-diazepan-3-yl, or
1-4,-diazocan-3-yl, each of which is optionally substituted with
one or two groups independently hydroxyl, amino, fluoro, oxo, or
lower alkyl optionally substituted with hydroxy, fluoro, or amino.
In some embodiments, R.sub.4 is 2,4-imidazolidinyl,
2,3-pyrazolidinyl, 2,3-dihydrofuranyl, or 2,5-dihydrofuranyl,
piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl
or 1,1-dioxo-1-thiomorpholinyl, each of which is optionally
substituted with one or two groups independently hydroxyl, amino,
fluoro, oxo, or lower alkyl optionally substituted with hydroxy,
fluoro, or amino.
[0253] In some embodiments, R.sub.2 and R.sub.4 are hydrogen, and
R.sub.3 is optionally substituted heterocycloalkyl. In some
embodiments, R.sub.2 and R.sub.4 are hydrogen and R.sub.3 is
optionally substituted morpholinyl, optionally substituted
piperazinyl, optionally substituted pyrrolidinyl, optionally
substituted piperidinyl, optionally substituted azetidinyl,
optionally substituted 1,4-diazepanyl, or optionally substituted
1,4-diazocanyl. In some embodiments, R.sub.2 and R.sub.4 are
hydrogen and R.sub.3 is pyrrolidin-1-yl, morpholin-4-yl,
piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,
azetidin-1-yl, 1,4-diazepan-1-yl, or 1-4,-diazocan-1-yl, each of
which is optionally substituted with one or two groups
independently hydroxyl, amino, fluoro, oxo, or lower alkyl
optionally substituted with hydroxy, fluoro, or amino.
[0254] In some embodiments, R.sub.2 and R.sub.4 are hydrogen, and
R.sub.3 is optionally substituted amino. In some embodiments,
R.sub.2 and R.sub.4 are hydrogen and R.sub.3 is substituted amino,
which is substituted with optionally substituted heterocycloalkyl.
In some embodiments, R.sub.2 and R.sub.4 are hydrogen, and R.sub.3
is substituted amino, which is substituted with optionally
substituted morpholinyl, optionally substituted piperazinyl,
optionally substituted pyrrolidinyl, optionally substituted
piperidinyl, optionally substituted azetidinyl, optionally
substituted 1,4-diazepanyl, or optionally substituted
1,4-diazocanyl.
[0255] In some embodiments, R.sub.2 and R.sub.3 are hydrogen, and
R.sub.4 is optionally substituted heterocycloalkyl. In some
embodiments, R.sub.2 and R.sub.3 are hydrogen, and R.sub.4 is
optionally substituted morpholinyl, optionally substituted
piperazinyl, optionally substituted pyrrolidinyl, optionally
substituted piperidinyl, optionally substituted azetidinyl,
optionally substituted 1,4-diazepanyl, or optionally substituted
1,4-diazocanyl. In some embodiments, R.sub.2 and R.sub.4 are
hydrogen and R.sub.3 is pyrrolidin-1-yl, morpholin-4-yl,
piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,
azetidin-1-yl, 1,4-diazepan-1-yl, or 1-4,-diazocan-1-yl, each of
which is optionally substituted with one or two groups
independently hydroxyl, amino, fluoro, oxo, or lower alkyl
optionally substituted with hydroxy, fluoro, or amino.
[0256] In some embodiments, R.sub.2 and R.sub.3 are hydrogen, and
R.sub.4 is optionally substituted amino. In some embodiments,
R.sub.2 and R.sub.4 are hydrogen and R.sub.3 is substituted amino,
which is substituted with optionally substituted heterocycloalkyl.
In some embodiments, R.sub.2 and R.sub.4 are hydrogen, and R.sub.3
is substituted amino, which is substituted with optionally
substituted morpholinyl, optionally substituted piperazinyl,
optionally substituted pyrrolidinyl, optionally substituted
piperidinyl, optionally substituted azetidinyl, optionally
substituted 1,4-diazepanyl, or optionally substituted
1,4-diazocanyl.
[0257] In some embodiments, R.sub.5 is hydrogen, halo, cyano,
optionally substituted alkoxy, or optionally substituted alkyl. In
some embodiments, R.sub.5 is hydrogen.
[0258] In some embodiments, R.sub.6 is hydrogen or optionally
substituted amino. In some embodiments, R.sub.6 is hydrogen or
amino. In some embodiments, R.sub.6 is hydrogen. In some
embodiments, R.sub.6 is amino.
[0259] In some embodiments, R.sub.7, R.sub.11, R.sub.13, and
R.sub.14 are independently hydrogen, cyano, optionally substituted
lower alkyl, halo, or methoxy. In some embodiments, R.sub.7,
R.sub.11, R.sub.13, and R.sub.14 are independently hydrogen, cyano,
fluoro, chloro, methyl, hydroxymethyl, --CH.sub.2F, or methoxy. In
some embodiments, R.sub.7, R.sub.11, R.sub.13, and R.sub.14 are
hydrogen. In some embodiments, R.sub.7 is fluoro or chloro, and
R.sub.11, R.sub.13, and R.sub.14 are hydrogen. In some embodiments,
R.sub.11 is fluoro or chloro, and R.sub.7, R.sub.13, and R.sub.14
are hydrogen.
[0260] In some embodiments, R.sub.8, R.sub.9, and R.sub.10 are
independently hydrogen, cyano, halo, hydroxy, carboxy, optionally
substituted alkoxy, optionally substituted cycloalkyloxy,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted amino,
optionally substituted acyl, optionally substituted alkoxycarbonyl,
optionally substituted aminocarbonyl, or E.
[0261] In some embodiments, at least one of R.sub.8, R.sub.9, and
R.sub.10 is halo. In some embodiments, at least one of R.sub.8,
R.sub.9, and R.sub.10 is fluoro or chloro. In some embodiments, at
least one of R.sub.8, R.sub.9, and R.sub.10 is optionally
substituted amino. In some embodiments, at least one of R.sub.8,
R.sub.9, and R.sub.10 is optionally substituted alkoxy. In some
embodiments, at least one of R.sub.8, R.sub.9, and R.sub.10 is
alkoxy substituted with optionally substituted amino or optionally
substituted heterocycloalkyl.
[0262] In some embodiments, at least one of R.sub.8, R.sub.9, and
R.sub.10 is E, where E is an electrophilic group capable of forming
a covalent bond with a cysteine residue of a protein.
[0263] In some embodiments, at least one of R.sub.8, R.sub.9, and
R.sub.10 is selected from
##STR00053##
[0264] In some embodiments, at least one of R.sub.8, R.sub.9, and
R.sub.10 is
##STR00054##
In some embodiments, at least one of R.sub.8, R.sub.9, and R.sub.10
is
##STR00055##
[0265] In some embodiments, R.sub.8 is
##STR00056##
and R.sub.9 and R.sub.10 are hydrogen. In some embodiments, R.sub.8
is
##STR00057##
and R.sub.9 and R.sub.10 are hydrogen. In some embodiments,
R.sub.10 is
##STR00058##
and R.sub.8 and R.sub.9 are hydrogen. In some embodiments, R.sub.10
is
##STR00059##
and R.sub.8 and R.sub.9 are hydrogen.
[0266] In some embodiments, R.sub.8 is fluoro, and R.sub.9 and
R.sub.10 are hydrogen. In some embodiments, R.sub.8 is chloro, and
R.sub.9 and R.sub.10 are hydrogen. In some embodiments, R.sub.10 is
fluoro, and R.sub.8 and R.sub.9 are hydrogen. In some embodiments,
R.sub.10 is chloro, and R.sub.8 and R.sub.9 are hydrogen.
[0267] In some embodiments, R.sub.8 is optionally substituted
alkoxy, and R.sub.9 and R.sub.10 are hydrogen. In some embodiments,
R.sub.9 is optionally substituted alkoxy, and R.sub.8 and R.sub.10
are hydrogen.
[0268] In some embodiments, R.sub.12 is hydrogen, halo, cyano,
--CONH.sub.2, --NHCOCH.sub.3, or optionally substituted lower
alkyl. In some embodiments, R.sub.12 is hydrogen, fluoro, chloro,
cyano, methyl, ethyl, propyl, --CF.sub.3, --CH.sub.2F, --CHF.sub.2,
--CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2F, --CH.sub.2CHF.sub.2,
--CH.sub.2OH, --CONH.sub.2, --CH.sub.2CONH.sub.2, or
--NHCOCH.sub.3. In some embodiments, R.sub.12 is hydrogen. In some
embodiments, R.sub.12 is fluoro. In some embodiments, R.sub.12 is
methyl. In some embodiments, R.sub.12 is --CH.sub.2OH.
[0269] In some embodiments, X.sub.1 is C--R.sub.2 or N, X.sub.2 is
C--R.sub.11 or N, X.sub.3 is C--R.sub.12 or N, X.sub.4 is
C--R.sub.13 or N, and X.sub.5 is C--R.sub.14 or N.
[0270] In some embodiments, X.sub.1 is C--R.sub.2, X.sub.2 is
C--R.sub.11, X.sub.3 is C--R.sub.12, X.sub.4 is C--R.sub.13, and
X.sub.5 is C--R.sub.14.
[0271] In some embodiments, X.sub.1 is N, X.sub.2 is C--R.sub.11,
X.sub.3 is C--R.sub.12, X.sub.4 is C--R.sub.13, and X.sub.5 is
C--R.sub.14.
[0272] In some embodiments, X.sub.1 is C--R.sub.2, X.sub.2 is N,
X.sub.3 is C--R.sub.12, X.sub.4 is C--R.sub.13, and X.sub.5 is
C--R.sub.14.
[0273] In some embodiments, X.sub.1 is C--R.sub.2, X.sub.2 is
C--R.sub.11, X.sub.3 is N, X.sub.4 is C--R.sub.13, and X.sub.5 is
C--R.sub.14.
[0274] In some embodiments, X.sub.1 is C--R.sub.2, X.sub.2 is
C--R.sub.11, X.sub.3 is C--R.sub.12, X.sub.4 is N, and X.sub.5 is
C--R.sub.14.
[0275] In some embodiments, X.sub.1 is C--R.sub.2, X.sub.2 is
C--R.sub.11, X.sub.3 is C--R.sub.12, X.sub.4 is C--R.sub.13, and
X.sub.5 is N.
[0276] In some embodiments, X.sub.1 is N, X.sub.2 is N, X.sub.3 is
C--R.sub.12, X.sub.4 is C--R.sub.13, and X.sub.5 is
C--R.sub.14.
[0277] In some embodiments, X.sub.1 is N, X.sub.2 is C--R.sub.11,
X.sub.3 is N, X.sub.4 is C--R.sub.13, and X.sub.5 is
C--R.sub.14.
[0278] In some embodiments, X.sub.1 is C--R.sub.2, X.sub.2 is N,
X.sub.3 is N, X.sub.4 is C--R.sub.13, and X.sub.5 is
C--R.sub.14.
[0279] In some embodiments, X.sub.1 is N, X.sub.2 is N, X.sub.3 is
N, X.sub.4 is C--R.sub.13, and X.sub.5 is C--R.sub.14.
[0280] In another aspect, the present disclosure provides a
compound or pharmaceutically acceptable salt thereof, wherein the
compound is chosen from the group consisting of: [0281]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)phen-
yl)acetamide [0282]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)phen-
yl)acetamide [0283]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)acetamide [0284]
8-(2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[4,3-d]pyrimidin-2-amine
[0285]
8-(2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,2-d]pyrimidin-2--
amine [0286]
8-(2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2-amine
[0287]
8-(5-chloro-2-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyr-
imidin-2-amine [0288]
8-(3-chlorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2-amine
[0289]
8-(3-fluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2--
amine [0290]
8-(2,6-difluorophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2-ami-
ne [0291]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)-
pyrido[3,4-d]pyrimidin-2-amine [0292]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-morpholinophenyl)pyri-
do[3,4-d]pyrimidin-2-amine [0293]
8-(3-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrim-
idin-2-amine [0294]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]-
pyrimidin-2-amine [0295]
8-(4-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrim-
idin-2-amine [0296]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]-
pyrimidin-2-amine [0297]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)pyrido[3,-
4-d]pyrimidin-2-amine [0298]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-morpholinophenyl)pyri-
do[3,4-d]pyrimidin-2-amine [0299]
8-phenyl-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine
[0300]
8-(2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimi-
din-2-amine [0301]
8-(2-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-a-
mine [0302]
8-(2,6-difluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-
-2-amine [0303]
8-(5-chloro-2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyri-
midin-2-amine [0304]
8-(3-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-a-
mine [0305]
8-(3-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidin-2-a-
mine [0306]
N-(4-fluoro-3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin--
8-yl)phenyl)acetamide [0307]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyr-
ido[3,4-d]pyrimidin-2-amine [0308]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-(piperazin-1-yl)pheny-
l)pyrido[3,4-d]pyrimidin-2-amine [0309]
8-(3-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d-
]pyrimidin-2-amine [0310]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[-
3,4-d]pyrimidin-2-amine [0311]
8-(4-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d-
]pyrimidin-2-amine [0312]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyrido[-
3,4-d]pyrimidin-2-amine [0313]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)pyr-
ido[3,4-d]pyrimidin-2-amine [0314]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-(piperazin-1-yl)pheny-
l)pyrido[3,4-d]pyrimidin-2-amine [0315]
N1-(1-(2-fluoroethyl)azetidin-3-yl)-N4-(8-(2-fluorophenyl)pyrido[3,4-d]py-
rimidin-2-yl)benzene-1,4-diamine [0316]
N1-(1-(2-fluoroethyl)azetidin-3-yl)-N4-(8-(3-(2-morpholinoethoxy)phenyl)p-
yrido[3,4-d]pyrimidin-2-yl)benzene-1,4-diamine [0317]
N1-(8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)pyrido[3,4-d]pyrimidin-2-yl)-
-N4-(1-(2-fluoroethyl)azetidin-3-yl)benzene-1,4-diamine [0318]
N1-(8-(5-chloro-2-fluorophenyl)pyrido[3,4-d]pyrimidin-2-yl)-N4-(1-(2-fluo-
roethyl)azetidin-3-yl)benzene-1,4-diamine [0319]
8-(3-aminophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine [0320]
8-(3-aminophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
[0321]
8-(3-aminophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine
[0322]
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acetamid-
e [0323]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
cetamide [0324]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
cetamide [0325] N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine
[0326] 8-(2-fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0327] 8-(2-chlorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0328]
8-(5-chloro-2-fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0329] 8-(3-chlorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0330] 8-(3-fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0331]
8-(2,6-difluorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0332]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)quinazoli-
n-2-amine [0333]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-morpholinophenyl)quin-
azolin-2-amine [0334]
8-(3-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0335]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(4-morpholinophenyl)quinaz-
olin-2-amine [0336]
8-(4-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0337]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(4-morpholinophenyl)quinaz-
olin-2-amine [0338]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)quinazoli-
n-2-amine [0339]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-morpholinophenyl)quin-
azolin-2-amine [0340]
8-phenyl-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine [0341]
8-(2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
[0342]
8-(2-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
[0343]
8-(2,6-difluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
[0344]
8-(5-chloro-2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-
-2-amine [0345]
8-(3-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
[0346]
8-(3-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
[0347]
N-(4-fluoro-3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)-
acetamide [0348]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)qui-
nazolin-2-amine [0349]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-(piperazin-1-yl)pheny-
l)quinazolin-2-amine [0350]
8-(3-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-
-amine [0351]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)quinazo-
lin-2-amine [0352]
8-(4-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-
-amine [0353]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)quinazo-
lin-2-amine [0354]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)qui-
nazolin-2-amine [0355]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(4-(piperazin-1-yl)pheny-
l)quinazolin-2-amine [0356]
N1-(1-(2-fluoroethyl)azetidin-3-yl)-N4-(8-(2-fluorophenyl)quinazolin-2-yl-
)benzene-1,4-diamine [0357]
N1-(1-(2-fluoroethyl)azetidin-3-yl)-N4-(8-(3-(2-morpholinoethoxy)phenyl)q-
uinazolin-2-yl)benzene-1,4-diamine [0358]
N1-(8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)quinazolin-2-yl)-N4-(1-(2-fl-
uoroethyl)azetidin-3-yl)benzene-1,4-diamine [0359]
N1-(8-(5-chloro-2-fluorophenyl)quinazolin-2-yl)-N4-(1-(2-fluoroethyl)azet-
idin-3-yl)benzene-1,4-diamine [0360]
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acr-
ylamide [0361]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)acrylamide [0362]
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)phenyl)acr-
ylamide [0363]
N-(3-(2-((4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)phenyl)acr-
ylamide [0364]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)acrylamide [0365]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-
-yl)phenyl)acrylamide [0366]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidin-8-
-yl)phenyl)acrylamide [0367]
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)phenyl)acrylamide [0368]
N-(3-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)acrylamide [0369]
N-(3-(2-((4-(azetidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
phenyl)acrylamide [0370]
N-(3-(2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)acrylamide tert-butyl
3-((4-((8-(3-acrylamidophenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)am-
ino)azetidine-1-carboxylate [0371]
N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)acrylamide [0372]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)phenyl)acrylamide [0373]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
2-d]pyrimidin-8-yl)phenyl)acrylamide [0374]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[4,-
3-d]pyrimidin-8-yl)phenyl)acrylamide [0375]
N-(3-(2-((4-(piperidin-4-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl-
)phenyl)acrylamide [0376]
N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido[3,4-d]pyri-
midin-8-yl)phenyl)acrylamide [0377]
N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acrylamide [0378]
(R)--N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)phenyl)acrylamide [0379]
(S)--N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)phenyl)acrylamide [0380]
(S)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide [0381]
(R)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide [0382]
(R)--N-(3-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)acrylamide [0383]
(S)--N-(3-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)acrylamide [0384]
(R)--N-(3-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)acrylamide [0385]
(S)--N-(3-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)acrylamide [0386]
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
phenyl)acrylamide [0387]
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)-
phenyl)acrylamide [0388]
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)-
phenyl)acrylamide [0389]
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide [0390]
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]p-
yrimidin-8-yl)phenyl)acrylamide [0391]
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]p-
yrimidin-8-yl)phenyl)acrylamide [0392]
N-(3-(2-((2-methoxy-4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide [0393]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino-
)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [0394]
N-(3-(2-((2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido[-
3,4-d]pyrimidin-8-yl)phenyl)acrylamide [0395]
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryl-
amide [0396]
N-(3-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide [0397]
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [0398]
N-(3-(2-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [0399]
N-(3-(2-((2-methoxy-4-(piperidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide [0400]
N-(3-(2-((4-(azetidin-3-ylamino)-2-methoxyphenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [0401]
N-(3-(2-((2-methoxy-4-((1-methylazetidin-3-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide tert-butyl
3-((4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-3-methoxyphenyl)amin-
o)azetidine-1-carboxylate [0402]
N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)-2-methoxyphenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide [0403]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino-
)quinazolin-8-yl)phenyl)acrylamide [0404]
N-(3-(2-((2-methoxy-4-(piperidin-4-ylamino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide [0405]
N-(3-(2-((2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide [0406]
N-(3-(2-((2-methoxy-4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [0407]
(R)--N-(3-(2-((2-methoxy-4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [0408]
(S)--N-(3-(2-((2-methoxy-4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [0409]
(S)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)-2-methoxyphenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [0410]
(R)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)-2-methoxyphenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [0411]
(R)--N-(3-(2-((4-(2-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [0412]
(S)--N-(3-(2-((4-(2-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [0413]
(R)--N-(3-(2-((4-(3-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [0414]
(S)--N-(3-(2-((4-(3-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [0415]
N-(3-(7-fluoro-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide [0416]
N-(3-(7-fluoro-2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide [0417]
N-(3-(7-chloro-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide [0418]
N-(3-(7-chloro-2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide [0419]
N-(3-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide [0420]
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)-7-methylquinazolin-8-yl)phe-
nyl)acrylamide [0421]
N-(3-(7-ethyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acrylam-
ide [0422]
N-(3-(7-fluoro-2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide [0423]
N-(3-(7-fluoro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [0424]
N-(3-(7-fluoro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [0425]
N-(3-(7-chloro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [0426]
N-(3-(7-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [0427]
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [0428]
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-methylquina-
zolin-8-yl)phenyl)acrylamide [0429]
N-(3-(7-ethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [0430]
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-7-fluoroquinazolin-8-yl)-
phenyl)acrylamide [0431]
N-(3-(7-fluoro-2-((4-(piperidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)-
acrylamide [0432]
N-(3-(2-((4-(azetidin-3-ylamino)phenyl)amino)-7-fluoroquinazolin-8-yl)phe-
nyl)acrylamide
[0433]
N-(3-(7-fluoro-2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide tert-butyl
3-((4-((8-(3-acrylamidophenyl)-7-fluoroquinazolin-2-yl)amino)phenyl)amino-
)azetidine-1-carboxylate [0434]
N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)-7-fluoroquinazoli-
n-8-yl)phenyl)acrylamide [0435]
N-(3-(7-fluoro-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide [0436]
N-(3-(7-chloro-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide [0437]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)-7-methyl-
quinazolin-8-yl)phenyl)acrylamide [0438]
N-(3-(7-ethyl-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [0439]
N-(3-(7-fluoro-2-((4-(piperidin-4-ylamino)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [0440]
N-(3-(7-fluoro-2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide [0441]
N-(3-(7-fluoro-2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide [0442]
(R)--N-(3-(7-fluoro-2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide [0443]
(S)--N-(3-(7-fluoro-2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide [0444]
(S)--N-(3-(7-fluoro-2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [0445]
(R)--N-(3-(7-fluoro-2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [0446]
(R)--N-(3-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)phenyl)acrylamide [0447]
(S)--N-(3-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)phenyl)acrylamide [0448]
(R)--N-(3-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)phenyl)acrylamide [0449]
(S)--N-(3-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)phenyl)acrylamide [0450]
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acrylamide
[0451]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide [0452]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide [0453]
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide [0454]
N-(3-(2-((4-(piperidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamid-
e [0455]
N-(3-(2-((4-(azetidin-3-ylamino)phenyl)amino)quinazolin-8-yl)phen-
yl)acrylamide [0456]
N-(3-(2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide tert-butyl
3-((4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)amino)azetidin-
e-1-carboxylate [0457]
N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [0458]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [0459]
N-(3-(2-((4-(piperidin-4-ylamino)phenyl)amino)quinazolin-8-yl)phenyl)acry-
lamide [0460]
N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide [0461]
N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)phenyl)acr-
ylamide [0462]
(R)--N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)pheny-
l)acrylamide [0463]
(S)--N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)pheny-
l)acrylamide [0464]
(S)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [0465]
(R)--N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [0466]
(R)--N-(3-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [0467]
(S)--N-(3-(2-(4-(2-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide [0468]
(R)--N-(3-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [0469]
(S)--N-(3-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [0470]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-y-
l)phenyl)acetamide [0471]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-y-
l)phenyl)acetamide [0472]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acetamide [0473]
8-(2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[4,3-d]pyrimidin-2-a-
mine [0474]
8-(2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,2-d]pyrimidin-2-a-
mine [0475]
8-(2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidin-2-a-
mine [0476]
8-(5-chloro-2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyri-
midin-2-amine [0477]
8-(3-chlorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidin-2-a-
mine [0478]
8-(3-fluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidin-2-a-
mine [0479]
8-(2,6-difluorophenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidin-
-2-amine [0480]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyr-
ido[3,4-d]pyrimidin-2-amine [0481]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-morpholinopyridin-3-y-
l)pyrido[3,4-d]pyrimidin-2-amine [0482]
8-(3-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d-
]pyrimidin-2-amine [0483]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido[-
3,4-d]pyrimidin-2-amine [0484]
8-(4-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido[3,4-d-
]pyrimidin-2-amine [0485]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyrido[-
3,4-d]pyrimidin-2-amine [0486]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)pyr-
ido[3,4-d]pyrimidin-2-amine [0487]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-morpholinopyridin-3-y-
l)pyrido[3,4-d]pyrimidin-2-amine [0488]
8-phenyl-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-2-amine
[0489]
8-(2-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]-
pyrimidin-2-amine [0490]
8-(2-chlorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimid-
in-2-amine [0491]
8-(2,6-difluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyr-
imidin-2-amine [0492]
8-(5-chloro-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4--
d]pyrimidin-2-amine [0493]
8-(3-chlorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimid-
in-2-amine [0494]
8-(3-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimid-
in-2-amine [0495]
N-(4-fluoro-3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyri-
midin-8-yl)phenyl)acetamide [0496]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3--
yl)pyrido[3,4-d]pyrimidin-2-amine [0497]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyrid-
in-3-yl)pyrido[3,4-d]pyrimidin-2-amine [0498]
8-(3-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido-
[3,4-d]pyrimidin-2-amine [0499]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)p-
yrido[3,4-d]pyrimidin-2-amine [0500]
8-(4-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)pyrido-
[3,4-d]pyrimidin-2-amine [0501]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)p-
yrido[3,4-d]pyrimidin-2-amine [0502]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3--
yl)pyrido[3,4-d]pyrimidin-2-amine [0503]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyrid-
in-3-yl)pyrido[3,4-d]pyrimidin-2-amine [0504]
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(2-fluorophenyl)pyrido[3,4-d]py-
rimidin-2-yl)pyridine-2,5-diamine [0505]
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(3-(2-morpholinoethoxy)phenyl)p-
yrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine [0506]
N5-(8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)pyrido[3,4-d]pyrimidin-2-yl)-
-N2-(1-(2-fluoroethyl)azetidin-3-yl)pyridine-2,5-diamine [0507]
N5-(8-(5-chloro-2-fluorophenyl)pyrido[3,4-d]pyrimidin-2-yl)-N2-(1-(2-fluo-
roethyl)azetidin-3-yl)pyridine-2,5-diamine [0508]
8-(3-aminophenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-amine
[0509]
8-(3-aminophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-2-amine
[0510]
8-(3-aminophenyl)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinaz-
olin-2-amine [0511]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)acetamide
[0512]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)phe-
nyl)acetamide [0513]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)acetamide [0514]
N-(6-morpholinopyridin-3-yl)-8-phenylquinazolin-2-amine [0515]
8-(2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-amine
[0516]
8-(2-chlorophenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-amine
[0517]
8-(5-chloro-2-fluorophenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-amin-
e [0518]
8-(3-chlorophenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-amine
[0519]
8-(3-fluorophenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-amine
[0520]
8-(2,6-difluorophenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-am-
ine [0521]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridi-
n-3-yl)quinazolin-2-amine [0522]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-morpholinopyridin-3-y-
l)quinazolin-2-amine [0523]
8-(3-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-
-amine [0524]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)quinazo-
lin-2-amine [0525]
8-(4-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-
-amine [0526]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)quinazo-
lin-2-amine [0527]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(6-morpholinopyridin-3-yl)qui-
nazolin-2-amine [0528]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-morpholinopyridin-3-y-
l)quinazolin-2-amine [0529]
8-phenyl-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-2-amine
[0530]
8-(2-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-2-amine
[0531]
8-(2-chlorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-2--
amine [0532]
8-(2,6-difluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-2-ami-
ne [0533]
8-(5-chloro-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)qu-
inazolin-2-amine [0534]
8-(3-chlorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-2-amine
[0535]
8-(3-fluorophenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-2--
amine [0536]
N-(4-fluoro-3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)p-
henyl)acetamide [0537]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3--
yl)quinazolin-2-amine [0538]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyrid-
in-3-yl)quinazolin-2-amine [0539]
8-(3-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinaz-
olin-2-amine [0540]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)q-
uinazolin-2-amine [0541]
8-(4-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinaz-
olin-2-amine [0542]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3-yl)q-
uinazolin-2-amine [0543]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N-(6-(piperazin-1-yl)pyridin-3--
yl)quinazolin-2-amine [0544]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N-(6-(piperazin-1-yl)pyrid-
in-3-yl)quinazolin-2-amine [0545]
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(2-fluorophenyl)quinazolin-2-yl-
)pyridine-2,5-diamine [0546]
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(3-(2-morpholinoethoxy)phenyl)q-
uinazolin-2-yl)pyridine-2,5-diamine [0547]
N5-(8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)quinazolin-2-yl)-N2-(1-(2-fl-
uoroethyl)azetidin-3-yl)pyridine-2,5-diamine [0548]
N5-(8-(5-chloro-2-fluorophenyl)quinazolin-2-yl)-N2-(1-(2-fluoroethyl)azet-
idin-3-yl)pyridine-2,5-diamine [0549]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)acrylamide [0550]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acrylamide [0551]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-yl)phen-
yl)acrylamide [0552]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-yl)phen-
yl)acrylamide [0553]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)acrylamide [0554]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrim-
idin-8-yl)phenyl)acrylamide [0555]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrim-
idin-8-yl)phenyl)acrylamide [0556]
N-(3-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)acrylamide [0557]
N-(3-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)acrylamide [0558]
N-(3-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)phenyl)acrylamide [0559]
N-(3-(2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)phenyl)acrylamide tert-butyl
3-((5-((8-(3-acrylamidophenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridin-2-
-yl)amino)azetidine-1-carboxylate [0560]
N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)phenyl)acrylamide [0561]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [0562]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,2-d]pyrimidin-8-yl)phenyl)acrylamide [0563]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[4,3-d]pyrimidin-8-yl)phenyl)acrylamide [0564]
N-(3-(2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)phenyl)acrylamide [0565]
N-(3-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)acrylamide [0566]
N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)phenyl)acrylamide [0567]
(R)--N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)acrylamide [0568]
(S)--N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)acrylamide [0569]
(S)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide [0570]
(R)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide [0571]
(R)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide [0572]
(S)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide [0573]
(R)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide [0574]
(S)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide [0575]
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)phenyl)acrylamide [0576]
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-
-8-yl)phenyl)acrylamide [0577]
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-
-8-yl)phenyl)acrylamide [0578]
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)acrylamide [0579]
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,2-d]pyrimidin-8-yl)phenyl)acrylamide [0580]
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4-
,3-d]pyrimidin-8-yl)phenyl)acrylamide
[0581]
N-(3-(2-((2-methoxy-6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)a-
mino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [0582]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxypyridin-3-yl-
)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [0583]
N-(3-(2-((2-methoxy-6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [0584]
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl-
)acrylamide [0585]
N-(3-(2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)-
phenyl)acrylamide [0586]
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide [0587]
N-(3-(2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [0588]
N-(3-(2-((2-methoxy-6-(piperidin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)-
phenyl)acrylamide [0589]
N-(3-(2-((6-(azetidin-3-ylamino)-2-methoxypyridin-3-yl)amino)quinazolin-8-
-yl)phenyl)acrylamide [0590]
N-(3-(2-((2-methoxy-6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)qu-
inazolin-8-yl)phenyl)acrylamide tert-butyl
3-((5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-6-methoxypyridin-2-y-
l)amino)azetidine-1-carboxylate [0591]
N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)-2-methoxypyridin-3-yl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [0592]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxypyridin-3-yl-
)amino)quinazolin-8-yl)phenyl)acrylamide [0593]
N-(3-(2-((2-methoxy-6-(piperidin-4-ylamino)pyridin-3-yl)amino)quinazolin--
8-yl)phenyl)acrylamide [0594]
N-(3-(2-((2-methoxy-6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [0595]
N-(3-(2-((2-methoxy-6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [0596]
(R)--N-(3-(2-((2-methoxy-6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quina-
zolin-8-yl)phenyl)acrylamide [0597]
(S)--N-(3-(2-(2-methoxy-6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [0598]
(S)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)-2-methoxypyridin-3-yl)amin-
o)quinazolin-8-yl)phenyl)acrylamide [0599]
(R)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)-2-methoxypyridin-3-yl)amin-
o)quinazolin-8-yl)phenyl)acrylamide [0600]
(R)--N-(3-(2-((6-(2-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)phenyl)acrylamide [0601]
(S)--N-(3-(2-((6-(2-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)phenyl)acrylamide [0602]
(R)--N-(3-(2-((6-(3-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)phenyl)acrylamide [0603]
(S)--N-(3-(2-((6-(3-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)phenyl)acrylamide [0604]
N-(3-(7-fluoro-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)-
acrylamide [0605]
N-(3-(7-fluoro-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)quinazolin-8--
yl)phenyl)acrylamide [0606]
N-(3-(7-chloro-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)-
acrylamide [0607]
N-(3-(7-chloro-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)quinazolin-8--
yl)phenyl)acrylamide [0608]
N-(3-(7-methyl-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)-
acrylamide [0609]
N-(3-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)-7-methylquinazolin-8--
yl)phenyl)acrylamide [0610]
N-(3-(7-ethyl-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)a-
crylamide [0611]
N-(3-(7-fluoro-2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)p-
henyl)acrylamide [0612]
N-(3-(7-fluoro-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [0613]
N-(3-(7-fluoro-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [0614]
N-(3-(7-chloro-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [0615]
N-(3-(7-chloro-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [0616]
N-(3-(7-methyl-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [0617]
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-methy-
lquinazolin-8-yl)phenyl)acrylamide [0618]
N-(3-(7-ethyl-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [0619]
N-(3-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)-7-fluoroquinazolin-
-8-yl)phenyl)acrylamide [0620]
N-(3-(7-fluoro-2-((6-(piperidin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)p-
henyl)acrylamide [0621]
N-(3-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)-7-fluoroquinazolin-8--
yl)phenyl)acrylamide [0622]
N-(3-(7-fluoro-2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)qui-
nazolin-8-yl)phenyl)acrylamide tert-butyl
3-((5-((8-(3-acrylamidophenyl)-7-fluoroquinazolin-2-yl)amino)pyridin-2-yl-
)amino)azetidine-1-carboxylate [0623]
N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)-7-fluoroqui-
nazolin-8-yl)phenyl)acrylamide [0624]
N-(3-(7-fluoro-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)-
amino)quinazolin-8-yl)phenyl)acrylamide [0625]
N-(3-(7-chloro-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)-
amino)quinazolin-8-yl)phenyl)acrylamide [0626]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)-7--
methylquinazolin-8-yl)phenyl)acrylamide [0627]
N-(3-(7-ethyl-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [0628]
N-(3-(7-fluoro-2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)quinazolin-8-
-yl)phenyl)acrylamide [0629]
N-(3-(7-fluoro-2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [0630]
N-(3-(7-fluoro-2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin--
8-yl)phenyl)acrylamide [0631]
(R)--N-(3-(7-fluoro-2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [0632]
(S)--N-(3-(7-fluoro-2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [0633]
(S)--N-(3-(7-fluoro-2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [0634]
(R)--N-(3-(7-fluoro-2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [0635]
(R)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)phenyl)acrylamide [0636]
(S)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)phenyl)acrylamide [0637]
(R)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)phenyl)acrylamide [0638]
(S)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)phenyl)acrylamide [0639]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)acrylamid-
e [0640]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [0641]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [0642]
N-(3-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)phe-
nyl)acrylamide [0643]
N-(3-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)phenyl)acr-
ylamide [0644]
N-(3-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl)phenyl-
)acrylamide [0645]
N-(3-(2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)quinazolin-8-
-yl)phenyl)acrylamide tert-butyl
3-((5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)pyridin-2-yl)amino)az-
etidine-1-carboxylate [0646]
N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)quinazolin-8-
-yl)phenyl)acrylamide [0647]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)qui-
nazolin-8-yl)phenyl)acrylamide [0648]
N-(3-(2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)quinazolin-8-yl)pheny-
l)acrylamide [0649]
N-(3-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)quinazolin--
8-yl)phenyl)acrylamide [0650]
N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl)phen-
yl)acrylamide [0651]
(R)--N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl-
)phenyl)acrylamide [0652]
(S)--N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl-
)phenyl)acrylamide [0653]
(S)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide [0654]
(R)--N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide [0655]
(R)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [0656]
(S)--N-(3-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [0657]
(R)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [0658]
(S)--N-(3-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [0659]
8-(4-aminopyridin-2-yl)-N-(4-morpholinophenyl)quinazolin-2-amine
[0660]
8-(4-aminopyridin-2-yl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
[0661]
8-(4-aminopyridin-2-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinaz-
olin-2-amine [0662]
N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)acetamide
[0663]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)p-
yridin-4-yl)acetamide [0664]
N-(4-morpholinophenyl)-8-(pyridin-2-yl)quinazolin-2-amine [0665]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(4-morpholinophenyl)quinazolin-2-
-amine [0666]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(4-morpholinophenyl)quinazo-
lin-2-amine [0667]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(4-morpholinophenyl)quinazolin-2-
-amine [0668]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(4-morpholinophenyl)quinazo-
lin-2-amine [0669]
N-(4-(piperazin-1-yl)phenyl)-8-(pyridin-2-yl)quinazolin-2-amine
[0670]
N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin-4-yl)ace-
tamide [0671]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(4-(piperazin-1-yl)phenyl)quinaz-
olin-2-amine [0672]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(4-(piperazin-1-yl)phenyl)q-
uinazolin-2-amine [0673]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(4-(piperazin-1-yl)phenyl)quinaz-
olin-2-amine [0674]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(4-(piperazin-1-yl)phenyl)q-
uinazolin-2-amine [0675]
N1-(1-(2-fluoroethyl)azetidin-3-yl)-N4-(8-(4-(2-morpholinoethoxy)pyridin--
2-yl)quinazolin-2-yl)benzene-1,4-diamine [0676]
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide [0677]
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide [0678]
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide [0679]
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide [0680]
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide [0681]
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide [0682]
N-(2-(2-((2-methoxy-4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0683]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino-
)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0684]
N-(2-(2-((2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido[-
3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0685]
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl-
)acrylamide [0686]
N-(2-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridi-
n-4-yl)acrylamide [0687]
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-4-yl)acrylamide [0688]
N-(2-(2-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [0689]
N-(2-(2-((2-methoxy-4-(piperidin-1-yl)phenyl)amino)quinazolin-8-yl)pyridi-
n-4-yl)acrylamide [0690]
N-(2-(2-((4-(azetidin-3-ylamino)-2-methoxyphenyl)amino)quinazolin-8-yl)py-
ridin-4-yl)acrylamide [0691]
N-(2-(2-((2-methoxy-4-((1-methylazetidin-3-yl)amino)phenyl)amino)quinazol-
in-8-yl)pyridin-4-yl)acrylamide tert-butyl
3-((4-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-yl)amino)-3-methoxypheny-
l)amino)azetidine-1-carboxylate [0692]
N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)-2-methoxyphenyl)amino)quinazol-
in-8-yl)pyridin-4-yl)acrylamide [0693]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxyphenyl)amino-
)quinazolin-8-yl)pyridin-4-yl)acrylamide [0694]
N-(2-(2-((2-methoxy-4-(piperidin-4-ylamino)phenyl)amino)quinazolin-8-yl)p-
yridin-4-yl)acrylamide [0695]
N-(2-(2-((2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazo-
lin-8-yl)pyridin-4-yl)acrylamide [0696]
N-(2-(2-((2-methoxy-4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0697]
(R)--N-(2-(2-((2-methoxy-4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [0698]
(S)--N-(2-(2-((2-methoxy-4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [0699]
(S)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)-2-methoxyphenyl)amino)quin-
azolin-8-yl)pyridin-4-yl)acrylamide [0700]
(R)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)-2-methoxyphenyl)amino)quin-
azolin-8-yl)pyridin-4-yl)acrylamide [0701]
(R)--N-(2-(2-((4-(2-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [0702]
(S)--N-(2-(2-((4-(2-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [0703]
(R)--N-(2-(2-((4-(3-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [0704]
(S)--N-(2-(2-((4-(3-(aminomethyl)morpholino)-2-methoxyphenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [0705]
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)acrylamide [0706]
N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide [0707]
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,2-d]pyrimidin-8-yl)pyridin-4--
yl)acrylamide [0708]
N-(2-(2-((4-morpholinophenyl)amino)pyrido[4,3-d]pyrimidin-8-yl)pyridin-4--
yl)acrylamide [0709]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)acrylamide [0710]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-
-yl)pyridin-4-yl)acrylamide [0711]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[4,3-d]pyrimidin-8-
-yl)pyridin-4-yl)acrylamide [0712]
N-(2-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)pyridin-4-yl)acrylamide [0713]
N-(2-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide [0714]
N-(2-(2-((4-(azetidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
pyridin-4-yl)acrylamide [0715]
N-(2-(2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide tert-butyl
3-((4-((8-(4-acrylamidopyridin-2-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)phe-
nyl)amino)azetidine-1-carboxylate [0716]
N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide [0717]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0718]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
2-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide
[0719]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)py-
rido[4,3-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0720]
N-(2-(2-((4-(piperidin-4-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl-
)pyridin-4-yl)acrylamide [0721]
N-(2-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)pyrido[3,4-d]pyri-
midin-8-yl)pyridin-4-yl)acrylamide [0722]
N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)acrylamide [0723]
(R)--N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)pyridin-4-yl)acrylamide [0724]
(S)--N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)pyridin-4-yl)acrylamide [0725]
(S)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide [0726]
(R)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)acrylamide [0727]
(R)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide [0728]
(S)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide [0729]
(R)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide [0730]
(S)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide [0731]
N-(2-(7-fluoro-2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)-
acrylamide [0732]
N-(2-(7-fluoro-2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)pyr-
idin-4-yl)acrylamide [0733]
N-(2-(7-chloro-2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)-
acrylamide [0734]
N-(2-(7-chloro-2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)pyr-
idin-4-yl)acrylamide [0735]
N-(2-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)-
acrylamide [0736]
N-(2-(2-((2-methoxy-4-morpholinophenyl)amino)-7-methylquinazolin-8-yl)pyr-
idin-4-yl)acrylamide [0737]
N-(2-(7-ethyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)a-
crylamide [0738]
N-(2-(7-fluoro-2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin-
-4-yl)acrylamide [0739]
N-(2-(7-fluoro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [0740]
N-(2-(7-fluoro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [0741]
N-(2-(7-chloro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [0742]
N-(2-(7-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [0743]
N-(2-(7-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [0744]
N-(2-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-methylquina-
zolin-8-yl)pyridin-4-yl)acrylamide [0745]
N-(2-(7-ethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0746]
N-(2-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-7-fluoroquinazolin-8-yl)-
pyridin-4-yl)acrylamide [0747]
N-(2-(7-fluoro-2-((4-(piperidin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin-
-4-yl)acrylamide [0748]
N-(2-(2-((4-(azetidin-3-ylamino)phenyl)amino)-7-fluoroquinazolin-8-yl)pyr-
idin-4-yl)acrylamide [0749]
N-(2-(7-fluoro-2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)quinazoli-
n-8-yl)pyridin-4-yl)acrylamide tert-butyl
3-((4-((8-(4-acrylamidopyridin-2-yl)-7-fluoroquinazolin-2-yl)amino)phenyl-
)amino)azetidine-1-carboxylate [0750]
N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)-7-fluoroquinazoli-
n-8-yl)pyridin-4-yl)acrylamide [0751]
N-(2-(7-fluoro-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)-
quinazolin-8-yl)pyridin-4-yl)acrylamide [0752]
N-(2-(7-chloro-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)-
quinazolin-8-yl)pyridin-4-yl)acrylamide [0753]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)-7-methyl-
quinazolin-8-yl)pyridin-4-yl)acrylamide [0754]
N-(2-(7-ethyl-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)q-
uinazolin-8-yl)pyridin-4-yl)acrylamide [0755]
N-(2-(7-fluoro-2-((4-(piperidin-4-ylamino)phenyl)amino)quinazolin-8-yl)py-
ridin-4-yl)acrylamide [0756]
N-(2-(7-fluoro-2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)pyridin-4-yl)acrylamide [0757]
N-(2-(7-fluoro-2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)p-
yridin-4-yl)acrylamide [0758]
(R)--N-(2-(7-fluoro-2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-
-yl)pyridin-4-yl)acrylamide [0759]
(S)--N-(2-(7-fluoro-2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-
-yl)pyridin-4-yl)acrylamide [0760]
(S)--N-(2-(7-fluoro-2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [0761]
(R)--N-(2-(7-fluoro-2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [0762]
(R)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)pyridin-4-yl)acrylamide [0763]
(S)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)pyridin-4-yl)acrylamide [0764]
(R)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)pyridin-4-yl)acrylamide [0765]
(S)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)-7-fluoroquinazo-
lin-8-yl)pyridin-4-yl)acrylamide [0766]
N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)acrylamid-
e [0767]
N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
4-yl)acrylamide [0768]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
4-yl)acrylamide [0769]
N-(2-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin-4-
-yl)acrylamide [0770]
N-(2-(2-((4-(piperidin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin-4-yl)acr-
ylamide [0771]
N-(2-(2-((4-(azetidin-3-ylamino)phenyl)amino)quinazolin-8-yl)pyridin-4-yl-
)acrylamide [0772]
N-(2-(2-((4-((1-methylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-yl)py-
ridin-4-yl)acrylamide tert-butyl
3-((4-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-yl)amino)phenyl)amino)az-
etidine-1-carboxylate [0773]
N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-yl)py-
ridin-4-yl)acrylamide [0774]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)quinazoli-
n-8-yl)pyridin-4-yl)acrylamide [0775]
N-(2-(2-((4-(piperidin-4-ylamino)phenyl)amino)quinazolin-8-yl)pyridin-4-y-
l)acrylamide [0776]
N-(2-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)p-
yridin-4-yl)acrylamide [0777]
N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)pyridin-4--
yl)acrylamide [0778]
(R)--N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)pyrid-
in-4-yl)acrylamide [0779]
(S)--N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quinazolin-8-yl)pyrid-
in-4-yl)acrylamide [0780]
(S)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quinazolin-8-y-
l)pyridin-4-yl)acrylamide [0781]
(R)--N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)quinazolin-8-y-
l)pyridin-4-yl)acrylamide [0782]
(R)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0783]
(S)--N-(2-(2-((4-(2-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0784]
(R)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0785]
(S)--N-(2-(2-((4-(3-(aminomethyl)morpholino)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0786]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-y-
l)pyridin-4-yl)acetamide [0787]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-y-
l)pyridin-4-yl)acetamide [0788]
N-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)pyrido[4,3-d]pyrimidin-2-ami-
ne [0789]
N-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,2-d]pyrimi-
din-2-amine [0790]
N-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-2-ami-
ne [0791]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3--
yl)pyrido[3,4-d]pyrimidin-2-amine [0792]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)p-
yrido[3,4-d]pyrimidin-2-amine [0793]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)pyrido-
[3,4-d]pyrimidin-2-amine [0794]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)p-
yrido[3,4-d]pyrimidin-2-amine [0795]
N-(6-(piperazin-1-yl)pyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidin-
-2-amine [0796]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)acetamide [0797]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)-
pyrido[3,4-d]pyrimidin-2-amine [0798]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin--
3-yl)pyrido[3,4-d]pyrimidin-2-amine [0799]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)-
pyrido[3,4-d]pyrimidin-2-amine [0800]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin--
3-yl)pyrido[3,4-d]pyrimidin-2-amine [0801]
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(4-(2-morpholinoethoxy)pyridin--
2-yl)pyrido[3,4-d]pyrimidin-2-yl)pyridine-2,5-diamine [0802]
8-(4-aminopyridin-2-yl)-N-(6-morpholinopyridin-3-yl)quinazolin-2-amine
[0803]
8-(4-aminopyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)quinazol-
in-2-amine [0804]
8-(4-aminopyridin-2-yl)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)quinazo-
lin-2-amine [0805]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-yl)ace-
tamide [0806]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)pyridin-4--
yl)acetamide [0807]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-4-yl)acetamide [0808]
N-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)quinazolin-2-amine
[0809]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)quinaz-
olin-2-amine [0810]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)q-
uinazolin-2-amine [0811]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)quinaz-
olin-2-amine [0812]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-morpholinopyridin-3-yl)q-
uinazolin-2-amine [0813]
N-(6-(piperazin-1-yl)pyridin-3-yl)-8-(pyridin-2-yl)quinazolin-2-amine
[0814]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridi-
n-3-yl)quinazolin-2-amine [0815]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin--
3-yl)quinazolin-2-amine [0816]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin-3-yl)-
quinazolin-2-amine [0817]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N-(6-(piperazin-1-yl)pyridin--
3-yl)quinazolin-2-amine [0818]
N2-(1-(2-fluoroethyl)azetidin-3-yl)-N5-(8-(4-(2-morpholinoethoxy)pyridin--
2-yl)quinazolin-2-yl)pyridine-2,5-diamine [0819]
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)pyridin-4-yl)acrylamide [0820]
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-
-8-yl)pyridin-4-yl)acrylamide [0821]
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-
-8-yl)pyridin-4-yl)acrylamide [0822]
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0823]
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3-
,2-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0824]
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4-
,3-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0825]
N-(2-(2-((2-methoxy-6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)py-
rido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0826]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxypyridin-3-yl-
)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0827]
N-(2-(2-((2-methoxy-6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0828]
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridi-
n-4-yl)acrylamide [0829]
N-(2-(2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0830]
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-4-yl)acrylamide [0831]
N-(2-(2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)quinazoli-
n-8-yl)pyridin-4-yl)acrylamide [0832]
N-(2-(2-((2-methoxy-6-(piperidin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [0833]
N-(2-(2-((6-(azetidin-3-ylamino)-2-methoxypyridin-3-yl)amino)quinazolin-8-
-yl)pyridin-4-yl)acrylamide [0834]
N-(2-(2-((2-methoxy-6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)qu-
inazolin-8-yl)pyridin-4-yl)acrylamide tert-butyl
3-((5-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-yl)amino)-6-methoxypyrid-
in-2-yl)amino)azetidine-1-carboxylate [0835]
N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)-2-methoxypyridin-3-yl)amino)qu-
inazolin-8-yl)pyridin-4-yl)acrylamide [0836]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-2-methoxypyridin-3-yl-
)amino)quinazolin-8-yl)pyridin-4-yl)acrylamide [0837]
N-(2-(2-((2-methoxy-6-(piperidin-4-ylamino)pyridin-3-yl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [0838]
N-(2-(2-((2-methoxy-6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)q-
uinazolin-8-yl)pyridin-4-yl)acrylamide [0839]
N-(2-(2-((2-methoxy-6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)acrylamide [0840]
(R)--N-(2-(2-((2-methoxy-6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [0841]
(S)--N-(2-(2-((2-methoxy-6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [0842]
(S)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)-2-methoxypyridin-3-yl)amin-
o)quinazolin-8-yl)pyridin-4-yl)acrylamide [0843]
(R)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)-2-methoxypyridin-3-yl)amin-
o)quinazolin-8-yl)pyridin-4-yl)acrylamide [0844]
(R)--N-(2-(2-((6-(2-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)pyridin-4-yl)acrylamide [0845]
(S)--N-(2-(2-((6-(2-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)pyridin-4-yl)acrylamide [0846]
(R)--N-(2-(2-((6-(3-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)pyridin-4-yl)acrylamide [0847]
(S)--N-(2-(2-((6-(3-(aminomethyl)morpholino)-2-methoxypyridin-3-yl)amino)-
quinazolin-8-yl)pyridin-4-yl)acrylamide [0848]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide [0849]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)acrylamide [0850]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,2-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide [0851]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[4,3-d]pyrimidin-8-yl)pyri-
din-4-yl)acrylamide [0852]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide [0853]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,2-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide [0854]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[4,3-d]pyrim-
idin-8-yl)pyridin-4-yl)acrylamide [0855]
N-(2-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)acrylamide [0856]
N-(2-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)acrylamide
[0857]
N-(2-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)pyridin-4-yl)acrylamide [0858]
N-(2-(2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)pyridin-4-yl)acrylamide tert-butyl
3-((5-((8-(4-acrylamidopyridin-2-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyr-
idin-2-yl)amino)azetidine-1-carboxylate [0859]
N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0860]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0861]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,2-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0862]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[4,3-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0863]
N-(2-(2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidi-
n-8-yl)pyridin-4-yl)acrylamide [0864]
N-(2-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0865]
N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)pyridin-4-yl)acrylamide [0866]
(R)--N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)pyridin-4-yl)acrylamide [0867]
(S)--N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)pyrido[3,4-d]py-
rimidin-8-yl)pyridin-4-yl)acrylamide [0868]
(S)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0869]
(R)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0870]
(R)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0871]
(S)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0872]
(R)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0873]
(S)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [0874]
N-(2-(7-fluoro-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-
-4-yl)acrylamide [0875]
N-(2-(7-fluoro-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)quinazolin-8--
yl)pyridin-4-yl)acrylamide [0876]
N-(2-(7-chloro-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-
-4-yl)acrylamide [0877]
N-(2-(7-chloro-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)quinazolin-8--
yl)pyridin-4-yl)acrylamide [0878]
N-(2-(7-methyl-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-
-4-yl)acrylamide [0879]
N-(2-(2-((2-methoxy-6-morpholinopyridin-3-yl)amino)-7-methylquinazolin-8--
yl)pyridin-4-yl)acrylamide [0880]
N-(2-(7-ethyl-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin--
4-yl)acrylamide [0881]
N-(2-(7-fluoro-2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)p-
yridin-4-yl)acrylamide [0882]
N-(2-(7-fluoro-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)pyridin-4-yl)acrylamide [0883]
N-(2-(7-fluoro-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)pyridin-4-yl)acrylamide [0884]
N-(2-(7-chloro-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)pyridin-4-yl)acrylamide [0885]
N-(2-(7-chloro-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)pyridin-4-yl)acrylamide [0886]
N-(2-(7-methyl-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)pyridin-4-yl)acrylamide [0887]
N-(2-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-methy-
lquinazolin-8-yl)pyridin-4-yl)acrylamide [0888]
N-(2-(7-ethyl-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)acrylamide [0889]
N-(2-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)-7-fluoroquinazolin-
-8-yl)pyridin-4-yl)acrylamide [0890]
N-(2-(7-fluoro-2-((6-(piperidin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)p-
yridin-4-yl)acrylamide [0891]
N-(2-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)-7-fluoroquinazolin-8--
yl)pyridin-4-yl)acrylamide [0892]
N-(2-(7-fluoro-2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)qui-
nazolin-8-yl)pyridin-4-yl)acrylamide tert-butyl
3-((5-((8-(4-acrylamidopyridin-2-yl)-7-fluoroquinazolin-2-yl)amino)pyridi-
n-2-yl)amino)azetidine-1-carboxylate [0893]
N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)-7-fluoroqui-
nazolin-8-yl)pyridin-4-yl)acrylamide [0894]
N-(2-(7-fluoro-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)-
amino)quinazolin-8-yl)pyridin-4-yl)acrylamide [0895]
N-(2-(7-chloro-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)-
amino)quinazolin-8-yl)pyridin-4-yl)acrylamide [0896]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)-7--
methylquinazolin-8-yl)pyridin-4-yl)acrylamide [0897]
N-(2-(7-ethyl-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)a-
mino)quinazolin-8-yl)pyridin-4-yl)acrylamide [0898]
N-(2-(7-fluoro-2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)quinazolin-8-
-yl)pyridin-4-yl)acrylamide [0899]
N-(2-(7-fluoro-2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)qu-
inazolin-8-yl)pyridin-4-yl)acrylamide [0900]
N-(2-(7-fluoro-2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [0901]
(R)--N-(2-(7-fluoro-2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [0902]
(S)--N-(2-(7-fluoro-2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [0903]
(S)--N-(2-(7-fluoro-2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino-
)quinazolin-8-yl)pyridin-4-yl)acrylamide [0904]
(R)--N-(2-(7-fluoro-2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino-
)quinazolin-8-yl)pyridin-4-yl)acrylamide [0905]
(R)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)pyridin-4-yl)acrylamide [0906]
(S)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)pyridin-4-yl)acrylamide [0907]
(R)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)pyridin-4-yl)acrylamide [0908]
(S)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)-7-fluoroq-
uinazolin-8-yl)pyridin-4-yl)acrylamide [0909]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-yl)acr-
ylamide [0910]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)pyridin-4--
yl)acrylamide [0911]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-4-yl)acrylamide [0912]
N-(2-(2-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)pyr-
idin-4-yl)acrylamide [0913]
N-(2-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)pyridin-4--
yl)acrylamide [0914]
N-(2-(2-((6-(azetidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl)pyridi-
n-4-yl)acrylamide [0915]
N-(2-(2-((6-((1-methylazetidin-3-yl)amino)pyridin-3-yl)amino)quinazolin-8-
-yl)pyridin-4-yl)acrylamide [0916] tert-butyl
3-((5-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-yl)amino)pyridin-2-yl)am-
ino)azetidine-1-carboxylate [0917]
N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)quinazolin-8-
-yl)pyridin-4-yl)acrylamide [0918]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)qui-
nazolin-8-yl)pyridin-4-yl)acrylamide [0919]
N-(2-(2-((6-(piperidin-4-ylamino)pyridin-3-yl)amino)quinazolin-8-yl)pyrid-
in-4-yl)acrylamide [0920]
N-(2-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin-3-yl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [0921]
N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl)pyri-
din-4-yl)acrylamide [0922]
(R)--N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [0923]
(S)--N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [0924]
(S)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-4-yl)acrylamide [0925]
(R)--N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-4-yl)acrylamide [0926]
(R)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)acrylamide [0927]
(S)--N-(2-(2-((6-(2-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)acrylamide [0928]
(R)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)acrylamide [0929]
(S)--N-(2-(2-((6-(3-(aminomethyl)morpholino)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)acrylamide [0930]
(E)-4-(dimethylamino)-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)but-2-enamide [0931]
(E)-4-(dimethylamino)-N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)but-2-enamide [0932]
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [0933]
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,2-d]pyrimidin-8-yl)phenyl)but-2-enamide [0934]
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[4,3-d]pyrimidin-8-yl)phenyl)but-2-enamide [0935]
(E)-4-(dimethylamino)-N-(3-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)but-2-enamide [0936]
(E)-N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [0937]
(E)-4-(dimethylamino)-N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide
[0938]
(E)-4-(dimethylamino)-N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)a-
mino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [0939]
(E)-4-(dimethylamino)-N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [0940]
(E)-4-(dimethylamino)-N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)ami-
no)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [0941]
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)pro-
piolamide [0942]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)propiolamide [0943]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)propiolamide [0944]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)phenyl)propiolamide [0945]
(E)-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl-
)but-2-enamide [0946]
(Z)--N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pheny-
l)but-2-enamide [0947]
(Z)-3-fluoro-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)phenyl)but-2-enamide [0948]
(E)-3-fluoro-N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)phenyl)but-2-enamide [0949]
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)met-
hacrylamide [0950]
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)eth-
enesulfonamide [0951]
(E)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)phenyl)but-2-enamide [0952]
(Z)--N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)but-2-enamide [0953]
(Z)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)but-2-enamide [0954]
(E)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)but-2-enamide [0955]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)methacrylamide [0956]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)ethenesulfonamide [0957]
3,3-difluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)phenyl)acrylamide [0958]
3-methyl-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)but-2-enamide [0959]
(E)-4-(dimethylamino)-N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)-
phenyl)but-2-enamide [0960]
(E)-4-(dimethylamino)-N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-
-8-yl)phenyl)but-2-enamide [0961]
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)phenyl)but-2-enamide [0962]
(E)-4-(dimethylamino)-N-(3-(2-((4-(piperidin-1-yl)phenyl)amino)quinazolin-
-8-yl)phenyl)but-2-enamide [0963]
(E)-N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-y-
l)phenyl)-4-(dimethylamino)but-2-enamide [0964]
(E)-4-(dimethylamino)-N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
phenyl)amino)quinazolin-8-yl)phenyl)but-2-enamide [0965]
(E)-4-(dimethylamino)-N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)a-
mino)quinazolin-8-yl)phenyl)but-2-enamide [0966]
(E)-4-(dimethylamino)-N-(3-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quin-
azolin-8-yl)phenyl)but-2-enamide [0967]
(E)-4-(dimethylamino)-N-(3-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)ami-
no)quinazolin-8-yl)phenyl)but-2-enamide [0968]
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)propiolamide
[0969]
N-(3-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)pr-
opiolamide [0970]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)p-
ropiolamide [0971]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)quinazoli-
n-8-yl)phenyl)propiolamide [0972]
(E)-N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)but-2-enami-
de [0973]
(Z)--N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)b-
ut-2-enamide [0974]
(Z)-3-fluoro-N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)bu-
t-2-enamide [0975]
(E)-3-fluoro-N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)bu-
t-2-enamide [0976]
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)methacrylamide
[0977]
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)ethenesu-
lfonamide [0978]
(E)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phen-
yl)but-2-enamide [0979]
(Z)--N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phe-
nyl)but-2-enamide [0980]
(Z)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [0981]
(E)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [0982]
(Z)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)but-2-enamide [0983]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)m-
ethacrylamide [0984]
3,3-difluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [0985]
3-methyl-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)but-2-enamide [0986]
(E)-3-fluoro-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)but-2-enamide [0987]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)e-
thenesulfonamide [0988]
(E)-4-(dimethylamino)-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [0989]
(E)-4-(dimethylamino)-N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [0990]
(E)-4-(dimethylamino)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide
[0991]
(E)-4-(dimethylamino)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin--
3-yl)amino)pyrido[3,2-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide
[0992]
(E)-4-(dimethylamino)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[4,3-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [0993]
(E)-4-(dimethylamino)-N-(2-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [0994]
(E)-N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide
[0995]
(E)-4-(dimethylamino)-N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide
[0996]
(E)-4-(dimethylamino)-N-(2-(2-((6-((1-methylpiperidin-4-yl)amino)p-
yridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide
[0997]
(E)-4-(dimethylamino)-N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3--
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide
[0998]
(E)-4-(dimethylamino)-N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3--
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide
[0999]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)propiolamide [1000]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)propiolamide [1001]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)propiolamide [1002]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)propiolamide [1003]
(E)-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
pyridin-4-yl)but-2-enamide [1004]
(Z)--N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl-
)pyridin-4-yl)but-2-enamide [1005]
(Z)-3-fluoro-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)but-2-enamide [1006]
(E)-3-fluoro-N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)but-2-enamide [1007]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)methacrylamide [1008]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)ethenesulfonamide [1009]
(E)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)but-2-enamide [1010]
(Z)--N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]-
pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1011]
(Z)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1012]
(E)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1013]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)methacrylamide [1014]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)pyridin-4-yl)ethenesulfonamide [1015]
3,3-difluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [1016]
3-methyl-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1017]
(E)-4-(dimethylamino)-N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)but-2-enamide [1018]
(E)-4-(dimethylamino)-N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1019]
(E)-4-(dimethylamino)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1020]
(E)-4-(dimethylamino)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[3,2-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1021]
(E)-4-(dimethylamino)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)py-
rido[4,3-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1022]
(E)-4-(dimethylamino)-N-(2-(2-((4-(piperidin-1-yl)phenyl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1023]
(E)-N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide [1024]
(E)-4-(dimethylamino)-N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide
[1025]
(E)-4-(dimethylamino)-N-(2-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)a-
mino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1026]
(E)-4-(dimethylamino)-N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1027]
(E)-4-(dimethylamino)-N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)ami-
no)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1028]
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)propiolamide [1029]
N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyri-
din-4-yl)propiolamide [1030]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)propiolamide [1031]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)pyridin-4-yl)propiolamide [1032]
(E)-N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridi-
n-4-yl)but-2-enamide [1033]
(Z)--N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrid-
in-4-yl)but-2-enamide [1034]
(Z)-3-fluoro-N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)pyridin-4-yl)but-2-enamide [1035]
(E)-3-fluoro-N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8--
yl)pyridin-4-yl)but-2-enamide [1036]
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)methacrylamide [1037]
N-(2-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4--
yl)ethenesulfonamide [1038]
(E)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)pyridin-4-yl)but-2-enamide [1039]
(Z)--N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)pyridin-4-yl)but-2-enamide [1040]
(Z)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1041]
(E)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)but-2-enamide [1042]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)methacrylamide [1043]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)pyridin-4-yl)ethenesulfonamide [1044]
3,3-difluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4--
d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [1045]
3-methyl-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]py-
rimidin-8-yl)pyridin-4-yl)but-2-enamide [1046]
(E)-4-(dimethylamino)-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)but-2-enamide [1047]
(E)-4-(dimethylamino)-N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1048]
(E)-4-(dimethylamino)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1049]
(E)-4-(dimethylamino)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[3,2-d]pyrimidin-8-yl)phenyl)but-2-enamide [1050]
(E)-4-(dimethylamino)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)pyrido[4,3-d]pyrimidin-8-yl)phenyl)but-2-enamide [1051]
(E)-4-(dimethylamino)-N-(3-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1052]
(E)-N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)pyrido[3-
,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [1053]
(E)-4-(dimethylamino)-N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide
[1054]
(E)-4-(dimethylamino)-N-(3-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin--
3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1055]
(E)-4-(dimethylamino)-N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amin-
o)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1056]
(E)-4-(dimethylamino)-N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3--
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1057]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)propiolamide [1058]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)propiolamide [1059]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)propiolamide [1060]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)pyr-
ido[3,4-d]pyrimidin-8-yl)phenyl)propiolamide [1061]
(E)-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)-
phenyl)but-2-enamide [1062]
(Z)--N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl-
)phenyl)but-2-enamide [1063]
(Z)-3-fluoro-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)but-2-enamide [1064]
(E)-3-fluoro-N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimi-
din-8-yl)phenyl)but-2-enamide [1065]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)methacrylamide [1066]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phen-
yl)ethenesulfonamide [1067]
(E)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)but-2-enamide [1068]
(Z)--N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]-
pyrimidin-8-yl)phenyl)but-2-enamide [1069]
(Z)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1070]
(E)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1071]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)methacrylamide [1072]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-d]pyrim-
idin-8-yl)phenyl)ethenesulfonamide [1073]
3,3-difluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrid-
o[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1074]
3-methyl-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,-
4-d]pyrimidin-8-yl)phenyl)but-2-enamide [1075]
(E)-4-(dimethylamino)-N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)but-2-enamide [1076]
(E)-4-(dimethylamino)-N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quin-
azolin-8-yl)pyridin-4-yl)but-2-enamide [1077]
(E)-4-(dimethylamino)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)quinazolin-8-yl)pyridin-4-yl)but-2-enamide [1078]
(E)-4-(dimethylamino)-N-(2-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)quin-
azolin-8-yl)pyridin-4-yl)but-2-enamide [1079]
(E)-N-(2-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide [1080]
(E)-4-(dimethylamino)-N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
pyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-yl)but-2-enamide
[1081]
(E)-4-(dimethylamino)-N-(2-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin--
3-yl)amino)quinazolin-8-yl)pyridin-4-yl)but-2-enamide [1082]
(E)-4-(dimethylamino)-N-(2-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amin-
o)quinazolin-8-yl)pyridin-4-yl)but-2-enamide [1083]
(E)-4-(dimethylamino)-N-(2-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3--
yl)amino)quinazolin-8-yl)pyridin-4-yl)but-2-enamide [1084]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-yl)pro-
piolamide [1085]
N-(2-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)pyridin-4--
yl)propiolamide [1086]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-4-yl)propiolamide [1087]
N-(2-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)qui-
nazolin-8-yl)pyridin-4-yl)propiolamide [1088]
(E)-N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-yl-
)but-2-enamide [1089]
(Z)--N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-y-
l)but-2-enamide [1090]
(Z)-3-fluoro-N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyr-
idin-4-yl)but-2-enamide [1091]
(E)-3-fluoro-N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyr-
idin-4-yl)but-2-enamide [1092]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-yl)met-
hacrylamide [1093]
N-(2-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin-4-yl)eth-
enesulfonamide [1094]
(E)-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-y-
l)pyridin-4-yl)but-2-enamide [1095]
(Z)--N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8--
yl)pyridin-4-yl)but-2-enamide [1096]
(Z)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [1097]
(E)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [1098]
(Z)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)pyridin-4-yl)but-2-enamide [1099]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-4-yl)methacrylamide [1100]
3,3-difluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)pyridin-4-yl)acrylamide [1101]
3-methyl-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)pyridin-4-yl)but-2-enamide [1102]
(E)-3-fluoro-N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)pyridin-4-yl)but-2-enamide [1103]
N-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-4-yl)ethenesulfonamide [1104]
(E)-4-(dimethylamino)-N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)but-2-enamide [1105]
(E)-4-(dimethylamino)-N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-
-8-yl)pyridin-4-yl)but-2-enamide [1106]
(E)-4-(dimethylamino)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)pyridin-4-yl)but-2-enamide [1107]
(E)-4-(dimethylamino)-N-(2-(2-((4-(piperidin-1-yl)phenyl)amino)quinazolin-
-8-yl)pyridin-4-yl)but-2-enamide [1108]
(E)-N-(2-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-y-
l)pyridin-4-yl)-4-(dimethylamino)but-2-enamide [1109]
(E)-4-(dimethylamino)-N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
phenyl)amino)quinazolin-8-yl)pyridin-4-yl)but-2-enamide [1110]
(E)-4-(dimethylamino)-N-(2-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)a-
mino)quinazolin-8-yl)pyridin-4-yl)but-2-enamide [1111]
(E)-4-(dimethylamino)-N-(2-(2-((4-(pyrrolidin-3-ylamino)phenyl)amino)quin-
azolin-8-yl)pyridin-4-yl)but-2-enamide [1112]
(E)-4-(dimethylamino)-N-(2-(2-((4-(2-(hydroxymethyl)morpholino)phenyl)ami-
no)quinazolin-8-yl)pyridin-4-yl)but-2-enamide [1113]
N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)propiolam-
ide [1114]
N-(2-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridi-
n-4-yl)propiolamide [1115]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
4-yl)propiolamide [1116]
N-(2-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)quinazoli-
n-8-yl)pyridin-4-yl)propiolamide [1117]
(E)-N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)but-2-
-enamide
[1118]
(Z)--N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4--
yl)but-2-enamide [1119]
(Z)-3-fluoro-N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-
-yl)but-2-enamide [1120]
(E)-3-fluoro-N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-
-yl)but-2-enamide [1121]
N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)methacryl-
amide [1122]
N-(2-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)ethenesul-
fonamide [1123]
(E)-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyri-
din-4-yl)but-2-enamide [1124]
(Z)--N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyr-
idin-4-yl)but-2-enamide [1125]
(Z)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [1126]
(E)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [1127]
(Z)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)but-2-enamide [1128]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
4-yl)methacrylamide [1129]
3,3-difluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [1130]
3-methyl-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)but-2-enamide [1131]
(E)-3-fluoro-N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)but-2-enamide [1132]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
4-yl)ethenesulfonamide [1133]
(E)-4-(dimethylamino)-N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)but-2-enamide [1134]
(E)-4-(dimethylamino)-N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quin-
azolin-8-yl)phenyl)but-2-enamide [1135]
(E)-4-(dimethylamino)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)am-
ino)quinazolin-8-yl)phenyl)but-2-enamide [1136]
(E)-4-(dimethylamino)-N-(3-(2-((6-(piperidin-1-yl)pyridin-3-yl)amino)quin-
azolin-8-yl)phenyl)but-2-enamide [1137]
(E)-N-(3-(2-((6-((1-acetylazetidin-3-yl)amino)pyridin-3-yl)amino)quinazol-
in-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [1138]
(E)-4-(dimethylamino)-N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)-
pyridin-3-yl)amino)quinazolin-8-yl)phenyl)but-2-enamide [1139]
(E)-4-(dimethylamino)-N-(3-(2-((6-((1-methylpiperidin-4-yl)amino)pyridin--
3-yl)amino)quinazolin-8-yl)phenyl)but-2-enamide [1140]
(E)-4-(dimethylamino)-N-(3-(2-((6-(pyrrolidin-3-ylamino)pyridin-3-yl)amin-
o)quinazolin-8-yl)phenyl)but-2-enamide [1141]
(E)-4-(dimethylamino)-N-(3-(2-((6-(2-(hydroxymethyl)morpholino)pyridin-3--
yl)amino)quinazolin-8-yl)phenyl)but-2-enamide [1142]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)propiolam-
ide [1143]
N-(3-(2-((6-(piperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)-
phenyl)propiolamide [1144]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)propiolamide [1145]
N-(3-(2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)amino)qui-
nazolin-8-yl)phenyl)propiolamide [1146]
(E)-N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)but-2-
-enamide [1147]
(Z)--N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)but--
2-enamide [1148]
(Z)-3-fluoro-N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phe-
nyl)but-2-enamide [1149]
(E)-3-fluoro-N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phe-
nyl)but-2-enamide [1150]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)methacryl-
amide [1151]
N-(3-(2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)ethenesul-
fonamide [1152]
(E)-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-y-
l)phenyl)but-2-enamide [1153]
(Z)--N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8--
yl)phenyl)but-2-enamide [1154]
(Z)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1155]
(E)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1156]
(Z)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)phenyl)but-2-enamide [1157]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)methacrylamide [1158]
3,3-difluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1159]
3-methyl-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)but-2-enamide [1160]
(E)-3-fluoro-N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quina-
zolin-8-yl)phenyl)but-2-enamide [1161]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)ethenesulfonamide [1162]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N2-(6-morpholinopyridin-3-yl)quina-
zoline-2,4-diamine [1163]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N2-(6-(piperazin-1-yl)pyridin-3-yl-
)quinazoline-2,4-diamine [1164]
N2-(6-morpholinopyridin-3-yl)-8-(pyridin-2-yl)quinazoline-2,4-diamine
[1165]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(6-morpholinopyridi-
n-3-yl)quinazoline-2,4-diamine [1166]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N2-(6-morpholinopyridin-3-yl)quina-
zoline-2,4-diamine [1167]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(6-morpholinopyridin-3-yl)-
quinazoline-2,4-diamine [1168]
N2-(6-(piperazin-1-yl)pyridin-3-yl)-8-(pyridin-2-yl)quinazoline-2,4-diami-
ne [1169]
8-(2-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyr-
imidine-2,4-diamine [1170]
8-(5-chloro-2-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyr-
imidine-2,4-diamine [1171]
8-(5-chloro-2-fluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-
-d]pyrimidine-2,4-diamine [1172]
8-(3-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidine-2-
,4-diamine [1173]
8-(2,6-difluorophenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4-d]pyrimidi-
ne-2,4-diamine [1174]
8-(2,6-difluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]py-
rimidine-2,4-diamine [1175]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)py-
rido[3,4-d]pyrimidine-2,4-diamine [1176]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(6-morpholinopyridin-3--
yl)pyrido[3,4-d]pyrimidine-2,4-diamine [1177]
8-(3-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4--
d]pyrimidine-2,4-diamine [1178]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)pyrido-
[3,4-d]pyrimidine-2,4-diamine [1179]
8-(4-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)pyrido[3,4--
d]pyrimidine-2,4-diamine [1180]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)pyrido-
[3,4-d]pyrimidine-2,4-diamine [1181]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)py-
rido[3,4-d]pyrimidine-2,4-diamine [1182]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(6-morpholinopyridin-3--
yl)pyrido[3,4-d]pyrimidine-2,4-diamine [1183]
8-(2-fluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)pyrido[3,4-d]pyrimi-
dine-2,4-diamine [1184]
N2-(6-(piperazin-1-yl)pyridin-3-yl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidi-
ne-2,4-diamine [1185]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(6-(piperazin-1-yl)pyridin-3-
-yl)pyrido[3,4-d]pyrimidine-2,4-diamine [1186]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido[3,4--
d]pyrimidine-2,4-diamine [1187]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido-
[3,4-d]pyrimidine-2,4-diamine [1188]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido[3,4--
d]pyrimidine-2,4-diamine [1189]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)pyrido-
[3,4-d]pyrimidine-2,4-diamine [1190]
N2-(4-(piperazin-1-yl)phenyl)-8-(pyridin-2-yl)pyrido[3,4-d]pyrimidine-2,4-
-diamine [1191]
8-(4-(2-morpholinoethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)quinazoline-
-2,4-diamine [1192]
8-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)quinaz-
oline-2,4-diamine [1193]
8-(5-(2-morpholinoethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)quinazoline-
-2,4-diamine [1194]
8-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-N2-(4-morpholinophenyl)quinaz-
oline-2,4-diamine [1195]
N2-(4-(piperazin-1-yl)phenyl)-8-(pyridin-2-yl)quinazoline-2,4-diamine
[1196]
8-(2-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)quinazoline-2,4-di-
amine [1197]
8-(5-chloro-2-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)quinazoline-2,4--
diamine [1198]
8-(3-fluorophenyl)-N2-(6-morpholinopyridin-3-yl)quinazoline-2,4-diamine
[1199]
8-(3-fluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)quinazoline--
2,4-diamine [1200]
8-(2,6-difluorophenyl)-N2-(6-morpholinopyridin-3-yl)quinazoline-2,4-diami-
ne [1201]
8-(5-chloro-2-fluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)q-
uinazoline-2,4-diamine [1202]
8-(2,6-difluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)quinazoline-2,4-
-diamine [1203]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)qu-
inazoline-2,4-diamine [1204]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(6-(piperazin-1-yl)pyridin-3-
-yl)quinazoline-2,4-diamine [1205]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(6-morpholinopyridin-3--
yl)quinazoline-2,4-diamine [1206]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(6-(piperazin-1-yl)pyri-
din-3-yl)quinazoline-2,4-diamine [1207]
8-(3-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)quinazoline-
-2,4-diamine [1208]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)quinaz-
oline-2,4-diamine [1209]
8-(4-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)quinazoline-
-2,4-diamine [1210]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)quinaz-
oline-2,4-diamine [1211]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(6-morpholinopyridin-3-yl)qu-
inazoline-2,4-diamine [1212]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(6-morpholinopyridin-3--
yl)quinazoline-2,4-diamine [1213]
8-(2-fluorophenyl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)quinazoline-2,4-dia-
mine [1214]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(6-(piperazin-1-yl)pyridin-3-
-yl)quinazoline-2,4-diamine [1215]
8-(2-fluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidine-2,4-dia-
mine [1216]
8-(5-chloro-2-fluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-
e-2,4-diamine [1217]
8-(3-fluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidine-2,4-dia-
mine [1218]
8-(2,6-difluorophenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidine-2,4-
-diamine [1219]
8-(5-chloro-2-fluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyr-
imidine-2,4-diamine [1220]
8-(2,6-difluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidi-
ne-2,4-diamine [1221]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3-
,4-d]pyrimidine-2,4-diamine [1222]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(4-(piperazin-1-yl)phenyl)py-
rido[3,4-d]pyrimidine-2,4-diamine [1223]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-morpholinophenyl)pyr-
ido[3,4-d]pyrimidine-2,4-diamine [1224]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-(piperazin-1-yl)phen-
yl)pyrido[3,4-d]pyrimidine-2,4-diamine [1225]
8-(3-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyri-
midine-2,4-diamine [1226]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d-
]pyrimidine-2,4-diamine [1227]
8-(4-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d]pyri-
midine-2,4-diamine [1228]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3,4-d-
]pyrimidine-2,4-diamine [1229]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)pyrido[3-
,4-d]pyrimidine-2,4-diamine [1230]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-morpholinophenyl)pyr-
ido[3,4-d]pyrimidine-2,4-diamine [1231]
8-(2-fluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)pyrido[3,4-d]pyrimidine-2-
,4-diamine [1232]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(4-(piperazin-1-yl)phenyl)py-
rido[3,4-d]pyrimidine-2,4-diamine [1233]
8-(2-fluorophenyl)-N2-(4-morpholinophenyl)quinazoline-2,4-diamine
[1234]
8-(2-fluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)quinazoline-2,4-diamine
[1235]
8-(5-chloro-2-fluorophenyl)-N2-(4-morpholinophenyl)quinazoline-2,4-
-diamine [1236]
8-(5-chloro-2-fluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)quinazoline-2,4--
diamine [1237]
8-(3-fluorophenyl)-N2-(4-morpholinophenyl)quinazoline-2,4-diamine
[1238]
8-(2,6-difluorophenyl)-N2-(4-morpholinophenyl)quinazoline-2,4-diamine
[1239]
8-(2,6-difluorophenyl)-N2-(4-(piperazin-1-yl)phenyl)quinazoline-2,-
4-diamine [1240]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)quinazol-
ine-2,4-diamine [1241]
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N2-(4-(piperazin-1-yl)phenyl)qu-
inazoline-2,4-diamine [1242]
8-(5-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-morpholinophenyl)qui-
nazoline-2,4-diamine [1243]
8-(3-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)quinazoline-2,4-d-
iamine [1244]
8-(3-(2-(dimethylamino)ethoxy)phenyl)-N2-(4-morpholinophenyl)quinazoline--
2,4-diamine [1245]
8-(4-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)quinazoline-2,4-d-
iamine [1246]
8-(4-(2-(dimethylamino)ethoxy)phenyl)-N2-(4-morpholinophenyl)quinazoline--
2,4-diamine [1247]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(4-morpholinophenyl)quinazol-
ine-2,4-diamine [1248]
8-(4-(2-(dimethylamino)ethoxy)-2-fluorophenyl)-N2-(4-morpholinophenyl)qui-
nazoline-2,4-diamine [1249]
8-(2-fluoro-4-(2-morpholinoethoxy)phenyl)-N2-(4-(piperazin-1-yl)phenyl)qu-
inazoline-2,4-diamine [1250]
(E)-N-(3-(4-amino-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)-4--
(dimethylamino)but-2-enamide [1251]
N-(3-(4-amino-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acrylam-
ide [1252]
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1253]
(E)-N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-
-yl)phenyl)-4-(dimethylamino)but-2-enamide [1254]
N-(3-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1255]
(E)-N-(3-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)ami-
no)quinazolin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [1256]
N-(3-(4-amino-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)propiol-
amide [1257]
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)propiolamide [1258]
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)ethenesulfonamide [1259]
N-(3-(4-amino-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)methacr-
ylamide [1260]
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)methacrylamide [1261]
(E)-N-(2-(4-amino-2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4--
yl)-4-(dimethylamino)but-2-enamide [1262]
N-(2-(4-amino-2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)a-
crylamide [1263]
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)acrylamide [1264]
(E)-N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-
-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide [1265]
N-(2-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)q-
uinazolin-8-yl)pyridin-4-yl)acrylamide [1266]
(E)-N-(2-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)ami-
no)quinazolin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide
[1267]
N-(2-(4-amino-2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-
-4-yl)propiolamide [1268]
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)propiolamide [1269]
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
pyridin-4-yl)ethenesulfonamide [1270]
(E)-N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phen-
yl)-4-(dimethylamino)but-2-enamide [1271]
N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)a-
crylamide [1272]
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [1273]
(E)-N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinaz-
olin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [1274]
N-(3-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1275]
(E)-N-(3-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3--
yl)amino)quinazolin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide
[1276]
N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)phenyl)p-
ropiolamide [1277]
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)propiolamide [1278]
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)ethenesulfonamide [1279]
(E)-N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)phenyl)-4-(dimethylamino)but-2-enamide [1280]
N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)ph-
enyl)acrylamide [1281]
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)acrylamide [1282]
(E)-N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [1283]
N-(3-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1284]
(E)-N-(3-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)ami-
no)pyrido[3,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide
[1285]
N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin--
8-yl)phenyl)propiolamide [1286]
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)propiolamide [1287]
N-(3-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)ethenesulfonamide [1288]
(E)-N-(2-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-y-
l)pyridin-4-yl)-4-(dimethylamino)but-2-enamide [1289]
N-(2-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)py-
ridin-4-yl)acrylamide [1290]
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)acrylamide [1291]
(E)-N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d-
]pyrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide [1292]
N-(2-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [1293]
(E)-N-(2-(4-amino-2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)ami-
no)pyrido[3,4-d]pyrimidin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamid-
e [1294]
N-(2-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-
-8-yl)pyridin-4-yl)propiolamide [1295]
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)propiolamide [1296]
N-(2-(4-amino-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)pyridin-4-yl)ethenesulfonamide [1297]
(E)-N-(2-(4-amino-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyri-
din-4-yl)-4-(dimethylamino)but-2-enamide [1298]
N-(2-(4-amino-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)pyridin--
4-yl)acrylamide [1299]
N-(2-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)acrylamide [1300]
(E)-N-(2-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinaz-
olin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide [1301]
N-(2-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)a-
mino)quinazolin-8-yl)pyridin-4-yl)acrylamide [1302]
(E)-N-(2-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3--
yl)amino)quinazolin-8-yl)pyridin-4-yl)-4-(dimethylamino)but-2-enamide
[1303]
N-(2-(4-amino-2-((6-morpholinopyridin-3-yl)amino)quinazolin-8-yl)p-
yridin-4-yl)propiolamide [1304]
N-(2-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)propiolamide [1305]
N-(2-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)pyridin-4-yl)ethenesulfonamide [1306]
(E)-N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimid-
in-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [1307]
N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)acrylamide [1308]
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)acrylamide [1309]
N-(2-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)pyridin-4-yl)acrylamide [1310]
(E)-N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido-
[3,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamide [1311]
N-(3-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3-yl)a-
mino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1312]
(E)-N-(3-(4-amino-2-((6-((1-(2-fluoroethyl)azetidin-3-yl)amino)pyridin-3--
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)-4-(dimethylamino)but-2-enamid-
e [1313]
N-(3-(4-amino-2-((6-morpholinopyridin-3-yl)amino)pyrido[3,4-d]pyr-
imidin-8-yl)phenyl)propiolamide [1314]
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)propiolamide [1315]
N-(3-(4-amino-2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrido[3,4-
-d]pyrimidin-8-yl)phenyl)ethenesulfonamide tert-butyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-3-methoxyphenyl)piper-
azine-1-carboxylate [1316]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)pyrido[3,2-d]pyrimidin-8-
-yl)phenyl)acrylamide [1317]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-
-yl)phenyl)acrylamide [1318]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrido[4,3-d]p-
yrimidin-8-yl)phenyl)acrylamide [1319]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide [1320]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)pyrido[3,2-d]p-
yrimidin-8-yl)phenyl)acrylamide [1321]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1322]
N-(3-(7-(hydroxymethyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1323]
8-(3-acrylamidophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazo-
line-7-carboxamide [1324]
N-(3-(7-(2-amino-2-oxoethyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1325]
N-(3-(7-acetamido-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide [1326]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-fluoroquinazolin-8-yl-
)phenyl)acrylamide [1327]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-chloroquinazolin-8-yl-
)phenyl)acrylamide [1328]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-(hydroxymethyl)quinaz-
olin-8-yl)phenyl)acrylamide [1329]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-(2-amino-2-oxoethyl)q-
uinazolin-8-yl)phenyl)acrylamide [1330]
2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-8-(3-acrylamidophenyl)quinazo-
line-7-carboxamide [1331]
N-(3-(7-acetamido-2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide [1332]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide [1333]
N-(3-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1334]
N-(3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1335]
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-methylpiperazin-1-y-
l)benzamide [1336]
N-(3-(2-((2-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1337]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-fluorophenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1338]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-chlorophenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1339]
5-(4-acetylpiperazin-1-yl)-2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amin-
o)benzamide [1340]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)-2-(hydroxymethyl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1341]
N-(2-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1342]
N-(2-chloro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1343]
N-(2-(hydroxymethyl)-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1344]
N-(2-methoxy-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1345]
N-(2-(fluoromethyl)-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide [1346]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-fluor-
ophenyl)acrylamide [1347]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-chlor-
ophenyl)acrylamide [1348]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-(hydr-
oxymethyl)phenyl)acrylamide [1349]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-(fluo-
romethyl)phenyl)acrylamide [1350]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-metho-
xyphenyl)acrylamide [1351]
N-(6-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-2-yl)acrylamid-
e [1352]
N-(6-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
2-yl)acrylamide [1353]
N-(6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
2-yl)acrylamide [1354]
N-(6-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
2-yl)acrylamide [1355]
N-(4-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-2-yl)acrylamid-
e [1356]
N-(4-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
2-yl)acrylamide [1357]
N-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
2-yl)acrylamide [1358]
N-(4-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
2-yl)acrylamide [1359]
N-(5-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-3-yl)acrylamid-
e [1360]
N-(5-(2-((4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
3-yl)acrylamide [1361]
N-(5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
3-yl)acrylamide [1362]
N-(5-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
3-yl)acrylamide [1363]
N-(2-(2-((2-chloro-4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)-
acrylamide [1364]
N-(2-(2-((2-chloro-4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin-
-4-yl)acrylamide [1365]
N-(2-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [1366]
N-(2-(2-((4-(4-acetylpiperazin-1-yl)-2-chlorophenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [1367]
N-(2-(2-((2-fluoro-4-morpholinophenyl)amino)quinazolin-8-yl)pyridin-4-yl)-
acrylamide [1368]
N-(2-(2-((2-fluoro-4-(piperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin-
-4-yl)acrylamide [1369]
N-(2-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [1370]
N-(2-(2-((4-(4-acetylpiperazin-1-yl)-2-fluorophenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [1371]
2-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-yl)amino)-5-morpholinobenzam-
ide [1372]
2-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-yl)amino)-5-(piper-
azin-1-yl)benzamide [1373]
2-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-yl)amino)-5-(4-methylpiperaz-
in-1-yl)benzamide [1374]
5-(4-acetylpiperazin-1-yl)-2-((8-(4-acrylamidopyridin-2-yl)quinazolin-2-y-
l)amino)benzamide [1375]
N-(2-(2-((2-(hydroxymethyl)-4-morpholinophenyl)amino)quinazolin-8-yl)pyri-
din-4-yl)acrylamide [1376]
N-(2-(2-((2-(hydroxymethyl)-4-(piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-4-yl)acrylamide [1377]
N-(2-(2-((2-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [1378]
N-(2-(2-((4-(4-acetylpiperazin-1-yl)-2-(hydroxymethyl)phenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [1379]
N-(2-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-fluoroquinaz-
olin-8-yl)pyridin-4-yl)acrylamide [1380]
N-(2-(7-chloro-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [1381]
N-(2-(7-fluoro-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-4-yl)acrylamide [1382]
N-(3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-fluoroquinaz-
olin-8-yl)phenyl)acrylamide [1383]
N-(3-(7-chloro-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1384]
N-(2-(7-(2-amino-2-oxoethyl)-2-((2-chloro-4-(4-methylpiperazin-1-yl)pheny-
l)amino)quinazolin-8-yl)pyridin-4-yl)acrylamide [1385]
N-(2-(7-(2-amino-2-oxoethyl)-2-((2-fluoro-4-(4-methylpiperazin-1-yl)pheny-
l)amino)quinazolin-8-yl)pyridin-4-yl)acrylamide [1386]
N-(2-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-(hydroxymeth-
yl)quinazolin-8-yl)pyridin-4-yl)acrylamide [1387]
N-(2-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-(hydroxymeth-
yl)quinazolin-8-yl)pyridin-4-yl)acrylamide [1388]
8-(4-acrylamidopyridin-2-yl)-2-((2-chloro-4-(4-methylpiperazin-1-yl)pheny-
l)amino)quinazoline-7-carboxamide [1389]
8-(4-acrylamidopyridin-2-yl)-2-((2-fluoro-4-(4-methylpiperazin-1-yl)pheny-
l)amino)quinazoline-7-carboxamide [1390]
N-(3-(7-fluoro-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1391]
N-(3-(7-(2-amino-2-oxoethyl)-2-((2-chloro-4-(4-methylpiperazin-1-yl)pheny-
l)amino)quinazolin-8-yl)phenyl)acrylamide [1392]
N-(3-(7-(2-amino-2-oxo
ethyl)-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1393]
N-(3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-(hydroxymeth-
yl)quinazolin-8-yl)phenyl)acrylamide [1394]
N-(3-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-(hydroxymeth-
yl)quinazolin-8-yl)phenyl)acrylamide [1395]
8-(3-acrylamidophenyl)-2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amin-
o)quinazoline-7-carboxamide [1396]
8-(3-acrylamidophenyl)-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amin-
o)quinazoline-7-carboxamide [1397]
N-(3-(2-((4-(4-methylpiperazin-1-yl)oxazol-2-yl)amino)quinazolin-8-yl)phe-
nyl)acrylamide [1398]
N-(3-(2-((4-(4-methylpiperazin-1-yl)thiazol-2-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [1399]
N-(3-(2-((4-(4-methylpiperazin-1-yl)thiophen-2-yl)amino)quinazolin-8-yl)p-
henyl)acrylamide [1400]
N-(3-(2-((4-(4-methylpiperazin-1-yl)-1H-imidazol-2-yl)amino)quinazolin-8--
yl)phenyl)acrylamide [1401]
N-(3-(2-((2-(4-methylpiperazin-1-yl)-1H-imidazol-5-yl)amino)quinazolin-8--
yl)phenyl)acrylamide [1402]
N-(3-(2-((4-methoxy-3-(4-methylpiperazin-1-yl)-1H-pyrazol-5-yl)amino)quin-
azolin-8-yl)phenyl)acrylamide [1403]
N-(3-(2-((3-(4-methylpiperazin-1-yl)isoxazol-5-yl)amino)quinazolin-8-yl)p-
henyl)acrylamide [1404]
N-(3-(2-((5-(4-methylpiperazin-1-yl)pyrimidin-2-yl)amino)quinazolin-8-yl)-
phenyl)acrylamide
[1405]
N-(3-(2-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1406]
N-(3-(2-((2-(4-methylpiperazin-1-yl)thiazol-5-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [1407]
N-(3-(2-((5-(4-methylpiperazin-1-yl)thiophen-2-yl)amino)quinazolin-8-yl)p-
henyl)acrylamide [1408]
N-(5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)oxazol-2-
-yl)acrylamide [1409]
N-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-imid-
azol-2-yl)acrylamide [1410]
N-(1-methyl-5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)-1H-imidazol-2-yl)acrylamide [1411]
N-(2-(2-(4-(4-methylpiperazin-1-yl)phenylamino)quinazolin-8-yl)pyrimidin--
4-yl)acrylamide [1412]
N-(6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyrimidi-
n-4-yl)acrylamide [1413]
N-(5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)isoxazol-
-3-yl)acrylamide [1414]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyra-
zol-5-yl)acrylamide [1415]
N-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)thiazol--
5-yl)acrylamide [1416]
N-(5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)thiazol--
2-yl)acrylamide [1417]
N-(5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)thiophen-
-2-yl)acrylamide [1418]
N-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)thiophen-
-2-yl)acrylamide [1419]
1-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)morpholi-
no)prop-2-en-1-one [1420]
(R)-1-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)morp-
holino)prop-2-en-1-one [1421]
(S)-1-(2-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)morp-
holino)prop-2-en-1-one [1422]
1-(2-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)mo-
rpholino)prop-2-en-1-one [1423]
1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)piperidi-
n-1-yl)prop-2-en-1-one [1424]
(R)-1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pipe-
ridin-1-yl)prop-2-en-1-one [1425]
(S)-1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pipe-
ridin-1-yl)prop-2-en-1-one [1426]
1-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)pi-
peridin-1-yl)prop-2-en-1-one [1427]
(R)-1-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-y-
l)piperidin-1-yl)prop-2-en-1-one [1428]
(S)-1-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-y-
l)piperidin-1-yl)prop-2-en-1-one [1429]
1-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)piperidi-
n-1-yl)prop-2-en-1-one [1430]
N-(1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)piperidi-
n-4-yl)acrylamide [1431]
1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyrrolid-
in-1-yl)prop-2-en-1-one [1432]
(R)-1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyrr-
olidin-1-yl)prop-2-en-1-one [1433]
(S)-1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyrr-
olidin-1-yl)prop-2-en-1-one [1434]
1-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
rrolidin-1-yl)prop-2-en-1-one [1435]
(S)-1-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-y-
l)pyrrolidin-1-yl)prop-2-en-1-one [1436]
(R)-1-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-y-
l)pyrrolidin-1-yl)prop-2-en-1-one [1437]
N-(1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyrrolid-
in-3-yl)acrylamide [1438]
N-(1-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)piperidi-
n-3-yl)acrylamide [1439]
N-(1-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)pi-
peridin-3-yl)acrylamide [1440]
1-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)piperazi-
n-1-yl)prop-2-en-1-one [1441]
N-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyrimidi-
n-2-yl)acrylamide [1442]
N-(6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyrazin--
2-yl)acrylamide [1443]
N-(3-(2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [1444]
N-(2-fluoro-3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1445]
N-(2-chloro-3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1446]
N-(6-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-2-yl)acrylamide [1447]
N-(4-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-2-yl)acrylamide [1448]
N-(5-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-3-yl)acrylamide [1449] tert-butyl
4-(4-((8-(2-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate [1450] tert-butyl
4-(4-((8-(2-chlorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate [1451] tert-butyl
4-(4-((8-(3-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate [1452] tert-butyl
4-(4-((8-(5-chloro-2-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-
-1-carboxylate [1453] tert-butyl
4-(4-((8-(3-chlorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate [1454] tert-butyl
4-(4-((8-phenylquinazolin-2-yl)amino)phenyl)piperazine-1-carboxylate
[1455] tert-butyl
4-(4-((8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)quinazolin-2-yl)amino)phe-
nyl)piperazine-1-carboxylate [1456]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)p-
ropionamide [1457]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-methylquinazolin-8-yl-
)phenyl)acrylamide [1458]
N-(3-(2-((6-(4-acetylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [1459]
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-fluoro-
phenyl)acrylamide [1460]
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)propionamide [1461]
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phen-
yl)-4-(dimethylamino)but-2-enamide [1462]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1463]
N-(3-(2-((4-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1464]
N-(5-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-3-yl)acrylamide [1465]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1466]
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-c-
hlorophenyl)-4-(dimethylamino)but-2-enamide [1467]
N-(2-fluoro-3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1468]
(E)-4-(dimethylamino)-N-(2-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl-
)amino)quinazolin-8-yl)phenyl)but-2-enamide [1469]
N-(3-(2-((4-((2-fluoroethyl)(methyl)amino)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [1470]
N-(2-fluoro-3-(2-((4-((2-fluoroethyl)(methyl)amino)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1471]
N-(3-(2-((4-((2-hydroxyethyl)amino)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide [1472]
N-(4-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1473]
N-(2-cyano-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [1474]
N-(3-(2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1475]
1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-5,6-dih-
ydropyridin-1(2H)-yl)prop-2-en-1-one [1476]
N-(3-(2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1477]
N-(4-chloro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1478]
N-(3-(2-((3-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [1479]
N-(3-(2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1480] methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-ca-
rboxylate [1481]
N-(3-(2-((4-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1482]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)oxy)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1483]
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide [1484]
N-(2-fluoro-3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1485]
N-(3-(2-((5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1486]
N-(3-(2-((4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide [1487]
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-N-methylpipera-
zine-1-carboxamide [1488]
N-(3-(2-((4-(4-propionylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pheny-
l)acrylamide [1489]
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-methylpiperazin-1-y-
l)benzamide [1490]
N-(3-(2-((5-cyano-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide [1491]
N-(3-(7-fluoro-2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpipera-
zine-2-carboxylate [1492]
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpipera-
zine-2-carboxylic acid [1493]
N-(3-(2-((4-(2-oxooxazolidin-3-yl)phenyl)amino)quinazolin-8-yl)phenyl)acr-
ylamide [1494]
N-(3-(2-((4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1495]
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpipera-
zine-2-carboxamide [1496]
N-(3-(2-((4-(1H-imidazol-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylam-
ide [1497]
N-(3-(2-((4-(3-oxomorpholino)phenyl)amino)quinazolin-8-yl)pheny-
l)acrylamide [1498]
N-(3-(2-((4-(2-oxopyrrolidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acr-
ylamide [1499]
N-(3-(2-((4-(2-oxoimidazolidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide [1500]
N-(3-(2-((4-(3-hydroxypyrrolidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide [1501]
N-(3-(2-((4-((1-(2-hydroxyethyl)azetidin-3-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1502]
N-(4-cyano-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide methyl
2-acrylamido-6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)benzoate [1503]
N-(3-(2-((4-(1,4-oxazepan-4-yl)phenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide methyl
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-methylpiperazin-1-y-
l)benzoate [1504]
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1505]
N-(3-(2-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [1506]
N-(3-(2-((4-(2-methoxyethoxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de [1507]
N-(3-(2-((4-(2-hydroxyethoxy)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide [1508]
N-(3-(2-((4-(2-(azetidin-1-yl)ethoxy)phenyl)amino)quinazolin-8-yl)phenyl)-
acrylamide [1509]
N-(3-(2-((4-(2-(dimethylamino)ethoxy)phenyl)amino)quinazolin-8-yl)phenyl)-
acrylamide [1510]
N-(3-(2-((4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide [1511]
N-(3-(2-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide [1512]
(S)--N-(3-(2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [1513]
(S)--N-(3-(2-((4-((tetrahydrofuran-3-yl)amino)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1514]
(R)--N-(3-(2-((4-((tetrahydrofuran-3-yl)amino)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1515]
N-(3-(2-((4-(4-methyl-3-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide [1516]
N-(3-(2-((4-(3-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acry-
lamide [1517]
(R)--N-(3-(2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide [1518]
N-(3-(2-((4-((1-acetylpiperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide [1519]
(S)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide [1520]
N-(3-(2-((4-((1-acetylazetidin-3-yl)oxy)phenyl)amino)quinazolin-8-yl)phen-
yl)acrylamide [1521]
(R)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide [1522]
N-(3-(2-((4-((1-acetylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide [1523]
N-(3-(2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide [1524]
(S)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1525]
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1526]
(R)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1527]
(R)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1528]
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide [1529]
(R)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide [1530]
N-(3-(2-((4-((2-fluoroethyl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acr-
ylamide [1531]
N-(3-(2-((4-((2,2-difluoroethyl)amino)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide [1532]
N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide [1533]
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1534]
N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1535]
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-yl)amino)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide [1536]
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1537]
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide [1538]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1539]
N-(3-(2-((3,5-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1540]
N-(3-(2-((2,6-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1541]
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1542]
N-(3-(2-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1543]
N-(3-(2-((2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1544]
N-(3-(2-((3,5-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1545]
N-(3-(2-((2,3-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1546]
N-(3-(2-((2,6-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1547]
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1548]
N-(3-(2-((2-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1549]
N-(3-(2-((2-cyano-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acryl amide [1550]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxyphenyl)amino)quin-
azolin-8-yl)phenyl)acryl amide
[1551]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-2-(hydroxymethyl)ph-
enyl)amino)quinazolin-8-yl)phenyl)acrylamide [1552]
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-(2-hydroxyethyl)pip-
erazin-1-yl)benzamide [1553] N-(3-(2-((2-fluoro-4-(4-(2-fluoro
ethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acryl
amide [1554]
N-(3-(2-((2-chloro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino-
)quinazolin-8-yl)phenyl)acryl amide [1555]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)-2-methoxyphenyl)amino)quina-
zolin-8-yl)phenyl)acryl amide [1556]
N-(3-(2-((2-cyano-4-(4-(2-fluoro
ethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acryl
amide [1557]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)phe-
nyl)amino)quinazolin-8-yl)phenyl)acryl amide [1558]
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-(2-fluoro
ethyl)piperazin-1-yl)benzamide [1559]
N-(3-(2-((2-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1560]
N-(3-(2-((2-chloro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1561]
N-(3-(2-((2-cyano-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1562]
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-methoxyphenyl)-
amino)quinazolin-8-yl)phenyl)acrylamide [1563]
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-(2-hydroxy-2-methyl-
propyl)piperazin-1-yl)benzamide [1564]
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-(hydroxymethyl-
)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide [1565]
N-(3-(2-((2-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acryl amide [1566]
N-(3-(2-((2-chloro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [1567]
N-(3-(2-((2-cyano-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1568]
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-(2-hydroxypropyl)pi-
perazin-1-yl)benzamide [1569]
N-(3-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)-2-methoxyphenyl)amino)qui-
nazolin-8-yl)phenyl)acrylamide [1570]
N-(3-(2-((2-(hydroxymethyl)-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1571]
N-(3-(2-((3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1572]
N-(3-(2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1573]
N-(3-(2-((3-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1574]
N-(3-(2-((3-cyano-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1575]
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-(2-hydroxyethyl)pip-
erazin-1-yl)benzamide [1576]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(hydroxymethyl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1577]
N-(3-(2-((3-fluoro-4-(4-(2-fluoro
ethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide
[1578]
N-(3-(2-((3-chloro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino-
)quinazolin-8-yl)phenyl)acrylamide [1579]
N-(3-(2-((3-cyano-4-(4-(2-fluoro
ethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide
[1580]
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-(2-fluoroeth-
yl)piperazin-1-yl)benzamide [1581]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)-3-(hydroxymethyl)phenyl)ami-
no)quinazolin-8-yl)phenyl)acrylamide [1582]
N-(3-(2-((3-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1583]
N-(3-(2-((3-chloro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1584]
N-(3-(2-((3-cyano-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1585]
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-(2-hydroxy-2-methyl-
propyl)piperazin-1-yl)benzamide [1586]
N-(3-(2-((4-(4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-3-(hydroxymet-
hyl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide [1587]
N-(3-(2-((3-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acryl amide [1588]
N-(3-(2-((3-chloro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acryl amide [1589]
N-(3-(2-((3-cyano-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acryl amide [1590]
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-(2-hydroxypropyl)pi-
perazin-1-yl)benzamide [1591]
N-(3-(2-((3-(hydroxymethyl)-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1592]
(S)--N-(3-(2-((3-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino-
)quinazolin-8-yl)phenyl)acryl amide [1593]
(R)--N-(3-(2-((3-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino-
)quinazolin-8-yl)phenyl)acryl amide [1594]
N-(3-(2-((3-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acryl amide [1595]
N-(3-(2-((3-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acryl amide [1596]
N-(3-(2-((2-fluoro-4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)-
quinazolin-8-yl)phenyl)acryl amide [1597]
N-(3-(2-((2-fluoro-4-((1-(2-fluoro
ethyl)piperidin-4-yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acryl
amide [1598]
N-(3-(2-((3-fluoro-4-((1-(2-hydroxyethyl)piperidin-4-yl)amino)phen-
yl)amino)quinazolin-8-yl)phenyl)acryl amide [1599]
N-(3-(2-((3-fluoro-4-((1-(2-fluoro
ethyl)piperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acryl
amide [1600]
N-(3-(2-((4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1601]
N-(3-(2-((4-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1602]
N-(3-(2-((4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1603]
N-(3-(2-((4-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1604]
N-(3-(2-((4-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide [1605]
N-(3-(2-((4-(((3S,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide [1606]
N-(3-(2-((4-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide [1607]
N-(3-(2-((4-(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide [1608]
N-(3-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1609]
N-(3-(2-((5-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1610]
N-(4-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-2-yl)acrylamide [1611]
N-(5-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-3-yl)acrylamide [1612]
N-(2-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-4-yl)acrylamide [1613]
N-(6-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-2-yl)acrylamide [1614]
N-(4-fluoro-3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1615]
N-(2-fluoro-3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1616]
N-(4-fluoro-3-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [1617]
N-(5-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-3-yl)acrylamide [1618]
N-(4-(2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-2-yl)acrylamide [1619]
N-(4-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-2-yl)acrylamide [1620]
N-(4-(2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-2-yl)acrylamide [1621]
N-(5-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-3-yl)acrylamide [1622]
N-(5-(2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-3-yl)acrylamide [1623]
N-(4-fluoro-3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1624]
N-(4-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-2-yl)acrylamide [1625]
N-(4-(2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-2-yl)acrylamide [1626]
N-(5-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-3-yl)acrylamide [1627]
N-(5-(2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-3-yl)acrylamide [1628]
N-(3-(2-((6-(4-(2-fluoroethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1629]
N-(3-(2-((5-(4-(2-fluoroethyl)piperazin-1-yl)pyridin-2-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide [1630]
N-(4-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-2-yl)acrylamide [1631]
N-(2-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-4-yl)acrylamide [1632]
N-(6-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-2-yl)acrylamide [1633]
N-(4-fluoro-3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1634]
N-(4-fluoro-3-(2-((6-(4-(2-fluoroethyl)piperazin-1-yl)pyridin-3-yl)amino)-
quinazolin-8-yl)phenyl)acrylamide [1635]
N-(5-(2-((6-(4-(2-fluoroethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)pyridin-3-yl)acrylamide [1636]
N-(4-(2-((6-(4-(2-fluoroethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)pyridin-2-yl)acrylamide [1637]
N-(4-(2-((2-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-2-yl)acrylamide [1638]
N-(4-(2-((3-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-2-yl)acrylamide [1639]
N-(5-(2-((2-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-3-yl)acrylamide [1640]
N-(5-(2-((3-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-3-yl)acrylamide [1641]
N-(3-(2-((6-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyridin-3-yl)amin-
o)quinazolin-8-yl)phenyl)acrylamide [1642]
N-(3-(2-((5-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyridin-2-yl)amin-
o)quinazolin-8-yl)phenyl)acrylamide [1643]
N-(4-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-2-yl)acrylamide [1644]
N-(5-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-3-yl)acrylamide [1645]
N-(2-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-4-yl)acrylamide [1646]
N-(6-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-2-yl)acrylamide [1647]
N-(4-fluoro-3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1648]
N-(2-fluoro-3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1649]
N-(4-fluoro-3-(2-((6-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyridin--
3-yl)amino)quinazolin-8-yl)phenyl)acrylamide [1650]
N-(5-(2-((6-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyridin-3-yl)amin-
o)quinazolin-8-yl)pyridin-3-yl)acrylamide [1651]
N-(4-(2-((6-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)pyridin-3-yl)amin-
o)quinazolin-8-yl)pyridin-2-yl)acrylamide [1652]
N-(4-(2-((2-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1653]
N-(4-(2-((3-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1654]
N-(5-(2-((2-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)pyridin-3-yl)acrylamide [1655]
N-(5-(2-((3-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)pyridin-3-yl)acrylamide [1656]
N-(3-(2-((6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)amino)quinazo-
lin-8-yl)phenyl)acrylamide [1657]
N-(3-(2-((5-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-2-yl)amino)quinazo-
lin-8-yl)phenyl)acrylamide [1658]
N-(4-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quinazolin-8--
yl)pyridin-2-yl)acrylamide [1659]
N-(5-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quinazolin-8--
yl)pyridin-3-yl)acrylamide [1660]
N-(2-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quinazolin-8--
yl)pyridin-4-yl)acrylamide [1661]
N-(6-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quinazolin-8--
yl)pyridin-2-yl)acrylamide [1662]
N-(4-fluoro-3-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [1663]
N-(2-fluoro-3-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [1664]
N-(4-fluoro-3-(2-((6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)amin-
o)quinazolin-8-yl)phenyl)acrylamide [1665]
N-(5-(2-((6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)amino)quinazo-
lin-8-yl)pyridin-3-yl)acrylamide [1666]
N-(4-(2-((6-(4-(2-hydroxypropyl)piperazin-1-yl)pyridin-3-yl)amino)quinazo-
lin-8-yl)pyridin-2-yl)acrylamide [1667]
N-(4-(2-((2-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-2-yl)acrylamide [1668]
N-(4-(2-((3-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-2-yl)acrylamide [1669]
N-(5-(2-((2-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-3-yl)acrylamide [1670]
N-(5-(2-((3-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)pyridin-3-yl)acrylamide [1671]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-7-methylquina-
zolin-8-yl)phenyl)acrylamide [1672]
N-(3-(7-fluoro-2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1673]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-7-(hydroxymet-
hyl)quinazolin-8-yl)phenyl)acrylamide [1674]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide [1675]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-7-methylquinaz-
olin-8-yl)phenyl)acrylamide [1676]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-7-(hydroxymeth-
yl)quinazolin-8-yl)phenyl)acrylamide [1677]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)pyrido[3,4-d]py-
rimidin-8-yl)phenyl)acrylamide [1678]
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)-7-m-
ethylquinazolin-8-yl)phenyl)acrylamide [1679]
N-(3-(7-fluoro-2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1680]
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)-7-(-
hydroxymethyl)quinazolin-8-yl)phenyl)acrylamide [1681]
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)pyri-
do[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1682]
N-(3-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-7-methylquin-
azolin-8-yl)phenyl)acrylamide [1683]
N-(3-(7-fluoro-2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [1684]
N-(3-(7-(hydroxymethyl)-2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide
[1685]
N-(3-(2-((4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)pyrido-
[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1686]
N-(4-(7-fluoro-2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1687]
N-(4-(7-fluoro-2-((3-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)ami-
no)quinazolin-8-yl)pyridin-2-yl)acrylamide [1688]
N-(4-(7-fluoro-2-((3-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1689]
N-(4-(7-fluoro-2-((3-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl-
)phenyl)amino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1690]
N-(4-(7-fluoro-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-2-yl)acrylamide [1691]
N-(4-(7-fluoro-2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1692]
N-(4-(7-fluoro-2-((2-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)ami-
no)quinazolin-8-yl)pyridin-2-yl)acrylamide [1693]
N-(4-(7-fluoro-2-((2-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1694]
N-(4-(7-fluoro-2-((2-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl-
)phenyl)amino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1695]
N-(4-(7-fluoro-2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)pyridin-2-yl)acrylamide [1696]
N-(3-(7-fluoro-2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1697]
N-(3-(7-fluoro-2-((3-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)ami-
no)quinazolin-8-yl)phenyl)acrylamide [1698]
N-(3-(7-fluoro-2-((3-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1699]
N-(3-(7-fluoro-2-((3-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl-
)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide [1700]
N-(3-(7-fluoro-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1701]
N-(3-(7-fluoro-2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1702]
N-(3-(7-fluoro-2-((2-fluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)ami-
no)quinazolin-8-yl)phenyl)acrylamide [1703]
N-(3-(7-fluoro-2-((2-fluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1704]
N-(3-(7-fluoro-2-((2-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl-
)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide [1705]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)phenyl)acrylamide [1706]
N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1707]
(R)--N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1708]
(S)--N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide [1709]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide [1710]
N-(3-(2-((3,5-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)phenyl)acrylamide [1711]
N-(3-(2-((2,6-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)phenyl)acrylamide [1712]
N-(3-(2-((2,6-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1713]
N-(3-(2-((3,5-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1714]
N-(3-(2-((2,5-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide [1715]
N-(3-(2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1716]
N-(3-(2-((2-chloro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1717]
N-(3-(2-((2-cyano-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1718]
N-(3-(2-((2-methoxy-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [1719]
N-(3-(2-((2-(hydroxymethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1720]
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-(2-methoxyethyl)pip-
erazin-1-yl)benzamide [1721]
N-(3-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1722]
N-(3-(2-((3-chloro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1723]
N-(3-(2-((3-cyano-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide [1724]
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-(2-methoxyethyl)pip-
erazin-1-yl)benzamide [1725]
N-(3-(2-((3-(hydroxymethyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1726]
N-(3-(2-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1727]
N-(3-(2-((5-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide [1728]
N-(4-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-2-yl)acrylamide [1729]
N-(5-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-3-yl)acrylamide [1730]
N-(2-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-4-yl)acrylamide [1731]
N-(6-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)pyridin-2-yl)acrylamide [1732]
N-(4-fluoro-3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1733]
N-(2-fluoro-3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1734]
N-(4-fluoro-3-(2-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [1735]
N-(5-(2-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-3-yl)acrylamide [1736]
N-(4-(2-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)pyridin-2-yl)acrylamide [1737]
N-(4-(2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-2-yl)acrylamide [1738]
N-(4-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-2-yl)acrylamide [1739]
N-(5-(2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-3-yl)acrylamide [1740]
N-(5-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-3-yl)acrylamide [1741]
N-(4-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-2-yl)acrylamide [1742]
N-(5-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-3-yl)acrylamide [1743]
N-(2-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-4-yl)acrylamide [1744]
N-(6-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-2-yl)acrylamide [1745]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)-4-fluorophenyl)acrylamide [1746]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)-2-fluorophenyl)acrylamide [1747]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)-5-fluorophenyl)acrylamide [1748]
N-(5-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)-2-fluorophenyl)acrylamide [1749]
N-(4-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-2-yl)acrylamide [1750]
N-(5-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-3-yl)acrylamide [1751]
N-(2-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-4-yl)acrylamide [1752]
N-(6-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)pyridin-2-yl)acrylamide [1753]
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)-4-fluorophenyl)acrylamide [1754]
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)-2-fluorophenyl)acrylamide [1755]
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)-5-fluorophenyl)acrylamide [1756]
N-(5-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)-2-fluorophenyl)acrylamide [1757]
N-(4-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-2-yl)acrylamide [1758]
N-(5-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-3-yl)acrylamide [1759]
N-(2-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-4-yl)acrylamide [1760]
N-(6-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)pyridin-2-yl)acrylamide [1761]
N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)-4-fluorophenyl)acrylamide [1762]
N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)-2-fluorophenyl)acrylamide [1763]
N-(4-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1764]
N-(5-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)pyridin-3-yl)acrylamide [1765]
N-(2-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)pyridin-4-yl)acrylamide [1766]
N-(6-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1767]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)-4-fluorophenyl)acrylamide [1768]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)-2-fluorophenyl)acrylamide [1769]
N-(4-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)pyridin-2-yl)acrylamide [1770]
N-(5-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)pyridin-3-yl)acrylamide [1771]
N-(2-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)pyridin-4-yl)acrylamide [1772]
N-(6-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)pyridin-2-yl)acrylamide [1773]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)-4-fluorophenyl)acrylamide [1774]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)-2-fluorophenyl)acrylamide [1775]
N-(4-(2-((2,3-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)pyridin-2-yl)acrylamide [1776]
N-(5-(2-((2,3-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)pyridin-3-yl)acrylamide [1777]
N-(2-(2-((2,3-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)pyridin-4-yl)acrylamide [1778]
N-(6-(2-((2,3-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)pyridin-2-yl)acrylamide [1779]
N-(3-(2-((2,3-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)-4-fluorophenyl)acrylamide [1780]
N-(3-(2-((2,3-difluoro-4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)-2-fluorophenyl)acrylamide [1781]
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)-7-methylquina-
zolin-8-yl)phenyl)acrylamide [1782]
N-(3-(7-fluoro-2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide [1783]
N-(3-(7-(hydroxymethyl)-2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1784]
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)pyrido[3,4-d]p-
yrimidin-8-yl)phenyl)acrylamide [1785]
N-(4-(7-fluoro-2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)pyridin-2-yl)acrylamide [1786]
N-(4-(7-fluoro-2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1787]
N-(4-(7-fluoro-2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)pyridin-2-yl)acrylamide [1788]
N-(3-(7-fluoro-2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1789]
N-(3-(7-fluoro-2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)acrylamide [1790]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)--
7-methylquinazolin-8-yl)phenyl)acrylamide [1791]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)--
7-fluoroquinazolin-8-yl)phenyl)acrylamide [1792]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)--
7-(hydroxymethyl)quinazolin-8-yl)phenyl)acrylamide [1793]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1794]
N-(4-(2-((4-(2,3-difluoro-4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)--
7-fluoroquinazolin-8-yl)pyridin-2-yl)acrylamide [1795]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
-7-methylquinazolin-8-yl)phenyl)acrylamide [1796]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
-7-fluoroquinazolin-8-yl)phenyl)acrylamide [1797]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
-7-(hydroxymethyl)quinazolin-8-yl)phenyl)acrylamide [1798]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1799]
N-(4-(2-((4-(2,3-difluoro-4-(2-hydroxypropyl)piperazin-1-yl)phenyl)amino)-
-7-fluoroquinazolin-8-yl)pyridin-2-yl)acrylamide [1800]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)-7-methylquinazolin-8-yl)phenyl)acrylamide [1801]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)-7-fluoroquinazolin-8-yl)phenyl)acrylamide [1802]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)-7-(hydroxymethyl)quinazolin-8-yl)phenyl)acrylamide [1803]
N-(3-(2-((4-(2,3-difluoro-4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1804]
N-(4-(2-((4-(2,3-difluoro-4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)-7-fluoroquinazolin-8-yl)pyridin-2-yl)acrylamide [1805]
N-(3-(2-((4-(2,3-difluoro-4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-7-
-methylquinazolin-8-yl)phenyl)acrylamide [1806]
N-(3-(2-((4-(2,3-difluoro-4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-7-
-fluoroquinazolin-8-yl)phenyl)acrylamide [1807]
N-(3-(2-((4-(2,3-difluoro-4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-7-
-(hydroxymethyl)quinazolin-8-yl)phenyl)acrylamide [1808]
N-(3-(2-((4-(2,3-difluoro-4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)py-
rido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1809]
N-(4-(2-((4-(2,3-difluoro-4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-7-
-fluoroquinazolin-8-yl)pyridin-2-yl)acrylamide [1810]
N-(3-(2-((4-(2,3-difluoro-4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)--
7-methylquinazolin-8-yl)phenyl)acrylamide [1811]
N-(3-(2-((4-(2,3-difluoro-4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)--
7-fluoroquinazolin-8-yl)phenyl)acrylamide
[1812]
N-(3-(2-((4-(2,3-difluoro-4-(2-methoxyethyl)piperazin-1-yl)phenyl)-
amino)-7-(hydroxymethyl)quinazolin-8-yl)phenyl)acrylamide [1813]
N-(3-(2-((4-(2,3-difluoro-4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)p-
yrido[3,4-d]pyrimidin-8-yl)phenyl)acrylamide [1814]
N-(4-(2-((4-(2,3-difluoro-4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)--
7-fluoroquinazolin-8-yl)pyridin-2-yl)acrylamide [1815]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)-5-fluorophenyl)acrylamide [1816]
N-(5-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)-2-fluorophenyl)acrylamide [1817]
N-(2-fluoro-5-(2-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [1818]
N-(3-fluoro-5-(2-((6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-3-yl)amino-
)quinazolin-8-yl)phenyl)acrylamide [1819]
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide [1820]
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide [1821]
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide [1822]
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-2-fluorophenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1823]
N-(3-(2-((4-(1H-pyrazol-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de [1824]
N-(3-(2-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide [1825]
N-(3-(2-((2,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide [1826]
N-(3-(2-((2,5-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1827]
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide [1828]
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)phenyl)acrylamide [1829] and
N-(3-(2-((4-(4-(2-amino-2-oxo
ethyl)piperazin-1-yl)-3-fluorophenyl)amino)quinazolin-8-yl)phenyl)acrylam-
ide.
[1830] In yet another aspect, the present disclosure provides a
compound chosen from the compounds set forth in Table 1 below and
pharmaceutically acceptable salts thereof.
TABLE-US-00001 TABLE 1 Illustrative Compounds of the Present
Invention Compound No. Chemical Name C001
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C002
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-
8-yl)phenyl)acrylamide C003
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C004
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine C005
N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-
d]pyrimidin-8-yl)phenyl)acrylamide C006 tert-butyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-
yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate C007
8-(5-chloro-2-fluorophenyl)-N-(4-
morpholinophenyl)quinazolin-2-amine C008
8-(3-chlorophenyl)-N-(4-morpholinophenyl)quinazolin-2- amine C009
8-(3-fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2- amine C010
8-(2-fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2- amine C011
8-(2-chlorophenyl)-N-(4-morpholinophenyl)quinazolin-2- amine C012
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-
d]pyrimidin-8-yl)phenyl)acrylamide C013 tert-butyl
4-(4-((8-(2-fluorophenyl)quinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C014 tert-butyl
4-(4-((8-(2-chlorophenyl)quinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C015 tert-butyl
4-(4-((8-(3-fluorophenyl)quinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C016 tert-butyl
4-(4-((8-(5-chloro-2-fluorophenyl)quinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C017 tert-butyl
4-(4-((8-(3-chlorophenyl)quinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C018 tert-butyl
4-(4-((8-phenylquinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C019 tert-butyl
4-(4-((8-(2-fluoro-5-(2- morpholinoethoxy)phenyl)quinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C020
N-(3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)propionamide C021
N-(3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C022
N-(3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acetamide C023
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-
morpholinophenyl)quinazolin-2-amine C024
8-(5-chloro-2-fluorophenyl)-N-(4-(piperazin-1-
yl)phenyl)quinazolin-2-amine C025
8-(3-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2- amine
C026 8-(2-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-
amine C027
8-(3-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2- amine
C028 8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-
1-yl)phenyl)quinazolin-2-amine C029
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-
8-yl)phenyl)acrylamide C030
8-phenyl-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine C031
8-(2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2- amine
C032 N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-
8-yl)phenyl)acrylamide C033
N-(3-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C034
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C035
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-
methylquinazolin-8-yl)phenyl)acrylamide C036
N-(3-(2-((6-(4-acetylpiperazin-1-yl)pyridin-3-
yl)amino)quinazolin-8-yl)phenyl)acrylamide C037
N-(3-(7-(hydroxymethyl)-2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C038
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-
8-yl)-2-fluorophenyl)acrylamide C039
N-(5-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-
8-yl)pyridin-3-yl)acrylamide C040 N-(5-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)pyridin-3-yl)acrylamide C041
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-
yl)amino)quinazolin-8-yl)phenyl)acrylamide C042
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)propionamide C043
N-(3-(2-((2-chloro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C044
N-(3-(2-((2-fluoro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C045
N-(2-fluoro-3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C046
N-(3-(2-((2-(4-methylpiperazin-1-yl)pyrimidin-5-
yl)amino)quinazolin-8-yl)phenyl)acrylamide C047
N-(5-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-
yl)amino)quinazolin-8-yl)pyridin-3-yl)acrylamide C048
N-(2-fluoro-3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-
yl)amino)quinazolin-8-yl)phenyl)acrylamide C049
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-
8-yl)-2-fluorophenyl)acrylamide C050
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)-4-
(dimethylamino)but-2-enamide C051
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-
8-yl)-2-chlorophenyl)acrylamide C052
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)but-2-enamide C053
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C054
N-(2-chloro-3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C055
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-
yl)amino)quinazolin-8-yl)phenyl)acrylamide C056
N-(3-(2-((4-(4-(2,2-difluoroethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C057
N-(4-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)pyridin-2-yl)acrylamide C058
N-(5-(2-((4-(4-(2-fluoroethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)pyridin-3-yl)acrylamide C059
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C060
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)-2-chlorophenyl)-4-
(dimethylamino)but-2-enamide C061
N-(2-fluoro-3-(2-((4-(4-(2-fluoroethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C062
(E)-4-(dimethylamino)-N-(2-fluoro-3-(2-((4-(4-
methylpiperazin-1-yl)phenyl)amino)quinazolin-8-
yl)phenyl)but-2-enamide C063
N-(2-methoxy-3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C064
N-(3-(2-((4-((2-
fluoroethyl)(methyl)amino)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C065 N-(2-fluoro-3-(2-((4-((2-
fluoroethyl)(methyl)amino)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C066 N-(3-(2-((4-((2-
hydroxyethyl)amino)phenyl)amino)quinazolin-8- yl)phenyl)acrylamide
C067 N-(4-fluoro-3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C068
N-(2-cyano-3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C069
N-(3-(2-((3-fluoro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C070
1-(4-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)piperazin-1-yl)prop- 2-en-1-one
C071 1-(3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)-5,6-dihydropyridin-
1(2H)-yl)prop-2-en-1-one C072
N-(3-(2-((3-chloro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C073
N-(4-chloro-3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C074
N-(3-(2-((3-cyano-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C075
N-(3-(2-((3-methoxy-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C076 methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-
yl)amino)phenyl)piperazine-1-carboxylate C077
N-(3-(2-((4-(3-(hydroxymethyl)-4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C078
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C079
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C080
N-(2-fluoro-3-(2-((4-((3-fluoro-1-methylpiperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C081
N-(3-(2-((5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-
yl)amino)quinazolin-8-yl)phenyl)acrylamide C082
N-(3-(2-((4-(4-(2-hydroxyacetyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C083
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-
N-methylpiperazine-1-carboxamide C084
N-(3-(2-((4-(4-propionylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C085
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-
methylpiperazin-1-yl)benzamide C086
N-(3-(2-((5-cyano-6-(4-methylpiperazin-1-yl)pyridin-3-
yl)amino)quinazolin-8-yl)phenyl)acrylamide C087
N-(3-(7-fluoro-2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C088
N-(3-(7-fluoro-2-((4-(4-(2-fluoroethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C089 methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-
yl)amino)phenyl)-1-methylpiperazine-2-carboxylate C090
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-
1-methylpiperazine-2-carboxylic acid C091
N-(3-(2-((4-(2-oxooxazolidin-3-yl)phenyl)amino)quinazolin-
8-yl)phenyl)acrylamide C092
N-(3-(2-((4-(4-(methylsulfonyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C093
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-
1-methylpiperazine-2-carboxamide C094
N-(3-(2-((4-(1H-imidazol-1-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C095
N-(3-(2-((4-(3-oxomorpholino)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C096
N-(3-(2-((4-(2-oxopyrrolidin-1-yl)phenyl)amino)quinazolin-
8-yl)phenyl)acrylamide C097 N-(3-(2-((4-(2-oxoimidazolidin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C098
N-(3-(2-((4-(3-hydroxypyrrolidin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C099
N-(3-(2-((4-((1-(2-hydroxyethyl)azetidin-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C100
N-(4-cyano-3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C101 methyl
2-acrylamido-6-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)benzoate C102
N-(3-(2-((4-(1,4-oxazepan-4-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C103
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C104 methyl
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-
(4-methylpiperazin-1-yl)benzoate C105
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C106
N-(3-(2-((4-(4-methyl-2-oxopiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C107
N-(3-(2-((4-(2-methoxyethoxy)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C108
N-(3-(2-((4-(2-hydroxyethoxy)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C109 N-(3-(2-((4-(2-(azetidin-1-
yl)ethoxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C110
N-(3-(2-((4-(2- (dimethylamino)ethoxy)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C111 N-(3(2-((4-((tetrahydro-2H-pyran-4-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C112
N-(3-(2-((4-((tetrahydro-2H-pyran-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C113
(S)-N-(3-(2-((4-((tetrahydrofuran-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C114
(S)-N-(3-(2-((4-((tetrahydrofuran-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C115
(R)-N-(3-(2-((4-((tetrahydrofuran-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C116
N-(3-(2-((4-(4-methyl-3-oxopiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C117
N-(3-(2-((4-(3-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C118 N-(3-(2-((4-((1-methylpiperidin-4-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide
C119 (R)-N-(3-(2((4-((tetrahydrofuran-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C120
N-(3-(2-((4-((1-acetylpiperidin-4-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C121
(S)-N-(3-(2-((4-((1-methylpyrrolidin-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C122
N-(3-(2-((4-((1-acetylazetidin-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C123
(R)-N-(3-(2-((4-((1-methylpyrrolidin-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C124
N-(3-(2-((4-((1-acetylazetidin-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C125
N-(3-(2-((4-((1-acetylpiperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C126
N-(3-(2-((4-((1-methylpiperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C127
(S)-N-(3-(2-((4-((1-methylpyrrolidin-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C128
(S)-N-(3-(2-((4-((1-acetylpyrrolidin-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C129
(R)-N-(3-(2-((4-((1-methylpyrrolidin-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C130
(R)-N-(3-(2-((4-((1-acetylpyrrolidin-3-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C131
(S)-N-(3-(2-((4-((1-acetylpyrrolidin-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C132
N-(3-(2-((4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)-1H-pyrazol-5- yl)acrylamide C133
(R)-N-(3-(2-((4-((1-acetylpyrrolidin-3-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C134
N-(3-(2-((4-((2-fluoroethyl)amino)phenyl)amino)quinazolin-
8-yl)phenyl)acrylamide C135 N-(3-(2-((4-((2,2-
difluoroethyl)amino)phenyl)amino)quinazolin-8- yl)phenyl)acrylamide
C136 N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C137
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C138
N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C139
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C140
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-
yl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C141
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C142
N-(3-(2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C143
N-(3-(2-((3-fluoro-4-(4-(2-hydroxy-2-
methylpropyl)piperazin-1-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C144
N-(3-(2-((2-fluoro-4-((1-(2-hydroxyethyl)piperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C145
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C146
N-(3-(2-((3,5-difluoro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C147
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C148
N-(3-(2-((2,6-difluoro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C149
N-(3-(2-((2-fluoro-4-(4-(2-hydroxy-2-
methylpropyl)piperazin-1-yl)phenyl)amino)quinazolin-
8-yl)phenyl)acrylamide C150
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C151
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C152
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C153
N-(3-(2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C154
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-2-
fluorophenyl)amino)quinazolin-8-yl)phenyl)acrylamide C155
N-(3-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C156
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C157
N-(3-(2-((2-fluoro-4-((1-(2-fluoroethyl)piperidin-4-
yl)oxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C158
N-(3-(2-((4-(1H-pyrazol-1-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C159
N-(3-(2-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C160
N-(3-(2-((2,5-difluoro-4-(4-methylpiperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C161
N-(3-(2-((2,5-difluoro-4-(4-(2-methoxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C162
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide C163
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxy-2-
methylpropyl)piperazin-1-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C164
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-3-
fluorophenyl)amino)quinazolin-8-yl)phenyl)acrylamide C165
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-
methylpropyl)piperazin-1-yl)phenyl)amino)quinazolin-8-
yl)phenyl)acrylamide C166
N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-
yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide
[1831] In some embodiments, a compound of Formula I binds to a
kinase including, but not limited to, Abl, Aktl, Akt2, Akt3, ALK,
Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1,
c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1,
FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha,
Gsk3beta, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk,
Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, KDR, Kit, Lck, Lyn, MAP2K1,
MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB,
PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1,
Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB,
Yes, and Zap70, including any mutated versions thereof. For
example, the compound of Formula I binds to a kinase selected from
the group consisting of EGFR, HER2, HER4, KDR, ALK, ARKS, BLK, BTK,
FMS, ITK, JAK1, JAK2, JAK3, PLK1, PLK2, PLK3, PLK4, FAK, and SNARK
In some embodiments, the compound of Formula I binds to a kinase
selected from the group consisting of EGFR mutants such as EGFR del
E746-A750, EGFR del E747-E749/A750P, EGFR del E747-S752/P753S, EGFR
del E747-T751/Sins/A750P, EGFR del S7524759, EGFR G719S, EGFR
G719C, EGFR L861Q, EGFR L858R, EGFR T790M, EGFR L858R/T790M. For
example, the compound of Formula I binds to a kinase which is EGFR
L858R, EGFR T790M or EGFR L858R/T790M mutant. In some embodiments,
a compound of Formula I binds to a kinase including, but not
limited to, Abl, Aktl, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk,
Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1,
EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,
Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,
Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1,
Jnk2, Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2,
Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC
alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src,
Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including any
mutated versions thereof, with a Kd which is lower than 50 .mu.M,
25 .mu.M, 10 .mu.M, 5 .mu.M, or 1 .mu.M as measured in an in vitro
assay. For example, the compound of Formula I binds to a kinase
selected from the group consisting of EGFR, EGFR L858R, EGFR T790M,
EGFR del E746-A750, or EGFR L858R/T790M mutant, Her2, Her4, Fak,
FGFR1, FGFR2, FGFR3, FGFR4, Btk, Met, Pim1, Pim2, Pim3, Pyk2, KDR,
Src and Ret, and any mutated versions thereof with a Kd which is
lower than 50 .mu.M, 25 .mu.M, 10 .mu.M, 5 .mu.M, or 1 .mu.M as
measured in an in vitro assay. In some embodiments, the compound of
Formula I binds to a kinase selected from the group consisting of
Btk, KDR, EGFR, EGFR L858R, EGFR T790M or EGFR L858R/T790M mutant
with a Kd which is lower than 50 .mu.M, 25 .mu.M, 10 .mu.M, 5
.mu.M, or 1 .mu.M as measured in an in vitro assay. For example,
the compound of Formula I binds to a kinase which is EGFR, EGFR
L858R, EGFR T790M, EGFR del E746-A750, EGFR L858R/T790M mutant with
a Kd which is lower than 50 .mu.M, 25 .mu.M, 10 .mu.M, 5 .mu.M, or
1 .mu.M as measured in an in vitro assay.
[1832] In some embodiments, a compound of Formula I inhibits a
kinase including, but not limited to, Abl, Aktl, Akt2, Akt3, ALK,
Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1,
c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1,
FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha,
Gsk3beta, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk,
Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, KDR, Kit, Lck, Lyn, MAP2K1,
MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB,
PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1,
Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB,
Yes, and Zap70, including any mutated versions thereof. For
example, the compound of Formula I inhibits a kinase selected from
the group consisting of EGFR, Btk, Fak, FGFR1, FGFR2, FGFR3, FGFR4,
Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Src
and Ret, and any mutated versions thereof. In some embodiments, the
compound of Formula I inhibits a kinase selected from the group
consisting of EGFR, EGFR L858R, EGFR del E746-A750, EGFR T790M or
EGFR L858R/T790M mutant. For example, the compound of Formula I
inhibits a kinase which is EGFR or EGFR L858R/T790M mutant. In some
embodiments, a compound of Formula I inhibits a kinase including,
but not limited to, Abl, Aktl, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf,
Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1,
EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,
Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,
Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1,
Jnk2, Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2,
Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC
alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src,
Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including any
mutated versions thereof with an IC.sub.50 in an in vitro assay of
10 .mu.M, 5 .mu.M, 2 .mu.M, 1 .mu.M, 500 nM, 200 nM, 100 nM or less
as ascertained in an in vitro kinase assay. For example, the
compound of Formula I inhibits a kinase selected from the group
consisting of EGFR., HER2, HER3, HER4, KDR, ALK, ARKS, BLK, BTK,
FGFR1, FGFR2, FGFR3, FMS, ITK, JAK1, JAK2, JAK3, PLK1, PLK2, PLK3,
PLK4, FAK, and SNARK, Src and Ret, and any mutated versions thereof
with an IC.sub.50 in an in vitro assay of 10 .mu.M, 5 .mu.M, 2
.mu.M, 1 .mu.M, 500 nM, 200 nM, 100 nM or less as ascertained in an
in vitro kinase assay. In some embodiments, the compound of Formula
I inhibits a kinase selected from the group consisting of EGFR,
EGFR L858R, EGFR del E746-A750, EGFR T790M or EGFR L858R/T790M
mutant with an IC.sub.50 in an in vitro assay of 10 .mu.M, 5 .mu.M,
2 .mu.M, 1 .mu.M, 500 nM, 200 nM, 100 nM or less as ascertained in
an in vitro kinase assay. For example, the compound of Formula I
inhibits a kinase which is EGFR or EGFR L858R/T790M mutant with an
IC.sub.50 in an in vitro assay of 10 .mu.M, 5 .mu.M, 2 .mu.M, 1
.mu.M, 500 nM, 200 nM, 100 nM or less as ascertained in an in vitro
kinase assay.
[1833] In some embodiments, the compound of Formula I inhibits the
activity of one or more kinases selected from the group consisting
of EGFR, EGFR L858R, EGFR T790M or EGFR L858R/T790M with an
IC.sub.50 in an in vitro assay of 1 .mu.M, 500 nM, 200 nM, 100 nM,
50 nM, 25 nM or less as ascertained in an in vitro kinase
assay.
[1834] In some embodiments, the compound of Formula I selectively
inhibits the activity of one or more kinases selected from the
group consisting of Abl, Aktl, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf,
Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1,
EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,
Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,
Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1,
Jnk2, Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2,
Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC
alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src,
Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, including any
mutated versions thereof. For example, the compound of Formula I
selectively inhibits the activity of one or more kinases selected
from the group consisting of EGFR, EGFR L858R, EGFR T790M, EGFR del
E746-A750 or EGFR L858R/T790M, HER2, HER3, HER4, KDR, ALK, ARKS,
BLK, BTK, FGFR1, FGFR2, FGFR3, FMS, ITK, JAK1, JAK2, JAK3, PLK1,
PLK2, PLK3, PLK4, FAK, and SNARK, Src and Ret, In some embodiments,
the compound of Formula I selectively inhibits the activity of one
or more kinases selected from the group consisting of EGFR, EGFR
L858R, EGFR T790M, EGFR del E746-A750 or EGFR L858R/T790M
mutant.
[1835] In some embodiments, the compound of Formula I selectively
inhibits the activity of, EGFR L858R, EGFR T790M, EGFR del
E746-A750, or EGFR L858R/T790M mutant relative to one or more
kinases selected from the group consisting of ABL1, AKT1 (PKB
alpha), AURKB (Aurora B), BLK, BTK, CDK1/cyclin B, CHEK1 (CHK1),
CSF1R (FMS), CSNK1G2 (CK1 gamma 2), EGFR (ErbB1), FGFR1, FGFR2,
FGFR3, FGR, FLT3, FRAP1 (mTOR), FYN, IGF1R, IKBKB (IKK beta), NSR,
JAK1, JAK2, JAK3, KDR, KIT, LCK, LYN A, MAP2K1 (MEK1), MAP4K5
(KHS1), MAPK1 (ERK2), MAPK14 (p38 alpha), MAPKAPK2, MET (cMet),
PDGFRB (PDGFR beta), PIK3CA/PIK3R1 (p110 alpha/p85 alpha)PRKCB2
(PKC beta II), PTK2B (FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D,
RET, RPS6KB1 (p70S6K), SRC, SRMS (Srm), and YES1. In some
embodiments, the compound of Formula I selectively inhibits the
activity of one or more kinases selected from the group consisting
of EGFR L858R, EGFR T790M EGFR del E746-A750, or EGFR L858R/T790M
with an IC.sub.50 which is 1/2, 1/3.sup.th, 1/4.sup.th, 1/5.sup.th,
1/7.sup.th, 1/10.sup.th, 1/15.sup.th, 1/20.sup.th, 1/25.sup.th,
1/30.sup.th, 1/40.sup.th, 1/50.sup.th, 1/100.sup.th, 1/150.sup.th,
1/200.sup.th, 1/300.sup.th, 1/400.sup.th, 1/500.sup.th,
1/1000.sup.th, 1/2000.sup.th or less than the IC.sub.50 for a
kinase selected from the group consisting of ABL1, AKT1 (PKB
alpha), AURKB (Aurora B), BLK, BTK, CDK1/cyclin B, CHEK1 (CHK1),
CSNK1G2 (CK1 gamma 2), EGFR (ErbB1), FGFR1, FGFR2, FGFR3, FGR,
FLT3, FRAP1 (mTOR), FYN, IGF1R, IKBKB (IKK beta), INSR, JAK1, JAK2,
JAK3, KDR, KIT, LCK, LYN A, MAP2K1 (MEK1), MAP4K5 (KHS1), MAPK1
(ERK2), MAPK14 (p38 alpha), MAPKAPK2, MET (cMet), PDGFRB (PDGFR
beta), PIK3CA/PIK3R1 (p110 alpha/p85 alpha)PRKCB2 (PKC beta II),
PTK2B (FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D, RET, RPS6KB1
(p7056K), SRC, SRMS (Srm), and YES1.
[1836] In some embodiments, one or more compounds of Formula I are
capable of inhibiting cellular proliferation. For example, In some
embodiments, one or more compounds of Formula I inhibit
proliferation of tumor cells or tumor cell lines. For example, such
cell lines express a kinase which is EGFR L858R, EGFR T790M, EGFR
del E746-A750, or EGFR L858R/T790M mutant. In some embodiments, the
compounds of Formula I inhibit A549, A431, HCC827 or H1975 cell
proliferation in vitro or in an in vivo model such as a xenograft
mouse model. In some embodiments, in vitro cultured HCC827 or H1975
cell proliferation may be inhibited with an IC.sub.50 of less than
100 .mu.M, 75 .mu.M, 50 .mu.M, 25 .mu.M, 15 .mu.M, 10 .mu.M, 5
.mu.M, 3 .mu.M, 2 .mu.M, 1 .mu.M or less by one or more compounds
of Formula I.
B. Methods of Making
[1837] Compounds disclosed herein may be prepared by the routes
described below. Materials used herein are either commercially
available or prepared by synthetic methods generally known in the
art. These schemes are not limited to the compounds listed or by
any particular substituents, which are employed for illustrative
purposes. Although various steps of are described and depicted in
Scheme A, the steps in some cases may be performed in a different
order than the order shown in Scheme A. Various modifications to
these synthetic reaction schemes may be made and will be suggested
to one skilled in the art having referred to the disclosure
contained in this application. Numbering does not necessarily
correspond to that of claims or other tables.
##STR00060##
[1838] In Scheme A, A-1 is reacted with A-2 in the presence of a
base. Suitable bases include Cs.sub.2CO.sub.3, NaH, KH, t-BuOK,
LiH, and CaH.sub.2. Suitable solvents include, but are not limited
to, DMF, DMSO, DMA, and N-methyl piperidone. The reaction are
generally carried out at a temperature ranging from 25 to
240.degree. C. Suzuki cross-coupling reaction of A-3 with boronic
acid or ester A-4 in the presence of a base, such as
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, and a Pd
catalyst, gives compounds of Formula Ia. The reaction is generally
carried out at a temperature ranging from 25 to 180.degree. C. in a
suitable solvent such as 1,4-dioxane, water, tetrahydrofuran, or a
mixture thereof.
##STR00061##
[1839] In Scheme B, A-1 is reacted with A-5 in the presence of a
base. Suitable bases include Cs.sub.2CO.sub.3, NaH, KH, t-BuOK,
LiH, and CaH.sub.2. Suitable solvents include, but are not limited
to, DMF, DMSO, DMA, and N-methyl piperidone. The reaction are
generally carried out at a temperature ranging from 25 to
240.degree. C. Suzuki cross-coupling reaction of A-6 with boronic
acid or ester A-7 in the presence of a base, such as
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, and a Pd
catalyst, gives compounds of Formula I. The reaction is generally
carried out at a temperature ranging from 25 to 180.degree. C. in a
suitable solvent such as 1,4-dioxane, water, tetrahydrofuran, or a
mixture thereof.
C. Pharmaceutical Compositions and Formulations
[1840] In some embodiments, the compounds described herein are
formulated into pharmaceutical compositions. In specific
embodiments, pharmaceutical compositions are formulated in a
conventional manner using one or more physiologically acceptable
carriers comprising excipients and auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically. Proper formulation is dependent upon the
route of administration chosen. Any pharmaceutically acceptable
techniques, carriers, and excipients are used as suitable to
formulate the pharmaceutical compositions described herein:
Remington: The Science and Practice of Pharmacy, Nineteenth Ed
(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical
Dosage Forms, Marcel Decker, New York, N.Y., 1980; and
Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
(Lippincott Williams & Wilkins 1999).
[1841] Provided herein are pharmaceutical compositions comprising a
compound of Formula I, and a pharmaceutically acceptable
diluent(s), excipient(s), or carrier(s). In certain embodiments,
the compounds described are administered as pharmaceutical
compositions in which compounds of Formula I, are mixed with other
active ingredients, as in combination therapy. Encompassed herein
are all combinations of actives set forth in the combination
therapies section below and throughout this disclosure. In specific
embodiments, the pharmaceutical compositions include one or more
compounds of Formula I.
[1842] A pharmaceutical composition, as used herein, refers to a
mixture of a compound of Formula I, with other chemical components,
such as carriers, stabilizers, diluents, dispersing agents,
suspending agents, thickening agents, and/or excipients. In certain
embodiments, the pharmaceutical composition facilitates
administration of the compound to an organism. In some embodiments,
practicing the methods of treatment or use provided herein,
therapeutically effective amounts of compounds of Formula I,
provided herein are administered in a pharmaceutical composition to
a mammal having a disease or condition to be treated. In specific
embodiments, the mammal is a human. In certain embodiments,
therapeutically effective amounts vary depending on the severity of
the disease, the age and relative health of the subject, the
potency of the compound used and other factors. The compounds
described herein are used singly or in combination with one or more
therapeutic agents as components of mixtures.
[1843] In one embodiment, one or more compounds of Formula I, is
formulated in an aqueous solution. In specific embodiments, the
aqueous solution is selected from, by way of example only, a
physiologically compatible buffer, such as Hank's solution,
Ringer's solution, or physiological saline buffer. In other
embodiments, one or more compound of Formula I, is formulated for
transmucosal administration. In specific embodiments, transmucosal
formulations include penetrants that are appropriate to the barrier
to be permeated. In still other embodiments wherein the compounds
described herein are formulated for other parenteral injections,
appropriate formulations include aqueous or nonaqueous solutions.
In specific embodiments, such solutions include physiologically
compatible buffers and/or excipients.
[1844] In another embodiment, compounds described herein are
formulated for oral administration. Compounds described herein,
including compounds of Formula I, are formulated by combining the
active compounds with, e.g., pharmaceutically acceptable carriers
or excipients. In various embodiments, the compounds described
herein are formulated in oral dosage forms that include, by way of
example only, tablets, powders, pills, dragees, capsules, liquids,
gels, syrups, elixirs, slurries, suspensions and the like.
[1845] In certain embodiments, pharmaceutical preparations for oral
use are obtained by mixing one or more solid excipient with one or
more of the compounds described herein, optionally grinding the
resulting mixture, and processing the mixture of granules, after
adding suitable auxiliaries, if desired, to obtain tablets or
dragee cores. Suitable excipients are, in particular, fillers such
as sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as: for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth,
methylcellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or
others such as: polyvinylpyrrolidone (PVP or povidone) or calcium
phosphate. In specific embodiments, disintegrating agents are
optionally added. Disintegrating agents include, by way of example
only, cross-linked croscarmellose sodium, polyvinylpyrrolidone,
agar, or alginic acid or a salt thereof such as sodium
alginate.
[1846] In one embodiment, dosage forms, such as dragee cores and
tablets, are provided with one or more suitable coating. In
specific embodiments, concentrated sugar solutions are used for
coating the dosage form. The sugar solutions, optionally contain
additional components, such as by way of example only, gum arabic,
talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol,
and/or titanium dioxide, lacquer solutions, and suitable organic
solvents or solvent mixtures. Dyestuffs and/or pigments are also
optionally added to the coatings for identification purposes.
Additionally, the dyestuffs and/or pigments are optionally utilized
to characterize different combinations of active compound
doses.
[1847] In certain embodiments, therapeutically effective amounts of
at least one of the compounds described herein are formulated into
other oral dosage forms. Oral dosage forms include push-fit
capsules made of gelatin, as well as soft, sealed capsules made of
gelatin and a plasticizer, such as glycerol or sorbitol. In
specific embodiments, push-fit capsules contain the active
ingredients in admixture with one or more filler. Fillers include,
by way of example only, lactose, binders such as starches, and/or
lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In other embodiments, soft capsules, contain one or
more active compound that is dissolved or suspended in a suitable
liquid. Suitable liquids include, by way of example only, one or
more fatty oil, liquid paraffin, or liquid polyethylene glycol. In
addition, stabilizers are optionally added.
[1848] In other embodiments, therapeutically effective amounts of
at least one of the compounds described herein are formulated for
buccal or sublingual administration. Formulations suitable for
buccal or sublingual administration include, by way of example
only, tablets, lozenges, or gels. In still other embodiments, the
compounds described herein are formulated for parental injection,
including formulations suitable for bolus injection or continuous
infusion. In specific embodiments, formulations for injection are
presented in unit dosage form (e.g., in ampoules) or in multi-dose
containers. Preservatives are, optionally, added to the injection
formulations. In still other embodiments, the pharmaceutical
composition of a compound of Formula I is formulated in a form
suitable for parenteral injection as sterile suspension, solution
or emulsion in oily or aqueous vehicles. Parenteral injection
formulations optionally contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. In specific
embodiments, pharmaceutical formulations for parenteral
administration include aqueous solutions of the active compounds in
water-soluble form. In additional embodiments, suspensions of the
active compounds are prepared as appropriate oily injection
suspensions. Suitable lipophilic solvents or vehicles for use in
the pharmaceutical compositions described herein include, by way of
example only, fatty oils such as sesame oil, or synthetic fatty
acid esters, such as ethyl oleate or triglycerides, or liposomes.
In certain specific embodiments, aqueous injection suspensions
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, the suspension contains suitable stabilizers or agents
which increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions. Alternatively, in
other embodiments, the active ingredient is in powder form for
constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[1849] In still other embodiments, the compounds of Formula I are
administered topically. The compounds described herein are
formulated into a variety of topically administrable compositions,
such as solutions, suspensions, lotions, gels, pastes, medicated
sticks, balms, creams or ointments. Such pharmaceutical
compositions optionally contain solubilizers, stabilizers, tonicity
enhancing agents, buffers and preservatives.
[1850] In yet other embodiments, the compounds of Formula I are
formulated for transdermal administration. In specific embodiments,
transdermal formulations employ transdermal delivery devices and
transdermal delivery patches and can be lipophilic emulsions or
buffered, aqueous solutions, dissolved and/or dispersed in a
polymer or an adhesive. In various embodiments, such patches are
constructed for continuous, pulsatile, or on demand delivery of
pharmaceutical agents. In additional embodiments, the transdermal
delivery of the compounds of Formula I, is accomplished by means of
iontophoretic patches and the like. In certain embodiments,
transdermal patches provide controlled delivery of the compounds of
Formula I. In specific embodiments, the rate of absorption is
slowed by using rate-controlling membranes or by trapping the
compound within a polymer matrix or gel. In alternative
embodiments, absorption enhancers are used to increase absorption.
Absorption enhancers or carriers include absorbable
pharmaceutically acceptable solvents that assist passage through
the skin. For example, in one embodiment, transdermal devices are
in the form of a bandage comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound to the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
[1851] In other embodiments, the compounds of Formula I, are
formulated for administration by inhalation. Various forms suitable
for administration by inhalation include, but are not limited to,
aerosols, mists or powders. Pharmaceutical compositions of Formula
I, are conveniently delivered in the form of an aerosol spray
presentation from pressurized packs or a nebuliser, with the use of
a suitable propellant (e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas). In specific embodiments, the dosage unit of
a pressurized aerosol is determined by providing a valve to deliver
a metered amount. In certain embodiments, capsules and cartridges
of, such as, by way of example only, gelatin for use in an inhaler
or insufflator are formulated containing a powder mix of the
compound and a suitable powder base such as lactose or starch.
[1852] In still other embodiments, the compounds of Formula I, are
formulated in rectal compositions such as enemas, rectal gels,
rectal foams, rectal aerosols, suppositories, jelly suppositories,
or retention enemas, containing conventional suppository bases such
as cocoa butter or other glycerides, as well as synthetic polymers
such as polyvinylpyrrolidone, PEG, and the like. In suppository
forms of the compositions, a low-melting wax such as, but not
limited to, a mixture of fatty acid glycerides, optionally in
combination with cocoa butter is first melted.
[1853] In certain embodiments, pharmaceutical compositions are
formulated in any conventional manner using one or more
physiologically acceptable carriers comprising excipients and
auxiliaries which facilitate processing of the active compounds
into preparations which can be used pharmaceutically. Proper
formulation is dependent upon the route of administration chosen.
Any pharmaceutically acceptable techniques, carriers, and
excipients are optionally used as suitable. Pharmaceutical
compositions comprising a compound of Formula I, are manufactured
in a conventional manner, such as, by way of example only, by means
of conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or compression
processes.
[1854] Pharmaceutical compositions include at least one
pharmaceutically acceptable carrier, diluent or excipient and at
least one compound of Formula I, described herein as an active
ingredient. The active ingredient is in free-acid or free-base
form, or in a pharmaceutically acceptable salt form. In addition,
the methods and pharmaceutical compositions described herein
include the use of N-oxides, crystalline forms (also known as
polymorphs), as well as active metabolites of these compounds
having the same type of activity. All tautomers of the compounds
described herein are included within the scope of the compounds
presented herein. Additionally, the compounds described herein
encompass unsolvated as well as solvated forms with
pharmaceutically acceptable solvents such as water, ethanol, and
the like. The solvated forms of the compounds presented herein are
also considered to be disclosed herein. In addition, the
pharmaceutical compositions optionally include other medicinal or
pharmaceutical agents, carriers, adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure, buffers, and/or other
therapeutically valuable substances.
[1855] Methods for the preparation of compositions comprising the
compounds described herein include formulating the compounds with
one or more inert, pharmaceutically acceptable excipients or
carriers to form a solid, semi-solid or liquid. Solid compositions
include, but are not limited to, powders, tablets, dispersible
granules, capsules, cachets, and suppositories. Liquid compositions
include solutions in which a compound is dissolved, emulsions
comprising a compound, or a solution containing liposomes,
micelles, or nanoparticles comprising a compound as disclosed
herein. Semi-solid compositions include, but are not limited to,
gels, suspensions and creams. The form of the pharmaceutical
compositions described herein include liquid solutions or
suspensions, solid forms suitable for solution or suspension in a
liquid prior to use, or as emulsions. These compositions also
optionally contain minor amounts of nontoxic, auxiliary substances,
such as wetting or emulsifying agents, pH buffering agents, and so
forth.
[1856] In some embodiments, a pharmaceutical composition comprising
at least one compound of Formula I, illustratively takes the form
of a liquid where the agents are present in solution, in suspension
or both. Typically when the composition is administered as a
solution or suspension a first portion of the agent is present in
solution and a second portion of the agent is present in
particulate form, in suspension in a liquid matrix. In some
embodiments, a liquid composition includes a gel formulation. In
other embodiments, the liquid composition is aqueous.
[1857] In certain embodiments, useful aqueous suspension contain
one or more polymers as suspending agents. Useful polymers include
water-soluble polymers such as cellulosic polymers, e.g.,
hydroxypropyl methylcellulose, and water-insoluble polymers such as
cross-linked carboxyl-containing polymers. Certain pharmaceutical
compositions described herein comprise a mucoadhesive polymer,
selected for example from carboxymethylcellulose, carbomer (acrylic
acid polymer), poly(methylmethacrylate), polyacrylamide,
polycarbophil, acrylic acid/butyl acrylate copolymer, sodium
alginate and dextran.
[1858] Useful pharmaceutical compositions also, optionally, include
solubilizing agents to aid in the solubility of a compound of
Formula I. The term "solubilizing agent" generally includes agents
that result in formation of a micellar solution or a true solution
of the agent. Certain acceptable nonionic surfactants, for example
polysorbate 80, are useful as solubilizing agents, as can
ophthalmically acceptable glycols, polyglycols, e.g., polyethylene
glycol 400, and glycol ethers.
[1859] Furthermore, useful pharmaceutical compositions optionally
include one or more pH adjusting agents or buffering agents,
including acids such as acetic, boric, citric, lactic, phosphoric
and hydrochloric acids; bases such as sodium hydroxide, sodium
phosphate, sodium borate, sodium citrate, sodium acetate, sodium
lactate and tris-hydroxymethylaminomethane; and buffers such as
citrate/dextrose, sodium bicarbonate and ammonium chloride. Such
acids, bases and buffers are included in an amount required to
maintain pH of the composition in an acceptable range.
[1860] Additionally, useful compositions also, optionally, include
one or more salts in an amount required to bring osmolality of the
composition into an acceptable range. Such salts include those
having sodium, potassium or ammonium cations and chloride, citrate,
ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or
bisulfite anions; suitable salts include sodium chloride, potassium
chloride, sodium thiosulfate, sodium bisulfite and ammonium
sulfate.
[1861] Other useful pharmaceutical compositions optionally include
one or more preservatives to inhibit microbial activity. Suitable
preservatives include mercury-containing substances such as merfen
and thiomersal; stabilized chlorine dioxide; and quaternary
ammonium compounds such as benzalkonium chloride,
cetyltrimethylammonium bromide and cetylpyridinium chloride.
[1862] Still other useful compositions include one or more
surfactants to enhance physical stability or for other purposes.
Suitable nonionic surfactants include polyoxyethylene fatty acid
glycerides and vegetable oils, e.g., polyoxyethylene (60)
hydrogenated castor oil; and polyoxyethylene alkylethers and
alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
[1863] Still other useful compositions include one or more
antioxidants to enhance chemical stability where required. Suitable
antioxidants include, by way of example only, ascorbic acid and
sodium metabisulfite.
[1864] In certain embodiments, aqueous suspension compositions are
packaged in single-dose non-reclosable containers. Alternatively,
multiple-dose reclosable containers are used, in which case it is
typical to include a preservative in the composition.
[1865] In alternative embodiments, other delivery systems for
hydrophobic pharmaceutical compounds are employed. Liposomes and
emulsions are examples of delivery vehicles or carriers useful
herein. In certain embodiments, organic solvents such as
N-methylpyrrolidone are also employed. In additional embodiments,
the compounds described herein are delivered using a
sustained-release system, such as semipermeable matrices of solid
hydrophobic polymers containing the therapeutic agent. Various
sustained-release materials are useful herein. In some embodiments,
sustained-release capsules release the compounds for a few weeks up
to over 100 days. Depending on the chemical nature and the
biological stability of the therapeutic reagent, additional
strategies for protein stabilization are employed.
[1866] In certain embodiments, the formulations described herein
comprise one or more antioxidants, metal chelating agents, thiol
containing compounds and/or other general stabilizing agents.
Examples of such stabilizing agents, include, but are not limited
to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to
about 1% w/v methionine, (c) about 0.1% to about 2% w/v
monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about
0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v
polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)
arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)
pentosan polysulfate and other heparinoids, (m) divalent cations
such as magnesium and zinc; or (n) combinations thereof.
D. Routes of Administration
[1867] Suitable routes of administration include, but are not
limited to, oral, intravenous, rectal, aerosol, parenteral,
ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic,
nasal, and topical administration. In addition, by way of example
only, parenteral delivery includes intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intralymphatic, and
intranasal injections.
[1868] In certain embodiments, a compound as described herein is
administered in a local rather than systemic manner, for example,
via injection of the compound directly into an organ, often in a
depot preparation or sustained release formulation. In specific
embodiments, long acting formulations are administered by
implantation (for example subcutaneously or intramuscularly) or by
intramuscular injection. Furthermore, in other embodiments, the
drug is delivered in a targeted drug delivery system, for example,
in a liposome coated with organ-specific antibody. In such
embodiments, the liposomes are targeted to and taken up selectively
by the organ. In yet other embodiments, the compound as described
herein is provided in the form of a rapid release formulation, in
the form of an extended release formulation, or in the form of an
intermediate release formulation. In yet other embodiments, the
compound described herein is administered topically.
E. Kits/Articles of Manufacture
[1869] For use in the therapeutic applications described herein,
kits and articles of manufacture are also provided. In some
embodiments, such kits comprise a carrier, package, or container
that is compartmentalized to receive one or more containers such as
vials, tubes, and the like, each of the container(s) comprising one
of the separate elements to be used in a method described herein.
Suitable containers include, for example, bottles, vials, syringes,
and test tubes. The containers are formed from a variety of
materials such as glass or plastic.
[1870] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products Include those found in, e.g., U.S. Pat.
Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical
packaging materials include, but are not limited to, blister packs,
bottles, tubes, inhalers, pumps, bags, vials, containers, syringes,
bottles, and any packaging material suitable for a selected
formulation and intended mode of administration and treatment. For
example, the container(s) includes one or more compounds described
herein, optionally in a composition or in combination with another
agent as disclosed herein. The container(s) optionally have a
sterile access port (for example the container is an intravenous
solution bag or a vial having a stopper pierceable by a hypodermic
injection needle). Such kits optionally comprising a compound with
an identifying description or label or instructions relating to its
use in the methods described herein.
[1871] For example, a kit typically includes one or more additional
containers, each with one or more of various materials (such as
reagents, optionally in concentrated form, and/or devices)
desirable from a commercial and user standpoint for use of a
compound described herein. Non-limiting examples of such materials
include, but not limited to, buffers, diluents, filters, needles,
syringes; carrier, package, container, vial and/or tube labels
listing contents and/or instructions for use, and package inserts
with instructions for use. A set of instructions will also
typically be included. A label is optionally on or associated with
the container. For example, a label is on a container when letters,
numbers or other characters forming the label are attached, molded
or etched into the container itself, a label is associated with a
container when it is present within a receptacle or carrier that
also holds the container, e.g., as a package insert. In addition, a
label is used to indicate that the contents are to be used for a
specific therapeutic application. In addition, the label indicates
directions for use of the contents, such as in the methods
described herein. In certain embodiments, the pharmaceutical
compositions is presented in a pack or dispenser device which
contains one or more unit dosage forms containing a compound
provided herein. The pack for example contains metal or plastic
foil, such as a blister pack. Or, the pack or dispenser device is
accompanied by instructions for administration. Or, the pack or
dispenser is accompanied with a notice associated with the
container in form prescribed by a governmental agency regulating
the manufacture, use, or sale of pharmaceuticals, which notice is
reflective of approval by the agency of the form of the drug for
human or veterinary administration. Such notice, for example, is
the labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert. In some
embodiments, Compositions containing a compound provided herein
formulated in a compatible pharmaceutical carrier are prepared,
placed in an appropriate container, and labeled for treatment of an
indicated condition.
F. Methods of Use
[1872] The chemical entities described herein are useful in the
treatment, or in the preparation of a medicament for the treatment
of various disorders. For example, compounds of Formula I are
useful as inhibitors of protein kinases. In some embodiments, the
chemical entities described herein are inhibitors of one or more
kinases. For example, compounds of Formula I are inhibitors of EGFR
and of mutants of such kinase, including the EGFR del E746-A750,
EGFR del E747-E749/A750P, EGFR del E747-S752/P753S, EGFR del
E747-T751/Sins/A750P, EGFR del S752-1759, EGFR G719S, EGFR G719C,
EGFR L861Q, EGFR L858R, EGFR T790M or EGFR L858R/T790M mutant.
Thus, without wishing to be bound by any particular theory, the
compounds of Formula I are particularly useful for treating or
lessening the severity of a disease, condition, or disorder where
activation of one or more kinases, such as EGFR, which is
implicated in the disease, condition, or disorder. When activation
of EGFR kinase is implicated in a particular disease, condition, or
disorder, the disease, condition, or disorder may also be referred
to as "EGFR-mediated disease" or disease symptom. Accordingly, in
another aspect, the present invention provides a method for
treating or lessening the severity of a disease, condition, or
disorder where activation of EGFR and/or other kinases is
implicated in the disease state.
[1873] The inhibition of kinases may be assayed in vitro, in vivo
or in a cell line. In vitro assays include assays that determine
inhibition of either the phosphorylation activity or ATPase
activity of activated kinase. Alternate in vitro assays quantitate
the ability of the inhibitor to bind to kinase Inhibitor binding
may be measured by radiolabelling the inhibitor prior to binding,
isolating the inhibitor, complex and determining the amount of
radiolabel bound. Alternatively, inhibitor binding may be
determined by running a competition experiment where new inhibitors
are incubated with kinase bound to known radioligands. At 1
micro-molar concentration, one or more compounds of the present
invention exhibits at least about 50%, 60%, 70, 80%, 90% or even
higher inhibition of kinases including EGFR, EGFR L858R, EGFR del
E746-A750, EGFR T790M or EGFR L858R/T790M.
[1874] The chemical entities described herein may be prepared in
substantially pure form, typically by standard chromatographic
methods, prior to formulation in a pharmaceutically acceptable
form.
[1875] The chemical entities described herein may be used in
treating a variety of cancers. Cancers that can be prevented and/or
treated by the chemical entities, compositions, and methods
described herein include, but are not limited to, human sarcomas
and carcinomas, e.g. carcinomas, e.g., colon carcinoma, pancreatic
cancer, breast cancer, ovarian cancer, prostate cancer, thyroid
cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma,
osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma,
lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma,
mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma,
squamous cell carcinoma, basal cell carcinoma, adenocarcinoma,
sweat gland carcinoma, sebaceous gland carcinoma, papillary
carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary
carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma,
bile duct carcinoma, choriocarcinoma, seminoma, embryonal
carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung
carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial
carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma,
ependymoma, pinealoma, hemangioblastoma, acoustic neuroma,
oligodendroglioma, meningioma, melanoma, neuroblastoma,
retinoblastoma, leukemias, e.g., acute lymphocytic leukemia and
acute myelocytic leukemia (myeloblastic, promyelocytic,
myelomonocytic, monocytic and erythroleukemia); chronic leukemia
(chronic myelocytic (granulocytic) leukemia and chronic lymphocytic
leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and
non-Hodgkin's disease), multiple myeloma, Waldenstrom's
macroglobulinemia, and heavy chain disease.
[1876] In some embodiments, the chemical entities described herein
are used for the treatment of cancers of the [1877] i. digestive
system including, without limitation, the esophagus, stomach, small
intestine, colon (including colorectal), liver & intrahepatic
bile duct, gallbladder & other biliary, pancreas, and other
digestive organs; [1878] ii. respiratory system, including without
limitation, larynx, lung & bronchus, and other respiratory
organs; [1879] iii. skin; [1880] iv. thyroid; [1881] v. breast;
[1882] vi. genital system, including without limitation, uterine
cervix, ovary, and prostate; [1883] vii. urinary system, including
without limitation, urinary bladder and kidney and renal pelvis;
and [1884] viii. oral cavity & pharynx, including without
limitation, tongue, mouth, pharynx, and other oral cavity.
[1885] In some embodiments, the chemical entities described herein
are used for the treatment of colon cancer, liver cancer, lung
cancer, melanoma, thyroid cancer, breast cancer, ovarian cancer,
and oral cancer.
[1886] The chemical entities described herein may also be used in
conjunction with other well known therapeutic agents that are
selected for their particular usefulness against the condition that
is being treated. For example, the chemical entities described
herein may be useful in combination with at least one additional
anti-cancer and/or cytotoxic agents. Further, the chemical entities
described herein may also be useful in combination with other
inhibitors of parts of the signaling pathway that links cell
surface growth factor receptors to nuclear signals initiating
cellular proliferation.
[1887] Such known anti-cancer and/or cytotoxic agents that may be
used in combination with the chemical entities described herein
include:
[1888] (i) other antiproliferative/antineoplastic drugs and
combinations thereof, as used in medical oncology, such as
alkylating agents (for example cis-platin, oxaliplatin,
carboplatin, cyclophosphamide, nitrogen mustard, melphalan,
chlorambucil, busulphan, temozolamide and nitrosoureas);
antimetabolites (for example gemcitabine and antifolates such as
fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,
methotrexate, cytosine arabinoside, and hydroxyurea); antitumor
antibiotics (for example anthracyclines like adriamycin, bleomycin,
doxorubicin, daunomycin, epirubicin, idarubicin, mitomycinC,
dactinomycin and mithramycin); antimitotic agents (for example
vinca alkaloids like vincristine, vinblastine, vindesine and
vinorelbine and taxoids like taxol and taxotere and polokinase
inhibitors); and topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
topotecan and camptothecin);
[1889] (ii) cytostatic agents such as antioestrogens (for example
tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and
iodoxyfene), antiandrogens (for example bicalutamide, flutamide,
nilutamide and cyproterone acetate), LHRH antagonists or LHRH
agonists (for example goserelin, leuprorelin and buserelin),
progestogens (for example megestrol acetate), aromatase inhibitors
(for example as anastrozole, letrozole, vorazole and exemestane)
and inhibitors of 5a-reductase such as finasteride;
[1890] (iii) anti-invasion agents [for example c-Src kinase family
inhibitors like
4-(6-chloro-2,3methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy-
]-5-tetrahydropyran-4yloxyquinazoline (AZD0530; International
Patent Application WO 01/94341),
N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-met-
hylpyrimidin-4ylamino}thiazole-5-carboxamide (dasatinib,
BMS-354825; J. Med. Chern., 2004, 47, 66586661) and bosutinib
(SK1-606), and metalloproteinase inhibitors like marimastat,
inhibitors of urokinase plasminogen activator receptor function or
antibodies to Heparanase];
[1891] (iv) inhibitors of growth factor function: for example such
inhibitors include growth factor antibodies and growth factor
receptor antibodies (for example the anti-erbB2 antibody
trastuzumab [HerceptinTm], the anti-EGFR antibody panitumumab, the
anti-erbB 1 antibody cetuximab [Erbitux, C225] and any growth
factor or growth factor receptor antibodies disclosed by Stem et
at. Critical reviews in oncology/haematology, 2005, Vol. 54, pp
11-29); such inhibitors also include tyrosine kinase inhibitors,
for example inhibitors of the epidermal growth factor family (for
example EGFR family tyrosine kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-
-amine (gefltinib, ZD1839),
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
(erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazol-
in-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as
lapatinib); inhibitors of the hepatocyte growth factor family;
inhibitors of the insulin growth factor family; inhibitors of the
platelet-derived growth factor family such as imatinib and/or
nilotinib (AMN107); inhibitors of serine/threonine kinases (for
example Ras/Raf signalling inhibitors such as farnesyl transferase
inhibitors, for example sorafenib (BAY 43-9006), tipifarnib
(RI15777) and lonafarnib (5CH66336)), inhibitors of cell signalling
through MEK and/or AKT kinases, c-kit inhibitors, abl kinase
inhibitors, P13 kinase inhibitors, Plt3 kinase inhibitors, CSF-IR
kinase inhibitors, IGF receptor (insulin like growth factor) kinase
inhibitors; aurora kinase inhibitors (for example AZD1152,
PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459)
and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4
inhibitors;
[1892] (v) antiangiogenic agents such as those which inhibit the
effects of vascular endothelial growth factor, [for example the
anti-vascular endothelial cell growth factor antibody bevacizumab
(Avastin.TM.) and for example, a VEGF receptor tyrosine kinase
inhibitor such as vandetanib (ZD6474), vatalanib (PTK787),
sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034)
and 4.
{4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3pyrrolidin-1-ylpropoxy)qui-
nazoline (AZD2171; Example 240 within WO 00/47212), compounds such
as those disclosed in International Patent Applications WO
97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds
that work by other mechanisms (for example linomide, inhibitors of
integrin av-3 function and angiostatin));
[1893] (vi) vascular damaging agents such as Combretastatin A4 and
compounds disclosed in International Patent Applications WO
99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO
02/08213;
[1894] (vii) an endothelin receptor antagonist, for example
zibotentan (ZD4054) or atrasentan;
[1895] (viii) antisense therapies, for example those which are
directed to the targets listed above, such as ISIS 2503, an
anti-ras antisense;
[1896] (ix) gene therapy approaches, including for example
approaches to replace aberrant genes such as aberrant p53 or
aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug
therapy) approaches such as those using cytosine deaminase,
thymidine kinase or a bacterial nitroreductase enzyme and
approaches to increase subject tolerance to chemotherapy or
radiotherapy such as multi-drug resistance gene therapy; and
[1897] (x) immunotherapy approaches, including for example ex-vivo
and in-vivo approaches to increase the immunogenicity of subject's
tumor cells, such as transfection with cytokines such as
interleukin 2, interleukin 4 or granulocyte-macrophage colony
stimulating factor, approaches to decrease T-cell energy,
approaches using transfected immune cells such as
cytokine-transfected dendritic cells, approaches using
cytokine-transfected tumor cell lines and approaches using
anti-idiotypic antibodies.
[1898] In certain embodiments, the at least one chemical entity is
administered in combination with one or more agents chosen from
pacliataxel, bortezomib, dacarbazine, gemcitabine, trastuzumab,
bevacizumab, capecitabine, docetaxel, erlotinib, aromatase
inhibitors, such as AROMASIN.TM. (exemestane), and estrogen
receptor inhibitors, such as FASLODEX.TM. (fulvestrant).
[1899] When a chemical entity described herein is administered into
a human subject, the daily dosage will normally be determined by
the prescribing physician with the dosage generally varying
according to the age, weight, and response of the individual
subject, as well as the severity of the subject's symptoms.
[1900] In one exemplary application, a suitable amount of at least
one chemical entity is administered to a mammal undergoing
treatment for cancer, for example, breast cancer. Administration
typically occurs in an amount of between about 0.01 mg/kg of body
weight to about 100 mg/kg of body weight per day (administered in
single or divided doses), such as at least about 0.1 mg/kg of body
weight per day. A particular therapeutic dosage can include, e.g.,
from about 0.01 mg to about 1000 mg of the chemical entity, such as
including, e.g., from about 1 mg to about 1000 mg. The quantity of
the at least one chemical entity in a unit dose of preparation may
be varied or adjusted from about 0.1 mg to 1000 mg, such as from
about 1 mg to 300 mg, for example 10 mg to 200 mg, according to the
particular application. The amount administered will vary depending
on the particular IC.sub.50 value of the at least one chemical
entity used and the judgment of the attending clinician taking into
consideration factors such as health, weight, and age. In
combinational applications in which the at least one chemical
entity described herein is not the sole active ingredient, it may
be possible to administer lesser amounts of the at least one
chemical entity and still have therapeutic or prophylactic
effect.
[1901] In some embodiments, the pharmaceutical preparation is in
unit dosage form. In such form, the preparation is subdivided into
unit doses containing appropriate quantities of the active
component, e.g., an effective amount to achieve the desired
purpose.
[1902] The actual dosage employed may be varied depending upon the
requirements of the subject and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the at least one chemical entity. Thereafter, the dosage is
increased by small amounts until the optimum effect under the
circumstances is reached. For convenience, the total daily dosage
may be divided and administered in portions during the day if
desired.
[1903] The amount and frequency of administration of the at least
one chemical entities described herein, and if applicable other
chemotherapeutic agents and/or radiation therapy, will be regulated
according to the judgment of the attending clinician (physician)
considering such factors as age, condition and size of the subject
as well as severity of the disease being treated.
[1904] The chemotherapeutic agent and/or radiation therapy can be
administered according to therapeutic protocols well known in the
art. It will be apparent to those skilled in the art that the
administration of the chemotherapeutic agent and/or radiation
therapy can be varied depending on the disease being treated and
the known effects of the chemotherapeutic agent and/or radiation
therapy on that disease. Also, in accordance with the knowledge of
the skilled clinician, the therapeutic protocols (e.g., dosage
amounts and times of administration) can be varied in view of the
observed effects of the administered therapeutic agents (i.e.,
antineoplastic agent or radiation) on the subject, and in view of
the observed responses of the disease to the administered
therapeutic agents.
[1905] Also, in general, the at least one chemical entities
described herein need not be administered in the same
pharmaceutical composition as a chemotherapeutic agent, and may,
because of different physical and chemical characteristics, be
administered by a different route. For example, the chemical
entities/compositions may be administered orally to generate and
maintain good blood levels thereof, while the chemotherapeutic
agent may be administered intravenously. The determination of the
mode of administration and the advisability of administration,
where possible, in the same pharmaceutical composition, is well
within the knowledge of the skilled clinician. The initial
administration can be made according to established protocols known
in the art, and then, based upon the observed effects, the dosage,
modes of administration and times of administration can be modified
by the skilled clinician.
[1906] The particular choice of chemical entity (and where
appropriate, chemotherapeutic agent and/or radiation) will depend
upon the diagnosis of the attending physicians and their judgment
of the condition of the subject and the appropriate treatment
protocol.
[1907] The chemical entities described herein (and where
appropriate chemotherapeutic agent and/or radiation) may be
administered concurrently (e.g., simultaneously, essentially
simultaneously or within the same treatment protocol) or
sequentially, depending upon the nature of the proliferative
disease, the condition of the subject, and the actual choice of
chemotherapeutic agent and/or radiation to be administered in
conjunction (i.e., within a single treatment protocol) with the
chemical entity/composition.
[1908] In combinational applications and uses, the chemical
entity/composition and the chemotherapeutic agent and/or radiation
need not be administered simultaneously or essentially
simultaneously, and the initial order of administration of the
chemical entity/composition, and the chemotherapeutic agent and/or
radiation, may not be important. Thus, the at least one chemical
entity described herein may be administered first followed by the
administration of the chemotherapeutic agent and/or radiation; or
the chemotherapeutic agent and/or radiation may be administered
first followed by the administration of the at least one chemical
entity described herein. This alternate administration may be
repeated during a single treatment protocol. The determination of
the order of administration, and the number of repetitions of
administration of each therapeutic agent during a treatment
protocol, is well within the knowledge of the skilled physician
after evaluation of the disease being treated and the condition of
the subject. For example, the chemotherapeutic agent and/or
radiation may be administered first, and then the treatment
continued with the administration of the at least one chemical
entity described herein followed, where determined advantageous, by
the administration of the chemotherapeutic agent and/or radiation,
and so on until the treatment protocol is complete.
[1909] Thus, in accordance with experience and knowledge, the
practicing physician can modify each protocol for the
administration of a chemical entity/composition for treatment
according to the individual subject's needs, as the treatment
proceeds.
[1910] The attending clinician, in judging whether treatment is
effective at the dosage administered, will consider the general
well-being of the subject as well as more definite signs such as
relief of disease-related symptoms, inhibition of tumor growth,
actual shrinkage of the tumor, or inhibition of metastasis. Size of
the tumor can be measured by standard methods such as radiological
studies, e.g., CAT or MRI scan, and successive measurements can be
used to judge whether or not growth of the tumor has been retarded
or even reversed. Relief of disease-related symptoms such as pain,
and improvement in overall condition can also be used to help judge
effectiveness of treatment.
EXAMPLES
[1911] The following examples serve to more fully describe the
manner of using the invention. These examples are presented for
illustrative purposes and should not serve to limit the true scope
of the invention.
[1912] In carrying out the procedures of the methods described
herein, it is of course to be understood that references to
particular buffers, media, reagents, cells, culture conditions and
the like are not intended to be limiting, but are to be read so as
to include all related materials that one of ordinary skill in the
art would recognize as being of interest or value in the particular
context in which that discussion is presented. For example, it is
often possible to substitute one buffer system or culture medium
for another and still achieve similar, if not identical, results.
Those of skill in the art will have sufficient knowledge of such
systems and methodologies so as to be able, without undue
experimentation, to make such substitutions as will optimally serve
their purposes in using the methods and procedures disclosed
herein.
Example 1
Preparation of
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryl-
amide
##STR00062##
##STR00063##
[1914] A mixture of 2-amino-3-bromobenzoic acid (10.8 g, 50 mmol, 1
eq.) and urea (15 g, 250 mmol, 5 eq.) was stirred at 200.degree. C.
for 3 h, then cooled and poured into ice-water. The solid was
collected by filtration, washed with H.sub.2O for three times, and
dried in vacuo to afford 8-bromoquinazoline-2,4(1H,3H)-dione as a
yellow solid (12.1 g, ca. 100% yield).
##STR00064##
[1915] To a mixture of 8-bromoquinazoline-2,4(1H,3H)-dione (12.1 g,
50 mmol, 1 eq.) in POCl.sub.3 (130 mL) was added DMF (0.5 mL). The
mixture was stirred at 130.degree. C. for 12 h, then cooled to r.t.
and concentrated. The resulting residue was dissolved in EA (100
mL) and poured into ice-water with vigorous stirring. The organic
phase was separated and washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified via column chromatography (PE/EA==10:1, v/v) to afford
8-bromo-2,4-dichloroquinazoline as a yellow solid (9.1 g, 60%
yield).
##STR00065##
[1916] To a solution of ammonia hydroxide (25 mL, 330 mmol, 10 eq.)
in THF (50 mL) cooled to 0.degree. C. was added a solution of
8-bromo-2,4-dichloroquinazoline (9.1 g, 32.7 mmol, 1 eq.) in THF
(50 mL). The mixture was stirred at 0.degree. C. for 30 min, then
diluted with EA (100 mL), washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified via column chromatography (PE/EA=10:1, v/v) to afford
8-bromo-2-chloroquinazolin-4-amine as a yellow solid (7.1 g, 83.5%
yield).
##STR00066##
[1917] To a solution of 8-bromo-2-chloroquinazolin-4-amine (7.1 g,
27 mmol, 1 eq.) in THF (80 mL) at 70.degree. C. was added isopentyl
nitrite (14 mL, 108 mmol, 4 eq.) dropwise. The resulting mixture
was stirred at 70.degree. C. for 12 h, then cooled to r.t. and
concentrated. The resulting residue was purified via column
chromatography (PE/EA=5:1, v/v) to afford
8-bromo-2-chloroquinazoline as a yellow solid (1.5 g, 23%
yield).
##STR00067##
[1918] To a solution of 2-methoxy-4-morpholinoaniline (104 mg, 0.5
mmol, 1 eq.) and 8-bromo-2-chloroquinazoline (121 mg, 0.5 mmol, 1
eq.) in MeCN (10 mL) was added K.sub.2CO.sub.3 (138 mg, 1 mmol, 2
eq.). The mixture was stirred at 120.degree. C. for 12 h, then
cooled to r.t. and concentrated. The resulting residue was purified
via column chromatography (PE/EA=3:1, v/v) to afford
8-bromo-N-(2-methoxy-4-morpholinophenyl)quinazolin-2-amine as a
yellow solid (29 mg, 29% yield).
##STR00068##
[1919] To a solution of
8-bromo-N-(2-methoxy-4-morpholinophenyl)quinazolin-2-amine (60 mg,
0.15 mmol, 1 eq.) and
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (50 mg, 0.23
mmol, 1.5 eq.) in dioxane (4 mL) was added Na.sub.2CO.sub.3 (31.8
mg, 0.3 mmol, 2 eq.), followed by Pd(dppf)Cl.sub.2 (6 mg, 0.007
mmol, 0.05 eq.) under N.sub.2 protection. The mixture was stirred
at 90.degree. C. for 12 h, then cooled to r.t., diluted with EA (40
mL) and filtered. The filtrate was concentrated. The resulting
residue was purified via column chromatography (PE/EA=1/3, v/v) to
afford
8-(3-aminophenyl)-N-(2-methoxy-4-morpholinophenyl)quinazolin-2-amine
as a yellow solid (41 mg, 64% yield).
##STR00069##
[1920] To a solution of
8-(3-aminophenyl)-N-(2-methoxy-4-morpholinophenyl)quinazolin-2-amine
(41 mg, 0.1 mmol, 1 eq.) in THF (50 mL) was added DIEA (0.06 mL,
0.3 mmol, 3 eq.), followed by acryloyl chloride (0.01 mL, 0.12
mmol, 1.2 eq.). The resulting mixture was stirred at r.t. for 1 h,
then diluted with EA (10 mL), washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting residue
was purified via column chromatography (PE/EA=1:3, v/v) to afford
N-(3-(2-((2-methoxy-4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryl-
amide as a yellow solid (17.3 mg, 36% yield). LRMS (M+H.sup.+) m/z
calculated 482.2. found 482.1. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 9.07 (s, 1H), 8.58 (d, 1H), 8.09-8.11 (m, 1H), 7.81-7.84
(m, 3H), 7.71 (dd, 1H), 7.51-7.55 (m, 2H), 7.33-7.39 (m, 2H), 3.90
(s, 3H). 3.85 (t, 4H), 3.07 (t, 4H).
Example 2
Preparation of
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acrylamide
##STR00070##
##STR00071##
[1922] To a solution of 4-morpholinoaniline (154 mg, 0.86 mmol, 1
eq.) and 8-bromo-2-chloroquinazoline (210 mg, 0.86 mmol, 1 eq.) in
MeCN (10 mL) was added K.sub.2CO.sub.3 (138 mg, 1 mmol, 2 eq.), and
the mixture was stirred at 120.degree. C. for 12 h. The mixture was
cooled to r.t. and filtered. The filtrate was concentrated. The
resulting residue was purified via column chromatography
(PE/EA=1:1, v/v) to afford
8-bromo-N-(4-morpholinophenyl)quinazolin-2-amine as a brown solid
(170 mg, 51.5% yield).
##STR00072##
[1923] To a solution of
8-bromo-N-(4-morpholinophenyl)quinazolin-2-amine (77 mg, 0.2 mmol,
1 eq.) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
(66 mg, 0.3 mmol, 1.5 eq.) in dioxane (5 mL) and H.sub.2O (1 mL)
was added Na.sub.2CO.sub.3 (63 mg, 0.6 mmol, 3 eq.), followed by
Pd(dppf)Cl.sub.2 (16 mg, 0.006 mmol, 0.1 eq.) under N.sub.2
protection. The mixture was stirred at 90.degree. C. for 12 h, then
cooled to r.t., diluted with EA (30 mL) and filtered. The filtrate
was concentrated and the resulting residue was purified via column
chromatography (PE/EA=1:2, v/v) to afford
8-(3-aminophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine as a
yellow solid (61 mg 76.8% yield).
##STR00073##
[1924] To a solution of
8-(3-aminophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine (61 mg,
0.15 mmol, 1 eq.) in THF (5 mL) was added DIEA (0.12 mL, 0.6 mmol,
4 eq.), followed by acryloyl chloride (27 mg, 0.3 mmol, 2 eq.). The
resulting mixture was stirred at r.t. for 1 h, then washed with
brine, dried, concentrated and purified by column chromatography
(PE/EA=1:2, v/v) to afford
N-(3-(2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de as a yellow solid (25.1 mg, 38.7% yield) LRMS (M+H.sup.+) m/z
calculated 452.2. found 452.3. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 9.08 (s, 1H), 8.02-8.05 (m, 1H), 7.82-7.84 (m, 2H),
7.65-7.73 (m, 3H), 7.50-7.53 (m, 2H), 7.38 (t, 1H), 7.26-7.28 (m,
1H), 7.21 (s, 1H), 6.77-6.81 (m, 2H), 6.45 (dd, 1H), 6.20-6.26 (m,
1H), 5.77 (dd, 1H), 3.85 (t, 4H), 3.07 (t, 4H).
Example 3
Preparation of
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide
##STR00074##
##STR00075##
[1926] To a solution of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline
(331 mg, 1.5 mmol, 1 eq.) and 8-bromo-2-chloroquinazoline (363 mg,
1.5 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (0.14 mL, 1.8
mmol, 1.2 eq.). The mixture was stirred at 110.degree. C. for 12 h.
The solution was then cooled to r.t. and concentrated. The
resulting residue was dissolved in EA (20 mL), washed with aqueous
Na.sub.2CO.sub.3 solution, dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The resulting residue was purified via column
chromatography (EA/MeOH=5:1, v/v) to afford
8-bromo-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine
(140 mg, 22% yield).
##STR00076##
[1927] To a solution of
8-bromo-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine
(140 mg, 0.33 mmol, 1 eq.) and
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (110 mg, 0.5
mmol, 1.5 eq.) in dioxane (10 mL) and H.sub.2O (2 mL) was added
Na.sub.2CO.sub.3 (70 mg, 0.6 mmol, 3 eq.), followed by
Pd(dppf)Cl.sub.2 (25 mg, 0.03 mmol 0.1 eq.) under N.sub.2
protection. The mixture was stirred at 90.degree. C. under N.sub.2
protection for 12 h, then cooled to r.t., diluted with EA (10 mL)
and filtered. The filtrate was concentrated and the resulting
residue was purified via column chromatography (EA/MeOH=5:1, v/v)
to afford
8-(3-aminophenyl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)quinazoli-
n-2-amine (110 mg, 75.8% yield).
##STR00077##
[1928] To a solution of
8-(3-aminophenyl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)quinazoli-
n-2-amine (110 mg, 0.25 mmol, 1 eq.) in THF (5 mL) was added DIEA
(0.13 mL, 0.75 mmol, 3 eq.) followed by acryloyl chloride (27 mg,
0.3 mmol, 2 eq.). The resulting mixture was stirred at r.t. for 1
h, then diluted with EA (10 mL), washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting residue
was re-crystallized from EA to afford
8-(3-aminophenyl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)qu-
inazolin-2-amine as a yellow solid (32.7 mg, 26.4% yield) LRMS
(M+H.sup.+) m/z calculated 495.2. found 495.3. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 9.08 (s, 1H), 8.57 (d, 2H), 8.19 (s,
1H), 8.10 (s, 1H), 7.82-7.87 (m, 3H), 7.71 (dd, 1H), 7.52-7.54 (m,
2H), 7.35-7.42 (m, 2H), 6.43-6.54 (m, 2H), 6.26-6.37 (m, 2H), 5.78
(dd, 1H), 3.91 (s, 3H), 3.16 (t, 4H), 2.64 (t, 4H), 2.40 (s,
3H).
Example 4
Preparation of
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)p-
ropionamide
##STR00078##
[1930]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)propionamide (20 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 467.2. found 467.2. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 9.05 (s, 1H), 7.62-7.90 (m, 6H), 7.28-7.49 (m, 5H), 6.81
(d, 2H), 3.15 (t, 4H), 2.61 (t, 4H), 2.32-2.43 (m, 5H), 1.12 (t,
3H).
Example 5
Preparation of
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide
##STR00079##
##STR00080##
[1932] To a suspension of 4-(4-methylpiperazin-1-yl)aniline (9.55
g, 50 mmol, 1 eq.) and 8-bromo-2-chloroquinazoline (12.1 g, 50
mmol, 1 eq.) in n-BuOH (200 mL) was added TFA (7.6 mL, 100 mmol, 2
eq.). The mixture was stirred at 90.degree. C. for 12 h. The
solution was cooled to r.t. and the precipitate was collected by
filtration, washed with EA, dried in vacuo to afford
8-bromo-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine as a
green solid (17.2 g, 67%).
##STR00081##
[1933] To a solution of
8-bromo-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine
(17.2 g, 33.6 mmol, 1 eq.) and (3-aminophenyl)boronic acid (5.52 g,
40.3 mmol, 1.2 eq.) in dioxane (200 mL) and H.sub.2O (40 mL) was
added Na.sub.2CO.sub.3 (14.2 g, 134.4 mmol, 4 eq.), followed by
Pd(dppf)Cl.sub.2 (1.4 g, 1.7 mmol, 0.05 eq.) under N.sub.2
protection. The mixture was stirred at 90.degree. C. for 12 h, then
cooled to r.t., diluted with EA (30 mL) and filtered. The filtrate
was concentrated and the resulting residue was purified via column
chromatography (DCM/MeOH=20:1, v/v) to afford
8-(3-aminophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine
as a yellow solid (13.3 g, 96% yield).
##STR00082##
[1934] To a solution of
8-(3-aminophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-2-amine
(13.3 g, 32.4 mmol, 1 eq.) in DCM (400 mL) cooled in ice-bath was
added TEA (9. mL, 64.8 mmol, 2 eq.) was added acryloyl chloride
(3.1 mL, 39 mmol, 1.2 eq.) dropwise. The resulting mixture was
stirred at r.t. for 1 h, washed with brine, dried over anhydrous
N.sub.2SO.sub.4, concentrated and the resulting residue was
purified via column chromatography (DCM/MeOH=10:1, v/v) to afford
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide as a yellow solid (11 g, 73% yield). LRMS (M+H) m/z
calculated 465.2. found 465.1. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 9.06 (s, 1H), 8.00 (s, 1H), 7.49-7.97 (m, 8H), 7.34-7.39
(m, 2H), 6.81 (d, 2H), 6.42-6.48 (m, 1H), 6.22-6.31 (m, 1H), 5.76
(dd, 1H), 3.16 (t, 4H), 2.64 (t, 4H), 2.41 (s, 3H).
Example 6
Preparation of
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
cetamide
##STR00083##
[1936]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acetamide (20 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 453.2. found 453.2. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 9.08 (s, 1H), 7.63-7.90 (m, 6H), 7.50 (d, 2H), 7.38 (t,
1H), 7.23 (s, 2H), 6.83 (d, 2H), 3.17 (t, 4H), 2.61 (t, 4H), 2.34
(s, 3H), 2.19 (s, 3H).
Example 7
Preparation of
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide
##STR00084##
[1938]
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide (44.2 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 479.2. found 479.2. .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 9.07 (s, 1H), 7.47-7.92 (m, 9H), 7.38 (t, 1H), 7.22 (s,
1H), 6.81 (d, 2H), 6.42-6.46 (m, 2H), 5.77 (d, 1H), 3.21-3.24 (m,
4H), 2.75-2.81 (m, 4H), 2.63-2.65 (m, 2H), 1.22-1.29 (m, 3H).
Example 8
Preparation of
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide
##STR00085##
[1940]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide (653 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 493.2. found 493.1. .sup.1H NMR (DMSO-d6, 300 MHz)
.delta. 10.29 (s, 1H), 9.70 (s, 1 H), 9.30 (s, 1H), 7.75-8.01 (m,
6H), 7.32-7.51 (m, 3H), 6.73 (d, 2H), 6.44-6.53 (m, 1H), 6.24-6.53
(m, 1H), 5.75-5.79 (m, 1H), 3.54-3.56 (m, 4H), 2.90-3.00 (m, 4H),
2.04 (s, 3H).
Example 9
Preparation of
N-(3-(2-((6-(4-acetylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide
##STR00086##
[1942]
N-(3-(2-((6-(4-acetylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-
-yl)phenyl)acrylamide (10.4 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 494.2. found 494.1. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 9.10 (s, 1H), 8.51 (s, 1H), 8.11-8.13 (m, 1H), 7.32-7.89
(m, 9H), 6.26-6.58 (m, 3H), 5.78 (d, 1H), 3.40-3.77 (m, 8H), 2.16
(s, 3H).
Example 10
Preparation of
N-(3-(2-((6-(4-acetylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)ph-
enyl)acrylamide
##STR00087##
[1944]
N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-
-yl)phenyl)acrylamide (22 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H+) m/z calculated
466.2. found 465.9. 1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.18 (s,
1H), 8.33-8.42 (m, 2H), 7.82-7.93 (m, 4H), 7.39-7.49 (m, 3H),
6.40-6.63 (m, 3H), 5.80 (dd, 1H), 3.52-3.54 (m, 4H), 2.91-2.94 (m,
4H), 2.63 (s, 3H).
Example 11
Preparation of
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-fluoro-
phenyl)acrylamide
##STR00088##
[1946]
N-(3-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2--
fluorophenyl)acrylamide (9.1 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 497.2. found 497.2. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 9.09 (s, 1H), 8.54 (t, 1H), 7.78-7.80 (m, 3H), 7.53 (d,
2H), 7.23-7.43 (m, 4H), 7.10 (t, 1H), 6.71 (d, 2H), 6.30-6.50 (m,
2H), 5.84 (d, 1H), 4.64 (d, 2H), 3.35-3.38 (m, 4H), 3.00-3.13 (m,
4H), 2.84-2.89 (m, 2H), 1.34-1.43 (m, 3H).
Example 12
Preparation of
N-(5-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
3-yl)acrylamide
##STR00089##
[1948]
N-(5-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)py-
ridin-3-yl)acrylamide (23.7 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 494.2. found 494.2. .sup.1H NMR (DMSO-d6, 300 MHz)
.delta. 10.52 (s, 1H), 9.75 (s, 1H), 9.32 (s, 1H), 9.01 (s, 1H),
8.48-8.50 (m, 2H), 7.95 (dd, 2H), 7.70 (d, 2H), 7.45 (t, 1H), 6.72
(d, 2H), 6.28-6.55 (m, 2H), 5.82 (d, 1H), 3.50-3.56 (m, 4H),
2.90-3.02 (m, 4H), 2.05 (s, 3H).
Example 13
Preparation of
N-(5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
3-yl)acrylamide
##STR00090##
[1950]
N-(5-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)py-
ridin-3-yl)acrylamide (24.2 mg) was prepared as described for
N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)
amino)quinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z
calculated 466.2. found 465.9. .sup.1H NMR (CD.sub.3OD, 300 MHz)
.delta. 9.16 (s, 1H), 9.08 (s, 1H), 8.57 (s, 1H), 8.47-8.48 (s,
1H), 7.85-7.89 (m, 2H), 7.65 (d, 2H), 7.43 (t, 1H), 6.81 (d, 2H),
6.45-6.49 (m, 2H), 5.86 (dd, 1H), 3.17-3.20 (m, 4H), 2.90-2.93 (m,
4H), 2.59 (s, 3H).
Example 14
Preparation of tert-butyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-3-methoxyphenyl)piper-
azine-1-carboxylate
##STR00091##
##STR00092##
[1952] To a solution of tert-butyl
4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (450 mg, 1.5
mmol, 1 eq.) and 8-bromo-2-chloroquinazoline (363 mg, 1.5 mmol, 1
eq.) in n-BuOH (10 mL) was added TFA (0.14 mL, 1.8 mmol, 1.2 eq.).
The mixture was stirred at 110.degree. C. for 12 h, then cooled to
r.t. and concentrated. The resulting residue was dissolved in EA,
washed with aqueous Na.sub.2CO.sub.3 solution, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified via column chromatography (PE/EA=1:1, v/v) to afford
tert-butyl
4-(4-((8-bromoquinazolin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxy-
late as a yellow solid (110 mg, 13%).
##STR00093##
[1953] To a solution of tert-butyl
4-(4-((8-bromoquinazolin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxy-
late (110 mg, 0.2 mmol, 1 eq.) and
344,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (66 mg, 0.3
mmol, 1.5 eq.) in dioxane (10 mL) and H.sub.2O (2 mL) was added
Na.sub.2CO.sub.3 (43 mg, 0.4 mmol, 2 eq.), followed by
Pd(dppf)Cl.sub.2 (20 mg, 0.02 mmol, 0.1 eq.) under N.sub.2
protection. The mixture was stirred at 90.degree. C. under N.sub.2
protection for 12 h, then cooled to r.t., diluted with EA (20 mL)
and filtered. The filtrate was concentrated and the resulting
residue was purified via column chromatography (PE/EA=1:1, v/v) to
afford tert-butyl
4-(4-((8-(3-aminophenyl)quinazolin-2-yl)amino)-3-methoxyphenyl)piperazine-
-1-carboxylate (82 mg, 72% yield).
##STR00094##
[1954] To a solution of tert-butyl
4-(4-((8-(3-aminophenyl)quinazolin-2-yl)amino)-3-methoxyphenyl)piperazine-
-1-carboxylate (82 mg, 0.16 mmol, 1 eq.) in THF (5 mL) was added
DIEA (0.1 mL, 0.48 mmol, 3 eq.) followed by acryloyl chloride (30
mg, 0.32 mmol, 2 eq.). The resulting mixture was stirred at r.t.
for 1 h, then washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified via column chromatography (PE/EA=2:3, v/v) to afford
tert-butyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-3-methoxyphenyl)piper-
azine-1-carboxylate as a yellow solid (19.7 mg, 22% yield). LRMS
(M+H.sup.+) m/z calculated 581.3. found 581.2. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 9.09 (s, 1H), 8.58 (d, 2H), 8.11 (d,
1H), 7.82-7.87 (m, 3H), 7.73 (d, 1H), 7.52-7.54 (m, 1H), 7.36-7.41
(m, 2H), 6.45-6.55 (m, 2H), 6.21-6.35 (m, 2H), 5.78 (dd, 1H), 3.91
(s, 3H), 3.58 (t, 4H), 3.04 (t, 4H), 1.48 (s, 9H).
Example 15
Preparation of
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine
##STR00095##
##STR00096##
[1956] To a solution of
8-bromo-N-(4-morpholinophenyl)quinazolin-2-amine (77 mg, 0.2 mmol,
1 eq.) and phenylboronic acid (37 mg, 0.3 mmol, 1.5 eq.) in dioxane
(5 mL) and H.sub.2O (1 mL) was added Na.sub.2CO.sub.3 (63 mg, 0.6
mmol, 3 eq.), followed by Pd(dppf)Cl.sub.2 (16 mg, 0.006 mmol, 0.1
eq.) under N.sub.2 protection. The mixture was stirred at
90.degree. C. under N.sub.2 protection for 12 h, then cooled to
r.t., diluted with EA (15 mL) and filtered. The filtrate was
concentrated and the resulting residue was purified via column
chromatography (PE/EA=1:1, v/v) to afford
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. (30.3 mg, 39.4%
yield) LRMS (M+H.sup.+) m/z calculated 383.2. found 383.1. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 9.08 (s, 1H), 7.63-7.81 (m, 6H),
7.38-7.53 (m, 4H), 7.21 (s, 1H), 6.81 (d, 2H), 3.88 (t, 4H), 3.10
(t, 4H).
Example 16
Preparation of 8-(5-chloro-2-fluorophenyl)-N-(4-morpholinophenyl)
quinazolin-2-amine
##STR00097##
[1958]
8-(5-Chloro-2-fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amin-
e (80 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine LRMS (M+H.sup.+)
m/z calculated 435.1. found 435.1. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 9.08 (s, 1H), 7.76-7.79 (m, 2H), 7.61-7.64 (m, 1H),
7.54-7.56 (m, 2H), 7.24 (s, 1H), 7.15 (t, 1H), 6.82-6.85 (m, 2H),
3.88 (t, 4H), 3.10 (t, 4H).
Example 17
Preparation of 8-(3-chlorophenyl)-N-(4-morpholinophenyl)
quinazolin-2-amine
##STR00098##
[1960] 8-(3-Chlorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
(50.4 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 417.1. found 417.1. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.09 (s, 1H), 7.88 (s, 1H), 7.74-7.81 (m, 2H),
7.60-7.67 (m, 3H), 7.37-7.45 (m, 3H), 7.30 (s, 1H), 7.15 (t, 1H),
6.90 (d, 2H), 3.90 (t, 4H), 3.13 (t, 4H).
Example 18
Preparation of 8-(3-fluorophenyl)-N-(4-morpholinophenyl)
quinazolin-2-amine
##STR00099##
[1962] 8-(3-Fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
(58.6 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 401.2. found 401.2. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.59-7.83 (m, 5H), 7.37-7.57 (m, 3H),
7.31 (s, 1H), 7.13-7.19 (m, 1H), 6.86 (d, 2H), 3.90 (t, 4H), 3.13
(t, 4H).
Example 19
Preparation of 8-(2-fluorophenyl)-N-(4-morpholinophenyl)
quinazolin-2-amine
##STR00100##
[1964] 8-(2-Fluorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
(40.2 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 401.2. found 401.2. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.76-7.83 (m, 2H), 7.55-7.60 (m, 3H),
7.23-7.42 (m, 5H), 6.78 (d, 2H), 3.89 (t, 4H), 3.10 (t, 4H).
Example 20
Preparation of
8-(2-chlorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
##STR00101##
[1966] 8-(2-Chlorophenyl)-N-(4-morpholinophenyl)quinazolin-2-amine
(19.4 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 417.1. found 417.1. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.75-7.80 (m, 3H), 7.59-7.62 (m, 1H),
7.38-7.451 (m, 6H), 7.18 (s, 1H), 6.73 (d, 2H), 3.87 (t, 4H), 3.09
(t, 4H).
Example 21
Preparation of tert-butyl
4-(4-((8-(2-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate
##STR00102##
[1968] Tert-butyl
4-(4-((8-(2-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate (7.7 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 500.2. found 500.1. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.76-7.82 (m, 2H), 7.54-7.57 (m, 3H),
7.38-7.43 (m, 1H), 7.29-7.33 (m, 2H), 7.19-7.26 (m, 2H), 6.76-6.81
(m, 2H), 3.61 (t, 4H), 3.04 (t, 4H), 1.51 (s, 9H).
Example 22
Preparation of tert-butyl
4-(4-((8-(2-chlorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate
##STR00103##
[1970] Tert-butyl
4-(4-((8-(2-chlorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate (5.2 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 515.2. found 516.1. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.78 (t, 2H), 7.59 (d, 1H), 7.38-7.50
(m, 6H), 7.18 (s, 1H), 6.73 (d, 2H), 3.60 (m, 4H), 3.04 (m,
4H).
Example 23
Preparation of tert-butyl
4-(4-((8-(3-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate
##STR00104##
[1972] Tert-butyl
4-(4-((8-(3-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate (7.3 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 500.2. found 500.1. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.37-7.83 (m, 8H), 7.22-7.27 (m, 2H),
6.87 (d, 2H), 3.60-3.63 (m, 4H), 3.06-3.09 (m, 4H), 1.51 (s,
9H).
Example 24
Preparation of tert-butyl
4-(4-((8-(5-chloro-2-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-
-1-carboxylate
##STR00105##
[1974] Tert-butyl
4-(4-((8-(5-chloro-2-fluorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-
-1-carboxylate (3.2 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 500.2. found 500.1. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.37-7.83 (m, 8H), 7.22-7.27 (m, 2H),
6.87 (d, 2H), 3.60-3.63 (m, 4H), 3.06-3.09 (m, 4H), 1.51 (s,
9H).
Example 25
Preparation of tert-butyl
4-(4-((8-(3-chlorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate
##STR00106##
[1976] Tert-butyl
4-(4-((8-(3-chlorophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-carbox-
ylate (6.1 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 516.2. found 516.2. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.37-7.88 (m, 9H), 7.23 (s, 1H), 6.91
(d, 2H), 3.60-3.63 (m, 4H), 3.06-3.09 (m, 4H), 1.51 (s, 9H).
Example 26
Preparation of tert-butyl
4-(4-((8-phenylquinazolin-2-yl)amino)phenyl)piperazine-1-carboxylate
##STR00107##
[1978] Tert-butyl
4-(4-((8-phenylquinazolin-2-yl)amino)phenyl)piperazine-1-carboxylate
(7.6 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 482.2. found 482.2. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.10 (s, 1H), 7.40-7.81 (m, 9H), 7.21 (s, 1H), 6.84
(d, 2H), 3.60-3.63 (m, 4H), 3.05-3.09 (m, 4H), 1.51 (s, 9H).
Example 27
Preparation of
8-(5-chloro-2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amin-
e
##STR00108##
[1980]
8-(5-Chloro-2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin--
2-amine (13.5 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 434.1. found 434.2. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 9.07 (s, 1H), 7.37-7.79 (m, 8H), 6.85 (d, 2H),
3.12-3.15 (m, 8H).
Example 28
Preparation of
8-(3-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
##STR00109##
[1982]
8-(3-Chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
(20.1 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 416.2. found 416.2. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 9.07 (s, 1H), 7.30-7.85 (m, 10H), 6.89 (d, 2H),
3.12-3.15 (m, 8H).
Example 29
Preparation of
8-(2-chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
##STR00110##
[1984]
8-(2-Chlorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
(24.5 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 416.2. found 416.2. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 9.07 (s, 1H), 7.28-7.78 (m, 10H), 6.72 (d, 2H), 3.10
(m, 8H).
Example 30
Preparation of
8-(3-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
##STR00111##
[1986]
8-(3-Fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
(7.6 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 400.2. found 400.1. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.07 (s, 1H), 7.29-7.80 (m, 9H), 7.15 (t, 1H), 6.86
(d, 2H), 3.06-3.11 (m, 8H).
Example 31
Preparation of
8-phenyl-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
##STR00112##
[1988] 8-Phenyl-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
(14.6 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 382.2. found 382.2. .sup.1H NMR (CD3Cl3, 400 MHz)
.delta. 9.07 (s, 1H), 7.33-7.81 (m, 11H), 6.82 (d, 2H), 3.10 (m,
8H).
Example 32
Preparation of
8-(2-fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
##STR00113##
[1990]
8-(2-Fluorophenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine
(41.6 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 400.2. found 400.2. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 9.07 (s, 1H), 7.18-7.79 (m, 10H), 6.78 (d, 2H),
3.04-3.06 (m, 8H).
Example 33
Preparation of tert-butyl
4-(4-((8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)quinazolin-2-yl)amino)phe-
nyl)piperazine-1-carboxylate
##STR00114##
[1992] Tert-butyl
4-(4-((8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)quinazolin-2-yl)amino)phe-
nyl)piperazine-1-carboxylate (12.6 mg) was prepared as described
for N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS
(M+H.sup.+) m/z calculated 629.3. found 629.2. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 9.08 (s, 1H), 7.79 (t, 2H), 7.58-7.75
(m, 3H), 7.40 (t, 1H), 7.00-7.20 (m, 3H), 6.80 (d, 2H), 4.10 (t,
2H), 3.59-3.73 (m, 8H), 3.04-3.07 (m, 4H), 2.78 (t, 2H), 2.54-2.58
(m, 4H), 1.51 (s, 1H).
Example 34
Preparation of
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)quinazoli-
n-2-amine
##STR00115##
[1994]
8-(2-Fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-morpholinophenyl)qui-
nazolin-2-amine (11 mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 530.2. found 530.3. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 9.07 (s, 1H), 7.77 (t, 2H), 7.57 (d, 2H), 7.30-7.40
(m, 2H), 7.07-7.17 (m, 2H), 6.97-7.00 (m, 1H), 6.77 (d, 2H), 4.09
(t, 2H), 3.87 (t, 4H), 3.70 (t, 4H), 3.08 (t, 4H), 2.79 (t, 2H),
2.55 (t, 4H), 2.34 (s, 3H), 2.19 (s, 3H).
Example 35
Preparation of
8-(2-fluoro-5-(2-morpholinoethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)qui-
nazolin-2-amine
##STR00116##
[1996] 8-(2-Fluoro-5-(2-morpholino
ethoxy)phenyl)-N-(4-(piperazin-1-yl)phenyl)quinazolin-2-amine (53.4
mg) was prepared as described for
N-(4-morpholinophenyl)-8-phenylquinazolin-2-amine. LRMS (M+H.sup.+)
m/z calculated 529.3. found 529.3. .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 9.08 (s, 1H), 7.78 (t, 2H), 7.57 (d, 2H), 7.39 (t,
1H), 7.25 (s, 1H), 7.16 (t, 1H), 7.06-7.14 (m, 3H), 6.79 (d, 2H),
4.091 (t, 2H), 3.69 (t, 4H), 3.20 (m, 8H), 2.78 (t, 2H), 2.54 (m,
4H).
Example 36
Preparation of
N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)ph-
enyl)acrylamide
##STR00117##
##STR00118##
[1998] To a solution of 2-chloropyridin-3-amine (12.9 g, 0.1 mol, 1
eq.) and DMAP (13.4 g, 0.11 mmol, 1.1 eq.) in DCM (150 mL) was
added Boc.sub.2O (24.0 g, 0.11 mmol, 1.1 eq.) dropwise at r.t. The
resulting mixture was stirred at r.t. for 3 h, then concentrated.
The resulting residue was purified via flash column chromatography
(EA/PE=1/30, v/v) to afford tert-butyl
(2-chloropyridin-3-yl)carbamate (16.99 g, 74.2% yield).
##STR00119##
[1999] To a mixture of tert-butyl (2-chloropyridin-3-yl)carbamate
(2.29 g, 10 mmol, 1 eq.) in THF (50 mL) was added n-BuLi (12 mL,
2.5M, 30 mmol, 3 eq.) dropwise at -78.degree. C. under N.sub.2. The
mixture was stirred at -78.degree. C. for 1 h, then bubbled with
CO.sub.2 for 30 min, concentrated, washed by sat. Na.sub.2CO.sub.3
solution, and extracted by EA (100 mL.times.2). The water phase was
acidified with conc. HCl to pH 4-5, extracted with EA (100
mL.times.2). The combined organic phases were washed with brine,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford
3-((tert-butoxycarbonyl)amino)-2-chloroisonicotinic acid (2.1 g,
76.9% yield).
##STR00120##
[2000] A mixture of
3-((tert-butoxycarbonyl)amino)-2-chloroisonicotinic acid (7.26 g,
27 mmol, 1 eq.), (3-nitrophenyl)boronic acid (4.9 g, 29 mmol, 1.1
eq.), Na.sub.2CO.sub.3 (11.45 g, 110 mmol, 4 eq.) and
Pd(PPh.sub.3).sub.4 (1.54 g, 2.7 mmol, 0.1 eq.) in dioxane (100 mL)
and water (10 mL) was heated at 100.degree. C. overnight, then
cooled and concentrated. The resulting residue was dissolved in DCM
(30 mL) and filtered. The filtrate was concentrated to afford crude
3-((tert-butoxycarbonyl)amino)-2-(3-nitrophenyl)isonicotinic acid,
which was used in next step without further purification.
##STR00121##
[2001] To a solution of crude
3-((tert-butoxycarbonyl)amino)-2-(3-nitrophenyl)isonicotinic acid
(6.8 g, 19 mmol, 1 eq.) in DCM (50 mL) at r.t. was added TFA (10
mL, 108 mmol, 4 eq.) dropwise. The resulting mixture was stirred at
r.t. overnight, then concentrated. The residue was purified via
RP-HPLC to afford 3-amino-2-(3-nitrophenyl)isonicotinic acid as
yellow solid (4.7 g, 96% yield).
##STR00122##
[2002] A mixture of 3-amino-2-(3-nitrophenyl)isonicotinic acid (4.7
g, 18 mmol, 1 eq.) and urea (10.9 g, 180 mmol, 50 eq.) was stirred
at 200.degree. C. for 6 h, then cooled and poured into ice-water.
The solid was collected by filtration, then suspended in 5% aq.
NaOH and stirred at r.t. overnight. The solid was collected by
filtration, washed with H.sub.2O (100 mL.times.3) and dried in
vacuo to afford 8-(3-nitrophenyl)pyrido[3,4-d]pyrimidine-2,4-diol
(3.7 g, 71.8% yield).
##STR00123##
[2003] To a mixture of
8-(3-nitrophenyl)pyrido[3,4-d]pyrimidine-2,4-diol (3.7 g, 13 mmol,
1 eq.) in POCl.sub.3 (40 mL) was added DMF (0.5 mL). The mixture
was stirred at 130.degree. C. for 12 h, then cooled to r.t. and
concentrated. The residue was dissolved in EA (40 mL) and slowly
poured into ice-water with vigorous stirring. The organic phase was
separated, washed with brine, dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The resulting residue was purified via flash
column chromagraphy (PE/EA=4/1, v/v) to afford
2,4-dichloro-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidine (1.25 g, 30%
yield).
##STR00124##
[2004] To a solution of ammonia hydroxide (2.97 mL, 38.9 mmol, 10
eq.) in THF (5 mL) at 0.degree. C. was added a solution of
2,4-dichloro-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidine (1.25 g, 3.89
mmol, 1 eq.) in THF (25 mL). The mixture was stirred at 0.degree.
C. for 30 min, then diluted with EA (50 mL), washed with brine,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified via flash column chromagraphy
(DCM/MeOH=10:1, v:v) to afford
2-chloro-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-4-amine (0.517 g,
44% yield).
##STR00125##
[2005] To a solution of 4-morpholinoaniline (65 mg, 0.36 mmol, 1.1
eq.) and 2-chloro-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-4-amine
(100 mg, 0.33 mmol, 1 eq.) in n-BuOH (20 mL) was added TFA (75 mg,
0.66 mmol, 2 eq.). The mixture was stirred at 100.degree. C. for 12
h, then cooled to r.t. The precipitate was collected by filtration,
washed with MeOH (10 mL.times.2) and dired in vacuo to afford
N.sup.2-(4-morpholinophenyl)-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidine-2,4-
-diamine (95 mg, 65% yield).
##STR00126##
[2006] To a solution of
N.sup.2-(4-morpholinophenyl)-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidine-2,4-
-diamine (55 mg, 0.12 mmol, 1 eq.) and DIEA (32 mg, 0.24 mmol, 2
eq.) in EA (10 mL) was added Pd/C (5.5 mg, w/w>50%). The mixture
was stirred at r.t. under H.sub.2 atmosphere (1 atm) overnight,
then filtered and concentrated. The residue was purified via flash
column chromagraphy (DCM/MeOH=10:1, v:v) to afford
8-(3-aminophenyl)-N.sup.2-(4-morpholinophenyl)pyrido[3,4-d]pyrimidine-2,4-
-diamine (32 mg, 65% yield).
##STR00127##
[2007] To a solution of
8-(3-aminophenyl)-N'-(4-morpholinophenyl)pyrido[3,4-d]pyrimidine-2,4-diam-
ine (26 mg, 0.06 mmol, 1 eq.) in DCM (10 mL) was added DIEA (0.04
mL, 0.18 mmol, 3 eq.), followed by acryloyl chloride (0.006 mL,
0.12 mmol, 1.2 eq.). The resulting mixture was stirred at r.t. for
1 h, then washed with brine, dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The resulting residue was purified via RP-HPLC to
afford
N-(3-(4-amino-2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)ph-
enyl)acrylamide as yellow solid (8.3 mg, 30% yield). LRMS
(M+H.sup.+) m/z calculated 468.2. found 468.2. .sup.1H NMR
(CD.sub.3OD, 300 MHz) .delta. 8.60 (d, 1H), 8.15 (m, 1H), 8.05 (d,
1H), 7.74 (d, 1H), 7.60 (t, 1H), 7.45-7.48 (m, 3H), 7.03 (d, 2H),
6.43-6.49 (m, 2H), 5.85 (dd, 1H), 3.85-3.87 (m, 4H), 3.85-3.87 (m,
4H).
Example 37
Preparation of
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acr-
ylamide
##STR00128##
##STR00129##
[2009] To a solution of
2,4-dichloro-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidine (455 mg, 1.42
mmol, 1 eq.) in THF (10 mL) was added NaOH (1N, 5 mL, 5 mmol, 3.52
eq.). The mixture was stirred at r.t. for 2 h, then diluted with EA
(50 mL), washed with brine, dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The resulting residue was purified via flash
column chromagraphy (DCM/MeOH=10:1, v:v) to afford
2-chloro-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-4-ol (395 mg,
92.7% yield).
##STR00130##
[2010] To a solution of 4-morpholinoaniline (258 mg, 1.45 mmol, 1.1
eq.) and 2-chloro-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-4-ol (395
mg, 1.32 mmol, 1 eq.) in n-BuOH (20 mL) was added TFA (266 mg, 2.64
mmol, 2 eq.). The mixture was stirred at 100.degree. C. for 12 h,
then cooled to r.t. The precipitate was collected by filtration,
washed with MeOH (10 mL.times.2) and dired in vacuo to afford
2-((4-morpholinophenyl)amino)-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-4-o-
l (350 mg, 65% yield).
##STR00131##
[2011] A mixture of
2-((4-morpholinophenyl)amino)-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-4-o-
l (350 mg, 0.79 mmol, 1 eq.) in POCl.sub.3 (15 mL) was heated to
140.degree. C. for 2 h, then cooled to r.t. and concentrated. The
residue was dissolved in EA (50 mL) and slowly poured into
ice-water. The organic phase was separated, washed with brine,
dried over anhydrous Na.sub.2SO.sub.4, and concentrated to afford
4-chloro-N-(4-morpholinophenyl)-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-2-
-amine (305 mg, 83.8% yield).
##STR00132##
[2012] To a solution of
4-chloro-N-(4-morpholinophenyl)-8-(3-nitrophenyl)pyrido[3,4-d]pyrimidin-2-
-amine (305 mg, 0.66 mmol, 1 eq.) and DIEA (235 mg, 1.82 mmol, 2.76
eq.) in EA (15 mL) was added Pd/C (30 mg, w/w>50%). The mixture
was stirred at r.t. under H.sub.2 atmosphere (1 atm) overnight,
then filtered and concentrated. The resulting residue was purified
via flash column chromagraphy (PE/EA=1/4, v:v) to afford
8-(3-aminophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2-amine.
##STR00133##
[2013] To a solution of
8-(3-aminophenyl)-N-(4-morpholinophenyl)pyrido[3,4-d]pyrimidin-2-amine
(50 mg, 0.13 mmol, 1 eq.) in DCM (10 mL) was added TEA (35 mg, 0.35
mmol, 2.7 eq.), followed by acryloyl chloride (0.008 mL, 0.16 mmol,
1.2 eq.). The resulting mixture was stirred at r.t. for 1 h, then
washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified via RP-HPLC to afford
N-(3-(2-((4-morpholinophenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)phenyl)acr-
ylamide (4.1 mg, 6.9% yield). LRMS (M+H.sup.+) m/z calculated
453.2. found 453.1. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.44
(s, 1H), 8.53-8.55 (m, 2H), 7.90-8.34 (m, 3H), 7.56-7.75 (m, 3H),
7.05-7.28 (m, 2H), 6.43-6.49 (m, 2H), 5.81-5.87 (m, 1H), 3.84-3.96
(m, 4H), 3.18-3.38 (m, 4H).
Example 38
Preparation of
N-(3-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide
##STR00134##
##STR00135##
[2015] To a solution of 3-amino-4-methylbenzoic acid (100 g, 0.66
mol, 1.0 eq.) in AcOH (1.34 L) was added Ac.sub.2O (412 g, 4.04
mol, 6 eq.) dropwise at r.t. over 1 h. The mixture was stirred
overnight. The solid was collected by filtration, washed with EA
(200 mL.times.3) and dried in vacuo to afford
3-acetamido-4-methylbenzoic acid (123 g, 96.2% yield).
##STR00136##
[2016] To a solution of fuming HNO.sub.3 (500 mL) at 0-5.degree. C.
was added 3-acetamido-4-methylbenzoic acid (123 g, 0.637 mol, 1
eq.) in portions over 1 h. The mixture was stirred for 1.5 h, then
ice was added. The mixture was stirred for a further 30 min. The
solid was collected by filtration, and dried in vacuo to afford
3-acetamido-4-methyl-2-nitrobenzoic acid (82 g, 54% yield).
##STR00137##
[2017] To a solution of 3-acetamido-4-methyl-2-nitrobenzoic acid
(79 g, 0.33 mol, 1.0 eq.) in dioxane (400 mL) was added HCl (6 N,
200 mL) dropwise. The mixture was heated under reflux overnight,
then extracted with EA (200 mL.times.3). The combined organic
phases were dried over Na.sub.2SO.sub.4 and concentrated. The solid
was triturated with the mixed solvent (PE/EA=10/1, v/v) and
filtered to afford 3-amino-4-methyl-2-nitrobenzoic acid (60 g,
92.7% yield).
##STR00138##
[2018] To a solution of 3-amino-4-methyl-2-nitrobenzoic acid (48.5
g, 0.25 mol, 1.0 eq.) in HBr (500 mL) at 0.degree. C. was added
NaNO.sub.2 (30.7 g, 0.44 mol, 1.8 eq.) in water (100 mL) dropwise.
After 15 min, Cu powder (2.91 g, 0.045 mol, 0.18 eq.) was added in
portions. After 30 min, the mixture was heated at 60.degree. C. for
1 h, then cooled and added ice-water until a yellow precipitate
formed. The precipitate was filtered, washed with water and dried
in vacuo to afford 3-bromo-4-methyl-2-nitrobenzoic acid (56.7 g,
86.5% yield).
##STR00139##
[2019] To a solution of 3-bromo-4-methyl-2-nitrobenzoic acid (56.7
g, 0.22 mol, 1.0 eq.) and conc. HCl (50 mL) in EtOH (700 mL) was
added Fe (36.8 g, 0.66 mol, 3 eq.) in portions. The mixture was
heated under reflux overnight, then concentrated and adjusted to pH
8-9 with NaOH (1N) and filtered. The filtrate was neutralized to
pH.about.6, the resulting precipitate was filtered and dried in
vacuo to afford 2-amino-3-bromo-4-methylbenzoic acid (49.5 g, 97.8%
yield).
##STR00140##
[2020] A mixture of 2-amino-3-bromo-4-methylbenzoic acid (2.29 g,
10 mmol, 1 eq.) and urea (8.9 g, 150 mmol, 15 eq.) was stirred at
200.degree. C. for 3 h, then poured into ice-water. The solid was
collected by filtration, washed with H.sub.2O for three times, and
dried in vacuo to afford 8-bromo-7-methylquinazoline-2,4-diol (1.6
g, 64% yield).
##STR00141##
[2021] To a mixture of 8-bromo-7-methylquinazoline-2,4-diol (1.6 g,
6.2 mmol, 1 eq.) in POCl.sub.3 (20 mL) was added DMF (0.5 mL). The
mixture was stirred at 130.degree. C. for 12 h, then cooled to
r.t., and concentrated. The resulting residue was dissolved in EA
(50 mL) and poured into ice-water with vigorous stirring. The
organic phase was separated and washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting residue
was purified via column chromatography (PE/EA-10:1, v/v) to afford
8-bromo-2,4-dichloro-7-methylquinazoline as a white solid (1.2 g,
66.7% yield).
##STR00142##
[2022] To a solution of ammonia hydroxide (3 mL, 41 mmol, 10 eq.)
in THF (25 mL) cooled to 0.degree. C. was added a solution of
8-bromo-2,4-dichloro-7-methylquinazoline (1.2 g, 4.1 mmol, 1 eq.)
in THF (25 mL). The mixture was stirred at 0.degree. C. for 30 min,
then diluted with EA (50 mL), washed with brine, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting residue
was purified via column chromatography (PE/EA=10:1, v/v) to afford
8-bromo-2-chloro-7-methylquinazolin-4-amine as a white solid (1.0
g, 90.9% yield).
##STR00143##
[2023] To a solution of 8-bromo-2-chloro-7-methylquinazolin-4-amine
(1.0 g, 3.7 mmol, 1 eq.) in THF (20 mL) at 70.degree. C. was added
isopentyl nitrite (1.9 mL, 14.8 mmol, 4 eq.) dropwise. The
resulting mixture was stirred at 70.degree. C. for 12 h, then
cooled to r.t. and concentrated. The resulting residue was purified
via column chromatography (PE/EA=8:1, v/v) to afford
8-bromo-2-chloro-7-methylquinazoline as a yellow solid (540 mg,
56.8% yield).
##STR00144##
[2024] To a solution of 4-morpholinoaniline (186 mg, 1.05 mmol, 1
eq.) and 8-bromo-2-chloro-7-methylquinazoline (270 mg, 1.05 mmol, 1
eq.) in n-BuOH (10 mL) was added TFA (0.09 mL, 1.2 mmol, 1.2 eq).
The mixture was stirred at 80.degree. C. for 12 h, cooled to r.t.
and concentrated. The resulting residue was dissolved in EA (10
mL), washed with Na.sub.2CO.sub.3 solution, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified via column chromatography (PE/EA=3:1, v/v) to afford
8-bromo-7-methyl-N-(4-morpholinophenyl)quinazolin-2-amine as a
yellow solid (311 ma. 74.6% yield).
##STR00145##
[2025] To a solution of
8-bromo-7-methyl-N-(4-morpholinophenyl)quinazolin-2-amine (311 mg,
0.78 mmol, 1 eq.) and
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (213.7 mg,
1.56 mmol, 2 eq.) in dioxane (16 mL) and water (4 mL) was added
Na.sub.2CO.sub.3 (330 mg, 3.12 mmol, 4 eq.), followed by
Pd(dppf)Cl.sub.2 (65 mg, 0.08 mmol, 0.1 eq.) under N.sub.2
protection. The mixture was stirred at 90.degree. C. for 12 h under
N.sub.2 protection, cooled to r.t., diluted with EA (40 mL) and
filtered. The filtrate was concentrated and the resulting residue
was purified by column chromatography (PE/EA=1/2, v/v) to afford
8-(3-aminophenyl)-7-methyl-N-(4-morpholinophenyl)quinazolin-2-amine
(274 mg, 85.4% yield).
##STR00146##
[2026] To a solution of
8-(3-aminophenyl)-7-methyl-N-(4-morpholinophenyl)quinazolin-2-amine
(70 mg, 0.17 mmol, 1 eq.) in DCM (10 mL) was added DIEA (0.10 mL,
0.51 mmol, 3 eq.), followed by acryloyl chloride (0.017 mL, 0.20
mmol, 1.2 eq.). The resulting mixture was stirred at r.t. for 1 h,
diluted with EA, washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, and concentrated. The resulting residue was
purified via column chromatography (PE/EA=1:3, v/v) to afford
N-(3-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide (22 mg, 27.8% yield). LRMS (M+H.sup.+) m/z
calculated 466.2. found 466.2. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 9.06 (s, 1H), 8.07-8.11 (m, 1H), 7.14-7.66 (m, 9H),
6.69-6.76 (m, 2H), 6.18-6.47 (m, 2H), 5.75-5.79 (m, 1H), 3.85-3.90
(m, 4H), 3.03-3.10 (m, 4H), 2.41 (t, 4H), 2.41 (s, 3H).
Example 39
Preparation of
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00147##
[2028]
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (18.7 mg) was prepared as described for
N-(3-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide. LRMS (M+H.sup.+) m/z calculated 479.2. found 479.2. .sup.1H
NMR (DMSO-d6, 300 MHz) .delta. 10.32 (s, 1H), 9.65 (s, 1H), 9.20
(s, 1H), 7.96-7.99 (m, 1H), 7.81 (d, 1H), 7.31-7.56 (m, 5H), 7.00
(d, 1H), 6.63 (d, 2H), 6.09-6.52 (m, 2H) 5.73 (d, 1H), 2.90-2.95
(m, 8H), 2.55-2.59 (m, 3H), 2.38 (s, 3H).
Example 40
Preparation of
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-methylquinazolin-8-yl-
)phenyl)acrylamide
##STR00148##
[2030]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-7-methylquinazoli-
n-8-yl)phenyl)acrylamide (14.1 mg) was prepared as described for
N-(3-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide. LRMS (M+H.sup.+) m/z calculated 507.2. found 507.2. .sup.1H
NMR (CD.sub.3OD, 300 MHz) .delta. 9.05 (s, 1H), 8.06 (d, 1H), 7.74
(d, 1H), 7.50-7.53 (m, 4H), 7.31 (d, 1H), 7.07 (d, 1H), 6.72 (d,
2H), 6.39-6.45 (m, 2H), 5.77 (dd, 1H), 3.66-3.74 (m, 4H), 2.98-3.06
(m, 4H), 2.38 (s, 3H), 2.02 (s, 3H).
Example 41
Preparation of
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)propionamide
##STR00149##
[2032]
N-(3-(7-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)propionamide (40.8 mg) was prepared as described for
N-(3-(7-methyl-2-((4-morpholinophenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide. LRMS (M+H+) m/z calculated 481.3. found 481.0. 1H NMR
((DMSO-d6, 300 MHz) .delta. 10.00 (s, 1H), 9.60 (s, 1H), 9.19 (s,
1H), 7.79-7.86 (m, 2H), 7.31-7.57 (m, 5H), 6.96 (d, 1H), 6.66 (d,
2H), 3.15-3.28 (m, 6H), 2.73-2.89 (m, 4H), 2.28-2.33 (m, 6H), 1.05
(t, 3H).
Example 42
Preparation of
N-(3-(7-(hydroxymethyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide
##STR00150##
##STR00151##
[2034] To a solution of 8-bromo-2-chloro-7-methylquinazoline (2.7
g, 10.5 mmol, 1 eq.) and NBS (2.2 g, 12.6 mmol, 1.2 eq.) in
CCl.sub.4 (30 mL) was added BPO (254 mg, 1.05 mmol, 0.1 eq.). The
mixture was heated at 100.degree. C. overnight, cooled to r.t.,
washed with sat. NaHCO.sub.3 solution, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The resulting residue was
purified via column chromatography (PE/EA=10/1, v/v) to afford
8-bromo-7-(bromomethyl)-2-chloroquinazoline as a yellow solid (2.0
g, 57.1% yield).
##STR00152##
[2035] To a solution of 8-bromo-7-(bromomethyl)-2-chloroquinazoline
(1 g, 3.0 mmol, 1 eq.) in AcOH (50 mL) was added AgOAc (1 g, 6.0
mmol, 2 eq.). The mixture was heated at 100.degree. C. for 1.5 h,
cooled and concentrated. The resulting residue was purified via
column chromatography (PE/EA=5/1, v/v) to afford
(8-bromo-2-chloroquinazolin-7-yl)methyl acetated (756 mg, 80%
yield).
##STR00153##
[2036] To a solution of 4-(4-methylpiperazin-1-yl)aniline (56 mg,
0.291 mmol, 1.1 eq.) and (8-bromo-2-chloroquinazolin-7-yl)methyl
acetate (84 mg, 0.265 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA
(30 mg, 0.265 mmol, 1 eq.). The mixture was stirred at 80.degree.
C. for 12 h, cooled and concentrated. The resulting residue was
dissolved in EA (40 mL), washed with Na.sub.2CO.sub.3 solution,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The
resulting residue was purified via column chromatography
(DCM/MeOH=20:1, v/v) to afford
(8-bromo-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-7-yl)methy-
l acetate (52 mg, 42% yield).
##STR00154##
[2037] To a solution of
(8-bromo-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-7-yl)methy-
l acetate (52 mg, 0.11 mmol, 1 eq.) and
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (18 mg,
0.132 mmol, 1.2 eq.) in dioxane (10 mL) and water (1 mL) was added
Na.sub.2CO.sub.3 (23 mg, 0.22 mmol, 2 eq.), followed by
Pd(dppf)Cl.sub.2 (9 mg, 0.011 mmol, 0.1 eq.) under N.sub.2. The
mixture was stirred at 90.degree. C. for 12 h under N.sub.2. The
solution was cooled, diluted with EA and filtered. The filtrate was
concentrated and the resulting residue was purified via column
chromatography (DCM/MeOH=20:1, v/v) to afford
(8-(3-aminophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quin-
azolin-7-yl)methyl acetate (35.5 mg, 67% yield).
##STR00155##
[2038] To a solution of
(8-(3-aminophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
7-yl)methyl acetate (35.5 mg, 0.07 mmol, 1 eq.) in DCM (10 mL) was
added DIEA (28 mg, 0.22 mmol, 3 eq.), followed by acryloyl chloride
(7.24 mg, 0.08 mmol, 1.2 eq.). The resulting mixture was stirred at
r.t. for 1 h, diluted with EA (30 mL), washed with brine, dried
over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting
residue was purified v a column chromatography (DCM/MeOH=20:1, v/v)
to afford
(8-(3-acrylamidophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-7-yl)methyl acetate (23 mg, 27.8% yield).
##STR00156##
[2039] To a solution of
(8-(3-acrylamidophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-7-yl)methyl acetate (23 mg, 0.04 mmol, 1 eq.) in THF (8 mL)
was added NaOH (1N, 2 mL, 2 mmol, 50 eq.). The resulting mixture
was stirred at r.t. for 1 h, diluted with EA (10 mL), washed via
RP-HPLC to afford
N-(3-(7-(hydroxymethyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide (13.5 mg, 68.2% yield). LRMS
(M+H.sup.+) m/z calculated 494.2. found 494.9. .sup.1H NMR
(CD.sub.3OD, 300 MHz) .delta. 9.10 (s, 1H), 8.05 (d, 1H), 7.86 (d,
1H), 7.64 (d, 1H), 7.48-7.54 (m, 4H), 7.10 (t, 1H), 6.71 (d, 2H),
6.39-6.46 (m, 2H), 5.77 (d, 1H), 4.64 (d, 2H), 3.27-3.29 (m, 4H),
3.13-3.17 (m, 4H), 2.52 (s, 3H).
Example 43
Preparation of
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide
##STR00157##
##STR00158##
[2041] To a solution of 8-bromo-2-chloroquinazoline (15.4 g, 63.6
mmol, 1 eq.) and (3-aminophenyl)boronic acid (8.7 g, 63.6 mmol, 1
eq.) in dioxane/H.sub.2O (200 mL/20 mL) was added Na.sub.2CO.sub.3
(13.5 g, 127.2 mmol, 2 eq.), followed by Pd(dppf)Cl.sub.2 (2.6 g,
3.2 mmol, 0.05 eq.) under N.sub.2, then the mixture was stirred at
80.degree. C. for 12 h. Then the solution was cooled to r.t.,
concentrated and the residue was purified via column chromatography
(PE/EA=3:2, v/v) to afford 3-(2-chloroquinazolin-8-yl)aniline as
yellow solid (8.7 g, 53.7% yield).
##STR00159##
[2042] To a solution of 3-(2-chloroquinazolin-8-yl)aniline (8.7 g,
34 mmol, 1 eq.) in DCM (200 mL) cooled in ice-bath was added TEA
(9.5 mL, 68 mmol, 2 eq.), followed by acryloyl chloride (4.1 mL, 51
mmol, 1.5 eq.) dropwise. The resulting mixture was stirred at r.t.
for 1 h, then washed with brine, dried over anhydrous
N.sub.2SO.sub.4, concentrated and the residue was purified via
column chromatography (PE/EA=1:1, v:v) to afford
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide as yellow solid
(6.6 g, 65% yield).
##STR00160##
[2043] To a solution of (S)-tert-butyl
3-hydroxypyrrolidine-1-carboxylate (1.87 g, 10 mmol, 1 eq.) in DMA
(20 mL) cooled in ice-bath was added NaH (480 mg, 12 mmol, 1.2 eq.)
and the mixture was stirred at 0.degree. C. for 30 min, then
1-fluoro-4-nitrobenzene (1.41 g, 10 mmol, 1 eq) was added. The
resulting mixture was stirred at r.t. overnight, then poured into
ice-water (200 mL). The precipitate was collected by filtration,
washed with water and dried in vacuo to afford (S)-tert-butyl
3-(4-nitrophenoxy)pyrrolidine-1-carboxylate as yellow solid (3.08
g, 100% yield).
##STR00161##
[2044] To a solution of (S)-tert-butyl
3-(4-nitrophenoxy)pyrrolidine-1-carboxylate (3.08 g, 10 mmol, 1
eq.) in EA (10 mL) was added HCl/EA (6N, 30 mL) and the mixture was
stirred at r.t. for 1 h. Then the mixture was concentrated to
afford (S)-3-(4-nitrophenoxy)pyrrolidine hydrochloride as yellow
solid (2.44 g, 100% yield).
##STR00162##
[2045] To a solution of (S)-3-(4-nitrophenoxy)pyrrolidine
hydrochloride (2.44 g, 10 mmol, 1 eq.) in DCM (40 mL) cooled in
ice-bath was added TEA (4.0 g, 40 mmol, 4 eq.) followed by acetyl
chloride (1.57 g, 20 mmol, 2 eq.) dropwise. The resulting mixture
was stirred at r.t. for 1 h, then washed with brine, dried over
anhydrous NaSO.sub.4 and concentrated to afford
(S)-1-(3-(4-nitrophenoxy)pyrrolidin-1-yl)ethanone as brown oil (2.2
g, 88% yield).
##STR00163##
[2046] To a solution of
(S)-1-(3-(4-nitrophenoxy)pyrrolidin-1-yl)ethanone (2.2 g, 8.8 mmol,
1 eq.) in MeOH (20 mL) was added Pd/C (400 mg) and the resulting
mixture was stirred at hydrogen atmosphere at r.t. overnight. Then
the catalyst was removed by filtration and the filtrate was
concentrated to afford
(S)-1-(3-(4-aminophenoxy)pyrrolidin-1-yl)ethanone as brown solid
(1.7 g, 88% yield).
##STR00164##
[2047] To a solution of
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (154 mg, 0.5 mmol,
1 eq.) and (S)-1-(3-(4-aminophenoxy)pyrrolidin-1-yl)ethanone (110
mg, 0.5 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (286 mg, 2.5
mmol, 5 eq.) and the resulting mixture was stirred at 80.degree. C.
overnight. The mixture was concentrated and the residue was
dissolved in DCM, washed with Na.sub.2CO.sub.3 solution, dried over
anhydrous Na.sub.2SO.sub.4, then purified via column chromatography
(DCM/MeOH=10/1) to afford
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide as yellow solid (35.2 mg, 14.7% yield). LRMS
(M+H.sup.+) m/z calculated 494.2. found 494.2. .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 10.30 (s, 1H), 9.80 (s, 1H), 9.32 (s,
1H), 8.04 (s, 1H), 7.80-7.93 (m, 5H), 7.35-7.51 (m, 3H), 6.71 (t,
2H), 6.44-6.51 (m, 1H), 6.26 (d, 1H), 5.76 (dd, 1H), 4.86-4.94 (m,
1H), 3.48-3.76 (m, 3H), 3.28-3.31 (m, 1H), 1.93-2.16 (m, 5H).
Example 44
Preparation of
N-(3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00165##
[2049]
N-(3-(2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (25.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 499.2.1.
found 498.9. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.22 (s,
1H), 8.48 (d, 1H), 7.85-7.94 (m, 4H), 7.38-7.50 (m, 3H), 7.03 (s,
1H), 6.66 (d, 1H), 6.40-6.46 (m, 2H), 5.78-5.82 (m, 1H), 3.18-3.23
(m, 4H), 2.93-2.96 (m, 4H), 2.62 (s, 3H).
Example 45
Preparation of
N-(3-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00166##
[2051]
N-(3-(2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (59 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 483.6. found
483.9. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.21 (s, 1H), 8.37
(t, 1H), 7.85-7.97 (m, 4H), 7.40-7.51 (m, 3H), 6.83 (dd, 1H),
6.41-6.54 (m, 3H), 5.79-5.83 (m, 1H), 3.17-3.32 (m, 8H) 2.81 (s,
3H).
Example 46
Preparation of
N-(5-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)py-
ridin-3-yl)acrylamide
##STR00167##
[2053]
N-(5-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-
-yl)pyridin-3-yl)acrylamide (43.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 467.2. found
466.9. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.20 (s, 1H), 9.02
(s, 1 H), 8.53 (s, 2H), 8.18-8.31 (m, 2H), 7.90 (t, 2H), 7.47 (t,
1H), 6.39-6.64 (m, 3H), 5.84 (d, 1H) 3.40-3.45 (m, 4H), 2.55-2.620
(m, 4H), 2.34 (s, 3H).
Example 47
Preparation of
N-(2-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00168##
[2055]
N-(2-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (37.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 483.2. found
482.9. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.16 (s, 1H), 8.35
(t, 1H), 7.91 (d, 1H), 7.88 (d, 1H), 7.61 (d, 2H), 7.23-7.46 (m,
3H), 6.42-6.77 (m, 4H), 5.84 (d, 1H) 3.13-3.16 (m, 4H), 2.82-2.84
(m, 4H), 2.51 (s, 3H).
Example 48
Preparation of
N-(2-fluoro-3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide
##STR00169##
[2057]
N-(2-fluoro-3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)qui-
nazolin-8-yl)phenyl)acrylamide (135.5 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 484.2. found
483.9. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.02 (s, 1H), 9.75
(s, 1H), 9.31 (s, 1H), 8.25-8.31 (m, 2H), 8.12 (d, 1H), 7.97 (d,
1H), 7.82 (d, 1H), 7.45 (t, 1H), 7.29 (t, 1H), 7.17 (t, 1H),
6.67-6.76 (m, 1H), 6.29-6.46 (m, 2H), 5.81 (d, 1H), 3.26-3.37 (m,
4H), 2.41-2.49 (m, 4H), 2.24 (s, 3H).
Example 49
Preparation of
N-(3-(2-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)quinazolin-8-yl)-
phenyl)acrylamide
##STR00170##
[2059]
N-(3-(2-((2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide (31.9 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 467.2. found
466.9. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.18 (s, 1H), 9.66
(s, 1H), 9.33 (s, 1H), 8.75 (s, 2H), 7.80-8.04 (m, 4H), 7.32-7.47
(m, 3H), 6.19-6.46 (m, 2H), 5.74 (d, 1H), 3.55-3.61 (m, 4H),
2.39-2.42 (m, 4H), 2.32 (s, 3H).
Example 50
Preparation of
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-fluor-
ophenyl)acrylamide
##STR00171##
[2061]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-
-fluorophenyl)acrylamide (50.7 mg) was prepared as described for
(S)--N-(3-(2-((4-(1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 511.2. found
510.9. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.05 (s, 1H), 9.72
(s, 1H), 9.31 (s, 1H), 8.33 (t, 1H), 7.96 (d, 1H), 7.82 (d, 1H),
7.61 (d, 2H), 7.42 (t, 1H), 7.32 (t, 1H), 7.20 (t, 1H), 6.66-6.77
(m, 3H), 6.30-6.37 (m, 1H), 5.81 (d, 1H), 3.52-3.54 (m, 4H),
2.87-2.97 (m, 4H), 2.04 (s, 3H).
Example 51
Preparation of
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phen-
yl)-4-(dimethylamino)but-2-enamide
##STR00172##
[2063]
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)-4-(dimethylamino)but-2-enamide (46.9 mg) was prepared as
described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 550.3. found
549.9. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.17 (s, 1H),
7.76-7.99 (m, 6H), 7.42-7.53 (m, 3H), 6.81-6.97 (m, 3H), 6.31 (d,
1H), 3.68-3.75 (m, 4H), 3.19 (d, 2H), 3.02-3.10 (m, 4H) 2.30 (s,
6H), 2.18 (s, 3H).
Example 52
Preparation of
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-chlor-
ophenyl)acrylamide
##STR00173##
[2065]
N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-
-chlorophenyl)acrylamide (60.6 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 527.2. found
527.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.16 (s, 1H), 8.20
(d, 1H), 7.91 (d, 1H), 7.74 (d, 1H), 7.42-7.55 (m, 4H), 7.25 (d,
1H), 6.76 (d, 2H), 6.63-6.69 (m, 1H) 6.46-6.50 (m, 1H), 5.86 (d,
1H), 3.68-3.75 (m, 4H), 3.02-3.09 (m, 4H), 2.18 (s, 3H).
Example 53
Preparation of
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)qu-
inazolin-8-yl)phenyl)but-2-enamide
##STR00174##
[2067]
(E)-4-(dimethylamino)-N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)am-
ino)quinazolin-8-yl)phenyl)but-2-enamide (139.4 mg) was prepared as
described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 522.3. found
522.3. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.02 (s, 1H), 7.86
(s, 1H), 7.76 (d, 1H), 7.69 (d, 2H), 7.61 (d, 2H), 7.26-7.37 (m,
3H), 6.77-6.81 (m, 1H), 6.67 (d, 2H), 6.19 (d, 1H), 3.10 (d, 1H),
2.97-2.99 (m, 4H), 2.53-2.55 (m, 4H), 2.28 (s, 3H), 2.20 (s,
3H).
Example 54
Preparation of
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00175##
[2069]
N-(3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (43.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 497.2. found
497.2. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.14 (s, 1H), 8.00
(s, 1H), 7.93 (d, 1H), 7.82 (d, 2H), 7.73 (m, 2H), 7.38-7.52 (m,
3H), 6.79 (d, 2H), 6.36-6.47 (m, 2H) 5.77 (d, 1H), 4.72 (t, 1H),
4.56 (t, 1H), 3.10-3.13 (m, 4H), 2.73-2.87 (m, 6H).
Example 55
Preparation of
N-(2-chloro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00176##
[2071]
N-(2-chloro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (23.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 499.2. found
499.2. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.03 (s, 1H), 8.05
(d, 1H), 7.76 (d, 1H), 7.60 (d, 1H), 7.28-7.41 (m, 4H), 7.11 (d,
1H), 6.51-6.63 (m, 3H), 6.32-6.36 (m, 1H), 2.97-2.98 (m, 4H),
2.51-2.53 (m, 4H), 2.26 (s, 3H).
Example 56
Preparation of
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazol-
in-8-yl)phenyl)acrylamide
##STR00177##
[2073]
N-(3-(2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)qu-
inazolin-8-yl)phenyl)acrylamide (30.3 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 496.2. found
496.2. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.16 (s, 1H), 8.65
(d, 1H), 7.84-7.95 (m, 4H), 7.38-7.50 (m, 3H), 6.40-6.46 (m, 2H),
6.04 (d, 1H), 5.80 (d, 1H), 3.97 (s, 3H), 3.51-3.55 (m, 4H),
2.86-2.87 (m, 4H), 2.59 (s, 3H).
Example 57
Preparation of
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-2-c-
hlorophenyl)-4-(dimethylamino)but-2-enamide
##STR00178##
[2075]
(E)-N-(3-(2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)-2-chlorophenyl)-4-(dimethylamino)but-2-enamide (10.2 mg) was
prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 584.2. found
584.2. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.10 (s, 1H), 8.65
(d, 1H), 7.94 (s, 1H), 7.73-7.81 (m, 2H), 7.39-7.48 (m, 4H),
7.18-7.28 (m, 2H), 7.01-7.06 (m, 1H), 6.70 (d, 2H), 6.20 (d, 1H),
3.74-3.78 (m, 2H), 3.60-3.64 (m, 2H), 3.16 (d, 2H), 3.02-3.08 (m,
4H), 2.31 (s, 6H), 2.16 (s, 3H).
Example 58
Preparation of
N-(3-(2-((4-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00179##
[2077]
N-(3-(2-((4-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide (74.2 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 515.2. found
515.2. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.15 (s, 1H),
7.52-7.99 (m, 6H), 7.39-7.50 (m, 3H), 6.80 (d, 2H), 6.41-6.52 (m,
2H), 6.02 (t, 1H), 5.77-5.84 (m, 1H), 3.03-3.12 (m, 4H), 2.74-2.88
(m, 6H).
Example 59
Preparation of
N-(5-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)pyridin-3-yl)acrylamide
##STR00180##
[2079]
N-(5-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)pyridin-3-yl)acrylamide (36.2 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 498.2. found
498.2. .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta. 9.18 (s, 1H), 9.06
(s, 1H), 8.53-8.57 (m, 2H), 7.817-7.91 (m, 2H), 7.65 (d, 2H), 7.45
(t, 1H), 6.82 (d, 2H), 6.45-6.49 (m, 2H), 5.84-5.88 (m, 1H), 4.72
(t, 1H), 4.55 (t, 1H), 3.10-3.13 (m, 4H), 2.71-2.85 (m, 6H).
Example 60
Preparation of
N-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pyridin--
2-yl)acrylamide
##STR00181##
[2081]
N-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)py-
ridin-2-yl)acrylamide (10.9 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 466.2. found
466.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.90 (s, 1H), 9.73
(s, 1H), 9.32 (s, 1H), 8.60 (s, 1H), 8.46 (d, 1H), 7.97 (d, 1H),
7.87 (d, 1H), 7.66 (d, 2H), 7.39-7.48 (m, 2H), 6.63-6.74 (m, 3H),
6.22-6.28 (m, 1H), 5.77 (d, 1H), 3.03 (m, 4H), 2.51 (m, 4H), 2.25
(s, 3H).
Example 61
Preparation of
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide
##STR00182##
##STR00183##
[2083] To a solution of 1-fluoro-4-nitrobenzene (4.23 g, 30 mmol,
1.0 eq.) in DMSO (40 mL) was added TEA (9.1 g, 90 mmol, 3.0 eq.)
followed by 2-(piperazin-1-yl)ethanol (3.9 g, 30 mmol, 1.0 eq.) and
the mixture was stirred at 90.degree. C. overnight. The mixture was
poured into ice-water (400 mL), filtered and dried in vacuum to
afford 2-(4-(4-nitrophenyl)piperazin-1-yl)ethanol as a yellow solid
(7.2 g, 95.6%).
##STR00184##
[2084] To a solution of 2-(4-(4-nitrophenyl)piperazin-1-yl)ethanol
(3.6 g, 14.3 mmol) in MeOH (40 mL) was added Pd/C (700 mg) and the
resulting mixture was stirred at r.t. overnight. The mixture was
filtered, and the filtrate was concentrated to afford
2-(4-(4-aminophenyl)piperazin-1-yl)ethanol (2.8 g, 88% yield) as
yellow solid.
##STR00185##
[2085] To a suspension of
2-(4-(4-aminophenyl)piperazin-1-yl)ethanol (221 mg, 1 mmol, 1 eq.)
and 8-bromo-2-chloroquinazoline (243 mg, 1 mmol, 1 eq.) in n-BuOH
(10 mL) was added TFA (570 mg, 5 mmol, 5 eq.) and the resulting
mixture was stirred at 90.degree. C. overnight. The solution was
then cooled to r.t. and the precipitate was collected by
filtration, washed with EA, dried in vacuo to afford
2-(4-(4-((8-bromoquinazolin-2-yl)amino)phenyl)piperazin-1-yl)ethanol
as yellow solid (340 mg, 79%).
##STR00186##
[2086] To a solution of
2-(4-(4-((8-bromoquinazolin-2-yl)amino)phenyl)piperazin-1-yl)ethanol
(200 mg, 0.47 mmol, 1.0 eq.) and (3-aminophenyl)boronic acid (97
mg, 0.71 mmol, 1.5 eq.) in dioxane/H.sub.2O (10 mL/1 mL) was added
Na.sub.2CO.sub.3 (100 mg, 0.94 mmol, 2.0 eq.), followed by
Pd(dppf)Cl.sub.2 (38 mg, 0.05 mmol, 0.1 eq.) under N.sub.2. The
mixture was stirred at 90.degree. C. for 12 h. The mixture was
cooled to r.t., and concentrated. The resulting residue was
purified via column chromatography (DCM/MeOH=30:1, v/v) to afford
2-(4-(4-((8-(3-aminophenyl)quinazolin-2-yl)amino)phenyl)piperazin-1-yl)et-
hanol as a yellow solid (100 mg, 48% yield).
##STR00187##
[2087] To a solution of
2-(4-(4-((8-(3-aminophenyl)quinazolin-2-yl)amino)phenyl)piperazin-1-yl)et-
hanol (100 mg, 0.23 mmol, 1.0 eq.) in DCM (5 mL) cooled in ice-bath
was added TEA (46 mg, 0.46 mmol, 2.0 eq.) followed by acryloyl
chloride (62.1 mg, 0.69 mmol, 3.0 eq.) dropwise. The resulting
mixture was stirred at r.t. for 1 h, then washed with brine, dried
over anhydrous Na.sub.2SO.sub.4 and concentrated to afford
2-(4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)piperazin-1--
yl)ethyl acrylate as a yellow solid (100 mg, 79.4% yield).
##STR00188##
[2088] To a solution of
2-(4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)piperazin-1--
yl)ethyl acrylate (100 mg, 0.2 mmol, 1 eq.) in THF (2 mL) was added
1N NaOH (0.4 mL, 0.4 mmol, 2 eq.). The resulting mixture was
stirred at r.t. overnight, then washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, and concentrated. The resulting residue
was purified via column chromatography (DCM/MeOH=30:1, v/v) to
afford
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide (21 mg, 25.5% yield). LRMS (M+H.sup.+) m/z
calculated 495.2. found 495.2. .sup.1H NMR (DMSO-d6, 300 MHz)
.delta. 9.14 (s, 1H), 7.72-7.97 (m, 6H), 7.38-7.49 (m, 3H), 6.80
(d, 2H), 6.41-6.47 (m, 2H), 5.78 (d, 1H), 3.78 (t, 3H), 3.13-3.17
(m, 4H), 2.75-2.88 (m, 6H).
Example 62
Preparation of
(E)-4-(dimethylamino)-N-(2-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl-
)amino)quinazolin-8-yl)phenyl)but-2-enamide
##STR00189##
[2090]
(E)-4-(dimethylamino)-N-(2-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)-
phenyl)amino)quinazolin-8-yl)phenyl)but-2-enamide (45.5 mg) was
prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 540.3. found
540.3. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.17 (s, 1H), 8.34
(t, 1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.60 (d, 2H), 7.45 (t, 1H),
7.23-7.42 (m, 2H), 6.97-7.01 (m, 1H), 6.76 (d, 2H), 6.47 (d, 1H),
3.23 (d, 2H), 3.11 (m, 4H), 2.65-2.67 (m, 4H), 2.40 (s, 3H), 2.33
(s, 6H).
Example 63
Preparation of
N-(2-fluoro-3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide
##STR00190##
[2092]
N-(2-fluoro-3-(2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide (35.6 mg) was prepared as
described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 515.2. found
515.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.17 (s, 1H), 8.37
(t, 1H), 7.89 (d, 1H), 7.81 (d, 1H), 7.60 (d, 2H), 7.44 (t, 1H),
7.22-7.34 (m, 2H), 6.77 (d, 2H), 6.61-6.67 (m, 1H), 6.46 (dd, 1H),
5.84 (dd, 1H), 4.71 (t, 1H), 4.59 (t, 1H), 3.11 (t, 4H), 2.72-2.84
(m, 6H).
Example 64
Preparation of
1-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-5,6-dih-
ydropyridin-1(2H)-yl)prop-2-en-1-one
##STR00191##
[2094]
1-(3-(2-((4-(4-Methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-5-
,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (14.9 mg) was prepared
as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 455.2. found
455.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.96 (d, 1H),
7.52-7.60 (m, 4H), 7.19-7.36 (m, 2H), 6.81 (d, 2H), 6.14-6.75 (m,
2H), 5.99 (s, 1H), 5.48-5.52 (m, 1H), 4.52-4.62 (m, 2H), 3.74-3.87
(m, 2H), 3.20-3.25 (m, 4H), 2.76-2.80 (m, 4H), 2.39-2.47 (m,
5H).
Example 65
Preparation of
N-(2-cyano-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide
##STR00192##
[2096]
N-(2-cyano-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide (41.2 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 490.2. found
490.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.08 (s, 1H), 7.93
(d, 1H), 7.83 (d, 1H), 7.67-7.73 (m, 2H), 7.43 (d, 2H), 7.31-7.36
(m, 2H), 6.66 (d, 2H), 6.34-6.51 (m, 2H), 5.76-5.79 (m, 1H),
3.08-3.09 (m, 4H), 2.80-2.82 (m, 4H), 2.48 (s, 3H).
Example 66
Preparation of
N-(3-(2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00193##
[2098]
N-(3-(2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (33.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 483.2. found
483.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.07 (s, 1H), 7.92
(s, 1H), 7.72-7.77 (m, 4H), 7.29-7.41 (m, 4H), 6.73 (t, 1H),
6.20-6.35 (m, 2H), 5.64-5.67 (m, 1H), 2.60-2.65 (m, 4H), 2.30-2.34
(m, 4H), 2.05 (s, 3H).
Example 67
Preparation of
N-(3-(2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00194##
[2100]
N-(3-(2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (33.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 499.2. found
499.1. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.21 (s, 1H), 8.04
(s, 1H), 7.71-7.93 (m, 5H), 7.44-7.54 (m, 3H), 6.93 (d, 1H),
6.34-6.48 (m, 2H), 5.76-5.79 (m, 1H), 2.99-3.01 (m, 4H), 2.62-2.65
(m, 4H), 2.37 (s, 3H).
Example 68
Preparation of
N-(3-(2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide
##STR00195##
[2102]
N-(3-(2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide (122.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 495.2. found
495.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.10 (s, 1H), 7.88
(d, 1H), 7.69-7.76 (m, 3H), 7.32-7.38 (m, 5H), 6.65 (d, 1H),
6.25-6.33 (m, 2H), 5.66-5.69 (m, 1H), 3.31-3.34 (m, 5H), 3.10-3.15
(m, 2H), 2.83-2.85 (m, 5H).
Example 69
Preparation of
N-(3-(2-((3-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide
##STR00196##
[2104]
N-(3-(2-((3-cyano-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide (35.9 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 490.2. found
490.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.11 (s, 1H), 8.05
(d, 1H), 7.72-7.96 (m, 5H), 7.33-7.46 (m, 3H), 6.90 (d, 1H),
6.22-6.40 (m, 2H), 5.66-5.68 (m, 1H), 3.07-3.21 (m, 8H), 2.70 (s,
3H).
Example 70
Preparation of
N-(4-chloro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00197##
[2106]
N-(4-chloro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (43.4 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 499.2. found
499.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.18 (s, 1H), 8.05
(d, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.57-7.7.62 (m, 4H), 7.44 (t,
1H), 6.72 (d, 2H), 6.36-6.49 (m, 2H), 5.80 (d, 1H), 3.22-3.28 (m,
4H), 3.08-3.09 (m, 4H), 2.72 (s, 3H).
Example 71
Preparation of methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-ca-
rboxylate
##STR00198##
[2108] Methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)piperazine-1-ca-
rboxylate (31.4 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 509.2. found
509.2. .sup.1H NMR (CDCl3, 400 MHz) .delta. 9.08 (s, 1H), 8.01-8.02
(m, 1H), 7.83 (d, 2H), 7.72 (d, 2H), 7.67 (d, 3H), 7.50-7.52 (m,
2H), 7.34-7.40 (m, 2H), 6.81 (d, 2H), 6.46 (d 1H), 6.24-6.26 (m,
1H), 5.77 (d, 1H), 3.74 (s, 3H), 3.49-3.62 (m, 4H), 3.03-3.24 (m,
4H).
Example 72
Preparation of
N-(3-(2-((4-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide
##STR00199##
[2110]
N-(3-(2-((4-(3-(hydroxymethyl)-4-methylpiperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide (41.4 mg) was prepared as
described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 495.2. found
495.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.01 (s, 1H),
7.80-7.86 (m, 2H), 7.68 (d, 2H), 7.62 (d, 2H), 7.35-7.38 (m, 1H),
7.25-7.30 (m, 2H), 6.68 (d, 2H), 6.25-6.39 (m, 2H), 5.68 (d, 1H),
3.66-3.67 (m, 2H), 3.45 (d, 1H), 3.33 (d, 1H), 2.99 (d, 1H),
2.56-2.71 (m, 1H), 2.46 (s, 1H)
Example 73
Preparation of
N-(3-(2-((5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazoli-
n-8-yl)phenyl)acrylamide
##STR00200##
[2112]
N-(3-(2-((5-chloro-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)qui-
nazolin-8-yl)phenyl)acrylamide (41.4 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 500.2. found
500.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.08 (s, 1H), 8.32
(d, 1H), 8.03 (s, 1H), 7.63-7.84 (m, 4H), 7.26-7.51 (m, 4H),
6.30-6.44 (m, 2H), 5.74 (d, 1H), 3.31-3.33 (m, 4H), 2.70-2.74 (m,
4H), 2.45 (s, 3H).
Example 74
Preparation of
N-(3-(2-((4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide
##STR00201##
[2114]
N-(3-(2-((4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide (27.5 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 509.2. found
509.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.41 (s, 1H), 9.74
(s, 1H), 9.30 (s, 1H), 8.03 (s, 1H), 7.78-7.92 (m, 5H), 7.32-7.47
(m, 3H), 6.73 (d, 2H), 6.29-6.52 (m, 2H), 5.74-5.78 (m, 1H), 4.68
(t, 1H), 4.13 (d, 2H), 3.45-3.60 (m, 4H), 2.93-2.99 (m, 4H).
Example 75
Preparation of
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-N-methylpipera-
zine-1-carboxamide
##STR00202##
[2116]
4-(4-((8-(3-Acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-N-methyl-
piperazine-1-carboxamide (71.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 508.2. found
508.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.30 (s, 1H), 9.70
(d, 1H), 9.29 (s, 1H), 8.01 (s, 1H), 7.74-7.91 (m, 5H), 7.31-7.507
(m, 3H), 6.72 (d, 2H), 6.31-6.53 (m, 3H), 5.75-5.78 (m, 1H), 3.43
(s, 3H), 2.90-2.97 (m, 4H), 2.45-2.59 (m, 4H).
Example 76
Preparation of
N-(3-(2-((4-(4-propionylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pheny-
l)acrylamide
##STR00203##
[2118]
N-(3-(2-((4-(4-propionylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide (39.6 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 507.2. found
507.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.07 (s, 1H), 8.03
(brs, 1H), 7.81-7.83 (m, 2H), 7.65-7.72 (m, 3H), 7.49-7.53 (m, 3H),
7.33-7.39 (m, 2H), 6.79 (d, 3H), 6.45 (d, 1H), 6.23-6.28 (m, 1H),
5.76 (d, 1H), 3.76 (t, 2H), 3.59 (t, 2H), 3.01-3.05 (m, 4H), 2.39
(q, 2H), 1.18 (t, 3H).
Example 77
Preparation of
N-(3-(2-((5-cyano-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-
-8-yl)phenyl)acrylamide
##STR00204##
[2120]
N-(3-(2-((5-cyano-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quin-
azolin-8-yl)phenyl)acrylamide (55.4 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 491.2. found
491.2. .sup.1H NMR (CDCl3, 400 MHz) .delta. 9.05 (s, 1H), 8.64
(brs, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 7.73-7.85 (m, 3H), 7.28-7.54
(m, 5H), 6.28-6.43 (m, 2H), 5.74 (d, 1H), 3.56 (t, 4H), 2.68 (t,
4H), 2.43 (s, 3H).
Example 78
Preparation of
5-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-methylpiperazin-1-y-
l)benzamide
##STR00205##
[2122]
5-((8-(3-Acrylamidophenyl)quinazolin-2-yl)amino)-2-(4-methylpiperaz-
in-1-yl)benzamide (50.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 508.2. found
508.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.07 (s, 1H), 8.35
(dd, 1H), 7.88 (s, 1H), 7.71-7.78 (m, 4H), 7.31-7.40 (m, 3H), 6.88
(d, 1H), 6.29-6.37 (m, 2H), 5.67 (dd, 2H), 2.89 (t, 4H), 2.66 (brs,
4H), 2.37 (s, 3H).
Example 79
Preparation of
N-(3-(7-fluoro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00206##
[2124]
N-(3-(7-fluoro-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (45.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 483.2. found
483.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.10 (s, 1H), 8.02
(d, 1H), 7.88 (q, 1H), 7.80 (s, 1H), 7.65 (d, 2H), 7.51 (t, 1H),
7.20-7.30 (m, 2H), 6.76 (d, 2H), 6.37-6.47 (m, 2H), 5.79 (dd, 1H),
3.13 (t, 4H), 2.75 (t, 4H), 2.47 (s, 3H).
Example 80
Preparation of methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpipera-
zine-2-carboxylate
##STR00207##
[2126] Methyl
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpipera-
zine-2-carboxylate (34.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 523.2. found
523.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.16 (s, 1H), 8.05
(s, 1H), 7.92 (d, 1H), 7.84 (d, 2H), 7.75 (d, 2H), 7.40-7.53 (m,
3H), 6.79 (d, 2H), 6.38-6.51 (m, 2H), 5.79 (dd, 1H), 3.82 (s, 3H),
3.47 (d, 1H), 3.31 (d, 1H), 3.18 (dd, 1H), 3.03-3.07 (m, 1H),
2.87-2.97 (m, 2H), 2.45-2.51 (m, 1H), 2.40 (s, 1H).
Example 81
Preparation of
N-(3-(7-fluoro-2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide
##STR00208##
[2128]
N-(3-(7-fluoro-2-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide (34.0 mg) was prepared as
described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 515.2. found
515.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.11 (s, 1H), 8.01
(d, 1H), 7.88 (dd, 1H), 7.82 (s, 1H), 7.64 (d, 2H), 7.52 (t, 1H),
7.21-7.30 (m, 2H), 6.77 (d, 2H), 6.39-6.61 (m, 2H), 5.79 (dd, 1H),
4.72 (t, 1H), 4.60 (t, 1H), 3.12 (t, 4H), 2.86 (t, 1H), 2.75-2.80
(m, 5H).
Example 82
Preparation of
N-(3-(2-((4-(2-oxooxazolidin-3-yl)phenyl)amino)quinazolin-8-yl)phenyl)acr-
ylamide
##STR00209##
[2130]
N-(3-(2-((4-(2-oxooxazolidin-3-yl)phenyl)amino)quinazolin-8-yl)phen-
yl)acrylamide (71.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 452.2. found
452.1. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.30 (s, 1H), 9.95
(s, 1H), 9.36 (s, 1H), 8.06 (s, 1H), 7.81-7.96 (m, 5H), 7.48 (q,
2H), 7.41 (d, 1H), 7.29 (d, 2H), 6.43-6.47 (m, 1H), 6.26 (d, 1H),
5.75 (d, 1H), 4.42 (t, 2H), 3.97 (t, 2H).
Example 83
Preparation of
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpipera-
zine-2-carboxylic acid
##STR00210##
[2132]
4-(4-((8-(3-Acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methyl-
piperazine-2-carboxylic acid (32.3 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (MAI') m/z calculated 509.2. found
509.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.06 (s, 1H), 8.12
(s, 1H), 7.68-7.77 (m, 5H), 7.32-7.47 (m, 3H), 6.77 (d, 2H),
6.36-6.53 (m, 2H), 5.80 (d, 1H), 3.78 (d, 1H), 3.45 (d, 1H),
3.23-3.34 (m, 2H), 2.82-2.91 (m, 3H), 2.70 (s, 3H).
Example 84
Preparation of
N-(3-(2-((4-(1H-imidazol-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylam-
ide
##STR00211##
[2134]
N-(3-(2-((4-(1H-imidazol-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide (41.2 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 433.2. found
433.1. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.13 (s, 1H),
7.89-7.98 (m, 4H), 7.74-7.79 (m, 3H), 7.31-7.44 (m, 4H), 7.17 (d,
2H), 7.07 (s, 1H), 6.17-6.31 (m, 2H), 5.58 (dd, 1H).
Example 85
Preparation of
4-(4-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methylpipera-
zine-2-carboxamide
##STR00212##
[2136]
4-(4-((8-(3-Acrylamidophenyl)quinazolin-2-yl)amino)phenyl)-1-methyl-
piperazine-2-carboxamide (74.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 508.2. found
508.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.32 (s, 1H), 9.72
(s, 1H), 9.30 (s, 1H), 8.06 (s, 1H), 7.73-8.06 (m, 5H), 7.17-7.50
(m, 5H), 6.71 (d, 2 H), 6.43-651 (m, 1H), 6.30 (d, 1H), 5.75 (dd,
1H), 3.34-3.42 (m, 2H), 2.87 (t, 1H), 2.60-2.71 (m, 3H), 2.18-2.21
(m, 4H).
Example 86
Preparation of
N-(3-(2-((4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide
##STR00213##
[2138]
N-(3-(2-((4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide (24.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 529.2. found
529.1. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.33 (s, 1H), 9.74
(s, 1H), 9.31 (s, 1H), 8.02 (s, 1H), 7.76-7.93 (m, 5H), 7.41-7.50
(m, 2H), 7.34 (d, 1H), 7.75 (d, 2H), 6.42-6.50 (m, 1H), 6.28 (d,
1H), 5.77 (d, 1H), 3.22 (brs, 4H), 3.08 (brs, 4H), 2.93 (s,
3H).
Example 87
Preparation of
N-(3-(2-((4-(3-oxomorpholino)phenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de
##STR00214##
[2140]
N-(3-(2-((4-(3-oxomorpholino)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide (98.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 466.2. found
466.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.28 (s, 1H), 10.01
(s, 1H), 9.38 (s, 1H), 8.02 (s, 1H), 7.91-7.97 (m, 3H), 7.83-7.86
(m, 2H), 7.49 (t, 2H), 7.40 (d, 2H), 6.42-6.49 (m, 1H), 6.25 (dd,
1H), 5.75 (d, 1H), 4.17 (s, 2H), 3.95 (t, 2H), 3.62 (t, 2H).
Example 88
Preparation of
N-(3-(2-((4-(2-oxopyrrolidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acr-
ylamide
##STR00215##
[2142]
N-(3-(2-((4-(2-oxopyrrolidin-1-yl)phenyl)amino)quinazolin-8-yl)phen-
yl)acrylamide (67.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 450.2. found
450.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.29 (s, 1H), 9.92
(s, 1H), 9.35 (s, 1H), 8.04 (s, 1H), 7.93 (dd, 1H), 7.83-7.88 (m,
4H), 7.45-7.50 (m, 2H), 7.35-7.40 (m, 3H), 6.40-6.47 (m, 1H), 6.25
(dd, 1H), 5.75 (d, 1H), 3.73 (t, 2H), 2.45 (t, 2H), 2.02-2.06 (m,
2H).
Example 89
Preparation of
N-(3-(2-((4-(2-oxoimidazolidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide
##STR00216##
[2144]
N-(3-(2-((4-(2-oxoimidazolidin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide (12.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 451.2. found
451.1. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.43 (s, 1H), 9.82
(s, 1H), 9.34 (s, 1H), 8.08 (s, 1H), 7.94 (d, 1H), 7.82-7.88 (m,
4H), 7.40-7.50 (m, 3H), 7.30 (d, 2H), 6.82 (s, 1H), 6.50-6.54 (m,
1H), 6.25-6.29 (m, 1H), 5.75-5.78 (m, 1H), 3.74-3.78 (m, 2H),
3.35-3.39 (m, 2H).
Example 90
Preparation of
N-(3-(2-((4-((1-(2-hydroxyethyl)azetidin-3-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide
##STR00217##
[2146]
N-(3-(2-((4-((1-(2-hydroxyethyl)azetidin-3-yl)amino)phenyl)amino)qu-
inazolin-8-yl)phenyl)acrylamide (52.4 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 481.2. found
481.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.27 (s, 1H), 9.49
(s, 1H), 9.24 (s, 1H), 8.00 (s, 1H), 7.84-7.87 (m, 2H), 7.77 (d,
1H), 7.58 (d, 2H), 7.43-7.46 (m, 1H), 7.36-7.40 (m, 2H), 6.45-6.51
(m, 1H), 6.26-6.31 (m, 3H), 5.75-5.78 (m, 1H), 5.62 (d, 1H),
4.38-4.41 (m, 1H), 4.08-4.12 (m, 1H), 3.80-3.85 (m, 2H), 3.33-3.38
(m, 2H), 2.73-2.77 (m, 2H), 2.46-2.50 (m, 2H).
Example 91
Preparation of
N-(3-(2-((4-(3-hydroxypyrrolidin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide
##STR00218##
[2148]
N-(3-(2-((4-(3-hydroxypyrrolidin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide (30.8 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 452.2. found
452.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.29 (s, 1H), 9.52
(s, 1H), 9.24 (s, 1H), 8.04 (s, 1H), 7.85-7.87 (m, 2H), 7.77 (d,
1H), 7.66 (d, 2H), 7.43-7.47 (m, 1H), 7.36-7.40 (m, 1H), 7.32-7.33
(m, 1H), 6.45-6.51 (m, 1H), 6.24-6.31 (m, 3H), 5.74-5.77 (m, 1H),
4.90 (s, 1H), 4.36 (s, 1H), 3.30-3.37 (m, 1H), 3.21-3.23 (m, 1H),
3.13-3.15 (m, 1H), 2.95-2.98 (m, 1H), 1.94-2.06 (m, 1H), 1.76-1.88
(m, 1H).
Example 92
Preparation of
N-(4-cyano-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide
##STR00219##
[2150]
N-(4-cyano-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide (41.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 490.2. found
490.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.70 (s, 1H), 9.77
(s, 1H), 9.33 (s, 1H), 7.87-8.07 (m, 5H), 7.57 (d, 2H), 7.45-7.48
(m, 1H), 6.65 (d, 2H), 6.42-6.47 (m, 1H), 6.28-6.33 (m, 1H),
5.82-5.85 (m, 1H), 2.95-2.31 (m, 4H), 2.42-2.46 (m, 4H), 2.23 (s,
3H).
Example 93
Preparation of methyl
2-acrylamido-6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)benzoate
##STR00220##
[2152] Methyl
2-acrylamido-6-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)benzoate (21.2 mg) was prepared as described for
(S)--N-(3-(2-((4-(1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 523.2. found
523.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.13 (s, 1H), 8.34
(d, 1H), 7.65-7.83 (m, 3H), 7.54-7.57 (m, 2H), 7.41-7.44 (m, 1H),
7.28 (d, 1H), 6.77 (d, 2H), 6.39-6.42 (m, 2H), 5.83-5.87 (m, 1H),
3.13-3.18 (m, 7H), 2.90-2.94 (m, 4H), 2.60 (s, 3H).
Example 94
Preparation of methyl
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-methylpiperazin-1-y-
l)benzoate
##STR00221##
[2154] Methyl
2-((8-(3-acrylamidophenyl)quinazolin-2-yl)amino)-5-(4-methylpiperazin-1-y-
l)benzoate (10.9 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 523.2. found
523.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta.7.69 (s, 1H), 7.44
(d, 1H), 7.40-7.43 (m, 2H), 7.25-7.28 (m, 3H), 7.09-7.13 (m, 2H),
6.98-7.03 (m, 2H), 6.24-6.28 (m, 2H), 5.64-5.68 (m, 1H), 3.19-3.24
(m, 3H), 3.08-3.17 (m, 4H), 2.67-2.69 (m, 4H), 2.37 (s, 3H).
Example 95
Preparation of
N-(3-(2-((4-(1,4-oxazepan-4-yl)phenyl)amino)quinazolin-8-yl)phenyl)acryla-
mide
##STR00222##
[2156]
N-(3-(2-((4-(1,4-oxazepan-4-yl)phenyl)amino)quinazolin-8-yl)phenyl)-
acrylamide (38.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 466.2. found
466.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.30 (s, 1H), 9.54
(s, 1H), 9.25 (s, 1H), 8.02 (s, 1H), 7.87 (d, 2H), 7.78 (d, 1H),
7.65 (d, 2H), 7.39-7.47 (m, 2H), 7.30 (d, 1H), 6.44-6.51 (m, 3H),
6.24-6.29 (m, 1H), 5.75-5.78 (m, 1H), 3.63-3.67 (m, 2H), 3.46-3.52
(m, 6H), 1.83-1.86 (m, 2H).
Example 96
Preparation of
N-(3-(2-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide
##STR00223##
[2158]
N-(3-(2-((4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide (32.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 479.2. found
479.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.28 (s, 1H), 9.99
(s, 1H), 9.37 (s, 1H), 8.03 (s, 1H), 7.81-7.97 (m, 5H), 7.47-7.50
(m, 2H), 7.36-7.39 (m, 1H), 7.02 (d, 2H), 6.42-6.54 (m, 1H),
6.22-6.27 (m, 1H), 5.73-5.75 (m, 1H), 3.49-3.56 (m, 2H), 3.06 (s,
2H), 2.64-2.71 (m, 2H), 2.32 (s, 3H).
Example 97
Preparation of
N-(3-(2-((4-(2-methoxyethoxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de
##STR00224##
[2160]
N-(3-(2-((4-(2-methoxyethoxy)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide (85.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 441.2. found
441.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.01 (s, 1H), 7.89
(s, 1H), 7.59-7.76 (m, 5H), 7.25-7.38 (m, 3H), 6.60-6.63 (m, 3H),
6.24-6.34 (m, 2H), 5.64-5.67 (m, 1H), 3.89-3.91 (m, 2H), 3.58-3.60
(m, 2H), 3.31 (s, 3H).
Example 98
Preparation of
N-(3-(2-((4-(2-hydroxyethoxy)phenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de
##STR00225##
[2162]
N-(3-(2-((4-(2-hydroxyethoxy)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide (37.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 427.2. found
427.1. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.33 (s, 1H), 9.75
(s, 1H), 9.31 (s, 1H), 8.05 (s, 1H), 7.91 (d, 1H), 7.76-7.82 (m,
4H), 7.41-7.50 (m, 2H), 7.36 (d, 1H), 6.69 (d, 2 H), 6.45-6.49 (m,
1H), 6.24-6.28 (m, 1H), 5.74-5.77 (m, 1H), 4.81 (s, 1H), 3.85-3.88
(m, 2H), 3.66-3.69 (m, 2H).
Example 99
Preparation of
N-(3-(2-((4-(2-(dimethylamino)ethoxy)phenyl)amino)quinazolin-8-yl)phenyl)-
acrylamide
##STR00226##
[2164]
N-(3-(2-((4-(2-(dimethylamino)ethoxy)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide (98.5 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 454.2. found
454.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.32 (s, 1H), 9.77
(s, 1H), 9.32 (s, 1H), 8.01 (s, 1H), 7.79-7.93 (m, 5H), 7.36-7.50
(m, 3H), 6.69 (d, 2H), 6.67-6.73 (m, 1H), 6.24-6.28 (m, 1H),
5.74-5.77 (m, 1H), 4.01-4.04 (m, 2H), 2.90 (s, 2H), 2.44 (s,
6H).
Example 100
Preparation of
N-(3-(2-((4-(2-(azetidin-1-yl)ethoxy)phenyl)amino)quinazolin-8-yl)phenyl)-
acrylamide
##STR00227##
[2166]
N-(3-(2-((4-(2-(azetidin-1-yl)ethoxy)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide (41.4 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 466.2. found
466.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.04 (s, 1H),
7.79-7.83 (m, 2H), 7.64-7.72 (m, 4H), 7.28-7.37 (m, 3H), 6.63-6.70
(m, 3H), 6.28-6.37 (m, 2H), 5.68 (d, 1H), 4.08-4.12 (m, 4H),
3.99-4.01 (m, 2H), 3.20-3.24 (m, 2H), 2.39-2.43 (m, 2H).
Example 101
Preparation of
(S)--N-(3-(2-((4-((tetrahydrofuran-3-yl)amino)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide
##STR00228##
[2168]
(S)--N-(3-(2-((4-((tetrahydrofuran-3-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide (55.9 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 452.2. found
452.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.27 (s, 1H), 9.50
(s, 1H), 9.24 (s, 1H), 7.98 (s, 1H), 7.86-7.88 (m, 2H), 7.76-7.78
(m, 1H), 7.59 (d, 2H), 7.35-7.46 (m, 3H), 6.24-6.51 (m, 4H),
5.74-5.77 (m, 1H), 5.42-5.44 (m, 1H), 3.67-3.86 (m, 4H), 3.42-3.46
(m, 1H), 2.09-2.14 (m, 1H), 1.66-1.72 (m, 1H).
Example 102
Preparation of
N-(3-(2-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide
##STR00229##
[2170]
N-(3-(2-((4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide (103 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 467.2. found
467.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.30 (s, 1H), 9.76
(s, 1H), 9.31 (s, 1H), 8.04 (s, 1H), 7.77-7.92 (m, 5H), 7.32-7.50
(m, 3H), 6.71 (d, 2H), 6.44-6.50 (m, 1H), 6.24-6.29 (m, 1H),
5.75-5.78 (m, 1H), 4.34-4.38 (m, 1H), 3.82-3.86 (m, 2H), 3.42-3.48
(m, 2H), 1.87-1.92 (m, 2H), 1.47-1.56 (m, 2H).
Example 103
Preparation of
(S)--N-(3-(2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide
##STR00230##
[2172]
(S)--N-(3-(2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide (85 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 453.2. found
453.1. .sup.1H NMR (DMSO-d6, 300 MHz) .delta.10.29 (s, 1H), 9.77
(s, 1H), 9.31 (s, 1H), 8.04 (s, 1H), 7.77-7.93 (m, 5H), 7.33-7.51
(m, 3H), 6.65 (d, 2H), 6.43-6.52 (m, 1H), 6.22-6.28 (m, 1H),
5.74-5.78 (m, 1H), 4.84-4.88 (m, 1H), 3.69-3.87 (m, 4H), 2.12-2.19
(m, 1H), 1.85-1.94 (m, 1H).
Example 104
Preparation of
N-(3-(2-((4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00231##
[2174]
N-(3-(2-((4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (62.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 466.2. found
466.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta.10.25 (s, 1H), 9.47
(s, 1H), 9.24 (s, 1H), 7.75-7.96 (m, 4H), 7.34-7.59 (m, 5H),
6.30-6.47 (m, 4H), 5.74-5.78 (m, 1H), 5.07-5.10 (m, 1H), 3.84-3.88
(m, 2H), 3.28-3.44 (m, 2H), 1.79-1.83 (m, 2H), 1.29-1.32 (m,
2H).
Example 105
Preparation of
(R)--N-(3-(2-((4-((tetrahydrofuran-3-yl)amino)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide
##STR00232##
[2176]
(R)--N-(3-(2-((4-((tetrahydrofuran-3-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide (37.2 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 452.2. found
452.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.26 (s, 1H), 9.49
(s, 1H), 9.24 (s, 1H), 7.98 (s, 1H), 7.87 (d, 2H), 7.76 (d, 1H),
7.59 (d, 2H), 7.35-7.46 (m, 3H), 6.44-6.51 (m, 1H), 6.37 (d, 2H),
6.24-6.29 (m, 1H), 5.74-5.77 (m, 1H), 5.41-5.43 (m, 1H), 3.68-3.86
(m, 4H), 3.43-3.46 (m, 1H), 2.09-2.14 (m, 1H), 1.66-1.70 (m,
1H).
Example 106
Preparation of
(R)--N-(3-(2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide
##STR00233##
[2178]
(R)--N-(3-(2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide (55.0 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 453.2. found
453.1. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.29 (s, 1H), 9.76
(s, 1H), 9.31 (s, 1H), 8.04 (s, 1H), 7.78-7.93 (m, 5H), 7.33-7.50
(m, 3H), 6.66 (d, 2H), 6.44-6.50 (m, 1H), 6.23-6.28 (m, 1H),
5.74-5.77 (m, 1H), 4.85-4.87 (m, 1H), 3.37-3.86 (m, 4H), 2.12-2.17
(m, 1H), 1.89-1.91 (m, 1H).
Example 107
Preparation of
(S)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide
##STR00234##
[2180]
(S)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)oxy)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide (71.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 466.2. found
466.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.41 (s, 1H), 9.81
(s, 1H), 9.33 (s, 1H), 8.00 (s, 1H), 7.80-7.94 (m, 5H), 7.43-7.50
(m, 2H), 7.37 (d, 1H), 6.70 (d, 2H), 6.48-6.53 (m, 1H), 6.25-6.29
(m, 1H), 5.75-5.78 (m, 1H), 4.95 (s, 1H), 3.43 (m, 1H), 3.27-3.33
(m, 1H), 3.16-3.17 (m, 1H), 2.77 (s, 3H), 2.31-2.39 (m, 1H),
1.96-2.04 (m, 1H).
Example 108
Preparation of
N-(3-(2-((4-((1-acetylpiperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide
##STR00235##
[2182]
N-(3-(2-((4-((1-acetylpiperidin-4-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide (39.6 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 507.2. found
507.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.28 (s, 1H), 9.48
(s, 1H), 9.24 (s, 1H), 7.75-7.96 (m, 4H), 7.76 (d, 2H), 7.35-7.44
(m, 3H), 6.30-6.44 (m, 4H), 5.79 (d, 1H), 5.10 (d, 1H), 4.17-4.21
(m, 1H), 3.73-3.78 (m, 1H), 3.34 (s, 1H), 3.11-3.18 (m, 1H),
2.74-2.81 (m, 1H), 2.01 (s, 3H), 1.83-1.87 (m, 2H), 1.14-1.24 (m,
2H).
Example 109
Preparation of
N-(3-(2-((4-(4-methyl-3-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide
##STR00236##
[2184]
N-(3-(2-((4-(4-methyl-3-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide (72.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 479.2. found
479.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.30 (s, 1H), 9.71
(s, 1H), 9.30 (s, 1H), 8.05 (s, 1H), 7.75-7.91 (m, 5H), 7.34-7.51
(m, 3H), 6.72 (d, 2H), 6.44-6.51 (m, 1H), 6.25-6.30 (m, 1H), 5.75
(dd, 1H), 3.60 (s, 2H), 3.38-3.40 (m, 2H), 3.31-3.32 (m, 2H), 2.89
(s, 3H).
Example 110
Preparation of
(R)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide
##STR00237##
[2186]
(R)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)oxy)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide (131.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 466.2. found
466.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.30 (s, 1H), 9.74
(s, 1H), 9.31 (s, 1H), 8.05 (s, 1H), 7.76-7.92 (m, 5H), 7.32-7.50
(m, 3H), 6.61 (d, 2H), 6.44-6.51 (m, 1H), 6.24-6.28 (m, 1H), 5.76
(dd, 1H), 4.68-4.71 (m, 1H), 2.59-2.74 (m, 2H), 2.50-2.52 (m, 1H),
2.18-2.37 (m, 5H), 1.68-1.73 (m, 1H).
Example 111
Preparation of
N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide
##STR00238##
[2188]
N-(3-(2-((4-((1-acetylazetidin-3-yl)amino)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide (105.2 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 479.2. found
479.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.27 (s, 1H), 9.54
(s, 1H), 9.26 (s, 1H), 7.98 (s, 1H), 7.87 (d, 2H), 7.78 (d, 1H),
7.63 (d, 2H), 7.36-7.47 (m, 3H), 6.46-6.52 (m, 1H), 6.26-6.31 (m,
3H), 5.92 (d, 1H), 5.77 (dd, 1H), 4.37-4.41 (m, 1H), 4.02-4.15 (m,
2H), 3.75-3.78 (m, 1H), 3.55-3.58 (m, 1H), 1.77 (s, 3H).
Example 112
Preparation of
N-(3-(2-((4-((1-acetylazetidin-3-yl)oxy)phenyl)amino)quinazolin-8-yl)phen-
yl)acrylamide
##STR00239##
[2190]
N-(3-(2-((4-((1-acetylazetidin-3-yl)oxy)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide (66.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 480.2. found
480.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.30 (s, 1H), 9.80
(s, 1H), 9.32 (s, 1H), 8.04 (s, 1H), 7.92 (d, 1H), 7.79-7.83 (m,
4H), 7.34-7.51 (m, 3H), 6.59 (d, 2H), 6.45-6.52 (m, 1H), 6.25-6.29
(m, 1H), 5.75-5.78 (m, 1H), 4.86-4.89 (m, 1H), 4.47-4.51 (m, 1H),
4.21-4.26 (m, 1H), 4.00-4.03 (m, 1H), 3.69-3.72 (m, 1H), 1.79 (s,
3H).
Example 113
Preparation of
N-(3-(2-((4-(3-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acry-
lamide
##STR00240##
[2192]
N-(3-(2-((4-(3-oxopiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pheny-
l)acrylamide (8.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 465.2. found
465.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.31 (s, 1H), 9.71
(s, 1H), 9.30 (s, 1H), 8.05 (d, 2H), 7.89 (d, 1H), 7.75-7.84 (m,
4H), 7.33-7.50 (m, 3H), 6.72 (dd, 2H), 6.44-6.50 (m, 1H), 6.25-6.29
(m, 1H), 5.74-5.77 (m, 1H), 3.56 (s, 2H), 3.23-3.27 (m, 4H).
Example 114
Preparation of
(S)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00241##
[2194]
(S)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)amino)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide (14 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 465.2. found
465.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.26 (s, 1H), 9.47
(s, 1H), 9.24 (s, 1H), 7.98 (s, 1H), 7.87 (d, 2H), 7.76 (d, 1H),
7.56 (d, 2H), 7.36-7.47 (m, 3H), 6.46-6.51 (m, 1H), 6.24-6.36 (m,
3H), 5.75 (dd, 1H), 5.27 (d, 1H), 3.75-3.76 (m, 1H), 2.67-2.70 (m,
1H), 2.04-2.70 (m, 7H), 1.49-1.51 (m, 1H).
Example 115
Preparation of
(R)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00242##
[2196]
(R)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)amino)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide (36.4 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 493.2. found
493.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.28 (t, 1H), 9.52
(d, 1H), 9.25 (s, 1H), 7.96 (s, 1H), 7.86 (d, 2H), 7.76 (d, 1H),
7.61 (d, 2H), 7.35-7.49 (m, 3H), 6.38-6.53 (m, 3H), 6.27 (d, 1H),
5.76 (d, 1H), 5.48 (dd, 1H), 3.48-3.54 (m, 2H), 3.31-3.40 (m, 2H),
3.14-3.19 (m, 1H), 2.47-2.50 (m, 1H), 1.94 (d, 3H), 1.80-1.92 (m,
1H).
Example 116
Preparation of
(R)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00243##
[2198]
(R)--N-(3-(2-((4-((1-methylpyrrolidin-3-yl)amino)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide (54.8 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 465.2. found
465.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.11 (s, 1H), 7.99
(d, 1H), 7.78-7.82 (m, 3H), 7.63 (d, 2H), 7.35-7.49 (m, 3H),
6.36-6.50 (m, 4H), 6.29 (dd, 1H), 5.79 (dd, 1H), 4.14-4.17 (m, 1H),
3.54-3.61 (m, 2H), 3.31-3.38 (m, 2H), 2.96 (s, 3H), 2.85-2.88 (m,
1H), 2.02-2.05 (m, 1H).
Example 117
Preparation of
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)amino)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00244##
[2200]
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)amino)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide (57.4 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 493.2. found
493.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.27 (d, 1H), 9.51
(s, 1H), 9.25 (s, 1H), 7.97 (s, 1H), 7.66-7.88 (m, 3H), 7.61 (d,
2H), 7.37-7.47 (m, 3H), 6.39-6.52 (m, 3H), 6.26 (d, 1H), 5.76 (d,
1H), 5.47 (dd, 1H), 3.49-3.91 (m, 4H), 3.15-3.18 (m, 1H), 2.05-2.14
(m, 1H), 1.94 (d, 3H), 1.73-1.85 (m, 1H).
Example 118
Preparation of
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1H-pyra-
zol-5-yl)acrylamide
##STR00245##
[2202]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)-1-
H-pyrazol-5-yl)acrylamide (6.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 455.2. found
455.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 13.02 (s, 1H), 10.73
(s, 1H), 9.91 (t, 1H), 9.33 (s, 1H), 8.15 (d, 1H), 7.88 (d, 1H),
7.62 (d, 2H), 7.37-7.41 (m, 1H), 7.30 (s, 1H), 6.96 (d, 2H),
6.52-6.59 (m, 1H), 6.29 (dd, 1H), 5.76 (d, 1H), 3.08 (t, 4H), 2.46
(t, 4H), 2.34 (s, 3H).
Example 119
Preparation of
N-(2-methoxy-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide
##STR00246##
[2204]
N-(2-methoxy-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide (30.1 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 495.2. found
426.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 9.60 (d, 1H), 9.27
(s, 1H), 9.37 (s, 1H), 8.37 (d, 1H), 7.92 (d, 1H), 7.80 (d, 1H),
7.56 (d, 2H), 7.42 (t, 1H), 7.21 (t, 1H), 7.04 (d, 1H), 6.81-6.88
(m, 1H), 6.62 (d, 2H), 6.30 (d, 1H), 5.75 (d, 1H), 3.34 (s, 3H),
3.25 (t, 4H), 2.42 (t, 4H), 1.99 (s, 3H).
Example 120
Preparation of
N-(3-(2-((4-((2-fluoroethyl)(methyl)amino)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide
##STR00247##
[2206]
N-(3-(2-((4-((2-fluoroethyl)(methyl)amino)phenyl)amino)quinazolin-8-
-yl)phenyl)acrylamide (30.4 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 442.2. found
442.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.05 (s, 1H), 8.01
(s, 1H), 7.85 (s, 1H), 7.81 (d, 1H), 7.69 (d, 1H), 7.59 (d, 2H),
7.48 (d, 2H), 7.33-7.36 (m, 1H), 7.26-7.28 (m, 1H), 7.14 (d, 1H),
6.61 (d, 2H), 6.41-6.45 (m, 1H), 6.21-6.24 (m, 1H), 5.74-5.77 (m,
1H), 4.63 (t, 1H), 4.52 (t, 1H), 3.54-3.61 (m, 2H), 2.95 (s,
3H).
Example 121
Preparation of
N-(2-fluoro-3-(2-((4-((2-fluoroethyl)(methyl)amino)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide
##STR00248##
[2208]
N-(2-fluoro-3-(2-((4-((2-fluoroethyl)(methyl)amino)phenyl)amino)qui-
nazolin-8-yl)phenyl)acrylamide (32.4 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 460.2. found
460.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.06 (s, 1H), 8.58
(m, 1H), 7.76 (d, 2H), 7.57-7.58 (m, 1H), 7.46 (d, 2H), 7.37 (t,
1H), 7.30 (t, 1H), 7.20-7.23 (m, 1H), 7.14 (d, 1H), 6.53 (d, 2H),
6.44-6.49 (m, 1H), 6.24-6.31 (m, 1H), 5.79-5.82 (m, 1H), 4.62 (t,
1H), 4.50 (t, 1H), 3.51-3.60 (m, 2H), 2.93 (s, 3H).
Example 122
Preparation of
N-(3-(2-((4-((2-hydroxyethyl)amino)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide
##STR00249##
[2210]
N-(3-(2-((4-((2-hydroxyethyl)amino)phenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide (34.4 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 426.2. found
426.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.30 (s, 1H), 10.00
(s, 1H), 9.37 (s, 1H), 7.83-7.97 (m, 6H), 7.42-7.51 (m, 3H),
6.96-6.99 (m, 2H), 6.44-6.51 (m, 1H), 6.24-6.29 (m, 1H), 5.75-5.78
(m, 1H), 3.58 (t, 2H), 3.21 (t, 2H).
Example 123
Preparation of
N-(4-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl-
)phenyl)acrylamide
##STR00250##
[2212]
N-(4-fluoro-3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (38.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 483.2. found
483.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.14 (s, 1H),
7.80-7.96 (m, 4H), 7.64 (d, 1H), 7.39 (t, 1H), 7.27 (t, 1H), 6.76
(d, 2H), 6.62 (d, 2H), 6.36-6.45 (m, 2H), 5.78 (dd, 1H), 3.11 (t,
4H), 2.67 (t, 4H), 2.40 (s, 3H).
Example 124
Preparation of
1-(4-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)piperazi-
n-1-yl)prop-2-en-1-one
##STR00251##
[2214]
1-(4-(2-((4-(4-Methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)pi-
perazin-1-yl)prop-2-en-1-one (10.5 mg) was prepared as described
for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 458.2. found
458.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.06 (s, 1H), 7.72
(d, 2H), 7.39-7.43 (m, 2H), 7.18-7.30 (m, 2H), 7.00 (d, 2H),
6.65-6.72 (m, 1H), 6.40 (d, 1H), 5.79 (d, 1H), 4.06 (s, 2H), 3.89
(s, 2H), 3.41 (t, 4H), 3.24 (t, 4H), 2.66 (t, 4H), 2.41 (s,
3H).
Example 125
Preparation of
(R)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide
##STR00252##
[2216]
(R)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide (89.3 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 494.2. found
494.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.31 (s, 1H), 9.79
(s, 1H), 9.32 (s, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.79-7.91 (m,
4H), 7.42-7.51 (m, 2H), 7.36 (d, 1H), 6.71 (t, 2H), 6.45-6.51 (m,
1H), 6.26 (d, 1H), 5.74-5.77 (m, 1H), 4.90 (dd, 1H), 3.48-3.76 (m,
4H), 3.28-3.33 (m, 1H), 1.96-2.16 (m, 5H).
Example 126
Preparation of
N-(3-(2-((4-((2-fluoroethyl)amino)phenyl)amino)quinazolin-8-yl)phenyl)acr-
ylamide
##STR00253##
[2218]
N-(3-(2-((4-((2-fluoroethyl)amino)phenyl)amino)quinazolin-8-yl)phen-
yl)acrylamide (25.7 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 428.2. found
428.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.26 (s, 1H), 9.50
(s, 1H), 9.25 (s, 1H), 7.97 (d, 1H), 7.76-7.88 (m, 3H), 7.59-7.63
(m, 2H), 7.36-7.48 (d, 2H), 6.24-6.49 (m, 4H), 5.74-5.78 (m, 1H),
5.40-5.43 (m, 1H), 4.59 (t, 1H), 4.43 (t, 1H), 3.36-3.31 (m,
2H).
Example 127
Preparation of
N-(3-(2-((4-((2,2-difluoroethyl)amino)phenyl)amino)quinazolin-8-yl)phenyl-
)acrylamide
##STR00254##
[2220]
N-(3-(2-((4-((2,2-difluoroethyl)amino)phenyl)amino)quinazolin-8-yl)-
phenyl)acrylamide (29.6 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 446.2. found
446.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.01 (s, 1H), 7.86
(s, 1H), 7.56-7.78 (m, 1H), 7.68-7.70 (m, 2H), 7.49 (d, 2H),
7.25-7.39 (m, 3H), 6.26-6.45 (m, 4H), 5.66-5.80 (m, 2H), 3.28-3.36
(m, 2H).
Example 128
Preparation of
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide
##STR00255##
[2222] N-(3-(2-((4-(4-(2-amino-2-oxo
ethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide
(79.2 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 508.2. found
508.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.29 (s, 1H), 9.66
(s, 1H), 9.29 (s, 1H), 8.02 (s, 1H), 7.73-7.91 (m, 5H), 7.14-7.49
(m, 5H), 6.70 (d, 2H), 6.45-6.47 (m, 1H), 6.28-6.29 (m, 1H),
5.75-5.78 (m, 1H), 3.01-3.03 (m, 4H), 2.92 (s, 2H), 2.55-2.57 (m,
4H).
Example 129
Preparation of
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide
##STR00256##
[2224]
N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide (58.2 mg) was prepared as described for
(S)--N-(3-(2-((4-((1-acetylpyrrolidin-3-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 509.3. found
509.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.30 (s, 1H), 9.66
(s, 1H), 9.29 (s, 1H), 7.73-8.03 (m, 6H), 7.32-7.50 (m, 3H), 6.70
(d, 2H), 6.45-6.50 (m, 1H), 6.26-6.30 (m, 1H), 5.76 (d, 1H),
3.46-3.48 (m, 2H), 3.26 (s, 3H), 2.97 (m, 4H), 2.50-2.53 (m,
6H).
Example 130
Preparation of
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide
##STR00257##
##STR00258##
[2226] To a solution of tert-butyl
3-fluoro-4-hydroxypiperidine-1-carboxylate (10.07 g, 46 mmol, 1
eq.) in DMA (200 mL) cooled at 0.degree. C. was added NaH (3.7 g,
92 mmol, 2 eq.) in small portions and the resulting mixture was
stirred at 0.degree. C. for 30 min. Then 1-fluoro-4-nitrobenzene
(4.9 mL, 46 mmol, 1 eq.) was added slowly and the mixture was
stirred at r.t. overnight. The mixture was poured into ice-water
(1000 mL), extracted with EA (3.times.200 mL) and the organic
layers were combined, washed with brine (600 mL), dried over
anhydrous Na.sub.2SO.sub.4, concentrated and purified via column
chromatography (PE/EA=2/1) to afford tert-butyl
3-fluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate (8.7 g, 55.6%)
as a yellow solid.
##STR00259##
[2227] To a solution of HCl in MeOH (20 mL) was added tert-butyl
3-fluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate (1.7 g, 5 mmol)
and the resulting mixture was stirred at r.t. for 1 h. Then the
solution was concentrated to afford
3-fluoro-4-(4-nitrophenoxy)piperidine hydrochloride (1.38 g, 100%)
as yellow solid.
##STR00260##
[2228] To a solution of 3-fluoro-4-(4-nitrophenoxy)piperidine
hydrochloride (1.38 g, 5 mmol, 1 eq.) in MeOH (20 mL) was added
HOAc (2 mL) and HCHO (0.77 mL, 10 mmol, 2 eq.) followed by
NaBH.sub.3CN (630 mg, 10 mmol, 2 eq.) and the resulting mixture was
stirred at r.t. for 30 min. Then sat. Na.sub.2CO.sub.3 (50 mL) was
added, extracted with EA (3.times.50 mL) and the organic layers
were combined, washed with brine (200 mL), dired over anhydrous
Na.sub.2SO.sub.4 and concentrated to afford
3-fluoro-1-methyl-4-(4-nitrophenoxy)piperidine (1.26 g, 100%) as
yellow oil.
##STR00261##
[2229] To a solution of 3-fluoro-1-methyl-4-(4-nitrophenoxy)
piperidine (1.26 g, 5 mmol) in MeOH (20 mL) was added Pd/C (250 mg)
and the resulting mixture was stirred at r.t. overnight. The Pd/C
was removed by filtration and the filtrate was concentrated to
afford 4-((3-fluoro-1-methylpiperidin-4-yl)oxy)aniline (1.04 g,
93%).
##STR00262##
[2230] To a suspension of
4-((3-fluoro-1-methylpiperidin-4-yl)oxy)aniline (1.04 g, 4.6 mmol,
1.2 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (1.17
g, 3.8 mmol, 1 eq.) in n-BuOH (20 mL) was added TFA (2.6 g, 23
mmol, 5 eq.) and the resulting mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated, diluted with DCM (50 mL),
washed with sat. Na.sub.2CO.sub.3 (50 mL), dired over anhydrous
Na.sub.2SO.sub.4, concentrated and purified via column
chromatography (DCM/MeOH=20/1) to afford
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide (1.1 g, 58.2%) as yellow solid. LRMS
(M+H.sup.+) m/z calculated 498.2. found 498.2. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.07 (s, 1H), 7.88-7.91 (m, 2H), 7.82
(d, 1H), 7.71 (d, 1H), 7.66 (d, 2H), 7.36-7.51 (m, 5 H), 6.82 (d,
2H), 6.44 (d, 1H), 6.21-6.28 (m, 1H), 5.78 (d, 1H), 4.77-4.91 (m,
1H), 4.33-4.35 (m, 1H), 3.61-4.22 (m, 1H), 3.01-3.03 (m, 1H),
2.74-2.75 (m, 2H), 2.35-2.44 (m, 4H), 2.10-2.17 (m, 1H), 1.86-1.91
(m, 1H).
Example 131
Preparation of
N-(2-fluoro-3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00263##
[2232]
N-(2-fluoro-3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide (31.4 mg) was prepared as
described for
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 516.2.
found 516.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (s,
1H), 8.56-8.60 (m, 1H), 7.79 (d, 2H), 7.50-7.62 (m, 3H), 7.40-7.44
(m, 1H), 7.26-7.33 (m, 1H), 7.22-7.24 (m, 1H), 6.76-6.88 (m, 2H),
6.48 (d, 1H), 6.25-6.32 (m, 1H), 5.82 (d, 1H), 4.73-4.88 (m, 1H),
4.28-4.32 (m, 1H), 2.98-3.02 (m, 1H), 2.69-2.74 (m, 1H), 2.32-2.38
(m, 5H), 2.03-2.17 (m, 2H), 1.83-1.87 (m, 1H).
Example 132
Preparation of
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)oxy)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00264##
[2234]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)oxy)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide (87.7 mg) was prepared as described
for
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide. LRMS (MAI') m/z calculated 484.2. found
484.2. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.06 (s, 1H), 8.09
(s, 1H), 7.91 (s, 1H), 7.81 (d, 1H), 7.70 (d, 2H), 7.62 (d, 2H),
7.45 (d, 2H), 7.35-7.38 (m, 2H), 6.62 (d, 2H), 6.41-6.45 (m, 1H),
6.30-6.32 (m, 1H), 5.74 (d, 1H), 4.81-4.84 (m, 1H), 4.60 (t, 1H),
4.47 (t, 1H), 4.01 (t, 2H), 3.27 (t, 2H), 2.86-2.96 (m, 2H).
Example 133
Preparation of
N-(3-(2-((4-((1-acetylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide
##STR00265##
[2236]
N-(3-(2-((4-((1-acetylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide (101.7 mg) was prepared as described for
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 508.2.
found 508.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.29 (s, 1H),
9.76 (s, 1H), 9.31 (s, 1H), 8.03 (d, 1H), 7.77-7.92 (m, 5H),
7.33-7.50 (m, 3H), 6.73 (d, 2H), 6.44-6.50 (m, 1H), 6.24-6.28 (m,
1H), 5.74-5.77 (m, 1H), 4.40-4.42 (m, 1H), 3.76-3.78 (m, 1H),
3.62-3.63 (m, 1H), 3.16-3.33 (m, 2H), 2.02 (s, 3H), 1.79-1.90 (m,
2H), 1.44-1.56 (m, 2H).
Example 134
Preparation of
N-(3-(2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-8-yl)phe-
nyl)acrylamide
##STR00266##
[2238]
N-(3-(2-((4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide (94.3 mg) was prepared as described for
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 480.2.
found 480.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.10.29 (s, 1H),
9.74 (s, 1H), 9.31 (s, 1H), 8.04 (s, 1H), 7.76-7.92 (m, 4H),
7.41-7.49 (m, 2H), 6.33 (d, 1H), 6.68 (d, 2H), 6.44-6.50 (m, 1H),
6.25-6.29 (m, 1H), 5.76 (d, 1H), 4.14-4.16 (m, 1H), 2.57-2.58 (m,
2H), 2.11-2.17 (m, 5H), 1.81-1.83 (m, 2H), 1.55-1.59 (m, 2H).
Example 135
Preparation of
N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide
##STR00267##
[2240]
N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide (62.1 mg) was prepared as described
for
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 512.2.
found 512.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.29 (s, 1H),
9.75 (s, 1H), 9.31 (s, 1H), 8.04 (s, 1H), 7.91 (d, 1H), 7.76-7.87
(m, 4H), 7.42-7.50 (m, 2H), 7.33 (d, 1H), 6.69 (d, 2H), 6.44-6.51
(m, 1H), 6.27 (dd, 1H), 5.76 (dd, 1H), 4.60 (t, 1H), 4.48 (t, 1H),
4.17-4.19 (m, 1H), 2.59-2.74 (m, 4H), 2.26-2.32 (m, 2H), 1.85-1.89
(m, 2H), 1.54-1.57 (m, 2H).
Example 136
Preparation of
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide
##STR00268##
##STR00269##
[2242] To a solution of tert-butyl
4-hydroxypiperidine-1-carboxylate (603 mg, 3 mmol, 1 eq.) in DMA
(10 mL) cooled at 0.degree. C. was added NaH (180 mg, 4.5 mmol, 1.5
eq.) in small portions and the resulting mixture was stirred at
0.degree. C. for 30 min. Then 1-fluoro-4-nitrobenzene (423 mg, 3
mmol, 1 eq.) was added slowly. The mixture was stirred at r.t.
overnight. The mixture was poured into ice-water (100 mL),
extracted with EA (3.times.20 mL) and the organic layers were
combined, washed with brine (60 mL), dired over Na.sub.2SO.sub.4,
concentrated and purified via column chromatography (PE/EA=2/1) to
afford tert-butyl 4-(4-nitrophenoxy)piperidine-1-carboxylate (818
mg, 85%) as a yellow solid.
##STR00270##
[2243] To a solution of HCl in MeOH (20 mL) was added tert-butyl
4-(4-nitrophenoxy)piperidine-1-carboxylate (818 mg, 2.5 mmol). The
resulting mixture was stirred at r.t. for 1 h. The mixture was
concentrated to afford 4-(4-nitrophenoxy)piperidine hydrochloride
(760 mg, 100%) as a yellow solid.
##STR00271##
[2244] To a solution of 4-(4-nitrophenoxy)piperidine hydrochloride
(516 mg, 2 mmol, 1 eq.) in DMF (10 mL) was added K.sub.2CO.sub.3
(828 mg, 6 mmol, 3 eq.) followed by 2-bromoethanol (273 mg, 2.2
mmo, 1.1 eq.) and the resulting mixture was stirred at 90.degree.
C. for 12 h. The mixture was purified via column chromatography
(DCM/MeOH=10/1) to afford
2-(4-(4-nitrophenoxy)piperidin-1-yl)ethanol (240 mg, 45%) as a
white solid.
##STR00272##
[2245] To a solution of 2-(4-(4-nitrophenoxy)piperidin-1-yl)ethanol
(240 mg, 0.9 mmol) in MeOH (10 mL) was added Pd/C (50 mg) and the
resulting mixture was stirred at r.t. overnight. The Pd/C was
removed by filtration and the filtrate was concentrated to afford
2-(4-(4-aminophenoxy)piperidin-1-yl)ethanol (200 mg, 94%) as
colorless oil.
##STR00273##
[2246] To a suspension of
2-(4-(4-aminophenoxy)piperidin-1-yl)ethanol (83 mg, 0.35 mmol, 1.1
eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg,
0.32 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (180 mg, 1.6
mmol, 5 eq.) and the resulting mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated, diluted with DCM (20 mL),
washed with Na.sub.2CO.sub.3 solution (20 mL), dired over
Na.sub.2SO.sub.4, concentrated and purified via column
chromatography (DCM/MeOH=20/1) to afford
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide (65.8 mg, 40%) as yellow solid. LRMS
(M-H.sup.+) m/z calculated 510.2. found 510.2. .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 10.45 (s, 1H), 9.78 (s, 1H), 9.32 (s,
1H), 8.05 (s, 1H), 7.78-7.94 (m, 5H), 7.37-7.48 (m, 3H), 6.74 (d,
2H), 6.44-6.76 (m, 1H), 6.27 (d, 1H), 5.76 (d, 1H), 5.07 (s, 1H),
3.70-4.45 (m, 4H), 2.94-3.27 (m, 4H), 1.80-2.06 (m, 4H).
Example 137
Preparation of
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide
##STR00274##
##STR00275##
[2248] To a solution of tert-butyl
4-amino-3-fluoropiperidine-1-carboxylate (1.1 g, 4 mmol, 1.2 eq.)
in DMSO (4 mL) was added TEA (1.2 mL 8 mmol, 2 eq.) followed by
1-fluoro-4-nitrobenzene (465 mg, 3.3 mmol, 1 eq.) and the mixture
was stirred at 90.degree. C. overnight. The mixture was poured into
ice-water (40 mL), and the precipitate was collected by filtration,
dried in vacuum to afford tert-butyl
3-fluoro-4-((4-nitrophenyl)amino)piperidine-1-carboxylate (1.1 g,
100%) as yellow solid.
##STR00276##
[2249] To a solution of HCl in MeOH (10 mL) was added tert-butyl
3-fluoro-4-((4-nitrophenyl)amino)piperidine-1-carboxylate (678 mg,
2 mmol) and the resulting mixture was stirred at r.t. for 1 h. Then
the solution was concentrated to afford
3-fluoro-N-(4-nitrophenyl)piperidin-4-amine hydrochloride (624 mg,
100%) as yellow solid.
##STR00277##
[2250] To a solution of 3-fluoro-N-(4-nitrophenyl)piperidin-4-amine
hydrochloride (624 mg, 2 mmol, 1 eq.) in MeOH (5 mL) was added HOAc
(1 mL) and HCHO (0.3 mL, 4 mmol, 2 eq.) followed by NaBH.sub.3CN
(252 mg, 4 mmol, 2 eq.) and the resulting mixture was stirred at
r.t. for 30 min. Then to the mixture was added Na.sub.2CO.sub.3
solution (10 mL). The mixture was extracted with EA (3.times.10 mL)
and the organic layers were combined, washed with brine (40 mL),
dired over, concentrated and purified via column chromatography
(DCM/MeOH=30/1) to afford
3-fluoro-1-methyl-N-(4-nitrophenyl)piperidin-4-amine (310 mg,
61%).
##STR00278##
[2251] To a solution of
3-fluoro-1-methyl-N-(4-nitrophenyl)piperidin-4-amine (253 mg, 1
mmol) in MeOH (5 mL) was added Pd/C (50 mg) and the resulting
mixture was stirred at r.t. overnight. The Pd/C was removed by
filtration and the filtrate was concentrated to afford
N1-(3-fluoro-1-methylpiperidin-4-yl)benzene-1,4-diamine (210 mg,
96%) as dark oil.
##STR00279##
To a suspension of
N1-(3-fluoro-1-methylpiperidin-4-yl)benzene-1,4-diamine (210 mg,
0.95 mmol, 1 eq.) and
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (290 mg, 0.95 mmol,
1 eq.) in n-BuOH (10 mL) was added TFA (520 mg, 4.8 mmol, 5 eq.)
and the resulting mixture was stirred at 90.degree. C. overnight.
The mixture was concentrated, diluted with DCM (20 mL), washed with
Na.sub.2CO.sub.3 solution (20 mL), dired over Na.sub.2SO.sub.4,
concentrated and purified via column chromatography (DCM/MeOH=10/1)
to afford
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide (44.4 mg, 9.4%) as yellow solid.
LRMS (M+H) m/z calculated 497.2. found 497.2. .sup.1H NMR (DMSO-d6,
400 MHz) .delta. 10.26 (s, 1H), 9.49 (s, 1H), 9.24 (s, 1H),
7.76-7.96 (m, 4H), 7.56-7.60 (m, 2H), 7.35-7.47 (m, 3H), 6.43-6.51
(m, 3H), 6.25-6.30 (m, 1H), 5.77 (d, 1H), 5.03 (d, 1H), 473 (d,
1H), 2.99-3.04 (m, 1H), 2.75-2.78 (m, 1H), 2.44-2.59 (m, 1H),
2.15-2.27 (.sub.m, .sub.5H), 1.66-1.67 (m, 2H).
Example 138
Preparation of
N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide
##STR00280##
##STR00281##
[2253] To a solution of 1-methylpiperidin-4-amine (1.25 g, 11 mmol,
1.1 eq.) in DMSO (20 mL) was added TEA (4.2 mL 30 mmol, 3 eq.)
followed by 1-fluoro-4-nitrobenzene (1.41 g, 10 mmol, 1 eq.) and
the mixture was stirred at 90.degree. C. overnight. The mixture was
poured into ice-water (40 mL), and the precipitate was collected by
filtration, dried in vacuum to afford
1-methyl-N-(4-nitrophenyl)piperidin-4-amine (2 g, 85%) as a white
solid.
##STR00282##
[2254] To a solution of 1-methyl-N-(4-nitrophenyl)piperidin-4-amine
(2 g, 8.5 mmol) in MeOH (20 mL) was added Pd/C (200 mg) and the
resulting mixture was stirred at r.t. overnight. The Pc/C was
removed by filtration and the filtrate was concentrated to afford
N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine (1.7 g, 99%) as a
yellow solid.
##STR00283##
[2255] To a suspension of
N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine (103 mg, 0.5 mmol, 1
eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (155 mg,
0.5 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (290 mg, 2.5 mmol,
5 eq.) and the resulting mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated, diluted with DCM (20 mL),
washed with Na.sub.2CO.sub.3 solution (20 mL), dried over
Na.sub.2SO.sub.4, concentrated and purified via column
chromatography (DCM/MeOH=10/1) to afford
N-(3-(2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazolin-8-yl)p-
henyl)acrylamide (13.9 mg, 31%) as yellow solid. LRMS (M+H.sup.+)
m/z calculated 479.2. found 479.2. .sup.1H NMR (DMSO-d6, 400 MHz)
.delta. 10.24 (s, 1H), 9.45 (s, 1H), 9.23 (s, 1H), 7.97 (s, 1H),
7.85-7.89 (m, 2H), 7.76 (m, 1H), 7.56 (d, 2H), 7.35-7.43 (m, 3H),
6.30-6.37 (m, 4H), 5.77 (d, 1H), 4.99 (d, 1H), 2.69-2.72 (m, 2H),
2.17 (s, 3H), 1.99 (t, 2H), 1.79-1.82 (m, 2H), 1.29-1.32 (m,
2H).
Example 139
Preparation of
N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide
##STR00284##
##STR00285##
[2257] To a solution of tert-butyl 4-aminopiperidine-1-carboxylate
(5 g, 25 mmol, 1.1 eq.) in DMSO (50 mL) was added TEA (7.5 mL 54
mmol, 2.2 eq.) followed by 1-fluoro-4-nitrobenzene (5.4 g, 36 mmol,
1.4 eq.) and the mixture was stirred at 90.degree. C. overnight.
The mixture was poured into ice-water (500 mL), and the precipitate
was collected by filtration, dried in vacuum to afford tert-butyl
4-((4-nitrophenyl)amino)piperidine-1-carboxylate (6.7 g, 84%) as a
white solid.
##STR00286##
[2258] To a solution of HCl in MeOH (40 mL) was added tert-butyl
4-((4-nitrophenyl)amino)piperidine-1-carboxylate (3.7 g, 11.5
mmol). The resulting mixture was stirred at r.t. for 1 h. The Pd/C
was removed by filtration and the filtrate was concentrated to to
afford N-(4-nitrophenyl)piperidin-4-amine hydrochloride (2.96 g,
100%) as a yellow solid.
##STR00287##
[2259] To a solution of N-(4-nitrophenyl)piperidin-4-amine
hydrochloride (1.48 g, 5.8 mmol, 1 eq.) in DMF (15 mL) was added
K.sub.2CO.sub.3 (2.38 g, 17.3 mmol, 3 eq.) followed by
1-bromo-2-fluoroethane (1.08 g, 8.6 mmol, 1.5 eq.) and the
resulting mixture was stirred at 120.degree. C. for 2 h in
microwave reactor. The mixture was purified via column
chromatography (DCM/MeOH=30/1) to afford
1-(2-fluoroethyl)-N-(4-nitrophenyl)piperidin-4-amine (700 mg, 45%)
as a brown oil.
##STR00288##
[2260] To a solution of
1-(2-fluoroethyl)-N-(4-nitrophenyl)piperidin-4-amine (150 mg, 0.56
mmol) in MeOH (20 mL) was added Pd/C (20 mg) and the resulting
mixture was stirred at r.t. overnight. The Pd/C was removed by
filtration and the filtrate was concentrated to afford
N1-(1-(2-fluoroethyl)piperidin-4-yl)benzene-1,4-diamine (133 mg,
100%) as a brown oil.
##STR00289##
To a suspension of
N1-(1-(2-fluoroethyl)piperidin-4-yl)benzene-1,4-diamine (133 mg,
0.56 mmol, 1.7 eq.) and
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.32 mmol,
1 eq.) in n-BuOH (15 mL) was added TFA (290 mg, 2.5 mmol, 5 eq.)
and the resulting mixture was stirred at 90.degree. C. overnight.
The mixture was concentrated, diluted with DCM (20 mL), washed with
Na.sub.2CO.sub.3 solution (20 mL), dired over Na.sub.2SO.sub.4,
concentrated and purified via column chromatography (DCM/MeOH=20/1)
to afford
N-(3-(2-((4-((1-(2-fluoroethyl)piperidin-4-yl)amino)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide (27 mg, 16.3%) as yellow solid.
LRMS (M+H.sup.+) m/z calculated 511.3. found 511.2. .sup.1H NMR
(DMSO-d6, 300 MHz) .delta. 10.25 (s, 1H), 9.46 (s, 1H), 9.24 (s,
1H), 7.97 (s, 1H), 7.85-7.97 (m, 3H), 7.76 (dd, 1H), 7.57 (d, 2H),
7.35-7.45 (m, 3H), 6.25-6.53 (m, 4H), 5.76 (dd, 1H), 5.00 (d, 1H),
4.61 (t, 1H), 4.45 (t, 1H), 3.05-3.06 (m, 1H), 2.82-2.86 (m, 2H),
2.56-2.69 (m, 2H), 2.10-2.18 (m, 2H), 1.80-1.85 (m, 2H), 1.29-1.33
(m, 2H).
Example 140
Preparation of
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-yl)amino)phenyl)amino)quinazo-
lin-8-yl)phenyl)acrylamide
##STR00290##
##STR00291##
[2262] To a solution of N-(4-nitrophenyl)piperidin-4-amine
hydrochloride (1.48 g, 5.8 mmol, 1 eq.) in DMF (15 mL) was added
K.sub.2CO.sub.3 (2.38 g, 17.3 mmol, 3 eq.) followed by
1-bromo-2-fluoroethane (0.86 g, 6.9 mmol, 1.2 eq.) and the
resulting mixture was stirred at 90.degree. C. overnight. The
mixture was poured into ice-water (100 mL), extracted by EA
(3.times.40 mL), and the organic layers were combined, washed with
brine (150 mL), concentrated and purified via column chromatography
(DCM/MeOH=30/1) to afford
2-(4-((4-nitrophenyl)amino)piperidin-1-yl)ethanol (700 mg, 45%) as
a brown oil.
##STR00292##
[2263] To a solution of
2-(4-((4-nitrophenyl)amino)piperidin-1-yl)ethanol (150 mg, 0.56
mmol) in MeOH (15 mL) was added Pd/C (15 mg) and the resulting
mixture was stirred at r.t. overnight. The Pd/C was removed by
filtration and the filtrate was concentrated to afford
2-(4-((4-aminophenyl)amino)piperidin-1-yl)ethanol (133 mg, 100%) as
brown oil.
##STR00293##
[2264] To a suspension of
2-(4-((4-aminophenyl)amino)piperidin-1-yl)ethanol (153 mg, 0.56
mmol, 1.75 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide
(100 mg, 0.32 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (0.3 mL,
2.5 mmol, 5 eq.) and the resulting mixture was stirred at
90.degree. C. overnight. The mixture was concentrated, diluted with
DCM (20 mL), washed with Na.sub.2CO.sub.3 solution (20 mL), dired
over Na.sub.2SO.sub.4, concentrated and purified via column
chromatography (DCM/MeOH=10/1) to afford
N-(3-(2-((4-((1-(2-hydroxyethyl)piperidin-4-yl)amino)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide (51 mg, 31%) as yellow solid.
LRMS (M+H.sup.+) m/z calculated 509.3. found 509.2. .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 10.25 (s, 1H), 9.46 (s, 1H), 9.24 (s,
1H), 7.97 (s, 1H), 7.85-7.90 (m, 2H), 7.76 (dd, 1H), 7.57 (d, 2H),
7.35-7.46 (m, 3H), 6.44-6.51 (m, 1H), 6.26-6.34 (m, 3H), 5.76 (dd,
1H), 4.99 (d, 1H), 4.37-4.38 (m, 1H), 3.47-3.52 (m, 2H), 3.03-3.06
(m, 1H), 2.80-2.83 (m, 2H), 2.40 (t, 2H), 2.05-2.11 (m, 2H),
1.78-1.83 (m, 2H), 1.29-1.34 (m, 2H).
Example 141
Preparation of
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)quinazoli-
n-8-yl)phenyl)acrylamide
##STR00294##
[2266]
N-(3-(2-((4-((1-(2-fluoroethyl)azetidin-3-yl)amino)phenyl)amino)qui-
nazolin-8-yl)phenyl)acrylamide (117 mg) was prepared as described
for
N-(3-(2-((4-((3-fluoro-1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 483.2.
found 483.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.27 (s, 1H),
9.50 (s, 1H), 9.24 (s, 1H), 8.00 (s, 1H), 7.84-7.87 (m, 2H), 7.76
(d, 1H), 7.59 (d, 2H), 7.35-7.47 (m, 3H), 6.45-6.52 (m, 1H),
6.26-6.31 (m, 3H), 5.75-5.78 (m, 1H), 5.64 (d, 1H), 4.33-4.48 (m,
2H), 3.83-3.87 (m, 1H), 3.64-3.68 (m, 2H), 2.79-2.83 (m, 2H),
2.71-2.74 (m, 1H), 2.64-2.66 (m, 1H).
Example 142
Preparation of
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide
##STR00295##
##STR00296##
[2268] To a solution of 4-bromo-2-fluoro-1-nitrobenzene (2.2 g, 10
mmol, 1 eq.) and
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.81 g, 15
mmol, 1.5 eq.) in dioxane (80 mL) was added KOAc (1.96 g, 20 mmol,
2 eq.), followed by Pd(dppf)Cl.sub.2 (408 mg, 0.5 mmol, 0.05 eq.)
under N.sub.2 protection. The mixture was stirred at 90.degree. C.
for 12 h, then cooled to r.t. and concentrated. The resulting
residue was purified via column chromatography
(PE/EA=20/1.about.5/1, v/v) to afford
2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
as a white solid (2.1 g, 78.6% yield).
##STR00297##
[2269] To a solution of 1-methylpiperidin-4-amine (674 mg, 5.9
mmol, 1 eq.) and TEA (323 mg, 18.9 mmol, 3.2 eq.) in DCM (80 mL)
was added a pre-mixed slurry of Cu(AcO).sub.2 and
2-(3-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1.58 g, 5.9 mmol, 1 eq.). The blue mixture was then warmed to
30.degree. C. and stirred for 24 hs open to the air with a
condenser. The resulting residue was purified via column
chromatography (DCM/MeOH=20/1, v/v) to afford
N-(3-fluoro-4-nitrophenyl)-1-methylpiperidin-4-amine as a yellow
oil (224 g, 14.9% yield).
##STR00298##
[2270] To a solution of
N-(3-fluoro-4-nitrophenyl)-1-methylpiperidin-4-amine (224 mg, 0.88
mmol, 1 eq.) in MeOH (15 mL) was added Pd/C (50 mg, w/w>50%).
under H.sub.2 atmosphere (1 atm) and stirred overnight, then
filtered and concentrated to afford
3-fluoro-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine (127 mg,
64.5% yield).
##STR00299##
[2271] To a solution of
3-fluoro-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine (127 mg,
0.57 mmol, 1.2 eq.) and
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.47 mmol,
1 eq.) in n-BuOH (10 mL) was added TFA (0.14 mL, 1.8 mmol, 1.2
eq.). The mixture was stirred at 90.degree. C. for 12 h. The
solution was then cooled to r.t. and concentrated. The resulting
residue was dissolved in DCM (20 mL), washed with aqueous
Na.sub.2CO.sub.3 solution, dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The resulting residue was purified via column
chromatography (DCM/MeOH=10:1, v/v) to afford
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide (23.0 mg, 10% yield). LRMS
(M+H.sup.+) m/z calculated 497.2. found 497.2. .sup.1H NMR
(DMSO-d6, 300 MHz) .delta. 10.18 (s, 1H), 9.26 (s, 1H), 8.81 (s,
1H), 7.86-7.90 (m, 2H), 7.75-7.78 (m, 1H), 7.34-7.41 (m, 3H),
6.30-6.47 (m, 5H), 5.77 (d, 1H), 5.51 (d, 1H), 3.02-3.07 (m, 1H),
2.62-2.76 (m, 2H), 2.29 (s, 1H), 1.84-2.19 (m, 2H), 1.29-1.33 (m,
2H).
Example 143
Preparation of
N-(3-(2-((4-(1H-pyrazol-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de
##STR00300##
[2273]
N-(3-(2-((4-(1H-pyrazol-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide (78.6 mg) was prepared as described for
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 433.2.
found 433.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.30 (s, 1H),
10.07 (s, 1H), 9.39 (s, 1H), 8.28 (d, 1H), 7.41-8.07 (m, 12H),
6.20-6.51 (m, 3H), 5.70 (dd, 1H).
Example 144
Preparation of
N-(3-(2-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylami-
de
##STR00301##
[2275]
N-(3-(2-((4-(1H-pyrazol-4-yl)phenyl)amino)quinazolin-8-yl)phenyl)ac-
rylamide (28.9 mg) was prepared as described for
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 433.2.
found 433.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.31 (s, 1H),
9.88 (s, 1H), 9.35 (s, 1H), 7.31-8.06 (m, 14H), 6.28-6.51 (m,
2H).
Example 145
Preparation of
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide
##STR00302##
##STR00303##
[2277] To a suspension of 3-fluoro-4-nitrophenol (1.57 g, 10 mmol,
1 eq.), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.01 g, 10
mmol, 1 eq.) and PPh3 (3.9 g, 15 mmol, 1.5 eq.) in THF (100 mL) was
added DIAD (3.0 g, 15 mmol, 1.5 eq.) dropwise at 0.degree. C. and
the resulting mixture was stirred at r.t. overnight. The mixture
was concentrated and purified via column chromatography
(PE/EA=10/1) to afford tert-butyl
4-(3-fluoro-4-nitrophenoxy)piperidine-1-carboxylate (2.5 g, 67%) as
colorless oil.
##STR00304##
[2278] To a solution of HCl in MeOH (20 mL) was added tert-butyl
4-(3-fluoro-4-nitrophenoxy)piperidine-1-carboxylate (2.5 g, 7.3
mmol) and the resulting mixture was stirred at r.t. for 1 h. Then
the solution was concentrated to afford
4-(3-fluoro-4-nitrophenoxy)piperidine hydrochloride (1.83 g, 91%)
as white solid.
##STR00305##
[2279] To a solution of 4-(3-fluoro-4-nitrophenoxy)piperidine
hydrochloride (500 mg, 1.8 mmol, 1 eq.) in MeOH (10 mL) was added
HOAc (0.2 mL) and HCHO (0.2 mL, 3.6 mmol, 2 eq.) followed by
NaBH3CN (342 mg, 5.4 mmol, 3 eq.) and the resulting mixture was
stirred at r.t. for 30 min. Then sat. Na2CO3 (20 mL) was added,
extracted with EA (3.times.20 mL) and the organic layers were
combined, washed with brine (50 mL), dired over anhydrous
Na.sub.2SO.sub.4, concentrated to afford
4-(3-fluoro-4-nitrophenoxy)-1-methylpiperidine (450 mg, 98%) as red
oil.
##STR00306##
[2280] To a solution of
4-(3-fluoro-4-nitrophenoxy)-1-methylpiperidine (450 mg, 1.8 mmol)
in MeOH (10 mL) was added Pd/C (25 mg) and the resulting mixture
was stirred at r.t. overnight. The Pd/C was removed by filtration
and the filtrate was concentrated to afford
2-fluoro-4-((1-methylpiperidin-4-yl)oxy)aniline (401 mg, 98%) as
yellow oil.
##STR00307##
[2281] To a suspension of
2-fluoro-4-((1-methylpiperidin-4-yl)oxy)aniline (87 mg, 0.39 mmol,
1.2 eq) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100
mg, 0.32 mmol) in n-BuOH (5 mL) was added TFA (0.4 mL, 1.6 mmol, 5
eq.) and the resulting mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated, diluted with DCM (20 mL),
washed with sat. Na.sub.2CO.sub.3 (20 mL), dired over anhydrous
Na.sub.2SO.sub.4, concentrated and purified via column
chromatography (DCM/MeOH=10/1) to afford
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide (35.5 mg, 18%) as yellow solid. LRMS
(M+H.sup.+) m/z calculated 498.2. found 498.2. .sup.1H NMR
(CD.sub.3OD, 300 MHz) .delta. 9.23 (s, 1H), 8.32 (t, 1H), 7.86-7.94
(m, 4H), 7.42-7.50 (m, 3H), 6.77-6.81 (m, 1H), 6.38-6.55 (m, 3H),
5.80-5.83 (m, 1H), 4.41 (m, 1H), 2.89-2.92 (m, 2H), 2.65-2.66 (m,
2H), 2.51 (s, 3H), 2.01-2.07 (m, 2H), 2.02-2.07 (m, 2H).
Example 146
Preparation of
N-(3-(2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide
##STR00308##
[2283]
N-(3-(2-((3-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino-
)quinazolin-8-yl)phenyl)acrylamide (88 mg) was prepared as
described for
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 513.2.
found 513.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.26 (s, 1H),
9.92 (s, 1H), 9.35 (s, 1H), 8.04 (s, 1H), 7.77-7.95 (m, 4H),
7.36-7.57 (m, 4H), 6.79 (m, 1H), 6.43-6.50 (m, 1H), 6.22-6.27 (m,
1H), 4.33 (m, 1H), 5.73 (d, 1H), 4.43-4.44 (m, 1H), 3.53-3.56 (m,
2H), 3.17-3.18 (m, 2H), 2.89 (m, 4H), 2.46-2.56 (m, 4H).
Example 147
Preparation of
N-(3-(2-((3-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide
##STR00309##
[2285]
N-(3-(2-((3-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)ph-
enyl)amino)quinazolin-8-yl)phenyl)acrylamide (46.2 mg) was prepared
as described for
N-(3-(2-((2-fluoro-4-(1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 541.3.
found 541.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.24 (s, 1H),
9.90 (s, 1H), 9.34 (s, 1H), 8.03 (s, 1H), 7.72-7.95 (m, 4H),
7.35-7.61 (m, 4H), 6.78 (t, 1H), 6.42-6.49 (m, 1H), 5.71-5.75 (m,
1H), 4.09 (s, 1H), 2.87 (m, 4H), 2.64 (m, 4H), 2.25 (s, 2H), 1.23
(s, 6H).
Example 148
Preparation of
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quin-
azolin-8-yl)phenyl)acrylamide
##STR00310##
[2287]
N-(3-(2-((4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amin-
o)quinazolin-8-yl)phenyl)acrylamide (64.6 mg) was prepared as
described for
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinaz-
olin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 523.3.
found 523.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.30 (s, 1H),
9.68 (s, 1H), 9.28 (s, 1H), 8.03 (s, 1H), 7.72-7.92 (m, 5H),
7.30-7.50 (m, 3H), 6.67 (d, 2H), 6.23-6.52 (m, 2H), 5.74 (dd, 1H),
4.13 (s, 1H), 2.96 (m, 4H), 2.64 (m, 4H), 2.24 (s, 2H), 1.11 (s,
6H).
Example 149
Preparation of
N-(3-(2-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00311##
[2289]
N-(3-(2-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide (27.2 mg) was prepared as described
for
N-(3-(2-((2-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)quinazolin-
-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated 501.2.
found 501.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.20 (s, 1H),
10.13 (s, 1H), 9.39 (s, 1H), 7.82-8.05 (m, 4H), 7.37-7.60 (m, 5H),
6.41-6.44 (m, 1H), 6.23-6.24 (m, 1H), 5.71 (d, 1H), 2.97 (m, 4H),
2.38 (m, 4H), 2.21 (s, 3H).
Example 150
Preparation of
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide
##STR00312##
##STR00313##
[2291] To a solution of 2-(piperazin-1-yl)ethanol (1.56 g, 12 mmol,
1.2 eq.) in DMF (20 mL) was added K.sub.2CO.sub.3 (2.76 g, 20 mmol,
2 eq.) followed by 2,4-difluoro-1-nitrobenzene (1.59 g, 10 mmol, 1
eq.) and the mixture was stirred at 90.degree. C. overnight. The
mixture was poured into ice-water (200 mL), extracted by EA
(3.times.40 mL), and the organic layers were combined, washed with
brine (150 mL), concentrated to afford the mixture of
2-(4-(3-fluoro-4-nitrophenyl)piperazin-1-yl)ethanol and
2-(4-(5-fluoro-2-nitrophenyl)piperazin-1-yl)ethanol (2 g) which was
used without further purification.
##STR00314##
[2292] To a solution of the mixture of
2-(4-(3-fluoro-4-nitrophenyl)piperazin-1-yl)ethanol and
2-(4-(5-fluoro-2-nitrophenyl)piperazin-1-yl)ethanol (2 g in MeOH
(50 mL) was added Pd/C (200 mg) and the resulting mixture was
stirred at r.t. overnight. Pd/C was removed by filtration and the
filtrate was concentrated and purified via column chromatography
(10-95% CH3CN--H2O) to afford
2-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)ethanol (500 mg, 25%
for two steps) as a brown solid.
##STR00315##
[2293] To a suspension of
2-(4-(4-amino-3-fluorophenyl)piperazin-1-yl)ethanol (76 mg, 0.32
mmol, 1 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide
(100 mg, 0.32 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (0.2 mL,
1.6 mmol, 5 eq.) and the resulting mixture was stirred at
90.degree. C. overnight. The mixture was concentrated, diluted with
DCM (20 mL), washed with Na.sub.2CO.sub.3 solution (20 mL), dired
over anhydrous Na.sub.2SO.sub.4, concentrated and purified via
column chromatography (DCM/MeOH=10/1) to afford
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amin-
o)quinazolin-8-yl)phenyl)acrylamide (54 mg, 33%) as yellow solid.
LRMS (M+H.sup.+) m/z calculated 513.2. found 513.2. .sup.1H NMR
(DMSO-d6, 400 MHz) .delta. 10.22 (s, 1H), 9.30 (s, 1H), 8.97 (s,
1H), 7.76-7.93 (m, 5H), 7.36-7.45 (m, 3H), 6.78 (d, 1H), 6.46-6.52
(m, 2H), 6.26-6.30 (m, 1H), 5.77 (d, 1H), 4.44 (t, 1H), 3.53-3.57
(m, 2H), 3.06 (m, 4H), 2.51-2.54 (m, 4H), 2.44 (t, 2H).
Example 151
Preparation of
N-(3-(2-((2,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00316##
##STR00317##
[2295] To a solution of 1,3,5-trifluoro-2-nitrobenzene (500 mg, 5
mmol, 1.1 eq.) in DMSO (20 mL) was added TEA (1.4 mL 10 mmol, 2
eq.) followed by 1-methylpiperazine (885 mg, 5 mmol, 1 eq.) and the
mixture was stirred at 90.degree. C. overnight. The mixture was
poured into ice-water (200 mL), extracted with EA (3.times.50 mL),
and the organic phase were combined, washed with brine (150 mL),
dried over Na.sub.2SO.sub.4 and concentrated to afford a mixture of
two isomers (2 g, 90%) as brown solid.
##STR00318##
[2296] To a solution of a mixture of two isomers (200 mg, 0.8 mmol)
in MeOH (20 mL) was added Pd/C (20 mg) and the resulting mixture
was stirred at r.t. overnight. The Pd/C was removed by filtration
and the filtrate was concentrated and purified via column
chromatography (10-95% CH.sub.3CN--H.sub.2O) to afford
2,6-difluoro-4-(4-methylpiperazin-1-yl)aniline (160 mg, 94%) as
brown oil.
##STR00319##
[2297] To a suspension of
2,6-difluoro-4-(4-methylpiperazin-1-yl)aniline (73 mg, 0.32 mmol, 1
eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg,
0.32 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (180 mg, 1.6
mmol, 5 eq.) and the resulting mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated, diluted with DCM (20 mL),
washed with Na.sub.2CO.sub.3 solution (20 mL), dired over anhydrous
Na.sub.2SO.sub.4, concentrated and purified via column
chromatography afford
N-(3-(242,6-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8--
yl)phenyl)acrylamide (4.7 mg, 2%) as yellow solid. LRMS (M+H.sup.+)
m/z calculated 501.2. found 501.2. .sup.1H NMR (CD3Cl, 400 MHz)
.delta. 9.11 (s, 1H), 7.71-7.83 (m, 4H), 7.30-7.46 (m, 4H),
6.30-6.52 (m, 5H), 5.78 (d, 1H), 3.16-3.18 (m, 4H), 2.53-2.56 (m,
4H), 2.35 (s, 3H).
Example 152
Preparation of
N-(3-(2-((2-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide
##STR00320##
[2299]
N-(3-(2-((2-fluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)ph-
enyl)amino)quinazolin-8-yl)phenyl)acrylamide (16.4 mg) was prepared
as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
541.3. found 541.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.29
(s, 1H), 9.30 (s, 1H), 8.90 (s, 1H), 7.78-7.92 (m, 5H), 7.38-7.45
(m, 3H), 6.75 (dd, 1H), 6.48-6.52 (m, 2H), 6.30-6.38 (m, 1H), 5.75
(d, 1H), 4.12 (s, 1H), 3.03-3.05 (m, 4H), 2.63-2.65 (m, 4H), 2.25
(s, 2H).
Example 153
Preparation of
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00321##
##STR00322##
[2301] To a solution of 1,2,3-trifluoro-4-nitrobenzene (2.5 g, 14
mmol, 1.0 eq.) in DMF (20 mL) was added K.sub.2CO.sub.3 (3.8 g, 28
mmol, 2.0 eq.) followed by 2-(piperazin-1-yl)ethanol (1.8 g, 14
mmol, 1.0 eq.) at 0.degree. C. and the mixture was stirred at r.t.
overnight. The mixture was poured into ice-water (200 mL), filtered
and dried in vacuo to afford
2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-1-yl)ethanol (2.7 g,
67.5%).
##STR00323##
[2302] To a solution of
2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-1-yl)ethanol (2.7 g, 9.0
mmol) in MeOH (30 mL) was added Pd/C (270 mg) and the resulting
mixture was stirred at r.t. overnight. The Pd/C was removed by
filtration and the filtrate was concentrated to afford
2-(4-(4-amino-2,3-difluorophenyl)piperazin-1-yl)ethanol (2.39 g,
99% yield) as off-white solid.
##STR00324##
[2303] To a suspension of
2-(4-(4-amino-2,3-difluorophenyl)piperazin-1-yl)ethanol (83 mg,
0.32 mmol, 1 eq.) and
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.32 mmol,
1 eq.) in n-BuOH (5 mL) was added TFA (68 mg, 0.64 mmol, 2 eq.) and
the resulting mixture was stirred at 90.degree. C. overnight. The
mixture was concentrated, diluted with DCM (20 mL), washed with
Na.sub.2CO.sub.3 solution (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, concentrated and the residue was purified via
column chromatography (MeOH/DCM=1/30, v:v) to afford
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide as a yellow solid (16.3 mg, 9.5%
yield). LRMS (M+H.sup.+) m/z calculated 531.2. found 531.2. .sup.1H
NMR (CD.sub.3OD, 400 MHz) .delta. 9.21 (s, 1H), 7.19-8.01 (m, 10H),
8.90 (s, 1H), 6.41-6.49 (m, 3H), 5.86 (m, 1H), 3.98-4.01 (m, 3H),
3.70-3.76 (m, 3H), 3.40-3.49 (m, 2H), 3.37-3.39 (m, 4H), 3.18 (m,
2H).
Example 154
Preparation of
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-2-fluorophenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00325##
[2305] N-(3-(2-((4-(4-(2-amino-2-oxo
ethyl)piperazin-1-yl)-2-fluorophenyl)amino)quinazolin-8-yl)phenyl)acrylam-
ide (152.7 mg) was prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
526.2. found 526.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.23
(s, 1H), 9.31 (s, 1H), 8.99 (s, 1H), 7.77-7.93 (m, 5H), 7.15-7.45
(m, 5H), 6.79 (dd, 1H), 6.46-6.52 (m, 2H), 6.25-6.30 (m, 1H), 5.78
(d, 1H), 3.09-3.12 (m, 4H), 2.93 (s, 2H), 2.54-2.57 (m, 4H).
Example 155
Preparation of
N-(3-(2-((4-(4-(2-amino-2-oxoethyl)piperazin-1-yl)-3-fluorophenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00326##
[2307] N-(3-(2-((4-(4-(2-amino-2-oxo
ethyl)piperazin-1-yl)-3-fluorophenyl)amino)quinazolin-8-yl)phenyl)acrylam-
ide (30.8 mg) was prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
526.2. found 526.2. .sup.1H NMR (CD3Cl, 400 MHz) .delta. 9.00 (s,
1H), 7.72-7.83 (m, 5H), 7.66 (s, 1H), 7.42-7.45 (m, 3H), 7.34 (t,
1H), 7.16 (d, 1H), 6.98 (m, 1H), 6.72 (t, 1H), 6.16-6.37 (m, 2H),
5.61-5.67 (m, 2H), 3.00 (s, 2H), 2.93-2.96 (m, 4H), 2.62-2.64 (m,
4H).
Example 156
Preparation of
N-(3-(2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide
##STR00327##
[2309]
N-(3-(2-((2-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino-
)quinazolin-8-yl)phenyl)acrylamide (60.1 mg) was prepared as
described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
528.2. found 528.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.22
(s, 1H), 9.30 (s, 1H), 8.97 (s, 1H), 7.75-7.93 (m, 5H), 7.36-7.45
(m, 3H), 6.78 (dd, 1H), 6.44-6.52 (m, 2H), 6.25-6.30 (m, 1H), 5.78
(d, 1H), 3.48 (t, 2H), 3.26 (s, 3H), 3.04-3.06 (m, 4H), 2.50-2.53
(m, 6H).
Example 157
Preparation of
N-(3-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide
##STR00328##
[2311]
N-(3-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino-
)quinazolin-8-yl)phenyl)acrylamide (92.8 mg) was prepared as
described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
527.2. found 527.2. .sup.1H NMR (DMSO-d6, 300 MHz) .delta. 10.24
(s, 1H), 9.91 (s, 1H), 9.34 (s, 1H), 7.81-8.04 (m, 4H), 7.38-7.54
(m, 3H), 6.78 (t, 1H), 6.26-6.50 (m, 2H), 5.74 (d, 1H), 4.08 (q,
1H), 3.46 (t, 2H), 3.26 (d, 2H), 2.87 (m, 3H), 2.50-2.53 (m,
8H).
Example 158
Preparation of
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00329##
##STR00330##
[2313] To a solution of 1-methylpiperazine (0.57 g, 5.7 mmol, 1
eq.) in DMF (10 mL) was added K2CO3 (1.56 g, 11.3 mmol, 2 eq.)
followed by 1,2,3-trifluoro-4-nitrobenzene (1 g, 5.7 mmol, 1 eq.)
and the mixture was stirred at 0.degree. C. for 1 h. The mixture
was poured into ice-water (100 mL), extracted by EA (3.times.40
mL), and the organic layers were combined, washed with brine (150
mL), concentrated and purified via column chromatography (10-95%
CH3CN--H2O) to afford (1.3 g, 86%) as a yellow solid.
##STR00331##
[2314] To a solution of
1-(2,3-difluoro-4-nitrophenyl)-4-methylpiperazine (1.3 g, 5.4 mmol)
in MeOH (50 mL) was added Pd/C (200 mg) and the resulting mixture
was stirred at r.t. overnight. The catalyst was removed by
filtration and the filtrate was concentrated to afford
2,3-difluoro-4-(4-methylpiperazin-1-yl)aniline (1.3 g, 100%) as a
yellow solid.
##STR00332##
[2315] To a suspension of
2,3-difluoro-4-(4-methylpiperazin-1-yl)aniline (154 mg, 0.5 mmol, 1
eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (114 mg,
0.5 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (0.3 mL, 2.5 mmol,
5 eq.) and the resulting mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated, diluted with DCM (20 mL),
washed with Na.sub.2CO.sub.3 solution (20 mL), dired, concentrated
and purified via silica gel column (DCM/MeOH=10/1) to afford
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide (37 mg, 14%) as a yellow solid.
[2316] LRMS (M+H.sup.+) m/z calculated 501.2. found 501.2. .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 10.24 (s, 1H), 9.35-9.36 (m, 2H),
7.32-7.96 (m, 8H), 6.24-6.57 (m, 3H), 5.78 (d, 1H), 2.94-2.96 (m,
4H), 2.46-2.47 (m, 4H), 2.24 (s, 3H).
Example 159
Preparation of
N-(3-(2-((2,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide
##STR00333##
##STR00334##
[2318] To a solution of 1-methylpiperazine (0.57 g, 5.7 mmol, 1
eq.) in DMF (10 mL) was added K2CO3 (1.56 g, 11.3 mmol, 2 eq.)
followed by 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.7 mmol, 1 eq.)
and the mixture was stirred at 0.degree. C. for 1 hour. The mixture
was poured into ice-water (100 mL), extracted by EA (3.times.40
mL), and the organic layers were combined, washed with brine (150
mL), concentrated and purified via column chromatography (10-95%
CH.sub.3CN--H.sub.2O) to afford
1-(2,5-difluoro-4-nitrophenyl)-4-methylpiperazine (1.4 g, 93%) as
yellow solid.
##STR00335##
[2319] To a solution of
1-(2,5-difluoro-4-nitrophenyl)-4-methylpiperazine (1.4 g, 5.5 mmol)
in MeOH (50 mL) was added Pd/C (200 mg) and the resulting mixture
was stirred at r.t. overnight. The catalyst was removed by
filtration and the filtrate was concentrated to afford
2,5-difluoro-4-(4-methylpiperazin-1-yl)aniline (1.4 g, 100%).
##STR00336##
[2320] To a suspension of
2,5-difluoro-4-(4-methylpiperazin-1-yl)aniline (154 mg, 0.5 mmol, 1
eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (114 mg,
0.5 mmol, 1 eq.) in n-BuOH (10 mL) was added TFA (0.3 mL, 2.5 mmol,
5 eq.) and the resulting mixture was stirred at 90.degree. C.
overnight. The mixture was concentrated, diluted with DCM (20 mL),
washed with Na.sub.2CO.sub.3 solution (20 mL), dired, concentrated
and purified via column chromatography (DCM/MeOH=10/1) to afford
N-(3-(2-((2,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide (42 mg, 16%) as a yellow solid. LRMS
(M+H.sup.+) m/z calculated 501.2. found 501.2. .sup.1H NMR
(DMSO-d6, 300 MHz) .delta. 10.17 (s, 1H), 9.37 (s, 1H), 9.17 (s,
1H), 7.75-7.97 (m, 5H), 7.39-7.51 (m, 3H), 6.84-6.89 (m, 1H),
6.19-6.49 (m, 2H), 5.74 (dd, 1H), 2.91-2.94 (m, 4H), 2.45-2.49 (m,
4H), 2.23 (s, 3H).
Example 160
Preparation of
N-(3-(2-((2,5-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00337##
[2322]
N-(3-(2-((2,5-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide (55 mg) was prepared as
described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide. LRMS (M+H) m/z calculated 545.2.
found 545.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.13 (s,
1H), 8.31-8.36 (m, 1H), 7.74-7.82 (m, 4H), 7.30-7.40 (m, 3H),
6.77-6.82 (m, 3H), 6.21-6.38 (m, 2H), 5.64-5.66 (m, 1H), 3.65-3.68
(m, 2H), 3.54-3.56 (m, 2H), 3.32-3.37 (m, 3H), 3.17 (m, 6H),
2.99-3.01 (m, 2H).
Example 161
Preparation of
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00338##
##STR00339##
[2324] To a solution of 2-(piperazin-1-yl)ethanol (0.73 g, 5.6
mmol, 1 eq.) in DMF (10 mL) was added K.sub.2CO.sub.3 (1.56 g, 11.3
mmol, 2 eq.) followed by 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.6
mmol, 1 eq.) and the mixture was stirred at 0.degree. C. for 1
hour. The mixture was poured into ice-water (100 mL), extracted by
EA (3.times.40 mL), and the organic layers were combined, washed
with brine (150 mL), concentrated and purified via column
chromatography (10-95% CH.sub.3CN--H.sub.2O) to afford
2-(4-(2,5-difluoro-4-nitrophenyl)piperazin-1-yl)ethanol (0.65 g,
41%) as a yellow solid.
##STR00340##
[2325] To a solution of
2-(4-(2,5-difluoro-4-nitrophenyl)piperazin-1-yl)ethanol (0.65 g,
2.3 mmol) in MeOH (50 mL) was added Pd/C (100 mg) and the resulting
mixture was stirred at r.t. overnight. The Pd/C was removed by
filtration and the filtrate was concentrated to afford
2-(4-(4-amino-2,5-difluorophenyl)piperazin-1-yl)ethanol (0.58 g,
99%).
##STR00341##
[2326] To a suspension of
2-(4-(4-amino-2,5-difluorophenyl)piperazin-1-yl)ethanol (270 mg,
0.88 mmol, 1 eq.) and
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (225 mg, 0.88 mmol,
1 eq.) in n-BuOH (10 mL) was added TFA (0.5 mL, 4.4 mmol, 5 eq.)
and the resulting mixture was stirred at 90.degree. C. overnight.
The mixture was concentrated, diluted with DCM (20 mL), washed with
Na.sub.2CO.sub.3 solution (20 mL), dired, concentrated and purified
via column chromatography (DCM/MeOH=10/1) to afford
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide (120 mg, 26%) as yellow solid.
LRMS (M+H.sup.+) m/z calculated 531.2. found 531.2. 1H NMR
(DMSO-d6, 400 MHz) .delta. 10.18 (s, 1H), 9.37 (s, 1H), 9.17 (s,
1H), 7.97-7.94 (m, 3H), 7.83-7.74 (m, 2H), 7.50-7.39 (m, 3H),
6.90-6.85 (m, 1H), 6.48-6.41 (m, 1H), 6.23 (dd, 1H), 5.73 (dd, 1H),
4.42 (t, 1H), 3.55-3.50 (m, 2H), 2.94-2.91 (m, 4H), 2.55-2.54 (m,
4H), 2.44 (t, 2H).
Example 162
Preparation of
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)phenyl)acrylamide
##STR00342##
[2328]
N-(3-(2-((2,5-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-y-
l)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide (42 mg) was
prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
559.2. found 559.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.18
(s, 1H), 9.37 (s, 1H), 9.18 (s, 1H), 8.00-7.94 (m, 3H), 7.83-7.74
(m, 2H), 7.50-7.39 (m, 3H), 6.90-6.85 (m, 1H), 6.47-6.41 (m, 1H),
6.22 (dd, 1H), 5.75-5.71 (m, 1H), 4.12 (s, 1H), 2.92-2.91 (m, 4H),
2.65-2.64 (m, 4H), 2.24 (s, 2H), 1.11 (s, 6H).
Example 163
Preparation of
N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00343##
[2330]
N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide (55 mg) was prepared as
described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
545.2. found 545.2. .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.13
(s, 1H), 8.09-8.04 (m, 1H), 7.86-7.68 (m, 4H), 7.40-7.27 (m, 3H),
6.48-6.25 (m, 3H), 5.69 (dd, 1H), 3.67 (t, 2H), 3.58-3.55 (m, 2H),
3.36-3.33 (m, 3H), 3.25-3.20 (m, 7H), 3.04-3.01 (m, 2H).
Example 164
Preparation of
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phen-
yl)amino)quinazolin-8-yl)phenyl)acrylamide
##STR00344##
[2332]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-y-
l)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide (33 mg) was
prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
559.2. found 559.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.22
(s, 1H), 9.36 (s, 1H), 9.32 (s, 1H), 7.96-7.77 (m, 5H), 7.49-7.34
(m, 3H), 6.46-6.42 (m, 2H), 6.29-6.28 (m, 1H), 5.76 (dd, 1H), 4.11
(s, 1H), 2.95-2.93 (m, 4H), 2.67-2.66 (m, 4H), 2.25 (s, 2H), 1.12
(s, 6H).
Example 165
Preparation of
N-(3-(2-((2-fluoro-4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide
##STR00345##
##STR00346##
[2334] To a solution of tert-butyl
4-(4-amino-3-fluorophenoxy)piperidine-1-carboxylate (1.1 g, 3.6
mmol, 1 eq.) in THF (20 mL) cooled at 0.degree. C. was added TEA
(1.1 g, 10.8 mmol, 3 eq.) followed by pivaloyl chloride (0.6 mL,
4.3 mmol, 1.2 eq.) and the resulting mixture was stirred at r.t.
for 10 min. The mixture was diluted with EA (20 mL), washed with
brine (40 mL) and concentrated to afford tert-butyl
4-(3-fluoro-4-pivalamidophenoxy)piperidine-1-carboxylate (1.4 g,
100%).
##STR00347##
[2335] To a solution of HCl in MeOH (15 mL) was added tert-butyl
4-(3-fluoro-4-pivalamidophenoxy)piperidine-1-carboxylate (1.4 g,
3.6 mmol) and the resulting mixture was stirred at r.t. for 1 h.
Then the solution was concentrated to afford
N-(2-fluoro-4-(piperidin-4-yloxy)phenyl)pivalamide hydrochloride
(1.2 g, 100%).
##STR00348##
[2336] To a solution of
N-(2-fluoro-4-(piperidin-4-yloxy)phenyl)pivalamide hydrochloride
(1.2 g, 3.6 mmol, 1 eq.) in DMF (10 mL) was added K.sub.2CO.sub.3
(994 mg, 7.2 mmol, 2 eq.) followed by 1-bromo-2-fluoroethane (680
mg, 5.4 mmo, 1.5 eq.) and the resulting mixture was stirred at
120.degree. C. for 2 h in microwave reactor. The mixture was
purified via Prep-HPLC to afford
N-(2-fluoro-4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)pivalamide
(430 mg, 35%).
##STR00349##
[2337] To a solution of
N-(2-fluoro-4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)pivalamide
(430 mg, 1.3 mmol) in HOAc (8 mL) was added conc. HCl (4 mL) and
the resulting mixture was stirred at 110.degree. C. for 12 h. The
mixture was cooled and poured into ice-water (100 mL), basified
with Na.sub.2CO.sub.3 solution to PH=10, extracted with EA and the
organic phase was dried, concentrated and purified via column
chromatography (DCM/MeOH=10/1) to afford 2-fluoro-4-((1-(2-fluoro
ethyl)piperidin-4-yl)oxy)aniline (180 mg, 56%).
##STR00350##
[2338] To a suspension of
2-fluoro-4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)aniline (150 mg,
0.6 mmol, 1.2 eq) and
N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (154 mg, 0.5 mmol,
1 eq.) in n-BuOH (10 mL) was added TFA (285 mg, 2.5 mmol, 5 eq.)
and the resulting mixture was stirred at 90.degree. C. overnight.
The mixture was concentrated, diluted with DCM (20 mL), washed with
Na.sub.2CO.sub.3 solution (20 mL), dired over Na.sub.2SO.sub.4,
concentrated and purified via column chromatography (DCM/MeOH=10/1)
and Prep-HPLC to afford
N-(3-(2-((2-fluoro-4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide (45.8 mg, 17.3%). LRMS (M+H.sup.+)
m/z calculated 530.2. found 530.2. .sup.1H NMR (DMSO-d6, 400 MHz)
.delta. 10.24 (s, 1H), 9.37 (s, 1H), 8.41-8.45 (m, 1H), 7.76-8.09
(m, 5H), 7.37-7.52 (m, 3H), 7.04 (dd, 1H), 6.23-6.50 (m, 3H), 5.77
(dd, 1H), 4.44-4.58 (m, 3H), 2.52-2.66 (m, 5H), 2.39 (m, 2H),
1.90-1.95 (m, 2H), 1.71-1.76 (m, 2H).
Example 166
Preparation of
N-(3-(2-((2-fluoro-4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)-
quinazolin-8-yl)phenyl)acrylamide
##STR00351##
[2340]
N-(3-(2-((2-fluoro-4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)-
amino)quinazolin-8-yl)phenyl)acrylamide (32.3 mg) was prepared as
described for
N-(3-(2-((2-fluoro-4-((1-(2-fluoroethyl)piperidin-4-yl)oxy)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide. LRMS (M+H.sup.+) m/z calculated
528.2. found 528.2. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 10.22
(s, 1H), 9.32 (s, 1H), 9.08 (s, 1H), 7.73-7.93 (m, 5H), 7.36-7.45
(m, 3H), 6.87 (d, 1H), 6.44-6.56 (m, 2H), 6.24-6.29 (m, 1H), 5.76
(d, 1H), 4.33 (m, 1H), 3.52-3.56 (m, 2H), 2.75-2.81 (m, 2H),
1.91-1.97 (m, 2H), 1.65-1.71 (m, 2H).
Example 167
Preparation of
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate
##STR00352##
##STR00353##
[2342] 3.8 mL of refluxing EtOH/H2O (20/1) was slowly added to 100
mg of
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide and 1.2 eq of maleic acid till all
solid was dissolved, the mixture was slowly cooled down and stood
overnight, the precipitate was collected by filtration to give
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate (86.7 mg).
[2343] LRMS (M+H.sup.+) m/z calculated 513.2. found 513.2. .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 10.23 (s, 1H), 9.31 (s, 1H), 9.07
(s, 1H), 7.93-7.79 (m, 5H), 7.46-7.38 (m, 3H), 6.92-6.87 (m, 1H),
6.58-6.47 (m, 2H), 6.34 (dd, 1H), 6.03 (s, 2H), 5.77 (dd, 1H), 5.33
(s, 1H), 4.34 (s, 1H), 3.76-3.44 (m, 2H), 3.46-3.11 (m, 12H), 1.05
(t, 3H).
Example 168
Preparation of
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide maleate
##STR00354##
[2345]
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)ph-
enyl)acrylamide maleate was prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate.
[2346] LRMS (M+H.sup.+) m/z calculated 465.2. found 465.2. .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 10.27 (s, 1H), 9.72 (s, 1H), 9.31
(s, 1H), 7.92-7.90 (m, 3H), 7.83-7.77 (m, 3H), 7.50-7.36 (m, 3H),
6.76 (d, 2H), 6.51-6.44 (m, 1H), 6.28 (dd, 1H), 6.03 (s, 2H), 5.77
(dd, 1H), 3.31-3.19 (m, 8H), 2.83 (s, 3H).
Example 169
Preparation of
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-y-
l)phenyl)acrylamide maleate
##STR00355##
[2348]
N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazol-
in-8-yl)phenyl)acrylamide maleate was prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate.
[2349] LRMS (M+H.sup.+) m/z calculated 495.2. found 495.2. .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 10.31 (s, 1H), 9.64 (s, 1H), 9.28
(s, 1H), 8.02 (s, 1H), 7.91-7.71 (m, 5H), 7.49-7.33 (m, 3H), 6.69
(d, 2H), 6.46-6.43 (m, 1H), 6.29-6.28 (m, 1H), 5.75 (dd, 1H), 4.43
(s, 1H), 3.53 (t, 2H), 3.33 (t, 2H), 2.98-2.95 (m, 4H), 2.53-2.40
(m, 4H).
Example 170
Preparation of
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide maleate
##STR00356##
[2351]
N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)a-
mino)quinazolin-8-yl)phenyl)acrylamide maleate was prepared as
described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)q-
uinazolin-8-yl)phenyl)acrylamide maleate. LRMS (M+H+) m/z
calculated 531.2. found 531.2. 1H NMR (DMSO-d6, 400 MHz) .delta.
10.22 (s, 1H), 9.43 (s, 1H), 9.37 (s, 1H), 7.96 (dd, 1H), 7.84-7.81
(m, 3H), 7.69 (t, 1H), 7.48 (t, 1H), 7.41-7.37 (m, 2H), 6.65 (t,
1H), 6.50-6.44 (m, 1H), 6.28 (dd, 1H), 6.02 (d, 2H), 5.77 (dd, 1H),
3.75-3.72 (m, 2H), 3.44-3.06 (m, 12H).
Example 171
Preparation of
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide maleate
##STR00357##
[2353]
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate was prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate.
[2354] LRMS (M+H.sup.+) m/z calculated 501.2. found 501.2. .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 10.28 (s, 1H), 9.44 (s, 1H), 9.38
(s, 1H), 7.98 (dd, 1H), 7.81-7.95 (m, 3H), 7.71 (t, 1H), 7.48 (t,
1H), 7.41-7.37 (m, 2H), 6.65 (t, 1H), 6.50-6.44 (m, 1H), 6.28 (dd,
1H), 6.02 (s, 1.4H), 5.77 (dd, 1H), 2.86 (s, 3H).
Example 172
Preparation of
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate
##STR00358##
##STR00359##
[2356] 4.6 mL of refluxing iPrOH/H2O (20/1) was slowly added to 100
mg of
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide and 1.2 eq of maleic acid till all
solid was dissolved, the mixture was slowly cooled down and stood
overnight, the precipitate was collected by filtration to give
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate (72 mg).
[2357] LRMS (M+H.sup.+) m/z calculated 513.2. found 513.2. .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 10.23 (s, 1H), 9.32 (s, 1H), 9.07
(s, 1H), 7.93-7.79 (m, 5H), 7.46-7.38 (m, 3H), 6.92-6.87 (m, 1H),
6.58-6.47 (m, 2H), 6.27 (dd, 1H), 6.03 (s, 2H), 5.80-5.76 (m, 1H),
5.33 (s, 1H), 3.76-3.75 (m, 2H), 3.42-3.08 (m, 11H).
Example 173
Preparation of
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin--
8-yl)phenyl)acrylamide maleate
##STR00360##
[2359]
N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate was prepared as described for
N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quina-
zolin-8-yl)phenyl)acrylamide maleate.
[2360] LRMS (M+H.sup.+) m/z calculated 501.2. found 501.2. .sup.1H
NMR (DMSO-d6, 400 MHz) .delta. 10.28 (s, 1H), 9.44 (s, 1H), 9.38
(s, 1H), 7.98 (dd, 1H), 7.81-7.95 (m, 3H), 7.71 (t, 1H), 7.48 (t, 1
H), 7.41-7.37 (m, 2H), 6.65 (t, 1H), 6.50-6.44 (m, 1H), 6.28 (dd,
1H), 6.02 (s, 1.2H), 5.77 (dd, 1H), 2.86 (s, 3H).
Example 174
Preparation of
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide hydrochloride
##STR00361##
[2362] To a suspension of
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide (80 mg, 0.17 mol) in EA (10 mL) was added a solution of
HCl in dioxane (3M, 1 mL) dropwise at 0.degree. C. which resulted
in the formation of precipitate gradually. The precipitate was
filtered 30 min later to afford
N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)a-
crylamide hydrochloride as a brown solid (56 mg, 65% yield). LRMS
(M+H+) m/z calculated 465.2. found 465.2. .sup.1H NMR (DMSO-d6, 300
MHz) 10.8 (br, 1H), 10.5 (s, 1H), 9.77 (s, 1H), 9.31 (s, 1H), 8.02
(s, 1H), 7.77-7.93 (m, 5H), 7.42-7.51 (m, 2H), 7.35 (d, 1H), 6.77
(d, 2H), 6.50-6.55 (m, 1H), 6.23-6.30 (m, 1H), 5.76-5.79 (m, 1H),
3.60-3.64 (m, 2H), 3.45-3.50 (m, 2H), 2.98-3.15 (m, 4H), 2.81 (d,
3H).
Example 175
Inhibitory Activity Against EGFR, EGFR Mutants and Several Other
Kinases
[2363] Inhibitory activities of compounds against BTK, EGFR and
EGFR mutants (EGFR L858R, EGFR T790M, EGFR L858R/T790M), FGFR1,
FGFR2, JAK2, JAK3 and KDR were measured by Invitrogen using
Z'-LYTE.RTM. Method as briefly described in the following.
[2364] Test Compounds are screened in 1% DMSO (final) in the well.
For 10 point titrations, 3-fold serial dilutions are conducted from
the starting concentration. All ATP Solutions are diluted to a
4.times. working concentration in Kinase Buffer (50 mM HEPES pH
7.5, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 1 mM EGTA). Peptide/Kinase
Mixtures are diluted to a 2.times. working concentration in the
appropriate Kinase Buffers as described below.
[2365] (i) Peptide/Kinase Mixtures for measurement of EGFR
(ErbB1):
[2366] The 2.times. EGFR (ErbB1)/Tyr 04 mixture is prepared in 50
mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 4 mM MnCl.sub.2,
1 mM EGTA, 2 mM DTT. The final 10 .mu.L Kinase Reaction consists of
1.1-5.25 ng EGFR (ErbB1) and 2 .mu.M Tyr 04 in 50 mM HEPES pH 7.5,
0.01% BRIJ-35, 10 mM MgCl.sub.2, 2 mM MnCl.sub.2, 1 mM EGTA, 1 mM
DTT. After the 1 hour Kinase Reaction incubation, 5 .mu.L of a 1:64
dilution of Development Reagent B is added.
[2367] (ii) Peptide/Kinase Mixtures for measurement of EGFR (ErbB1)
L858R:
[2368] The 2.times. EGFR (ErbB1) L858R/Tyr 04 mixture is prepared
in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 4 mM
MnCl.sub.2, 1 mM EGTA, 2 mM DTT. The final 10 .mu.L Kinase Reaction
consists of 0.2-1.68 ng EGFR (ErbB1) L858R and 2 .mu.M Tyr 04 in 50
mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 2 mM MnCl.sub.2,
1 mM EGTA, 1 mM DTT. After the 1 hour Kinase Reaction incubation, 5
.mu.L of a 1:64 dilution of Development Reagent B is added.
[2369] (iii) Peptide/Kinase Mixtures for measurement of EGFR
(ErbB1) T790M: The 2.times. EGFR (ErbB1) T790M/Tyr 04 mixture is
prepared in 50 mM HEPES pH 6.5, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 1
mM EGTA, 0.02% NaN.sub.3. The final 10 .mu.L Kinase Reaction
consists of 3.9-30.2 ng EGFR (ErbB1) T790M and 2 .mu.M Tyr 04 in 50
mM HEPES pH 7.0, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 1 mM EGTA, 0.01%
NaN.sub.3. After the 1 hour Kinase Reaction incubation, 5 .mu.L of
a 1:64 dilution of Development Reagent B is added.
[2370] (iv) Peptide/Kinase Mixtures for measurement of EGFR (ErbB1)
T790M L858R: The 2.times. EGFR (ErbB1) T790M L858R/Tyr 04 mixture
is prepared in 50 mM HEPES pH 6.5, 0.01% BRIJ-35, 10 mM MgCl.sub.2,
1 mM EGTA, 0.02% NaN.sub.3. The final 10 .mu.L Kinase Reaction
consists of 0.38-4.22 ng EGFR (ErbB1) T790M L858R and 2 .mu.M Tyr
04 in 50 mM HEPES pH 7.0, 0.01% BRIJ-35, 10 mM MgCl.sub.2, 1 mM
EGTA, 0.01% NaN.sub.3. After the 1 hour Kinase Reaction incubation,
5 .mu.L of a 1:64 dilution of Development Reagent B is added.
[2371] (v) Peptide/Kinase Mixtures for measurement of BTK:
[2372] The 2.times. BTK/Tyr 01 mixture is prepared in 50 mM HEPES
pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final 10 .mu.L
Kinase Reaction consists of 1.04-10.4 ng BTK and 2 .mu.M Tyr Olin
50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. After
the 1 hour Kinase Reaction incubation, 5 .mu.L of a 1:256 dilution
of Development Reagent B is added.
[2373] (v) Peptide/Kinase Mixtures for measurement of FGFR1:
The 2.times. FGFR1/Tyr 04 mixture is prepared in 50 mM HEPES pH
7.5, 0.01% BRIJ-35, 10 mM MgCl2, 4 mM MnCl2, 1 mM EGTA, 2 mM DTT.
The final 10 .mu.L Kinase Reaction consists of 0.41-3.5 ng FGFR1
and 2 .mu.M Tyr 04 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM
MgCl2, 2 mM MnCl2, 1 mM EGTA, 1 mM DTT. After the 1 hour Kinase
Reaction incubation, 5 .mu.L of a 1:64 dilution of Development
Reagent B is added.
[2374] (v) Peptide/Kinase Mixtures for measurement of FGFR2:
The 2.times. FGFR2/Tyr 04 mixture is prepared in 50 mM HEPES pH
7.5, 0.01% BRIJ-35, 10 mM MgCl2, 4 mM MnCl2, 1 mM EGTA, 2 mM DTT.
The final 10 .mu.L Kinase Reaction consists of 0.19-2.36 ng FGFR2
and 2 .mu.M Tyr 04 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM
MgCl2, 2 mM MnCl2, 1 mM EGTA, 1 mM DTT. After the 1 hour Kinase
Reaction incubation, 5 .mu.L of a 1:64 dilution of Development
Reagent B is added.
[2375] (v) Peptide/Kinase Mixtures for measurement of JAK2:
The 2.times. JAK2/Tyr 06 mixture is prepared in 50 mM HEPES pH 7.5,
0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final 10 .mu.L Kinase
Reaction consists of 0.06-0.81 ng JAK2 and 2 .mu.M Tyr 06 in 50 mM
HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. After the 1
hour Kinase Reaction incubation, 50 .mu.L of a 1:64 dilution of
Development Reagent A is added.
[2376] (v) Peptide/Kinase Mixtures for measurement of JAK3:
The 2.times. JAK3/Tyr 06 mixture is prepared in 50 mM HEPES pH 7.5,
0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final 10 .mu.L Kinase
Reaction consists of 0.29-1.34 ng JAK3 and 2 .mu.M Tyr 06 in 50 mM
HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. After the 1
hour Kinase Reaction incubation, 5 .mu.L of a 1:64 dilution of
Development Reagent A is added.
[2377] (v) Peptide/Kinase Mixtures for measurement of KDR
(VEGFR2):
The 2.times. KDR (VEGFR2)/Tyr 01 mixture is prepared in 50 mM HEPES
pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final 10 .mu.L
Kinase Reaction consists of 0.5-11.7 ng KDR (VEGFR2) and 2 .mu.M
Tyr Olin 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA.
After the 1 hour Kinase Reaction incubation, 5 .mu.L of a 1:256
dilution of Development Reagent B is added.
[2378] Reaction starts by 30-second shaking of mixture consisting
of 2.5 .mu.L 4.times. test compound, 5 .mu.L 2.times. kinase
reaction mixture and 2.5 .mu.L 4.times. ATP Solution on Bar-coded
Corning, low volume NBS, black 384-well plate (Corning Cat. #3676).
Then the mixture is incubated for 60-minute at room temperature for
the kinase reaction, followed by addition of 5 .mu.L of a 1:1024
dilution of development reagent A and 30-second plate shake. The
mixture is then incubated for another 60-minute at room temperature
for development reaction. Finally fluorescence is read by plate
reader.
[2379] Table 2 shows % inhibition against EGFR, EGFR L858R, EGFR
T790M and EGFR L858R/T790M at 0.0137, 0.041 or 1 .mu.M of several
compounds of the invention using Z'-LYTE.RTM. method. The scale
utilized in Table 2 is as follows: ++ more than 50% inhibition and
+ less than 50% inhibition.
TABLE-US-00002 TABLE 2 Biological activity of illustrative
compounds against BTK, EGFR and EGFR L5858R/T790M EGFR EGFR EGFR
EGFR EGFR EGFR (Compound (Compound L858R T790M L858R/T790M
L858R/T790M at at (Compound (Compound (Compound at (Compound at
0.041 .mu.M) 1 .mu.M) at 1 .mu.M) at 1 .mu.M) 0.0137 .mu.M) 1
.mu.M) C001 ++ ++ ++ + ++ C002 + + ++ ++ C003 ++ ++ ++ ++ ++ C004 +
+ + ++ C005 ++ ++ + + C007 + + + + C008 + + + + C009 + + + + C010 +
+ + + C011 + + + + C012 + + ++ ++ C020 ++ C021 ++ ++ C022 ++ C023 +
+ C024 ++ C025 ++ C026 ++ C027 ++ C028 ++ C029 ++ ++ C030 ++ ++
C031 ++ ++ C032 ++ + ++ C033 ++ ++ C034 ++ ++ ++ C037 ++ C040 ++ ++
C041 ++ ++ C042 ++ + C043 ++ ++ C044 ++ ++ C045 ++ ++ C046 ++ ++
C047 ++ ++ C048 ++ ++ C049 ++ ++ C050 + ++ C051 + ++ C052 + ++ C053
+ ++ ++ ++ C054 ++ ++ C055 + ++ C056 + + C057 ++ ++ C058 + ++ C059
++ ++ C060 + ++ C061 + ++ C062 ++ ++ C063 ++ ++ C064 + + C065 + +
C066 + + C067 ++ ++ C068 ++ ++ C069 ++ ++ C070 + + C071 + + C072 +
++ C073 + ++ C074 + ++ C075 ++ ++ C076 + + C077 + ++ C078 ++ ++
C079 + ++ C080 ++ ++ C081 + ++ C082 + ++ C083 + ++ C084 + ++ C085 +
++ C086 + ++ C087 ++ ++ C088 ++ ++ C089 + + C090 + ++ C091 + + C092
+ + C093 + ++ C094 + + C095 + + C096 + + C097 + + C098 + + C099 ++
++ C100 + + C101 + ++ C102 + + C103 + ++ C104 + + C105 + ++ C109 +
++ C110 + ++ C111 + + C112 + + C113 + + C114 + + C115 + + C116 + +
C117 + + C118 ++ ++ C119 + + C120 + + C121 + ++ C122 + + C123 ++ ++
C124 + + C125 + + C126 ++ ++ C127 ++ ++ C128 + + C129 ++ ++ C130 +
+ C131 + + C132 + + C133 + + C134 + + C135 + + C136 + ++ C137 ++ ++
C138 ++ ++ C139 ++ ++ C140 ++ ++ C141 ++ ++ C142 C143 + ++ C144 ++
++ C145 + ++ C146 + ++ C147 + ++ C148 + + C149 + + C150 + + C151 +
++ C152 + ++ C153 + + C154 + + C155 + ++ C157 + C158 + C159 + C160
+ C161 + C164 + +
[2380] Table 3 shows % inhibition against BTK, JAK2 and FGFR1 at
0.041 .mu.M of several compounds of the invention using
Z'-LYTE.RTM. method. The scale utilized in Table 3 is as follows:
++ more than 50% inhibition and + less than 50% inhibition.
TABLE-US-00003 TABLE 3 Biological activity of illustrative
compounds against BTK, JAK2 and FGFR1 Compound No. BTK JAK2 FGFR1
C001 ++ ++ ++ C004 + ++ C005 ++ + C008 + ++ + C009 + ++ C012 ++ +
C020 ++ C021 ++ ++ ++ C022 ++ ++ ++ C023 + + + C025 ++ C026 + ++ ++
C027 ++ C031 ++ C032 ++ ++ C033 ++ + C036 + C040 ++ + C044 + C051 +
C053 ++ ++ ++ C054 ++ ++ C055 + + C059 ++ C075 ++ C109 ++ C110 ++
C111 ++ C112 ++ C113 ++ C114 ++ C115 ++ C116 ++ C117 ++ C118 ++
C119 ++ C120 ++ C121 ++ C122 ++ C123 ++ C124 ++ C125 ++ C126 ++
[2381] To determine IC.sub.50 of a compound against EGFR, EGFR
mutant and other kinases, a series of concentrations of the
compound were tested for the inhibition. IC.sub.50 was calculated
by plotting the concentration of compound vs the percentage of
inhibition in treated wells using GraphPad Prism 5. Table 4 shows
IC.sub.50 values of several compounds of the invention against
EGFR, EGFR L858R/T790M and several other kinases. The scale
utilized in Table 4 is as follows: +++ less than 100 nM, ++100-500
nM and + greater than 500 nM.
TABLE-US-00004 TABLE 4 IC.sub.50 of several illustrative compounds
against EGFR, EGFR L858R/T790M, BTK, FGFR1, FGFR2, KDR and JAK3
Compound EGFR No. EGFR L858R/T790M BTK FGFR1 FGFR2 KDR JAK3 C001
+++ C003 +++ C021 +++ +++ +++ +++ +++ +++ +++ C032 ++ +++ C034 +++
+++ C040 +++ +++ C041 +++ +++ +++ +++ +++ +++ C044 +++ +++ +++ ++
++ +++ C045 +++ C048 +++ +++ C049 +++ C054 +++ C057 +++ C059 +++
+++ +++ +++ ++ +++ +++ C061 +++ C063 +++ C067 +++ C068 +++ C072 +++
C074 +++ C075 +++ C077 +++ C078 +++ C079 ++ +++ +++ C080 +++ C081
+++ C085 ++ +++ +++ C087 +++ C088 +++ C099 +++ +++ +++ C103 +++
C105 +++ +++ +++ C106 + +++ +++ C107 + +++ +++ C108 ++ +++ +++ C109
+++ C110 +++ C118 +++ C121 +++ C123 +++ C126 +++ C127 +++ C129 +++
C137 +++ C138 +++ C139 +++ C140 +++ C141 +++ C145 +++ C147 +++ +++
+++ ++ ++ ++ C151 +++ +++ +++ ++ ++ ++ C156 +++ +++
Example 176
Inhibition of Cancer Cell Growth by Compounds Using MTT Assay
[2382] Inhibition of cell growth by compounds was measured using
MTT assay (Mosmann, T., Journal of Immunological Methods, 1983, 65,
55-63). Tumor cell lines were purchased from ATCC (American Type
Culture Collection, Manassas, Va.). All cell lines were maintained
in RPMI 1640 (Hyclone) supplemented with 10% fetal bovine serum
(FBS, Hyclone), glutamine (2 mM, Hyclone), and antibiotics
(penicillin 100 U/mL and streptomycin 50 .mu.g/mL) at 37.degree. C.
in a humidified atmosphere of 5% CO.sub.2 in air. Taxol (as a
positive control, Sigma) and compounds were dissolved in DMSO
(Sigma), and the final concentration of DMSO in the medium was 1%.
Tumor cells were plated in 96-well plates at densities of about
4000 cells/well of a 96-well plate and allowed to adhere/grow for
24 h. They were then treated with various concentrations of drug
for 72 h. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT, Sigma) was used to determine the number of viable
cells at the time of compound addition and the number of cells
remaining after 72 h compound exposure. The number of cells
remaining after 72 h was compared to the number of viable cells at
the time of compound addition by measuring the absorbance at 570
nm, allowing for the calculation of growth inhibition.
[2383] All concentrations of compounds were tested in triplicate
and controls were averaged over 4 wells. IC.sub.50 was calculated
by plotting the concentration of compound vs the percentage of
inhibition in treated wells using GraphPad Prism 5. Data for
representative compounds are shown below.
[2384] Tables 5 show IC.sub.50 values of several compounds of the
invention in A431, HCT827, H3255, H1299 and H1975 cells. H1299
cells have a mutation on NRAS, HCC827 cells have an exon 19
deletion (del E746-A750), H3255 cells have L858R mutation, and
H1975 cells have double EGFR mutations (L858R/T790M). The scale
utilized in Tables 5 is as follows: +++ less than 100 nM; ++
between 100 nM and 500 nM; and + greater than 500 nM.
TABLE-US-00005 TABLE 5 IC.sub.50 of several illustrative compounds
in A549, A431, H1299, HCC827, H3255 and H1975 cells Compound No
A431 HCC827 H3255 H1299 H1975 C001 + +++ + + ++ C002 + ++ + C003 +
+++ + + ++ C004 + + C005 ++ + C007 + + C008 + + C009 + + C010 + +
C011 + + + C012 + +++ ++ C020 + + C021 ++ +++ ++ ++ +++ C022 +++ +
C023 + + C024 + + C025 + + C026 + + C027 ++ + C028 + + C029 ++ +++
+ ++ C030 ++ ++ C031 + + C032 ++ +++ + ++ C033 +++ + ++ C034 + +++
+ +++ C035 + +++ + +++ C036 +++ + + C037 +++ +++ +++ C038 +++ +++
C039 +++ + ++ C040 ++ +++ ++ +++ C041 + +++ + + ++ C042 + C043 + ++
C044 + + + +++ C045 ++ +++ C046 + + +++ C047 + ++ C048 + +++ C049 +
++ C050 + C051 + ++ C052 ++ C053 ++ +++ C054 + ++ C055 ++ ++ C056 +
++ C057 ++ ++ C058 + +++ C059 ++ +++ ++ + +++ C060 + ++ C061 + +++
C062 ++ C063 + +++ C064 + C065 ++ C066 + C067 +++ C068 + ++ C069
+++ +++ C070 + C071 + C072 ++ ++ C073 ++ C074 ++ ++ C075 ++ +++
C076 + C077 +++ C078 + +++ C079 ++ ++ +++ C080 ++ +++ C081 ++ C082
++ C083 ++ C084 ++ C085 ++ + + +++ C086 ++ C087 ++ ++ C088 + + +
+++ C089 ++ C090 ++ C091 + ++ C092 ++ C093 ++ C094 ++ C095 ++ C096
+++ C097 ++ C098 +++ C099 ++ + + +++ C100 + C101 +++ C102 +++ C103
+++ ++ +++ C104 + C105 ++ +++ +++ +++ C106 +++ ++ +++ C107 +++ ++
+++ C108 + +++ C109 ++ +++ C110 +++ +++ C111 +++ C112 +++ C113 +++
C114 +++ C115 ++ C116 ++ C117 ++ C118 +++ ++ +++ C119 +++ C120 +++
C121 ++ +++ C122 +++ C123 +++ +++ C124 +++ C125 +++ C126 +++ +++
C127 +++ ++ +++ C128 +++ C129 +++ +++ C130 +++ C131 +++ C132 ++
C133 ++ C134 +++ C135 +++ C136 +++ +++ C137 ++ + +++ C138 ++ +++
C139 +++ ++ +++ C140 + + +++ C141 ++ +++ ++ +++ C142 +++ C143 +++
C144 +++ C145 ++ +++ + +++ C146 +++ C147 ++ +++ + +++ C148 +++ C149
+++ C150 +++ C151 ++ +++ + +++ C152 ++ ++ +++ C153 +++ C154 ++ C155
+++ C156 ++ +++ + +++ C157 + C158 ++ C159 + C160 ++ C161 + ++ C162
+ ++ C163 ++ C164 ++
Example 177
Inhibition of Tumor Growth in Xenograft Model
[2385] H1975 cells were implanted in BALB/c female nude mice and
grown as tumor xenografts. When tumors achieved 120-200 mm.sup.3,
mice were assigned into treatment and control groups using
randomized block design based upon their tumor volumes. Each group
contained 6 tumor-bearing mice. Tumors were measured twice weekly
in two dimensions using a caliper, and the tumor volume was
calculated from two-dimensional measurements using the equation
V=0.5.times.a.times.b.sup.2 where a and b are the long and short
diameters of the tumor, respectively. Relative tumor volume (RTV)
was defined as TV.sub.t/TV.sub.i, the ratio of the volume on a
given day (TV) and the volume at the start of treatment (TV.sub.i).
Relative tumor growth rate (TIC) was defined as
RTV.sub.T/RTV.sub.c, the ratio of relative tumor volume of
treatment group (RTV.sub.T) and relative tumor volume of control
group (RTV.sub.c) on a given day. Inhibition of tumor growth in a
H1975 tumor xenograft model by some compounds is shown below in
Table 6 and Table 7.
TABLE-US-00006 TABLE 6 In vivo activity of illustrative compounds
in H1975 tumor model Tumor Tumor Volume Volume Pre- Post- Compound
Dose treatment treatment T/C No. (mg/kg) Route Schedule (mm.sup.3)
(mm.sup.3) (%) Vehicle -- Oral QD .times. 14 152.8 2110.2 -- C021
60 Oral QD .times. 14 152.5 633.5 30.5 C041 30 Intra- QD .times. 14
151.7 1021.2 48.7 peri- toneal injection C059 60 Oral QD .times. 14
151.6 746.4 35.3 C103 30 Intra- QD .times. 14 150.9 748.7 35.8
peri- toneal injection C107 30 Intra- QD .times. 14 150.6 1341.7
63.6 peri- toneal injection
TABLE-US-00007 TABLE 7 In vivo activity of more illustrative
compounds in H1975 tumor model Tumor Tumor Volume Volume Pre- Post-
Compound Dose treatment treatment T/C No. (mg/kg) Route Schedule
(mm3) (mm3) (%) Vehicle -- Oral QD .times. 14 227 1613 -- C147 60
Oral QD .times. 14 240 898 55.7 C151 60 Oral QD .times. 14 229 462
28.6 C156 60 Oral QD .times. 14 232 594 36.8
[2386] While some embodiments have been shown and described,
various modifications and substitutions may be made thereto without
departing from the spirit and scope of the invention. For example,
for claim construction purposes, it is not intended that the claims
set forth hereinafter be construed in any way narrower than the
literal language thereof, and it is thus not intended that
exemplary embodiments from the specification be read into the
claims. Accordingly, it is to be understood that the present
invention has been described by way of illustration and not
limitations on the scope of the claims.
* * * * *