U.S. patent application number 14/398893 was filed with the patent office on 2015-06-18 for methods and compositions for raf kinase mediated diseases.
The applicant listed for this patent is ARIAD Pharmaceuticals, Inc.. Invention is credited to David C. Dalgarno, Wei-Sheng Huang, William C. Shakespeare, Yihan Wang, Xiaotian Zhu.
Application Number | 20150166591 14/398893 |
Document ID | / |
Family ID | 49551142 |
Filed Date | 2015-06-18 |
United States Patent
Application |
20150166591 |
Kind Code |
A1 |
Zhu; Xiaotian ; et
al. |
June 18, 2015 |
METHODS AND COMPOSITIONS FOR RAF KINASE MEDIATED DISEASES
Abstract
The invention features compounds, pharmaceutical compositions
and methods for treating patients who have an EGFR-driven cancer of
Formula (I), wherein the variables are as defined herein.
##STR00001##
Inventors: |
Zhu; Xiaotian; (Newton,
MA) ; Wang; Yihan; (Newton, MA) ; Shakespeare;
William C.; (Southborough, MA) ; Huang;
Wei-Sheng; (Acton, MA) ; Dalgarno; David C.;
(Brookline, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ARIAD Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
49551142 |
Appl. No.: |
14/398893 |
Filed: |
March 15, 2013 |
PCT Filed: |
March 15, 2013 |
PCT NO: |
PCT/US13/32713 |
371 Date: |
November 4, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61643228 |
May 5, 2012 |
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61723779 |
Nov 7, 2012 |
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61724283 |
Nov 8, 2012 |
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61801953 |
Mar 15, 2013 |
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Current U.S.
Class: |
514/86 ; 435/375;
514/275; 514/85; 514/90; 540/542; 544/105; 544/122; 544/243;
544/323; 544/57 |
Current CPC
Class: |
C07D 239/48 20130101;
C07F 9/6521 20130101; C07F 9/65583 20130101; C07D 403/12 20130101;
A61P 35/00 20180101; C07F 9/6584 20130101; C07F 9/6512 20130101;
A61K 31/506 20130101; A61K 31/675 20130101; C07F 9/28 20130101;
C07F 9/65586 20130101; A61K 31/505 20130101; A61K 45/06 20130101;
C07F 9/65846 20130101; C07F 9/6561 20130101; C07D 239/42
20130101 |
International
Class: |
C07F 9/6584 20060101
C07F009/6584; A61K 31/675 20060101 A61K031/675; A61K 45/06 20060101
A61K045/06; A61K 31/505 20060101 A61K031/505; C07D 403/12 20060101
C07D403/12; A61K 31/506 20060101 A61K031/506; C07F 9/28 20060101
C07F009/28; C07D 239/48 20060101 C07D239/48 |
Claims
1. A compound of the Formula: ##STR00342## or a pharmaceutically
acceptable salt thereof, wherein U.sup.1 and U.sup.2 are both N and
U.sup.3 is C--R.sup.e; or U.sup.3 is N, one of U.sup.1 and U.sup.2
is N, and the other is C--R.sup.d; or U.sup.3 is C--R.sup.e, one of
U.sup.1 and U.sup.2 is N, and the other is C--R.sup.d; V.sup.1 is
O, S, NR.sup.V, CO, CH.sub.2, or CF.sub.2; R.sup.V is H, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, or aryl;
R.sup.d is H, halo, CN, alkyl, cycloalkyl, alkoxy, haloalkyl,
alkenyl, haloalkenyl or halocycloalkyl; R.sup.e is H or NH.sub.2;
or, R.sup.d and R.sup.e, together with the ring atom to which each
is attached, form a 5- or 6-membered ring containing one, two or
three heteroatoms, independently selected from N, S and O, wherein
the 5- or 6-membered ring so formed is independently substituted by
R.sup.h; R.sup.h is H, C.sub.1-4 alkyl, or halo; R.sup.g is H, F,
--P(O)(R.sup.3A)(R.sup.3B), --S(O)N(R.sup.3C)(R.sup.3D),
--S(O).sub.2R.sup.3E, --C(O)N(R.sup.3F)(R.sup.3G),
--OC(O)N(R.sup.3F)(R.sup.3G), --NR.sup.3HC(O)OR.sup.3I, a 5- or
6-membered heterocyclic ring comprising 1, 2, 3 or 4 N atoms; each
R.sup.3A, R.sup.3B, R.sup.3C, R.sup.3D, R.sup.3E, R.sup.3F,
R.sup.3G, R.sup.3H, and R.sup.3I is, independently, selected from
H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
and heteroalkyl, or R.sup.3A and R.sup.3B, or R.sup.3C and
R.sup.3D, or R.sup.3F and R.sup.3G, together with the atom to which
each is attached, form an optionally substituted 5- or 6-membered
heterocyclic ring; R.sup.g2 is H, F, W.sup.1,
--P(O)(R.sup.3A)(R.sup.3B), --S(O)N(R.sup.3C)(R.sup.3D),
--S(O).sub.2R.sup.3E, --C(O)N(R.sup.3F)(R.sup.3G),
--OC(O)N(R.sup.3F)(R.sup.3G), --NR.sup.3HC(O)OR.sup.3I, C.sub.1-6
alkoxy, C.sub.1-4 alkyl, or, R.sup.g2 and R.sup.g together with the
atom to which each is attached form an optionally substituted 5- to
7-membered heterocyclic ring comprising 1-3 heteroatoms
independently selected from P, N, O and S; R.sup.g1 is H, F,
--OR.sup.2, --P(O)(R.sup.3A)(R.sup.3B),
--S(O)N(R.sup.3C)(R.sup.3D), --S(O).sub.2R.sup.3E,
--C(O)N(R.sup.3F)(R.sup.3G), --OC(O)N(R.sup.3F)(R.sup.3G),
--NR.sup.3HC(O)OR.sup.3I, or an optionally substituted 5- or
6-membered heterocyclic ring; Ring A is: ##STR00343## R.sup.b2 is
H, F, or an optionally substituted 5- or 6-membered heterocyclic
ring containing 1, 2 or 3 N or O atoms; R.sup.b4 is H, F, W.sup.1,
C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, C.sub.3-6 cycloalkoxy,
--OC(O)N(R.sup.5A)(R.sup.5B), --NR.sup.5CC(O)OR.sup.5D, or an
optionally substituted 5- or 6-membered heterocyclic ring
comprising 1, 2 or 3 N or O atoms; each R.sup.5A, R.sup.5B,
R.sup.5C, and R.sup.5D is independently selected from H, alkyl,
alkenyl, alkynyl, and heteroalkyl, or R.sup.5A and R.sup.5B,
together with the atom to which each is attached, form an
optionally substituted 5- or 6-membered heterocyclic ring; R.sup.a1
is H, halo, W.sup.1, --CN, --NO.sub.2, --R.sup.1, --OR.sup.2,
--O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.1)(YR.sup.2), --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2, or
##STR00344## X.sub.1 and X.sub.2 are each independently CH or N; or
R.sup.a1 and R.sup.b4, together with the atom to which each is
attached, form an optionally substituted 5- or 6-membered
heterocyclic ring comprising 1, 2 or 3 heteroatoms independently
selected from N and O; R.sup.a2 is H, halo, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy,
C.sub.2-6 alkenyloxy, C.sub.3-6 cycloalkyloxy or 4- to 7-membered
heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, alkoxy,
C.sub.2-6 alkenyloxy, cycloalkyloxy and heterocyclyl are optionally
substituted with one or more halo, amino, C.sub.1-6 alkylamino, or
di-C.sub.1-6 alkylamino groups; Y is independently a bond, --O--,
--S-- or --NR.sup.1--; R.sup.1 and R.sup.2 are independently H or
R.sup.15; R.sup.4 is alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and
heteroaryl; W.sup.1 is
--NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--CH.sub.2P(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--OP(O)C(R8)=CR9R10,
--NR.sup.7S(O).sub.2C(R.sup.9)(R.sup.10)(R.sup.X),
--NR.sup.7S(O).sub.2C(R.sup.11).dbd.CR.sup.9R.sup.10,
--NR.sup.7C(O)C.ident.C--R.sup.14,
--NR.sup.7C(O)C(R.sup.9)(R.sup.10)(R.sup.X), ##STR00345## R.sup.X
is halo; R.sup.7 is H, alkyl or heteroalkyl, wherein the alkyl and
heteroalkyl groups are independently optionally substituted with an
amino, alkylamino or dialkylamino group; R.sup.8 is C.sub.1-6
alkyl; R.sup.9 and R.sup.10 are independently H, halo,
--C(O)R.sup.16, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclyl or
heteroaryl, wherein R.sup.9 and R.sup.10, if not H, are optionally
substituted with one or more halo, amino, alkylamino, dialkylamino,
alkoxy, cycloalkyl, heterocyclyl or heteroaryl groups, wherein said
group, if not halo, is optionally substituted with one or more
halo, C.sub.1-4 alkyl, alkoxyl, halo(C.sub.1-4)alkyl or C.sub.3-7
cycloalkyl groups; R.sup.11 is H, halo, --C(O)--OR.sup.12, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroalkyl, heterocyclic, or heteroaryl, wherein R.sup.11, if not
H, is optionally substituted with one or more halo, amino, alkoxyl,
cycloalkyl, heterocyclic or heteroaryl groups, wherein said group,
if not halo, is optionally substituted with one or more halo or
alkyl, alkoxyl, cycloalkyl or heterocyclyl groups, wherein the
alkyl, alkoxyl, cycloalkyl and heterocyclyl group is optionally
substituted with one or more alkyl, halo or hydroxyl substituents;
or R.sup.9 and R.sup.11, taken together with the atom to which each
is attached, form a cycloalkenyl or heterocyclic ring; R.sup.12 is
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic, or heteroaryl; R.sup.13 is H or
C.sub.1-4 alkyl; R.sup.14 is R.sup.T or R.sup.W; R.sup.15 is alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroalkyl, 4- to 7-membered heterocyclyl, or heteroaryl, wherein
each R.sup.15 is optionally substituted with one or more halo,
cycloalkyl, heterocyclic or heteroaryl groups, wherein said
cycloalkyl, heterocyclic or heteroaryl groups(s) are independently
optionally substituted with one or more halo, alkyl, haloalkyl,
hydroxyalkyl, amino, dialkylamino or cycloalkyl groups; R.sup.16 is
OH, --O-alkyl, cycloalkyl, heterocyclyl, --NH.sub.2, --NH-alkyl, or
--N-dialkyl wherein the alkyl, cycloalkyl or heterocyclyl moiety is
optionally substituted with halo, amino, alkylamino, dialkylamino,
alkyl or hydroxyl; R.sup.T is H or --CH.sub.3; R.sup.W is halo;
substituted methyl; or an optionally substituted group selected
from (C.sub.2-6)alkyl, (C.sub.1-6)heteroalkyl, heterocyclyl, aryl
and heteroaryl; wherein the substituents on the optionally
substituted (C.sub.2-6)alkyl, (C.sub.1-6)heteroalkyl, heterocyclyl,
aryl and heteroaryl groups are selected from halo, haloalkyl,
alkoxy, heterocyclyl, substituted heterocyclyl, amino, alkylamino,
and dialkylamino, and in the case of an optionally substituted
heterocyclyl, the optional substituents may further be selected
from hydroxyl, alkyl, haloalkyl, hyroxyalkyl, alkoxyalkyl, amino,
alkylamino and dialkylamino; wherein (a) the compound is not one of
the following two compounds: ##STR00346## (b) at least one of
R.sup.a1, R.sup.g2, and R.sup.b4 is W.sup.1; (c) the compound
comprises at least one --P(O)(R.sup.3A)(R.sup.3B); and (d) the
compound further has one or more of the following features: R.sup.d
is halo(C.sub.3-5)cycloalkyl; R.sup.a2 is halo; substituted alkyl,
substituted alkoxy, or optionally substituted cycloalkyl, wherein
substituents on the alkyl, alkoxy or cycloalkyl groups are selected
from halo, amino and dialkylamino groups; R.sup.a1 is an optionally
substituted 4-membered heterocycle; R.sup.a1 is alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl or heteroalkyl, and is
substituted with one or more groups selected from halo, OH,
heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted
heteroaryl; R.sup.a1 is heterocyclyl or heterocyclyl-O--, wherein
R.sup.a1 is substituted with one or more groups selected from --OH,
halo, 4-membered heterocyclyl, substituted 4-membered heterocyclyl
and R.sup.18, wherein R.sup.18 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl or heteroalkyl, and R.sup.18 is optionally
substituted; R.sup.a1 and R.sup.b4, together with the atom to which
each is attached, form an optionally substituted 5-membered
heterocyclic ring; R.sup.a2 is an optionally substituted 4- to
7-membered membered heterocycle; R.sup.b4 is
--NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10 or --NR.sup.7C(O)C
C.ident.C--R.sup.W; R.sup.g1 is --OR.sup.2; R.sup.9or R.sup.10 is
cycloalkyl, --CO.sub.2H, --CO.sub.2-alkyl, --C(O)-heterocyclyl,
--C(O)NH.sub.2, --C(O)NH-alkyl or --C(O)N-dialkyl wherein an alkyl,
cycloalkyl or heterocyclyl substituent or portion of a substituent
is optionally substituted with amino, alkylamino, dialkylamino,
alkyl or hydroxyl; one or more of R.sup.9, R.sup.10 and R.sup.11 is
halo, haloalkyl, alkyl, alkoxy, heteroalkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroarylalkyl or arylalkyl wherein
alkyl, heterocylic, heteroaryl or aryl substituent, or an alkyl,
heterocylic, heteroaryl or aryl portion of a substituent, is
optionally substituted with one or more groups selected from halo,
haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino,
alkyl, alkenyl, SO.sub.2alkyl, oxo, heterocyclyl and heterocycle
substituted with one or more alkyl, amino alkylamino, dialkylamino,
hydroxyl, hydroxyalkyl, SO.sub.2alkyl substituents; and, R.sup.9
and R.sup.11, taken together with the atom to which each is
attached, form a cycloalkenyl or heterocyclic ring.
2. The compound of claim 1 or a pharmaceutically acceptable salt
thereof wherein: R.sup.d is H, halo, CN, alkyl, alkoxy, haloalkyl,
alkenyl, haloalkenyl or halocycloalkyl; W.sup.1 is
--NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--CH.sub.2P(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--OP(O)(R.sup.8).dbd.CR.sup.9R.sup.10,
--NR.sup.7S(O).sub.2C(R.sup.11).dbd.CR.sup.9R.sup.10,
--NR.sup.7C(O)C C.ident.C--R.sup.14, ##STR00347## R.sup.g is H,
--P(O)(R.sup.3A)(R.sup.3B), --S(O)N(R.sup.3C)(R.sup.3D),
--S(O).sub.2R.sup.3E, --C(O)N(R.sup.3F)(R.sup.3G),
--OC(O)N(R.sup.3F)(R.sup.3G), --NR.sup.3HC(O)OR.sup.3I, a 5- or
6-membered heterocyclic ring comprising 1, 2, 3 or 4 N atoms,
wherein each of R.sup.3A, R.sup.3B, R.sup.3C, R.sup.3D, R.sup.3E,
R.sup.3F, R.sup.3G, R.sup.3H, and R.sup.3I is, independently,
selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, and heteroalkyl, or R.sup.3A and R.sup.3B, or
R.sup.3C and R.sup.3D, or R.sup.3F and R.sup.3G, together with the
atoms to which each is attached, form an optionally substituted 5-
or 6-membered heterocyclic ring; and, R.sup.g1 is H, F,
--P(O)(R.sup.3A)(R.sup.3B), --S(O)N(R.sup.3C)(R.sup.3D),
--S(O).sub.2R.sup.3E, --C(O)N(R.sup.3F)(R.sup.3G),
--OC(O)N(R.sup.3F)(R.sup.3G), --NR.sup.3HC(O)OR.sup.3I, or an
optionally substituted 5- or 6-membered heterocyclic ring; wherein
the variable terms are as defined in claim 1.
3. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (IIIa)-(IIIe), or a pharmaceutically
acceptable salt thereof: ##STR00348## wherein R.sup.a1; R.sup.a2;
R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d; and
R.sup.h are as defined in claim 1.
4. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (IVa)-(IVe), or a pharmaceutically
acceptable salt thereof: ##STR00349## wherein R.sup.a2; R.sup.b2;
R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d; and R.sup.h are as
defined in claim 1.
5. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (Va)-(Ve), or a pharmaceutically
acceptable salt thereof: ##STR00350## wherein R.sup.a1; R.sup.a2;
R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d; and
R.sup.h are as defined in claim 1.
6. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (VIa)-(VIe), or a pharmaceutically
acceptable salt thereof: ##STR00351## wherein R.sup.a2; R.sup.b2;
R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d; and R.sup.h are as
defined in claim 1, and R.sup.a1 is selected from W.sup.1,
--R.sup.1, --C(O)YR.sup.2, --C(.dbd.S)YR.sup.2,
--C(.dbd.NR.sup.1)YR.sup.2, --C(.dbd.N--OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --S(O).sub.rR.sup.2, and
##STR00352## each Y is, independently, a bond, --O--, --S-- or
--NR.sup.1--; each occurrence of R.sup.1 and R.sup.2 is,
independently, selected from H, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic and heteroaryl; each of X.sub.1 and X.sub.2 is,
independently, selected from CH and N; W.sup.1 is as defined in
claim 1; and R.sup.4 is selected from alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic and heteroaryl.
7. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (VIIa)-(VIIe), or a pharmaceutically
acceptable salt thereof: ##STR00353## wherein R.sup.a1; R.sup.a2;
R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d; and R.sup.h are as
defined in claim 1.
8. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (VIIIa)-(VIIIe), or a pharmaceutically
acceptable salt thereof: ##STR00354## wherein R.sup.a2; R.sup.b2;
R.sup.g; R.sup.g1; R.sup.g2; R.sup.d; and R.sup.h are as defined in
claim 1, R.sup.a1 is selected from W.sup.1, --R.sup.1,
--C(O)YR.sup.2, --C(.dbd.S)YR.sup.2, --C(.dbd.NR.sup.1)YR.sup.2,
--C(.dbd.N--OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --S(O).sub.rR.sup.2, and
##STR00355## each Y is, independently, a bond, --O--, --S-- or
--NR.sup.1--; W.sup.1 is as defined in claim 1; each occurrence of
R.sup.1 and R.sup.2 is, independently, selected from H, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and
X.sub.2 is, independently, selected from CH and N; and R.sup.4 is
selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl.
9. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (IXa)-(IXe), or a pharmaceutically
acceptable salt thereof: ##STR00356## wherein R.sup.a1 is W.sup.1,
--R.sup.1, --C(O)YR.sup.2, --C(.dbd.S)YR.sup.2,
--C(.dbd.NR.sup.1)YR.sup.2, --C(.dbd.N--OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --S(O).sub.rR.sup.2, or
##STR00357## each Y is, independently, a bond, --O--, --S-- or
--NR.sup.1--; R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2;
R.sup.d; R.sup.h and W.sup.1 are as defined in claim 1; each
occurrence of R.sup.1 and R.sup.2 is, independently, selected from
H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl,
aryl, heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and
X.sub.2 is, independently, CH or N; and R.sup.4 is alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic or heteroaryl.
10. The compound of claim 1, 2 or 3, wherein said compound is
described by any of Formulas (Xa)-(Xe), or a pharmaceutically
acceptable salt thereof: ##STR00358## wherein R.sup.b2; R.sup.b4;
R.sup.g; R.sup.g1; R.sup.g2; R.sup.d; and R.sup.h are as defined in
claim 1, R.sup.a1 is selected from W.sup.1, --R.sup.1,
--C(O)YR.sup.2, --C(.dbd.S)YR.sup.2, --C(.dbd.NR.sup.1)YR.sup.2,
--C(.dbd.N--OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --S(O).sub.rR.sup.2, and
##STR00359## each Y is, independently, a bond, --O--, --S-- or
--NR.sup.1--; W.sup.1 is as defined in claim 1; each occurrence of
R.sup.1 and R.sup.2 is, independently, selected from H, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroalkyl, heterocyclic and heteroaryl; each of X.sub.1 and
X.sub.2 is, independently, selected from CH and N; and R.sup.4 is
selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl.
11. The compound of any of claims 1-10, or a pharmaceutically
acceptable salt thereof, wherein R.sup.a2 is H, halo, --CH.sub.3,
--CF.sub.3, --CH.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3,
--OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 or
--O-heterocyclyl.
12. The compound of any of claims 1-10, or a pharmaceutically
acceptable salt thereof, wherein R.sup.d is H, Cl, F, Br, I, CN,
CH.sub.3, CF.sub.3, --CH.sub.2CH.dbd.CH.sub.2, or cyclopropyl.
13. The compound of any of claims 1-6 or 8-10, or a
pharmaceutically acceptable salt thereof, wherein R.sup.b2 is
H.
14. The compound of any of claims 1-10, or a pharmaceutically
acceptable salt thereof, wherein R.sup.g1 is H,
--P(O)(R.sup.3A)(R.sup.3B) or --OR.sup.2 and R.sup.g2 is H, F,
C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, wherein R.sup.3A, R.sup.3B,
and R.sup.2 are as defined in claim 1.
15. The compound of any of claims 1-10, or a pharmaceutically
acceptable salt thereof, wherein R.sup.g is
--P(O)(R.sup.3A)(R.sup.3B), wherein R.sup.3A and R.sup.3B, are as
defined in claim 1.
16. The compound of claim 15, or a pharmaceutically acceptable salt
thereof, wherein R.sup.g is --P(O)(CH.sub.3).sub.2 or
--P(O)(CH.sub.2CH.sub.3).sub.2.
17. The compound of any of claims 1-10, or a pharmaceutically
acceptable salt thereof, wherein R.sup.g is --S(O).sub.2R.sup.3E),
wherein R.sup.3E is as defined in claim 1.
18. The compound of claim 17, or a pharmaceutically acceptable salt
thereof, wherein R.sup.g is --S(O).sub.2CH(CH.sub.3).sub.2.
19. The compound of any of claims 1-4 or 6-10, or a
pharmaceutically acceptable salt thereof, wherein R.sup.a1 is a 4-,
5-, 6- or 7-membered heterocycle which is optionally substituted
with one or more groups selected from halo and R.sup.17, wherein
R.sup.17 is an alkyl, cycloalkyl, heteroalkyl, 4- to 7-membered
heterocyclyl or heteroaryl group, wherein R.sup.17 is optionally
substituted with one or more halo, alkyl, cycloalkyl, heterocyclic
or heteroaryl groups, of which, said cycloalkyl, heterocyclic or
heteroaryl substituent is optionally substituted with one or more
halo, alkyl, haloalkyl, hydroxyalkyl, amino, dialkylamino or
cycloalkyl groups.
20. The compound of claim 19, or a pharmaceutically acceptable salt
thereof, wherein R.sup.a1 is selected from the following:
##STR00360## ##STR00361##
21. The compound of any of claims 1-3 or 5-10, or a
pharmaceutically acceptable salt thereof, wherein R.sup.a1 is
--OR.sup.2, as defined in claim 1.
22. The compound of claim 21, or a pharmaceutically acceptable salt
thereof, wherein R.sup.a1 is selected from the following:
##STR00362## ##STR00363##
23. The compound of any of claims 1-3 or 5-10, or a
pharmaceutically acceptable salt thereof, wherein R.sup.a1 is an
optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, or heteroalkyl group, wherein optional
substituents are selected from halo, cycloalkyl, heterocyclic or
heteroaryl groups, wherein said cycloalkyl, heterocyclic and
heteroaryl substituent(s) are independently optionally substituted
with one or more halo, alkyl, haloalkyl, hydroxyalkyl, amino,
dialkylamino or cycloalkyl groups.
24. The compound of claim 23, or a pharmaceutically acceptable salt
thereof wherein R.sup.a1 is selected from the following:
##STR00364##
25. The compound of claim 23, or a pharmaceutically acceptable salt
thereof wherein R.sup.a1 is of the Formula: ##STR00365## wherein:
J.sup.1 and J.sup.2 are independently H, halo or R.sup.J; or
J.sup.1 and J.sup.2 together with the atom to which each is
attached form an optionally substituted ring which is C.sub.3-8
cycloalkyl, 3- to 7-membered heterocyclic, or heteroaryl; J.sup.3
and J.sup.4 are independently H or R.sup.J; or J.sup.3 and J.sup.4
together with the atom to which each is attached form an optionally
substituted ring which is 3- to 7-membered heterocyclic or
heteroaryl ring; R.sup.J is C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl,
C.sub.1-8 heteroalkyl, or 3- to 7-membered heterocyclyl, wherein
each R.sup.J is independently selected from halo, haloalkyl,
hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino,
cycloalkyl, alkoxy, cycloalkoxy and heterocyclic groups, wherein
the alkyl, cycloalkyl, and heterocyclic groups on R.sup.J are
optionally substituted with one or more halo, alkyl, haloalkyl,
hydroxyalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino or
cycloalkyl groups; and, z is 1-3.
26. The compound of claim 25, or a pharmaceutically acceptable salt
thereof, wherein R.sup.a1 is selected from the following:
##STR00366##
27. The compound of any of claims 1-3 or 5-10, or a
pharmaceutically acceptable salt thereof, wherein R.sup.b4 is
--NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--NR.sup.7S(O).sub.2C(R.sup.9)(R.sup.10)(R.sup.X),
--NR.sup.7C(O)C.ident.C--R.sup.14, or
--NR.sup.7C(O)C(R.sup.9)(R.sup.10)(R.sup.X), wherein R.sup.7,
R.sup.9, R.sup.10, R.sup.11, R.sup.14, and R.sup.X are as defined
in claim 1.
28. The compound of claim 27, or a pharmaceutically acceptable salt
thereof, wherein R.sup.b4 is --NHC(O)CH.dbd.CH.sub.2 or is selected
from the following: ##STR00367## ##STR00368## ##STR00369##
29. The compound of claim 27, or a pharmaceutically acceptable salt
thereof, wherein R.sup.b4 is --NHC(O)C.ident.CH or is selected from
the following: ##STR00370## ##STR00371##
30. The compound of any of claims 19-24, or a pharmaceutically
acceptable salt thereof, wherein R.sup.b4 is W.sup.1 as defined in
claim 1.
31. The compound of claim 30, wherein R.sup.a2 is R.sup.a2 is H,
halo, --CH.sub.3, --CF.sub.3, --CH.sub.2CH.sub.3, --OCH.sub.3,
--OCF.sub.3, --OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 or --O-heterocyclyl.
32. The compound of claim 30 or 31, or a pharmaceutically
acceptable salt thereof, wherein R.sup.g is
--P(O)(R.sup.3A)(R.sup.3B), wherein R.sup.3A and R.sup.3B, are as
defined in claim 1.
33. The compound of claim 32, or a pharmaceutically acceptable salt
thereof, wherein R.sup.g is --P(O)(CH.sub.3).sub.2 or
--P(O)(CH.sub.2CH.sub.3).sub.2.
34. The compound of claim 30 or 31, or a pharmaceutically
acceptable salt thereof, wherein R.sup.g is --S(O).sub.2R.sup.3E),
wherein R.sup.3E is as defined in claim 1.
35. The compound of claim 34, or a pharmaceutically acceptable salt
thereof, wherein R.sup.g is --S(O).sub.2CH(CH.sub.3).sub.2.
36. The compound of any of claims 32-35 wherein R.sup.d is Cl, F,
Br, I, or CH.sub.3.
37. The compound of claim 1 or 2, wherein U.sup.1 is N, U.sup.2 is
C--R.sup.d, and U.sup.3 is C--R.sup.e.
38. The compound of claim 1 or 2, wherein U.sup.1 is C--R.sup.d,
U.sup.2 is N, and U.sup.3 is C--R.sup.e.
33. The compound of claim 1 or 2, wherein U.sup.1 is N, U.sup.2 is
N, and U.sup.3 is C--R.sup.e.
39. The compound of claim 1 or 2, wherein U.sup.1 is N; U.sup.2 is
C--R.sup.d; U.sup.3 is C--R.sup.e; R.sup.a2 is OCH.sub.3; R.sup.g
or R.sup.g1 is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and
R.sup.3B is, independently, selected from alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or
R.sup.3A and R.sup.3B, together with the atom to which each is
attached, form a 5- or 6-membered heterocyclic ring which is
unsubstituted or substituted; R.sup.b4 is W.sup.1 as defined in
claim 1.
40. The compound of any of claims 30-39, wherein R.sup.d is Cl.
41. The compound of claim 1 or 2, wherein U.sup.3 is N, one of
U.sup.1 and U.sup.2 is N, and the other is C--R.sup.d.
42. A method for treating an EGFR-driven cancer in a subject, said
method comprising administering to said subject a therapeutically
effective amount of a compound of any of claims 1-41, or a
pharmaceutically acceptable salt thereof.
43. A method for treating an EGFR-driven cancer in a subject, said
method comprising (a) providing a subject having an EGFR-driven
cancer characterized by the presence of a mutation in epidermal
growth factor receptor kinase (EGFR), and (b) administering to said
subject a therapeutically effective amount of a compound of any of
claims 1-41, or a pharmaceutically acceptable salt thereof.
44. The method of claim 43, wherein said EGFR-driven cancer is
characterized by the presence of one or more mutations selected
from: (i) L858R, (ii) T790M, (iii) both L858R and T790M, (iv)
delE746_A750, and (v) both delE746_A750 and T790M.
45. The method of any of claims 42-44, wherein said EGFR-driven
cancer is a non-small cell lung cancer (NSCLS); glioblastoma;
pancreatic cancer; head and neck cancer (e.g., squamous cell
carcinoma); breast cancer; colorectal cancer; epithelial cancer;
ovarian cancer; prostate cancer; or an adenocarcinoma.
46. The method of any of claims 42-45, further comprising
administering to said subject a first kinase inhibitor selected
from erlotinib, gefitinib, and pharmaceutically acceptable salts
thereof, within 6 days of administering said compound of any of
claims 1-31, wherein each of said compound of any of claims 1-31
and said first kinase inhibitor are administered in an amount that
together is sufficient to treat said EGFR-driven cancer.
47. A method of inhibiting the proliferation of a cell expressing
an EGFR mutant, said method comprising contacting said cell with a
compound of any of claims 1-31, or a pharmaceutically acceptable
salt thereof, in an amount sufficient to inhibit said
proliferation.
48. The method of claim 47, wherein said EGFR mutant is
characterized by the presence of one or more mutations in epidermal
growth factor receptor kinase (EGFR) selected from: (i) L858R, (ii)
T790M, (iii) both L858R and T790M, (iv) delE746_A750, and (v) both
delE746_A750 and T790M.
49. The method of claims 47 or 48, wherein said cell is a cancer
cell.
50. The method of claim 49, wherein said cancer cell is a cell from
a non-small cell lung cancer (NSCLS); glioblastoma; pancreatic
cancer; head and neck cancer (e.g., squamous cell carcinoma);
breast cancer; colorectal cancer; epithelial cancer; ovarian
cancer; prostate cancer; or an adenocarcinoma.
51. A method of treating an EGFR-driven cancer refractory to a
first kinase inhibitor selected from erlotinib, gefitinib, and
pharmaceutically acceptable salts thereof, in a subject, said
method comprising administering to said subject a compound of any
of claims 1-41, or a pharmaceutically acceptable salt thereof, in
an amount sufficient to treat said cancer.
52. A pharmaceutical composition comprising a compound of claim 1.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to pharmaceutical compositions and
methods for inhibiting the proliferation of cells.
[0002] In human clinical studies with non-small cell lung cancer
(NSCLC) patients, the kinase inhibitors, erlotinib and gefitinib
have been found to be effective, but in only a subset of patients.
It was later determined that the responsive patients had certain
mutations in the gene for epidermal growth factor receptor (EGFR).
The mutant forms of EGFR are enzymatically active without the need
for ligand stimulation. They are also particularly sensitive to
kinase inhibitors like erlotinib and gefitinib, which competitively
bind to the ATP binding site of the EGFR kinase domain. Those
mutations have been cataloged and described at length in the
scientific literature. They include small deletions or point
mutations in the kinase domain as has previously been written about
extensively. See e.g., Sharma, Nat. Rev. Cancer 7:169 (2007) (exon
19 mutations characterized by in-frame deletions of amino-acids 747
account for 45% of mutations, exon 21 mutations resulting in L858R
substitutions account for 40-45% of mutations, and the remaining
10% of mutations involve exon 18 and 20); Sordella et al., Science
305:1163 (2004); and Mulloy et al., Cancer Res. 67:2325 (2007).
[0003] Unfortunately, additional mutations in the EGFR gene, e.g.,
the T790M mutation, render drugs like erlotinib and gefitinib less
effective. Those mutations are associated with resistance to the
drugs and to relapse in patients with cancer cells having the T790M
mutation.
[0004] New therapies are needed for the treatment of EGFR-driven
cancers in which mutations confer resistance to front line tyrosine
kinase inhibitor ("TKI") therapies. In particular, new therapies
for inhibiting cells expressing such gefitinib-resistant or
erlotinib-resistant EGFR genes could be of profound benefit.
SUMMARY OF THE INVENTION
[0005] This invention relates to the discovery of a class of
compounds that inhibit EGFR and medically significant mutant forms
thereof. Those mutants include mutant EGFR proteins that are
enzymatically active in the absence of protein ligand and mutants
such as the T790M EGFR mutant that are resistant to the EGFR
inhibitors erlotinib and gefitinib. Compounds of this invention
possessing desirable selectivity for the intended biological
targets and advantageous pharmaceutical properties make them of
interest for treating cancers characterized by the expression of
EGFR or an EGFR mutant, especially in cases that are resistant or
refractory to erlotinib or gefitinib.
[0006] This invention provides a compound of Formula (I):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein
[0007] U.sup.1 and U.sup.2 are both N and U.sup.3 is C--R.sup.e; or
U.sup.3 is N, one of U.sup.1 and U.sup.2 is N, and the other is
C--R.sup.d; or U.sup.3 is C--R.sup.e, one of U.sup.1 and U.sup.2 is
N, and the other is C--R.sup.d;
[0008] V.sup.1 is O, S, NR.sup.V, CO, CH.sub.2, or CF.sub.2;
[0009] R.sup.V is H, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, or aryl;
[0010] R.sup.d is H, halo, CN, alkyl, cycloalkyl, alkoxy,
haloalkyl, alkenyl, haloalkenyl or halocycloalkyl;
[0011] R.sup.e is H or NH.sub.2; or, R.sup.d and R.sup.e, together
with the ring atom to which each is attached, form a 5- or
6-membered ring containing one, two or three heteroatoms,
independently selected from N, S and O, wherein the 5- or
6-membered ring so formed is substituted with R.sup.h which is
C.sub.1-4 alkyl or halo;
[0012] R.sup.g is H, F, --P(O)(R.sup.3A)(R.sup.3B),
--S(O)N(R.sup.3C)(R.sup.3D), --S(O).sub.2R.sup.3E,
--C(O)N(R.sup.3F)(R.sup.3G), --OC(O)N(R.sup.3F)(R.sup.3G),
--NR.sup.3HC(O)OR.sup.3I or a 5- or 6-membered heterocyclic ring
comprising 1, 2, 3 or 4 N atoms; [0013] each R.sup.3A, R.sup.3B,
R.sup.3C, R.sup.3D, R.sup.3E, R.sup.3F, R.sup.3G, R.sup.3H, and
R.sup.3I is independently selected from H, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, and heteroalkyl, or
R.sup.3A and R.sup.3B, or R.sup.3C and R.sup.3D, or R.sup.3F and
R.sup.3G, together with the atom to which each is attached, form an
unsubstituted or substituted 5- or 6-membered heterocyclic
ring;
[0014] R.sup.g2 is H, F, W.sup.1, --P(O)(R.sup.3A)(R.sup.3B),
--S(O)N(R.sup.3C)(R.sup.3D), --S(O).sub.2R.sup.3E,
--C(O)N(R.sup.3F)(R.sup.3G), --OC(O)N(R.sup.3F)(R.sup.3G),
--NR.sup.3HC(O)OR.sup.3I, C.sub.1-6 alkoxy or C.sub.1-4 alkyl;
[0015] or, R.sup.g2 and R.sup.g together with the atom to which
each is attached form an unsubstituted or substituted 5- to
7-membered heterocyclic ring comprising 1-3 heteroatoms
independently selected from P, N, O and S;
[0016] R.sup.g1 is H, F, --OR.sup.2, --P(O)(R.sup.3A)(R.sup.3B),
--S(O)N(R.sup.3C)(R.sup.3D), --S(O).sub.2R.sup.3E,
--C(O)N(R.sup.3F)(R.sup.3G), --OC(O)N(R.sup.3F)(R.sup.3G),
--NR.sup.3HC(O)OR.sup.3I, or substituted or unsubstituted 5- or
6-membered heterocyclic ring;
[0017] Ring A is:
##STR00003##
[0018] R.sup.b2 is H, F, or an optionally substituted 5- or
6-membered heterocyclic ring containing 1, 2 or 3 N or O atoms;
[0019] R.sup.b4 is H, F, W.sup.1, C.sub.1-6 alkoxy, C.sub.3-6
alkenyloxy, C.sub.3-6 cycloalkoxy, --OC(O)N(R.sup.5A)(R.sup.5B),
--NR.sup.5CC(O)OR.sup.5D, or substituted or unsubstituted 5- or
6-membered heterocyclic ring comprising 1, 2 or 3 N or O atoms;
[0020] each R.sup.5A, R.sup.5B, R.sup.5C and R.sup.5D is
independently H, alkyl, alkenyl, alkynyl or heteroalkyl, or
R.sup.5A and R.sup.5B, together with the atom to which each is
attached, form a substituted or unsubstituted 5- or 6-membered
heterocyclic ring;
[0021] R.sup.a1 is H, halo, W.sup.1, --CN, --NO.sub.2, --R.sup.1,
--OR.sup.2, --O--NR.sup.1R.sup.2, --NR.sup.1R.sup.2,
--NR.sup.1--NR.sup.1R.sup.2, --NR.sup.1--OR.sup.2, --C(O)YR.sup.2,
--OC(O)YR.sup.2, --NR.sup.1C(O)YR.sup.2, --SC(O)YR.sup.2,
--NR.sup.1C(.dbd.S)YR.sup.2, --OC(.dbd.S)YR.sup.2,
--C(.dbd.S)YR.sup.2, --YC(.dbd.NR.sup.1)YR.sup.2,
--YC(.dbd.N--OR.sup.1)YR.sup.2,
--YC(.dbd.N--NR.sup.1R.sup.2)YR.sup.2,
--YP(.dbd.O)(YR.sup.1)(YR.sup.2), --S(O).sub.rR.sup.2,
--SO.sub.2NR.sup.1R.sup.2, --NR.sup.1SO.sub.2NR.sup.1R.sup.2 or
##STR00004##
and X.sub.1 and X.sub.2 are each independently CH or N;
[0022] or R.sup.a1 and R.sup.b4, together with the atom to which
each is attached, form an optionally substituted 5- or 6-membered
heterocyclic ring comprising 1, 2 or 3 heteroatoms independently
selected from N and O;
[0023] R.sup.a2 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.3-6 cycloalkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyloxy,
C.sub.3-6 cycloalkyloxy or 4- to 7-membered heterocyclyl, wherein
the alkyl, alkenyl, cycloalkyl, alkoxy, C.sub.2-6 alkenyloxy,
cycloalkyloxy and heterocyclyl are unsubstituted or substituted
with one or more halo, amino, C.sub.1-6 alkylamino, or di-Cm
alkylamino groups;
[0024] Y is independently a bond, --O--, --S-- or --NR.sup.1--;
[0025] R.sup.1 and R.sup.2 are independently H or R.sup.15;
[0026] R.sup.4 is alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic and
heteroaryl;
[0027] W.sup.1 is --NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--C(O)C(R.sup.11)=CR.sup.9R.sup.10,
--CH.sub.2P(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--OP(O)C(R.sup.8).dbd.CR.sup.9R.sup.10,
--NR.sup.7S(O).sub.2C(R.sup.9)(R.sup.10)(R.sup.X),
--NR.sup.7S(O).sub.2C(R.sup.11).dbd.CR.sup.9R.sup.10,
--NR.sup.7C(O)C.ident.C--R.sup.14,
--NR.sup.7C(O)C(R.sup.9)(R.sup.10)(R.sup.X),
##STR00005##
[0028] R.sup.X is halo;
[0029] R.sup.7 is H, alkyl or heteroalkyl, wherein the alkyl and
heteroalkyl groups are independently optionally substituted with an
amino, alkylamino or dialkylamino group;
[0030] R.sup.8 is C.sub.1-6 alkyl;
[0031] R.sup.9 and R.sup.10 are independently H, halo,
--C(O)R.sup.16, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclyl or
heteroaryl, wherein R.sup.9 and R.sup.10, if not H, are optionally
substituted with one or more halo, amino, alkylamino, dialkylamino,
alkoxy, cycloalkyl, heterocyclyl or heteroaryl groups, wherein said
group, if not halo, is optionally substituted with one or more
halo, C.sub.1-4 alkyl, alkoxyl, halo(C.sub.1-4)alkyl or C.sub.3-7
cycloalkyl groups;
[0032] R.sup.11 is H, halo, --C(O)--OR.sup.12, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic, or heteroaryl, wherein R.sup.11, if not H, is
optionally substituted with one or more halo, amino, alkoxyl,
cycloalkyl, heterocyclic or heteroaryl groups, wherein said group,
if not halo, is optionally substituted with one or more halo or
alkyl, alkoxyl, cycloalkyl or heterocyclyl groups, wherein the
alkyl, alkoxyl, cycloalkyl and heterocyclyl group is optionally
substituted with one or more alkyl, halo or hydroxyl
substituents;
[0033] or R.sup.9 and R.sup.11, taken together with the atom to
which each is attached, form a cycloalkenyl or heterocyclic
ring;
[0034] R.sup.12 is alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclic, or
heteroaryl;
[0035] R.sup.13 is H or C.sub.1-4 alkyl;
[0036] R.sup.14 is R.sup.T or R.sup.W;
[0037] R.sup.15 is alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, 4- to 7-membered
heterocyclyl, or heteroaryl, wherein each R.sup.15 is optionally
substituted with one or more halo, cycloalkyl, heterocyclic or
heteroaryl groups, wherein said cycloalkyl, heterocyclic or
heteroaryl groups(s) are independently optionally substituted with
one or more halo, alkyl, haloalkyl, hydroxyalkyl, amino,
dialkylamino or cycloalkyl groups;
[0038] R.sup.16 is OH, --O-alkyl, cycloalkyl, heterocyclyl,
--NH.sub.2, --NH-alkyl, or --N-dialkyl wherein the alkyl,
cycloalkyl or heterocyclyl moiety is optionally substituted with
halo, amino, alkylamino, dialkylamino, alkyl or hydroxyl;
[0039] R.sup.T is H or --CH.sub.3;
[0040] R.sup.W is halo; substituted methyl; or an optionally
substituted group selected from (C.sub.2-6)alkyl,
(C.sub.1-6)heteroalkyl, heterocyclyl, aryl and heteroaryl; wherein
the substituents on the optionally substituted (C.sub.2-6)alkyl,
(C.sub.1-6)heteroalkyl, heterocyclyl, aryl and heteroaryl groups
are selected from halo, haloalkyl, alkoxy, heterocyclyl,
substituted heterocyclyl, amino, alkylamino, and dialkylamino, and
in the case of an optionally substituted heterocyclyl, the optional
substituents may further be selected from hydroxyl, alkyl,
haloalkyl, hyroxyalkyl, alkoxyalkyl, amino, alkylamino and
dialkylamino;
[0041] wherein
[0042] (a) the compound is not one of the following two
compounds:
##STR00006##
[0043] (b) at least one of R.sup.a1, R.sup.g2, and R.sup.b4 is
WI;
[0044] (c) the compound comprises at least one
--P(O)(R.sup.3A)(R.sup.3B); and
[0045] (d) the compound further has one or more of the following
features: [0046] Rd is halo(C.sub.3-5)cycloalkyl; [0047] R.sup.a2
is halo; substituted alkyl, substituted alkoxy, or optionally
substituted cycloalkyl, wherein substituents on the alkyl, alkoxy
or cycloalkyl groups are selected from halo, amino and dialkylamino
groups; [0048] R.sup.a1 is an optionally substituted 4-membered
heterocycle; [0049] R.sup.a1 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl or heteroalkyl, and is substituted with
one or more groups selected from halo, OH, heterocyclyl,
substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
[0050] R.sup.a1 is heterocyclyl or heterocyclyl-O--, wherein
R.sup.a1 is substituted with one or more groups selected from --OH,
halo, 4-membered heterocyclyl, substituted 4-membered heterocyclyl
and R.sup.18, wherein R.sup.18 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl or heteroalkyl, and R.sup.18 is optionally
substituted; [0051] R.sup.a1 and R.sup.b4, together with the atom
to which each is attached, form an optionally substituted
5-membered heterocyclic ring; [0052] R.sup.a2 is an optionally
substituted 4- to 7-membered membered heterocycle; [0053] R.sup.b4
is --NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10 or
--NR.sup.7C(O)C--C.dbd.C--R.sup.W; [0054] R.sup.g1 is --OR.sup.2;
[0055] R.sup.9or R.sup.10 is cycloalkyl, --CO.sub.2H,
--CO.sub.2-alkyl, --C(O)-heterocyclyl, --C(O)NH2, --C(O)NH-- alkyl
or --C(O)N-dialkyl wherein an alkyl, cycloalkyl or heterocyclyl
substituent or portion of a substituent is optionally substituted
with amino, alkylamino, dialkylamino, alkyl or hydroxyl; [0056] one
or more of R.sup.9, R.sup.10 and R.sup.11 is halo, haloalkyl,
alkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl or arylalkyl wherein alkyl,
heterocylic, heteroaryl or aryl substituent, or an alkyl,
heterocylic, heteroaryl or aryl portion of a substituent, is
optionally substituted with one or more groups selected from halo,
haloalkyl, hydroxyl, hydroxyalkyl, amino, alkylamino, dialkylamino,
alkyl, alkenyl, SO.sub.2alkyl, oxo, heterocyclyl and heterocycle
substituted with one or more alkyl, amino alkylamino, dialkylamino,
hydroxyl, hydroxyalkyl, SO.sub.2alkyl substituents; and, [0057]
R.sup.9 and R.sup.11, taken together with the atom to which each is
attached, form a cycloalkenyl or heterocyclic ring. [0058] Unless
otherwise specified, (a) each non-cyclic alkyl group contains 1-6
carbon atoms, each non-cyclic alkenyl or alkynyl group contains 2-8
carbon atoms, each cycloalkyl and cycloalkenyl group contains 3-13
carbon atoms, each cycloalkynyl group contains 8-13 carbon atoms,
and each heteroalkyl group is a branched or unbranched alkyl,
alkenyl or alkynyl group of up to 7 carbon atoms in addition to 1-4
heteroatoms independently selected from N, O, S and P; (b) each
heterocycle is a non-aromatic ring or ring system having five to
fourteen ring atoms of which one or more, preferably one to four,
is each a heteroatom independently selected from N, O, S or P, and
the remainder of ring atoms are carbon; (c) each aryl group is an
aromatic carbocyclic ring or ring system containing 6-14 ring
atoms; and (d) each heteroaryl moiety is an aromatic ring or ring
system having five to fourteen ring atoms of which one or more,
often one to four, is each a heteroatom independently selected from
N, O, S or P, and the remainder of ring atoms are carbon. Optional
substituents for the various embodiments of the invention are
illustrated in the copious examples and detailed disclosure below.
Briefly, optional substituents for alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl and
heterocyclyl moieties include among others, amino, alkylamino,
dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl,
alkylcarbonyl, hydroxy, alkoxy, acyloxy, haloalkoxy, .dbd.O,
.dbd.S, .dbd.NH, .dbd.NNR.sup.2R.sup.3, .dbd.NNHC(O)R.sup.2,
.dbd.NNHCO.sub.2R.sup.2, .dbd.NNHSO.sub.2R.sup.2 and
--P(O)(R.sup.3).sub.2. Optional substituents for the aryl and
heteroaryl moieties include among other groups, amino, alkylamino,
dialkylamino, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl,
aryl, heteroaryl, carbocyclyl, heterocyclyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylaminocarbonyloxy,
dialkylaminocarbonyloxy, nitro, cyano, carboxy, alkoxycarbonyl,
alkylcarbonyl, hydroxy, alkoxy, acyloxy, and haloalkoxy. [0059] The
foregoing definitions and non-limiting choices for substituents are
further elaborated upon and exemplified below, and collectively
apply to all subsequent occurrences except to the extent otherwise
specified.
[0060] In one embodiment of the compounds of Formula I,
[0061] R.sup.d is H, halo, CN, alkyl, alkoxy, haloalkyl, alkenyl,
haloalkenyl or halocycloalkyl;
[0062] W.sup.1 is --NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--CH.sub.2P(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--OP(O)C(R.sup.8).dbd.CR.sup.9R.sup.10,
--NR.sup.7S(O).sub.2C(R.sup.11).dbd.CR.sup.9R.sup.10,
--NR.sup.7C(O)C C.ident.C--R.sup.14,
##STR00007##
[0063] R.sup.g is H, --P(O)(R.sup.3A)(R.sup.3B),
--S(O)N(R.sup.3D)(R.sup.3D), --S(O).sub.2R.sup.3E,
--C(O)N(R.sup.3F)(R.sup.3G), --OC(O)N(R.sup.3F)(R.sup.3G),
--NR.sup.3HC(O)OR.sup.3I, a 5- or 6-membered heterocyclic ring
comprising 1, 2, 3 or 4 N atoms, wherein each of R.sup.3A,
R.sup.3B, R.sup.3D, R.sup.3D, R.sup.3E, R.sup.3F, R.sup.3G,
R.sup.3H, and R.sup.3I is, independently, selected from H, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and
heteroalkyl, or R.sup.3A and R.sup.3B, or R.sup.3D and R.sup.3D, or
R.sup.3F and R.sup.3G, together with the atoms to which each is
attached, form an optionally substituted 5- or 6-membered
heterocyclic ring; and,
[0064] R.sup.g1 is H, F, --P(O)(R.sup.3A)(R.sup.3B),
--S(O)N(R.sup.3D)(R.sup.3D), --S(O).sub.2R.sup.3E,
--C(O)N(R.sup.3F)(R.sup.3G), --OC(O)N(R.sup.3F)(R.sup.3G),
--NR.sup.3''C(O)OR.sup.3I, or an optionally substituted 5- or
6-membered heterocyclic ring; wherein the variable terms are as
defined for Formula (I).
[0065] In one embodiment of the compounds of the invention and
their pharmaceutically acceptable salts, U.sup.1 is N, U.sup.2 is
C--R.sup.d, and U.sup.3 is C--Re.
[0066] In another embodiment U.sup.1 is C--R.sup.d, U.sup.2 is N,
and U.sup.3 is C--R.sup.e.
[0067] In another embodiment U.sup.1 is N, U.sup.2 is N, and
U.sup.3 is C--R.sup.e.
[0068] In another embodiment U.sup.1 is N; U.sup.2 is C--R.sup.d;
U.sup.3 is C--R.sup.e; R.sup.a2 is OCH.sub.3. R.sup.g or R.sup.g1
is --P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is,
independently, selected from alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and
R.sup.3B, together with the atom to which each is attached, form a
5- or 6-membered heterocyclic ring which is unsubstituted or
substituted; R.sup.b4 is W.sup.1 as defined in Formula (I). In one
class of these compounds V.sup.1 is NH. In another V.sup.1 is O. In
certain embodiments of both classes R.sup.d is Cl. In certain
embodiments of both classes R.sup.g or R.sup.g1 is
--P(O)(CH.sub.3).sub.2 or --P(O)(CH.sub.2CH.sub.3).sub.2.
[0069] In another embodiment U.sup.3 is N, one of U.sup.1 and
U.sup.2 is N, and the other is C--R.sup.d.
[0070] Certain compounds of the invention are described by any of
Formulas (IIIa)-(IIIe), or a pharmaceutically acceptable salt
thereof:
##STR00008##
wherein R.sup.a1; R.sup.a2; R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1;
R.sup.g2; R.sup.d; and R.sup.h are as defined in Formula (I).
[0071] Other embodiments are described by any of Formulas
(IVa)-(IVe), or a pharmaceutically acceptable salt thereof:
##STR00009##
wherein R.sup.a2; R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2;
R.sup.d; and R.sup.h are as defined in Formula (I).
[0072] Further embodiments are described by any of Formulas
(Va)-(Ve), or a pharmaceutically acceptable salt thereof:
##STR00010##
wherein R.sup.a1; R.sup.a2; R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1;
R.sup.g2; R.sup.d; and R.sup.h are as defined in Formula (I).
[0073] Other embodiments are described by any of Formulas
(VIa)-(VIe), or a pharmaceutically acceptable salt thereof:
##STR00011##
wherein R.sup.a2; R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2;
R.sup.d; and R.sup.h are as defined in Formula (I), and R.sup.a1 is
selected from W.sup.1, --R.sup.1, --C(O)YR.sup.2,
--C(.dbd.S)YR.sup.2, --C(.dbd.NR.sup.1)YR.sup.2,
--C(.dbd.N--OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --S(O).sub.rR.sup.2, and
##STR00012##
each Y is, independently, a bond, --O--, --S-- or --NR.sup.1--;
[0074] each occurrence of R.sup.1 and R.sup.2 is, independently,
selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl; each
of X.sub.1 and X.sub.2 is, independently, selected from CH and
N;
[0075] W.sup.1 is as defined in Formula (I); and
[0076] R.sup.4 is selected from alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic and heteroaryl.
[0077] Certain embodiments in which Ring A is cyclopentyl are
described by any of Formulas (VIIa)-(VIIe), or a pharmaceutically
acceptable salt thereof:
##STR00013##
wherein R.sup.a1; R.sup.a2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2;
R.sup.d; and R.sup.h are as defined in Formula (I).
[0078] Other embodiments are described by any of Formulas
(VIIIa)-(VIIIe), or a pharmaceutically acceptable salt thereof:
##STR00014##
wherein R.sup.a2; R.sup.b2; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d;
and R.sup.h are as defined in Formula (I), R.sup.a1 is selected
from W.sup.1, --R.sup.1, --C(O)YR.sup.2, --C(.dbd.S)YR.sup.2,
--C(.dbd.NR.sup.1)YR.sup.2, --C(.dbd.N-OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --S(O).sub.rR.sup.2, and
##STR00015##
[0079] each Y is, independently, a bond, --O--, --S-- or
--NR.sup.1--;
[0080] W.sup.1 is as defined in Formula (I);
[0081] each occurrence of R.sup.1 and R.sup.2 is, independently,
selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl;
[0082] each of X.sub.1 and X.sub.2 is, independently, selected from
CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic and heteroaryl.
[0083] Further embodiments are described by any of Formulas
(IXa)-(IXe), or a pharmaceutically acceptable salt thereof:
##STR00016##
wherein R.sup.a1 is W.sup.1, --R.sup.1, --C(O)YR.sup.2,
--C(.dbd.S)YR.sup.2, --C(.dbd.NR.sup.1)YR.sup.2,
--C(.dbd.N--OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)YR.sup.2, --S(O).sub.rR.sup.2, or
##STR00017##
[0084] each Y is, independently, a bond, --O--, --S-- or
--NR.sup.1--;
[0085] R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d;
R.sup.h and W.sup.1 are as defined in Formula (I);
[0086] each occurrence of R.sup.1 and R.sup.2 is, independently,
selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl;
[0087] each of X.sub.1 and X.sub.2 is, independently, CH or N;
and
R.sup.4 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic or heteroaryl.
[0088] Other embodiments are described by described by any of
Formulas (Xa)-(Xe), or a pharmaceutically acceptable salt
thereof:
##STR00018##
wherein R.sup.b2; R.sup.b4; R.sup.g; R.sup.g1; R.sup.g2; R.sup.d;
and R.sup.h are as defined in Formula (I), R.sup.a1 is selected
from W.sup.1, --R.sup.1, --C(O)YR.sup.2, --C(.dbd.S)YR.sup.2,
--C(.dbd.NR.sup.1)YR.sup.2, --C(.dbd.N--OR.sup.1)YR.sup.2,
--C(.dbd.N--NR.sup.1R.sup.2)R.sup.2, --S(O).sub.rR.sup.2, and
##STR00019##
[0089] each Y is, independently, a bond, --O--, --S-- or
--NR.sup.1--;
[0090] W.sup.1 is as defined in Formula (I);
[0091] each occurrence of R.sup.1 and R.sup.2 is, independently,
selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
cycloalkynyl, aryl, heteroalkyl, heterocyclic and heteroaryl;
[0092] each of X.sub.1 and X.sub.2 is, independently, selected from
CH and N; and R.sup.4 is selected from alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic and heteroaryl.
[0093] [1] In one embodiment of any of the Formulas above, i.e.,
any of Formula I, III(a)-(e), IV(a)-(e), V(a)-(e), VI(a)-(e),
VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e), R.sup.a2 is H, F,
Cl, --CH.sub.3, --CF.sub.3, --CH.sub.2CH.sub.3, --OCH.sub.3,
--OCF.sub.3, --OCH.sub.2CH.sub.3 or -heterocyclyl-O--, e.g., a
4-membered heterocyclyl.
[0094] [2] In certain embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others the embodiment immediately
above, R.sup.d is H, Cl, F, Br, I, CN, CH.sub.3, CF.sub.3,
cyclopropyl or --CH.sub.2CH.sub.2.dbd.CH.sub.2.
[0095] [3] In particular embodiments of any of Formulas I,
III(a)-(e), IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e),
VIII(a)-(e), IX(a)-(e), and X(a)-(e), including among others each
of the embodiments immediately above, R.sup.b2 is H.
[0096] [4] In certain embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others each of the embodiments
immediately above, R.sup.g1 is H and R.sup.g2 is H, F, C.sub.1-6
alkyl, or C.sub.1-6 alkoxy.
[0097] [5] In certain embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others each of the embodiments
immediately above, R.sup.g is --P(O)(R.sup.3A)(R.sup.3B), wherein
R.sup.3A and R.sup.3B, are as defined in Formula (I). In some cases
R.sup.g is --P(O)(CH.sub.3).sub.2 or
--P(O)(CH.sub.2CH.sub.3).sub.2.
[0098] [6] In certain embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others each of the first four
embodiments immediately above, R.sup.g is --S(O).sub.2R.sup.3E),
wherein R.sup.3E is as defined in Formula (I). For example, in some
cases R.sup.g is --S(O).sub.2CH(CH.sub.3).sub.2.
[0099] [7] In certain embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others each of the embodiments
immediately above, R.sup.a1 is a 5- or 6-membered heteroaryl ring
optionally substituted with an --OH, halo, alkyl, substituted alkyl
substituent.
[0100] [8] In certain embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others each of the first six
embodiments immediately above, R.sup.a1 is a 4-, 5-, 6- or
7-membered heterocycle which is optionally substituted with one or
more groups selected from halo and R.sup.17. R.sup.17 is an alkyl,
cycloalkyl, heteroalkyl, 4- to 7-membered heterocyclyl or
heteroaryl group, and R.sup.17 is optionally substituted with one
or more halo, alkyl, cycloalkyl, heterocyclic or heteroaryl groups,
of which, the cycloalkyl, heterocyclic or heteroaryl substituent is
optionally substituted with one or more halo, alkyl, haloalkyl,
hydroxyalkyl, amino, dialkylamino or cycloalkyl groups.
[0101] In one class of compounds of the foregoing embodiment,
R.sup.a1, is selected from the following:
##STR00020## ##STR00021##
[0102] [9] In other embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others each of the first six
embodiments immediately above, R.sup.a1 is --OR.sup.2, as defined
in Formula (I). For example, R.sup.a1 is selected from the
following:
##STR00022## ##STR00023##
[0103] [10] In certain embodiments of any of Formulas I,
III(a)-(e), IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e),
VIII(a)-(e), IX(a)-(e), and X(a)-(e), including among others each
of the first six embodiments immediately above, R.sup.a1 is an
optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, or heteroalkyl group, wherein optional
substituents are selected from halo, cycloalkyl, heterocyclic or
heteroaryl groups, wherein said cycloalkyl, heterocyclic and
heteroaryl substituent(s) are independently optionally substituted
with one or more halo, alkyl, haloalkyl, hydroxyalkyl, amino,
dialkylamino or cycloalkyl groups. For example, R.sup.a1 may be
selected from the following:
##STR00024##
In other embodiments of any of Formulas I, III(a)-(e), IV(a)-(e),
V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and
X(a)-(e), including among others each of the first six embodiments
immediately above, R.sup.a1 is of the Formula:
##STR00025##
wherein:
[0104] J.sup.1 and J.sup.2 are independently H, halo or R.sup.J; or
J.sup.1 and J.sup.2 together with the atom to which each is
attached form an optionally substituted ring which is C.sub.3-8
cycloalkyl, 3- to 7-membered heterocyclic, or heteroaryl;
[0105] J.sup.3 and J.sup.4 are independently H or R.sup.J; or
J.sup.3 and J.sup.4 together with the atom to which each is
attached form an optionally substituted ring which is 3- to
7-membered heterocyclic or heteroaryl ring;
[0106] R.sup.J is C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-8
heteroalkyl, or 3- to 7-membered heterocyclyl, wherein each R.sup.J
is independently selected from halo, haloalkyl, hydroxyl,
hydroxyalkyl, amino, alkylamino, dialkylamino, cycloalkyl, alkoxy,
cycloalkoxy and heterocyclic groups, wherein the alkyl, cycloalkyl,
and heterocyclic groups on R.sup.J are optionally substituted with
one or more halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
amino, alkylamino, dialkylamino or cycloalkyl groups; and, z is
1-3.
[0107] By way of non-limiting example, R.sup.a1 may be selected
from the following:
##STR00026##
[0108] In particular embodiments of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), V(IIa)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), including among others each of the embodiments
immediately above, R.sup.b4 is
--NR.sup.7C(O)C(R.sup.11).dbd.CR.sup.9R.sup.10,
--NR.sup.7S(O).sub.2C(R.sup.9)(R.sup.10)(R.sup.X),
--NR.sup.7C(O)C.ident.C--R.sup.14, Or
--NR.sup.7C(O)C(R.sup.9)(R.sup.10)(R.sup.X), wherein R.sup.7,
R.sup.9, R.sup.10, R.sup.11, R.sup.14, and R.sup.X are as defined
in Formula (I).
##STR00027##
For example, in cases in which R.sup.b4 may be
--NHC(O)CH.dbd.CH.sub.2 or may be selected from the following:
##STR00028## ##STR00029##
[0109] In other embodiments R.sup.b4 is --NHC(O)C.ident.CH or may
be selected from the following:
##STR00030## ##STR00031##
[0110] In one class of compounds of any of Formulas I, III(a)-(e),
IV(a)-(e), V(a)-(e), VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e),
and X(a)-(e), and their pharmaceutically acceptable salts,
including compounds with the various R.sup.a1 groups disclosed
above, R.sup.b4 is W.sup.1 as defined in Formula (I). In one
subclass thereof, R.sup.a2 is H, halo, --CH.sub.3, --CF.sub.3,
--CH.sub.2CH.sub.3, --OCH.sub.3, --OCF.sub.3, --OCH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2N(CH.sub.3).sub.2 or --O-heterocyclyl. In a
particular embodiment of that subclass, R.sup.g is
--P(O)(R.sup.3A)(R.sup.3B), wherein R.sup.3A and R.sup.3B, are as
defined in Formula (I), e.g., R.sup.g is --P(O)(CH.sub.3).sub.2 or
--P(O)(CH.sub.2CH.sub.3).sub.2. In another embodiment of that
subclass, R.sup.g is --S(O).sub.2R.sup.3E), wherein R.sup.3E is as
defined in Formula (I), e.g., R.sup.g is
--S(O).sub.2CH(CH.sub.3).sub.2. In either embodiment of the
subclass, R.sup.d may be CI, F, Br, I, or CH.sub.3.
[0111] In certain embodiments of any of the above formulas,
R.sup.g1 is H and R.sup.g2 is H, F, C.sub.1-6 alkyl, or C.sub.1-6
alkoxy.
[0112] In particular embodiments of any of the above formulas,
R.sup.g is --P(O)(R.sup.3A)(R.sup.3B) or --S(O).sub.2R.sup.3E,
wherein R.sup.3A; R.sup.3B; and R.sup.3E are as defined in formula
(I). For example, R.sup.g can be selected from
--P(O)(CH.sub.3).sub.2 and --S(O).sub.2(CH(CH.sub.3).sub.2).
[0113] In certain embodiments of any of the above formulas,
R.sup.a1 is a 5 or 6 member heterocyclic ring including 1 or 2 N or
O atoms which is unsubstituted or substituted with an alkyl group.
For example, R.sup.a1 can be selected from any of the following
groups:
##STR00032##
[0114] In particular embodiments of any of the above formulas,
R.sup.a2 is methoxy; R.sup.d is CI, F, Br, I, or CH.sub.3; and
R.sup.g is --P(O)(CH.sub.3).sub.2 or
--S(O).sub.2(CH(CH.sub.3).sub.2).
[0115] In certain embodiments of the compounds of formula (I),
U.sup.1 is N, U.sup.2 is C--R.sup.d, and U.sup.3 is C--R.sup.e;
U.sup.1 is C--R.sup.d, U.sup.2 is N, and U.sup.3 is C--R.sup.e;
U.sup.1 is N, U.sup.2 is N, and U.sup.3 is C--R.sup.e; or U.sup.3
is N, one of U.sup.1 and U.sup.2 is N, and the other is
C--R.sup.d.
[0116] In still other embodiments of the compounds of formula (I),
U.sup.1 is N; U.sup.2 is C--R.sup.d; U.sup.3 is C--R.sup.e;
R.sup.a2 is OCH.sub.3; R.sup.g or R.sup.g1 is
--P(O)(R.sup.3A)(R.sup.3B); each of R.sup.3A and R.sup.3B is,
independently, selected from alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkynyl, and heteroalkyl, or R.sup.3A and
R.sup.3B, together with the atoms to which they are attached,
combine to form a 5- or 6-membered heterocyclic ring which is
unsubstituted or substituted; R.sup.b4 is
--NHC(O)C(R.sup.11).dbd.CR.sup.9R.sup.10; each occurrence of
R.sup.9 and R.sup.10 is, independently, selected from H, alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,
heteroalkyl, heterocyclic and heteroaryl; R.sup.11 is
--C(O)--OR.sup.12, --CH.sub.2N(CH.sub.3).sub.2, H, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic, or heteroaryl; and R.sup.12 is alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic, or heteroaryl. Exemplary compounds include those in
which V.sup.1 is NH, V.sup.1 is O, R.sup.d is Cl, R.sup.g or
R.sup.g1 is --P(O)(CH.sub.3).sub.2 or
--P(O)(CH.sub.2CH.sub.3).sub.2, and/or R.sup.b4 is
--NHC(O)C(R.sup.11).dbd.CH.sub.2. In particular embodiments,
R.sup.b4 is --NHC(O)C(R.sup.11).dbd.CH.sub.2; R.sup.11 is
--C(O)--OR.sup.12, --CH.sub.2N(CH.sub.3).sub.2, H, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic, or heteroaryl; R.sup.12 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl,
heterocyclic, or heteroaryl; R.sup.d is Cl; and R.sup.g or R.sup.g1
is selected from --P(O)(CH.sub.3).sub.2 and
--P(O)(CH.sub.2CH.sub.3).sub.2.
[0117] In one embodiment of the compounds of any of Formulas (I),
(Ia)-(Ic), (IIa)-(IIc), (IIIa)-(IIIe), (IVa)-(IVe), (Va)-(Ve),
(VIa)-(VIe), (VIIIa)-(VIIIe), (IXa)-(IXe), and (Xa)-(Xe), R.sup.b4
is --NHC(O)CH.dbd.CH.sub.2.
DETAILED DESCRIPTION
[0118] The invention features a method for treating an EGFR-driven
cancer in a subject by administering to the subject a
therapeutically effective amount of a compound of the invention, or
a pharmaceutically acceptable salt thereof.
[0119] In a related aspect, the invention features a method for
treating an EGFR-driven cancer in a subject, the method including
(a) providing a subject having an EGFR-driven cancer characterized
by the presence of a mutation in epidermal growth factor receptor
kinase (EGFR), and (b) administering to the subject a
therapeutically effective amount of a compound of the invention, or
a pharmaceutically acceptable salt thereof. In certain embodiments,
EGFR-driven cancer is characterized by the presence of one or more
mutations selected from: (i) L858R, (ii) T790M, (iii) both L858R
and T790M, (iv) delE746_A750, and (v) both delE746_A750 and
T790M.
[0120] In the above methods, the EGFR-driven cancer can be a
non-small cell lung cancer (NSCLS); glioblastoma; pancreatic
cancer; head and neck cancer (e.g., squamous cell carcinoma);
breast cancer; colorectal cancer; epithelial cancer; ovarian
cancer; prostate cancer; an adenocarcinoma, or any EGFR-driven
cancer described herein.
[0121] In certain embodiments of the above methods, the method
further includes administering to the subject a first kinase
inhibitor selected from erlotinib, gefitinib, and pharmaceutically
acceptable salts thereof, within 6 days (e.g., within 2 weeks, 1
week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or
simultaneously) of administering the compound of the invention
(e.g., a compound of any of Formulas (I), (Ia)-(Ic), (IIa)-(IIc),
(IIIa)-(IIIe), (IVa)-(IVe), (Va)-(Ve), (VIa)-(VIe),
(VIIIa)-(VIIIe), (IXa)-(IXe), and (Xa)-(Xe)), wherein each of the
compound of the invention and the first kinase inhibitor are
administered in an amount that together is sufficient to treat the
EGFR-driven cancer.
[0122] In a related aspect, the invention features a method of
inhibiting the proliferation of a cell expressing an EGFR mutant,
the method including contacting the cell with a compound of the
invention, or a pharmaceutically acceptable salt thereof, in an
amount sufficient to inhibit the proliferation. For example, the
EGFR mutant can be characterized by the presence of one or more
mutations in epidermal growth factor receptor kinase (EGFR)
selected from: (i) L858R, (ii) T790M, (iii) both L858R and T790M,
(iv) delE746_A750, (v) both delE746_A750 and T790M, and any other
EGFR mutations described herein. In certain embodiments, the cell
is a cancer cell (e.g., a cell from a non-small cell lung cancer
(NSCLS); glioblastoma; pancreatic cancer; head and neck cancer
(e.g., squamous cell carcinoma); breast cancer; colorectal cancer;
epithelial cancer; ovarian cancer; prostate cancer; an
adenocarcinoma, or any other EGFR expressing cancer described
herein).
[0123] The invention further features a method of treating an
EGFR-driven cancer refractory to a first kinase inhibitor selected
from erlotinib, gefitinib, and pharmaceutically acceptable salts
thereof, in a subject by administering to the subject a compound of
the invention, or a pharmaceutically acceptable salt thereof, in an
amount sufficient to treat the cancer.
[0124] In any of Formulas I, III(a)-(e), IV(a)-(e), V(a)-(e),
VI(a)-(e), VII(a)-(e), VIII(a)-(e), IX(a)-(e), and X(a)-(e), the
compound can be either in its free base form, or a pharmaceutically
acceptable salt.
[0125] The response criteria for the methods of the invention can
be graded according to the response evaluation criteria in solid
tumors (RECIST) guidelines (see Eur. J. Cancer 45:228 (2009)) that
define when cancer patients improve ("respond"), stay the same
("stabilize"), or worsen ("progression") during treatments. A
complete response is characterized by: (i) disappearance of all
target lesions; and (ii) any pathological lymph nodes (whether
target or non-target) must have reduction in short axis to <10
mm. A partial response is characterized by: (i) at least a 30%
decrease in the sum of diameters of target lesions, taking as
reference the baseline sum diameters. A progressive disease is
characterized by (i) at least a 5%, 10%, or 20% increase in the sum
of diameters of target lesions, taking as reference the smallest
sum on study (this includes the baseline sum if that is the
smallest on study); or (ii) the appearance of one or more new
lesions.
[0126] The term "administration" or "administering" refers to a
method of giving a dosage of a pharmaceutical composition to a
mammal, where the method is, e.g., oral, intravenous,
intraperitoneal, intraarterial, or intramuscular. The preferred
method of administration can vary depending on various factors,
e.g., the components of the pharmaceutical composition, site of the
potential or actual disease and severity of disease.
[0127] By "EGFR-driven cancer" is meant a cancer characterized by
inappropriately high expression of an EGFR gene or by a mutation in
an EGFR gene that alters the biological activity of an EGFR nucleic
acid molecule or polypeptide. EGFR-driven cancers can arise in any
tissue, including brain, blood, connective tissue, liver, mouth,
muscle, spleen, stomach, testis, and trachea. EGFR-driven cancers
can include non-small cell lung cancer (NSCLS), including one or
more of squamous cell carcinoma, adenocarcinoma, adenocarcinoma,
bronchioloalveolar carcinoma (BAC), BAC with focal invasion,
adenocarcinoma with BAC features, and large cell carcinoma; neural
tumors, such as glioblastomas; pancreatic cancer; head and neck
cancers (e.g., squamous cell carcinoma); breast cancer; colorectal
cancer; epithelial cancer, including squamous cell carcinoma;
ovarian cancer; prostate cancer; adenocarcinomas; and including
cancers which are EGFR mediated.
[0128] An "EGFR mutant" or "mutant" includes one or more deletions,
substitutions, or additions in the amino acid or nucleotide
sequences of EGFR protein, or EGFR coding sequence. The EGFR mutant
can also include one or more deletions, substitutions, or
additions, or a fragment thereof, as long as the mutant retains or
increases tyrosine kinase activity, compared to wild type EGFR. In
particular EGFR mutations, kinase or phosphorylation activity can
be increased (e.g., by at least 5%, 10%, 15%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or even 100%), as compared to wild type EGFR.
Particular EGFR mutants are described herein, where mutations are
provided relative to the position of an amino acid in human EGFR,
as described in the sequence provided in NCBI GenBank Reference
Sequence: NP.sub.--005219.2.
[0129] As used herein, the term "inhibiting the proliferation of a
cell expressing an EGFR mutant" refers to measurably slowing,
stopping, or reversing the growth rate of the EGFR-expressing cells
in vitro or in vivo. Desirably, a slowing of the growth rate is by
at least 10%, 20%, 30%, 50%, or even 70%, as determined using a
suitable assay for determination of cell growth rates (e.g., a cell
growth assay described herein). The EGFR mutant can be any EGFR
mutant described herein.
[0130] As used herein, the term "refractory" refers to a cancer
which is progressive in response to a given particular therapy. The
cancer can be refractory either from the initial administration of
the therapy; or become refractory over time in response to the
therapy.
[0131] The term "sequence identity" is meant the shared identity
between two or more nucleic acid sequence, or two or more amino
acid sequences, expressed in the terms of the identity between the
sequences. Sequence identity can be measured in terms of percentage
identity; the higher the percentage, the more identical the
sequences are. Homologs or orthologs of nucleic acid or amino acid
sequences possess a relatively high degree of sequence identity
when aligned using standard methods. Methods of alignment of
sequences for comparison are well known in the art. Various
programs and alignment algorithms are described in: Smith and
Watermann, Adv. Appl. Math. 2:482 (1981); Needleman and Wunsch, J.
Mol. Biol. 48:443 (1970); Pearson and Lipman, Proc. Natl. Acad.
Sci. U.S.A. 85:2444 (1988); Corpet et al., Nuc. Acid Res. 16:10881
(1988); Huang et al., Computer Appls. in the Biosciences 8:155
(1992); and Pearson et al., Meth. Mol. Biol. 24:307 (1994).
Altschul et al. (J. Mol. Biol. 215:403 (1990)) presents a detailed
consideration of sequence alignment methods and homology
calculations. The NCBI Basic Local Alignment Search Tool (BLAST)
(Altschul et al., J. Mol. Biol. 215:403 (1990)) is available from
several sources, including the National Center for Biological
Information (NCBI) website, for use in connection with the sequence
analysis programs blastp, blastn, blastx, tblastn, and tblastx.
Additional information can be found at the NCBI website. BLASTN is
used to compare nucleic acid sequences, while BLASTP is used to
compare amino acid sequences. To compare two nucleic acid
sequences, the option can be set as follows: -i is set to a file
containing the first nucleic acid sequence to be compared; -j is
set to a file containing the second nucleic acid sequence to be
compared; -p is set to blastn; -o is set to any desired file name;
-q is set to -1; -r is set to 2; and all other options are left at
their default setting. Once aligned, the number of matches is
determined by counting the number of positions where an identical
nucleotide or amino acid residue is present in both sequences. The
percent sequence identity is determined by dividing the number of
matches either by the length of the sequence set forth in the
identified sequence, or by an articulated length (such as 30, 35,
40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, or 400
consecutive nucleotides or amino acid residues from a sequence set
forth in an identified sequence), followed by multiplying the
resulting value by 100. One indication that two nucleic acid
molecules are closely related is that the two molecules hybridize
to each other under stringent conditions. Stringent conditions are
sequence-dependent and are different under different environmental
parameters.
[0132] Nucleic acid molecules that hybridize under stringent
conditions to an EGFR gene sequence typically hybridize to a probe
based on either an entire EGFR gene or selected portions of the
gene (e.g., the kinase domain or a segment of the gene that
contains the mutated codons described herein), under conditions
described above.
[0133] As used herein, the term "treating" refers to administering
a pharmaceutical composition for prophylactic and/or therapeutic
purposes. To "prevent disease" refers to prophylactic treatment of
a subject who is not yet ill, but who is susceptible to, or
otherwise at risk of, a particular disease. To "treat disease" or
use for "therapeutic treatment" refers to administering treatment
to a subject already suffering from a disease to improve or
stabilize the subject's condition. Thus, in the claims and
embodiments, treating is the administration to a subject either for
therapeutic or prophylactic purposes.
[0134] Where optional substitution of compounds of the invention is
indicated, but one or more optional substituents is not specified,
the substituent may be selected from those disclosed herein as
generally appropriate in the given context, e.g. on an alkyl
carbon, an aryl carbon, etc., and specifically include substitution
exemplified in the examples. Other parameters of functional groups
are also disclosed in detail below.
[0135] The term "alkyl" refers to linear, branched, cyclic, and
polycyclic non aromatic hydrocarbon groups, which may be
substituted or unsubstituted. Unless otherwise specified, "alkyl"
groups contain one to eight, and typically one to six carbon atoms.
Examples of alkyl include, without limitation, methyl, ethyl,
n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, cyclobutyl, pentyl, isopentyl tert-pentyl, cyclopentyl,
hexyl, isohexyl, cyclohexyl, and n-heptyl, among others. Exemplary
substituted alkyl groups include, without limitation, haloalkyl
groups (e.g., fluoromethyl, difluoromethyl, trifluoromethyl,
2-fluoroethyl, 3-fluoropropyl), hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, benzyl, substituted benzyl, and phenethyl, among
others. Note that as used herein, "alkyl" encompasses cyclic alkyl
groups, which if not otherwise specified, contain 3-8 carbon
atoms.
[0136] The term "alkoxy" refers to a subset of alkyl in which an
alkyl group as defined above with the indicated number of carbons
attached through an oxygen bridge, --O-alkyl, wherein the alkyl
group contains 1 to 8 carbons atoms and is substituted or
unsubstituted. Exemplary alkoxy groups include, without limitation,
methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy, n-butoxy,
s-pentoxy, --OCF.sub.3, and --O-cyclopropyl.
[0137] The term "haloalkyl" refers to a subset of alkyl in which an
alkyl group as defined above having one or more hydrogen atoms of
the alkyl substituted with a halogen atom. Exemplary haloalkyl
groups include, without limitation, fluoromethyl, trifluoromethyl,
trichloromethyl, pentafluoroethyl and the like.
[0138] The term "alkenyl" refers to a branched or unbranched
hydrocarbon group containing one or more double bonds and having
from 2 to 8 carbon atoms. An alkenyl may optionally include
monocyclic or polycyclic rings, in which each ring desirably has
from three to six members. The alkenyl group may be substituted or
unsubstituted. Alkenyl groups include, without limitation, vinyl,
allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.
[0139] The term "alkynyl" refers to a branched or unbranched
hydrocarbon group containing one or more triple bonds and having
from 2 to 8 carbon atoms. The alkynyl group may be substituted or
unsubstituted. Alkynyls include, without limitation, ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
[0140] The term "cycloalkyl" refers to cyclic or polycyclic
hydrocarbon groups of from 3 to 13 carbon atoms, any of which is
saturated. Cycloalkyl groups may be substituted or unsubstituted.
Exemplary cycloalkyl groups include, without limitation,
cyclopropyl, norbornyl, [2.2.2]bicyclooctane, and
[4.4.0]bicyclodecane, and the like, which, as in the case of other
alkyl moieties, may optionally be substituted.
[0141] The term "cycloalkenyl" refers to cyclic or polycyclic
hydrocarbon groups of from 3 to 13 carbon atoms, preferably from 5
to 8 carbon atoms, containing one or more double bonds.
Cycloalkenyl groups may be substituted or unsubstituted. Exemplary
cycloalkenyl groups include, without limitation, cyclopentenyl,
cyclohexenyl, and cyclooctenyl.
[0142] The term "cycloalkynyl" refers to cyclic or polycyclic
hydrocarbon groups of from 5 to 13 carbon atoms containing one or
more triple bonds. Cycloalkynyl groups may be substituted or
unsubstituted.
[0143] The term "heteroalkyl" means a branched or unbranched alkyl,
alkenyl, or alkynyl group having from 1 to 14 carbon atoms in
addition to 1, 2, 3 or 4 heteroatoms independently selected from
the group consisting of N, O, S, and P. Heteroalkyls include,
without limitation, tertiary amines, secondary amines, ethers,
thioethers, amides, thioamides, carbamates, thiocarbamates,
hydrazones, imines, phosphodiesters, phosphoramidates,
sulfonamides, and disulfides. A heteroalkyl may optionally include
monocyclic, bicyclic, or tricyclic rings, in which each ring
desirably has three to six members. The heteroalkyl group may be
substituted or unsubstituted. Examples of heteroalkyls include,
without limitation, polyethers, such as methoxymethyl and
ethoxyethyl.
[0144] As used herein, "heterocyclic ring" and "heterocyclyl" refer
to non-aromatic ring systems having five to fourteen ring atoms in
which one or more ring carbons, preferably one to four, are each
replaced by a heteroatom such as N, O, S, or P, which may be used
alone or as part of a larger moiety as in "heterocyclyl-alkyl" (a
heterocyclyl-substituted C.sub.1-6 alkyl), "heterocyclyl-alkoxy" (a
heterocyclyl-substituted C.sub.1-6 alkoxy), or
"heterocycloxy-alkyl" (a heterocycloxy-substituted C.sub.1-6
alkyl), and includes aralkyl, aralkoxy, and aryloxyalkyl groups.
Heterocyclic rings may be substituted or unsubstituted and may
include one, two, or three fused or unfused ring systems.
Desirably, the heterocyclic ring is a 5- to 7-membered monocyclic
or 7- to 14-membered bicyclic heterocyclic ring consisting of 2 to
6 carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected
from N, O, and S and including any bicyclic group in which any of
the above-defined heterocyclic rings is fused to a benzene ring.
Exemplary heterocyclic rings include, without limitation,
3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,
3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl,
4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl,
4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl,
N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,
benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl,
and benzothianyl. A heterocyclyl group can include two or more of
the ring systems listed above. Heterocyclic rings include those in
which a non-aromatic heteroatom-containing ring is fused to one or
more aromatic or non-aromatic rings, such as in an indolinyl,
chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the
radical or point of attachment is on the non-aromatic
heteroatom-containing ring.
[0145] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl" (an aryl-substituted C.sub.1-6 alkyl), "aralkoxy" (an
aryl-substituted C.sub.1-6 alkoxy), or "aryloxyalkyl" (an
aryloxy-substituted C.sub.1-6 alkyl), refers to aromatic monocyclic
or polycyclic ring groups having six to fourteen ring atoms, such
as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, and 2-anthracyl and
includes aralkyl, aralkoxy, and aryloxyalkyl groups. An "aryl" ring
may be substituted or unsubstituted. The term "aryl" includes fused
polycyclic aromatic ring systems in which an aromatic ring is fused
to one or more rings. Non-limiting examples of aryl groups include
phenyl, hydroxyphenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl,
trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl,
anthryl, phenanthro, 1-naphthyl, 2-naphthyl, 1-anthracyl, and
2-anthracyl. Also included within the scope of the term "aryl", as
it is used herein, is a group in which an aromatic ring is fused to
one or more non-aromatic rings, such as in a indanyl,
phenanthridinyl, or tetrahydronaphthyl, where the radical or point
of attachment is on the aromatic ring.
[0146] The term "heteroaryl" as used herein refers to stable
heterocyclic, and polyheterocyclic aromatic moieties having 5-14
ring atoms. Heteroaryl groups may be substituted or unsubstituted
and include both monocyclic and polycyclic ring systems. Examples
of typical heteroaryl rings include 5-membered monocyclic rings,
such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl,
isothiazolyl, furazanyl, isoxazolyl, and thiazolyl; 6-membered
monocyclic rings, such as pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, and triazinyl; and polycyclic heterocyclic rings, such
as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,
isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
benzothiazole, benzimidazole, tetrahydroquinoline cinnolinyl,
pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl,
phenothiazinyl, and phenoxazinyl (see e.g. Katritzky, Handbook of
Heterocyclic Chemistry). Exemplary heteroaryl rings include,
without limitation, 2-furanyl, 3-furanyl, N-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl,
4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl,
2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,
4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl,
5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,
3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,
indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,
benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, and
benzoisoxazolyl. Heteroaryl groups further include a group in which
a heteroaromatic ring is fused to one or more aromatic or
nonaromatic rings where the radical or point of attachment is on
the heteroaromatic ring, such as tetrahydroquinoline,
tetrahydroisoquinoline, and pyrido[3,4-d]pyrimidinyl,
imidazo[1,2-a]pyrimidyl, imidazo[1,2-a]pyrazinyl,
imidazo[1,2-a]pyiridinyl, imidazo[1,2-c]pyrimidyl,
pyrazolo[1,5-a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidyl,
imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidyl,
pyrazolo[1,5-b][1,2,4]triazine, quinolyl, isoquinolyl, quinoxalyl,
imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl, triazolopyrimidyl, and
pyridopyrazinyl.
[0147] An aryl group or heteroaryl group may contain one or more
substituents. Exemplary substituents for aryl or heteroaryl group
include halogen (F, Cl, Br or I), alkyl, alkenyl, alkynyl,
heteroalkyl, --NO.sub.2, --CN, --R.sup.A, --OR.sup.B,
--S(O).sub.rR.sup.B, (wherein r is 0, 1 or 2),
--SO.sub.2NR.sup.AR.sup.B, --NR.sup.AR.sup.B, --O--NR.sup.AR.sup.B,
--NR.sup.A--NR.sup.AR.sup.B, --(CO)YR.sup.B, --O(CO)YR.sup.B,
--NR.sup.A(CO)YR.sup.B, --S(CO)YR.sup.B,
--NR.sup.AC(.dbd.S)YR.sup.B, --OC(.dbd.S)YR.sup.B,
--C(.dbd.S)YR.sup.B, --YC(.dbd.NR.sup.A)YR.sup.B,
--YC(.dbd.N--OR.sup.A)YR.sup.B,
--YC(.dbd.N--NR.sup.AR.sup.B)YR.sup.B, --COCOR.sup.B,
--COMCOR.sup.B (where M is a C.sub.1-6 alkyl group),
--YP(O)(YR.sup.C)(YR.sup.C), --P(O)(R.sup.C).sub.2,
--Si(R.sup.C).sub.3, --NR.sup.ASO.sub.2R.sup.B, and
--NR.sup.ASO.sub.2NR.sup.AR.sup.B, wherein each occurrence of Y is,
independently, --O--, --S--, --NR.sup.A--, or a chemical bond
(i.e., --(CO)YR.sup.B thus encompasses --C(.dbd.O)R.sup.B,
--C(.dbd.O)OR.sup.B, and --C(.dbd.O)NR.sup.AR.sup.B).
[0148] R.sup.C is selected from alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and
heterocyclyl. At each occurrence, each of R.sup.A and R.sup.B is,
independently, selected from hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and
heterocyclyl.
[0149] Each of R.sup.A, R.sup.B and R.sup.C optionally bears one or
more substituents selected from amino, alkylamino, dialkylamino,
aminocarbonyl, halogen, alkyl, aryl, heteroalkyl, heteroaryl,
carbocycle, heterocycle, alkylaminocarbonyl, dial kylaminocarbonyl,
alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano,
carboxy, alkoxycarbonyl, alkylcarbonyl, alkoxy, haloalkoxy groups,
hydroxy, protected hydroxyl groups (e.g., --O--X, where X is acyl,
phenyl, substituted phenyl, benzyl, substituted benzyl, phenethyl,
or substituted phenethyl), -M-heteroaryl, -M-heterocycle, -M-aryl,
-M-OR.sup.B, -M-SR.sup.B, -M-NR.sup.AR.sup.B,
-M-OC(O)NR.sup.AR.sup.B, -M-C(.dbd.NR.sup.B)NR.sup.AR.sup.B,
-M-C(.dbd.NR.sup.A)OR.sup.B, -M-P(.dbd.O)(R.sup.C)2,
Si(R.sup.C).sub.3, -M-NR.sup.AC(O)R.sup.B, -M-NR.sup.AC(O)OR.sup.B,
-M-C(O)R.sup.B, -M-C(.dbd.S)R.sup.B, -M-C(.dbd.S)NR.sup.AR.sup.B,
-M-C(O)NR.sup.AR.sup.B, -M-C(O)NR.sup.B-M-NR.sup.AR.sup.B,
-M-NR.sup.BC(NR.sup.A)NR.sup.AR.sup.B,
-M-NR.sup.AC(S)NR.sup.AR.sup.B, -M-S(O).sub.2R.sup.A, -M-C(O)
R.sup.A, -M-OC(O) R.sup.A, -MC(O)SR.sup.B,
-M-S(O).sub.2NR.sup.AR.sup.B, --C(O)-M-C(O)R.sup.B, -MCO.sub.2RB,
-MC(.dbd.O)NR.sup.AR.sup.B, -M-C(.dbd.NH)NR.sup.AR.sup.B, and
-M-OC(.dbd.NH)NR.sup.AR.sup.B, wherein M is a C.sub.1-6 alkyl
group. Non-limiting illustrations of a substituted R.sup.A, R.sup.B
or R.sup.C group include haloalkyl and trihaloalkyl, alkoxyalkyl,
halophenyl, chloromethyl, trichloromethyl, trifluoromethyl,
methoxyethyl, alkoxyphenyl, halophenyl, --CH.sub.2-aryl,
--CH.sub.2-heterocycle, --CH.sub.2C(O)NH.sub.2,
--C(O)CH.sub.2N(CH.sub.3).sub.2, --CH.sub.2CH.sub.2OH,
--CH.sub.2OC(O)NH.sub.2, --CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NEt.sub.2, --CH.sub.2OCH.sub.3,
--C(O)NH.sub.2, --CH.sub.2CH.sub.2-heterocycle,
--C(.dbd.S)CH.sub.3, --C(.dbd.S)NH.sub.2, --C(.dbd.NH)NH.sub.2,
--C(.dbd.NH)OEt, --C(O)NH-cyclopropyl,
--C(O)NHCH.sub.2CH.sub.2-heterocycle,
--C(O)NHCH.sub.2CH.sub.2OCH.sub.3,
--C(O)CH.sub.2CH.sub.2NHCH.sub.3, --CH.sub.2CH.sub.2F,
--C(O)CH.sub.2-heterocycle, --CH.sub.2C(O)NHCH.sub.3,
--CH.sub.2CH.sub.2P(.dbd.O)(CH.sub.3).sub.2, and
--Si(CH.sub.3).sub.3.
[0150] An alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, heteroalkyl,
cycloalkyl, cycloalkenyl, cycloalkynyl, or heterocyclic group may
contain one or more substituents selected from those listed above
for aryl and heteroaryl groups, in addition to .dbd.O, .dbd.S,
.dbd.NH, .dbd.NNR.sup.AR.sup.B, .dbd.NNHC(O)R.sup.B,
.dbd.NNHCO.sub.2RB, or .dbd.NNHSO.sub.2RB, wherein R.sup.A and
R.sup.B are as defined above.
[0151] In drawings of chemical structures in this document, atoms
not indicated by label or line are understood to be H.
[0152] Other features and advantages of the invention will be
apparent from the following detailed description and the
claims.
EGFR Mutants
[0153] The EGFR-driven cancers which can be treated using the
compositions and method of the invention include, for example, EGFR
mutants including one or more deletions, substitutions, or
additions in the amino acid or nucleotide sequences of EGFR, or
fragments thereof.
[0154] Mutations in EGFR can occur in any part of the EGFR
sequence. Generally, EGFR mutants arise from mutations in the
kinase domain (i.e., exons 18-24 in the EGFR sequence) or in the
extracellular domain (i.e., exons 2-16 in the EGFR sequence). For
example, mutations typically occur in the kinase domain, including
one or more of a point mutation in exon 18 (e.g., L688P, V689M,
P694L/S, N700D, L703V, E709K/Q/A/GN, 1715S, L718P, G719C/A/S/R, or
S720P/F), a deletion in exon 19 that may or may not include an
insertion (e.g., delG719, delE746_E749, delE746_A750,
delE746_A750insRP, delE746_A750insQP, delE746_T751,
delE746_T751insA/I/V, delE746_T751insVA, delE746_S752,
delE746_S752insAN/D, delE746_P53insLS, delL747_E749, delL747_A750,
delL747_A750insP, delL747_T751, delL747_T751 insP/S/Q, delL747_T751
insPI, delL747_S752, delL747_S752insQ, delL747_P753,
delL747_P753insS/Q, delL747_L754insSR, delE749_A750,
delE749_A750insRP, delE749_T751, delT751.sub.--1759,
delT751.sub.--1759insS/N, or delS752.sub.--1759), a duplication in
exon 19 (e.g., K739.sub.--144dupKIPVAI), a point mutation in exon
19 (e.g., L730F, W731Stop, P733L, G735S, V742A, E746V/K, A750P,
T7511, S752Y, P753S, A754P, or D761Y), an in-frame insertion in
exon 20 (e.g., D761_E762insEAFQ, A767_S768insTLA, V769_D770insY,
V769_D770insCV, V769_D770insASV, D770_N771insD/G, D770_N771insNPG,
D770_N771insSVQ, P772_H773insNN, P772_H773insYNP, or
V774_C775insHV), a deletion in exon 20 that may or may not include
an insertion (e.g., delM766_A767, delM766_A767insAI, delA767_V769,
delD770, or delP772_H773insNP), a duplication in exon 20 (e.g.,
S768_D770dupSVD, A767_V769dupASV, or H773dupH), a point mutation in
exon 20 (e.g., D761N, A763V, V765A/M, S7681, V769L/M, S7681, P772R,
N771T, H773R/Y/L, V774M, R776G/H/C, G779S/F, T783A, T784F, L792P,
L798H/F, T790M, R803W, K806E, or L814P), or a point mutation in
exon 21 (e.g., G810S, N826S, L833V, H835L, L838V, A839T, K846R,
T8471, H850N, V8511/A, 1853T, L858M/R, A859T, L861Q/R, G863D,
A864T, E866K, or G873E). In lung cancer, activation mutants are
typical, and 90% deletion of 746-750 (ELREA) and L858R result in
sustained phosphorylation of EGFR without ligand stimulation. In
particular, drug resistance in 50% of lung cancers arises from the
T790M point mutation.
[0155] For example, in glioblastoma, mutations typically, but not
exclusively, occur in the extracellular domain, including EGFR
variant I (EGFRvI) lacking the extracellular domain and resembling
the v-erbB oncoprotein; EGFRvII lacking 83 amino acids from domain
IV; and EGFRvIII lacking amino acids 30-297 from domains I and II,
which is the most common amplification and is reported in 30-50% of
glioblastomas and 5% of squamous cell carcinoma. Other mutations
for glioblastoma include one or more of point mutations in exon 2
(e.g., D46N or G63R), exon 3 (e.g., R108K in domain I), exon 7
(e.g., T263P or A289D/TN in domain II), exon 8 (e.g., R324L or
E330K), exon 15 (e.g., P596L or G598V in domain IV), or exon 21
(L861Q in the kinase domain).
[0156] EGFR mutants also include those with a combination of two or
more mutations, as described herein. Exemplary combinations include
S7681 and G719A; S7681 and V769L; H773R and W731Stop; R776G and
L858R; R776H and L861Q; T790M and L858R; T790M and delE746_A750;
R803W and delE746_T751insVA; delL747_E749 and A750P; delL747_S752
and E746V; delL747_S752 and P753S; P772_H773insYNP and H773Y;
P772_H773insNP and H773Y; and D770_N771insG and N771T. Other
exemplary combinations include any including T790M (e.g., T790M and
L858R or T790M and delE746_A750, with or without concomitant
inhibition of single mutants L858R and delE746_A750).
[0157] EGFR mutants can be either activation mutants or resistant
mutants. Activation mutants include those with substitutions that
increase drug sensitivity (e.g., G719C/S/A, delE746_A750, or
L858R). Resistant mutants include those with substitutions that
increase drug resistance (e.g., T790M or any combination including
T790M).
[0158] EGFR-driven cancers include those having any mutant
described herein. For example, EGFRvIII is commonly found in
glioblastoma and has also been reported in breast, ovarian,
prostate, and lung carcinomas. Exemplary EGFR-driven cancers:
glioblastoma, lung cancer (e.g., squamous cell carcinoma, non-small
cell lung cancer, adenocarcinoma, bronchioloalveolar carcinoma
(BAC), BAC with focal invasion, adenocarcinoma with BAC features,
and large cell carcinoma), pancreatic cancer, head and neck cancers
(e.g., squamous cell carcinoma), breast cancer, colorectal cancer,
epithelial cancer (e.g., squamous cell carcinoma), ovarian cancer,
and prostate cancer.
[0159] In particular, the invention described herein would benefit
patient populations having higher risk for TKI-resistant mutations.
About 8,000 to 16,000 new cases per year can be estimated based on:
incidence of non-small cell lung cancer (about 160,000 new cases in
the U.S.), the response to erlonitinib in the general population
(about 10%, resulting in a sensitive population of 16,000), the
presence of activation mutations (10-20% in white and 30-40% in
Asian population, resulting in a sensitive population of
16,000-32,000), acquisition of secondary resistance (most if not
all patients, resulting in a sensitive population of
16,000-32,000), and percentage of patients carrying the T790M point
mutations (about 50%, resulting in a sensitive population of
8,000-16,000). Patients having TKI-resistant mutations include
those patients having cancers resistant to one or more of
erlotinib, gefitinib, CL-387,785, BIBW 2992 (CAS Reg. No.
439081-18-2), Cl-1033, neratinib (HKI-272), MP-412 (AV-412),
PF-299804, AEE78, and XL64.
[0160] In particular, the inventions relates to treatment of
EGFR-driven cancers having the T790M point mutation. Generally,
reversible inhibitors (e.g., C1-1033, neratinib (HKI-272), and
PF-299804) are less potent in cell lines having the T790M mutation
and do not inhibit T790M at clinically achievable concentrations.
Since the ATP Km of T790M and WT are similar, concentrations that
inhibit the mutant will inhibit the WT and result in
gastrointestinal and cutaneous events.
[0161] An EGFR mutant also includes other amino acid and nucleotide
sequences of EGFR with one or more deletions, substitutions, or
additions, such as point mutations, that retain or increase
tyrosine kinase or phosphorylation activity. Where the mutant is a
protein or polypeptide, preferable substitutions are conservative
substitutions, which are substitutions between amino acids similar
in properties such as structural, electric, polar, or hydrophobic
properties. For example, the substitution can be conducted between
basic amino acids (e.g., Lys, Arg, and His), or between acidic
amino acids (e.g., Asp and Glu), or between amino acids having
non-charged polar side chains (e.g., Gly, Asn, Gin, Ser, Thr, Tyr,
and Cys), or between amino acids having hydrophobic side chains
(e.g., Ala, Val, Leu, Ile, Pro, Phe, and Met), or between amino
acids having branched side chains (e.g., Thr, Val, Leu, and Ile),
or between amino acids having aromatic side chains (e.g., Tyr, Trp,
Phe, and His).
[0162] Where the mutant is a nucleic acid, the DNA encoding an EGFR
mutant protein may comprise a nucleotide sequence capable of
hybridizing to a complement sequence of the nucleotide sequence
encoding an EGFR mutant, as defined herein, under stringent
conditions. As used herein, the stringent conditions include low,
medium or high stringent conditions. An example of the stringent
conditions includes hybridization at approximately 42-55.degree. C.
in approximately 2-6.times.SSC, followed by wash at approximately
50-65.degree. C. in approximately 0.1-1.times.SSC containing
approximately 0.1-0.2% SDS, where 1.times.SSC is a solution
containing 0.15 M NaCl and 0.015 M Na citrate, pH 7.0. Wash can be
performed once or more. In general, stringent conditions may be set
at a temperature approximately 5.degree. C. lower than a melting
temperature (Tm) of a specific nucleotide sequence at defined ionic
strength and pH.
[0163] The amino acid and nucleotide sequences of EGFR and DNAs
encoding them are available from known databases such as NCBI
GenBank (USA), EMBL (Europe), etc. For example, GenBank accession
numbers for EGFR [Homo sapiens] include MIM131550, AA128420,
NM.sub.--005228, NP.sub.--005219.2, and GeneID: 1956.
Characterization of EGFR-Driven Cancers
[0164] The compositions and methods of the invention can be used to
treat subjects having an EGFR-driven cancer (i.e., cancers
characterized by EGFR mutant expression or overexpression). EGFR
mutant expression or overexpression can be determined in a
diagnostic or prognostic assay by evaluating levels of EGFR mutants
in biological sample, or secreted by the cell (e.g., via an
immunohistochemistry assay using anti-EGFR antibodies or
anti-p-EGFR antibodies; FACS analysis, etc.). Alternatively, or
additionally, one can measure levels of EGFR mutant-encoding
nucleic acid or mRNA in the cell, e.g., via fluorescent in situ
hybridization using a nucleic acid based probe corresponding to an
EGFR mutant-encoding nucleic acid or the complement thereof; (FISH;
see WO98/45479, published October, 1998), Southern blotting,
Northern blotting, or polymerase chain reaction (PCR) techniques,
such as real time quantitative PCR (RT-PCR). One can also study
EGFR mutant expression by measuring shed antigen in a biological
sample, such as serum, e.g., using antibody-based assays (see also,
e.g., U.S. Pat. No. 4,933,294, issued Jun. 12, 1990; WO91/05264,
published Apr. 18, 1991; U.S. Pat. No. 5,401,638, issued Mar. 28,
1995; and Sias et al., J. Immunol. Methods 132:73 (1990)). Aside
from the above assays, various in vivo assays are available to the
skilled practitioner. For example, one can expose cells within the
body of the mammal to an antibody which is optionally labeled with
a detectable label, e.g., a radioactive isotope, and binding of the
antibody to cells in the mammal can be evaluated, e.g., by external
scanning for radioactivity or by analyzing a biopsy taken from a
mammal previously exposed to the antibody.
[0165] Examples of biological properties that can be measured in
isolated cells include mRNA expression, protein expression, and DNA
quantification. Additionally, the DNA of cells isolated by the
methods of the invention can be sequenced, or certain sequence
characteristics (e.g., polymorphisms and chromosomal abnormalities)
can be identified using standard techniques, e.g., FISH or PCR. The
chemical components of cells, and other analytes, may also be
assayed after isolation. Cells may also be assayed without lysis,
e.g., using extracellular or intracellular stains or by other
observation, e.g., morphology or growth characteristics in various
media.
[0166] While any hybridization technique can be used to detect the
gene rearrangements, one preferred technique is fluorescent in situ
hybridization (FISH). FISH is a cytogenetic technique which can be
used to detect and localize the presence or absence of specific DNA
or RNA sequences on chromosomes. FISH incorporates the use of
fluorescently labeled nucleic acid probes which bind only to those
parts of the chromosome with which they show a high degree of
sequence similarity.
[0167] Fluorescence microscopy can be used to find out where the
fluorescent probe bound to the chromosome. The basic steps of FISH
are outlined below. Exemplary FISH probes include Vysis EGFR
SpectrumOrangel CEP SpectrumGreen Probe (Abbott, Downers Grove,
Ill.), which hybridizes to band 7p12; and ZytoLight SPEC EGFR/CEN 7
Dual Color Probe (ZytoVision), which hybridizes to the
alpha-satellite sequences of the centromere of chromosome 7.
[0168] For FISH, a probe is constructed that is long enough to
hybridize specifically to its target (and not to similar sequences
in the genome), but not too large to impede the hybridization
process. Probes are generally labeled with fluorophores, with
targets for antibodies, with biotin, or any combination thereof.
This can be done in various ways, for example using random priming,
nick translation, and PCR using tagged nucleotides.
[0169] Generally, a sample or aliquot of a population of cells is
used for FISH analysis. For example, in one method of preparation,
cells are trypsinized to disperse into single cells, cytospun onto
glass slides, and then fixed with paraformaldehyde before storing
in 70% ethanol. For preparation of the chromosomes for FISH, the
chromosomes are firmly attached to a substrate, usually glass.
After preparation, the probe is applied to the chromosome RNA and
starts to hybridize. In several wash steps, all unhybridized or
partially hybridized probes are washed away. If signal
amplification is necessary to exceed the detection threshold of the
microscope (which depends on many factors such as probe labeling
efficiency, the kind of probe, and the fluorescent dye),
fluorescent tagged antibodies or strepavidin are bound to the tag
molecules, thus amplifying the fluorescence.
[0170] An epifluorescence microscope can be used for observation of
the hybridized sequences. The white light of the source lamp is
filtered so that only the relevant wavelengths for excitation of
the fluorescent molecules arrive onto the sample. Emission of the
fluorochromes happens, in general, at larger wavelengths, which
allows one to distinguish between excitation and emission light by
mean of another optical filter. With a more sophisticated filter
set, it is possible to distinguish between several excitation and
emission bands, and thus between several fluorochromes, which
allows observation of many different probes on the same strand.
[0171] Depending on the probes used, FISH can have resolution
ranging from huge chromosomes or tiny (.about.100 kilobase)
sequences. The probes can be quantified simply by counting dots or
comparing color.
[0172] Allele-specific quantitative real time-PCR may also be used
to identify a nucleic acid encoding a mutant EGFR protein (see, for
e.g., Diagnostic Innovations DxS BCR-ABL T3151 Mutation Test Kit,
and Singer et al., Methods in Molec. Biol. 181:145 (2001)). This
technique utilizes Taq DNA polymerase, which is extremely effective
at distinguishing between a match and a mismatch at the 3'-end of
the primer (when the 3'-base is mismatched, no efficient
amplification occurs). Using this technique, the 3'-end of the
primer may be designed to specifically hybridize to a nucleic acid
sequence that corresponds to a codon that encodes a mutant amino
acid in an EGFR mutant, as described herein. In this way, the
specific mutated sequences can be selectively amplified in a
patient sample. This technique further utilizes a Scorpion probe
molecule, which is a bifunctional molecule containing a PCR primer,
a fluorophore, and a quencher. The fluorophore in the probe
interacts with a quencher, which reduces fluorescence. During a PCR
reaction, when the Scorpion probe binds to the amplicon, the
fluorophore and quencher in the Scorpion probe become separated,
which leads to an increase in fluorescence from the reaction tube.
Any of the primers described herein may be used in allele-specific
quantitative real time PCR.
[0173] A biological sample can be analyzed to detect a mutation in
an EGFR gene, or expression levels of an EGFR gene, by methods that
are known in the art. For example, methods such as direct nucleic
acid sequencing, altered hybridization, aberrant electrophoretic
gel migration, binding or cleavage mediated by mismatch binding
proteins, single-strand conformational polymorphism (SSCP)
analysis, or restriction fragment length polymorphism (RFLP)
analysis of PCR products derived from a patient sample can be used
to detect a mutation in an EGFR gene; ELISA can be used to measure
levels of EGFR polypeptide; and PCR can be used to measure the
level of an EGFR nucleic acid molecule.
[0174] Any of these techniques may be used to facilitate detection
of a mutation in a candidate gene, and each is well known in the
art; examples of particular techniques are described, without
limitation, in Orita et al. (Proc. Natl. Acad. Sci. USA 86:2766
(1989)) and Sheffield et al. (Proc. Natl. Acad. Sci. USA 86:232
(1989)). Furthermore, expression of the candidate gene in a
biological sample (e.g., a biopsy) may be monitored by standard
Northern blot analysis or may be aided by PCR (see, e.g., Ausubel
et al., Current Protocols in Molecular Biology, John Wiley &
Sons, New York, N.Y. (1995); PCR Technology: Principles and
Applications for DNA Amplification, H. A. Ehrlich, Ed., Stockton
Press, NY; Yap et al., Nucl. Acids. Res. 19:4294 (1991)).
[0175] One skilled in the art may identify in a nucleic acid or
protein sequence a residue (e.g., amino acid or nucleotide) or
codon that corresponds to a residue or codon in wild-type EGFR or
EGFR mutants using a number of sequence alignment software programs
(e.g., NCBI BLAST website). Such software programs may allow for
gaps in the alignment of the compared sequences. Using such
software, one skilled in the art may identify a nucleotide, amino
acid, or amino acid that corresponding to a specific nucleotide,
amino acid, or codon in wild-type EGFR or EGFR mutants.
[0176] Levels of EGFR expression (e.g., DNA, mRNA, or protein) in a
biological sample can be determined by using any of a number of
standard techniques that are well known in the art or described
herein. Exemplary biological samples include plasma, blood, sputum,
pleural effusion, bronchoalveolar lavage, or biopsy, such as a lung
biopsy and lymph node biopsy. For example, EGFR expression in a
biological sample (e.g., a blood or tissue sample) from a patient
can be monitored by standard northern blot analysis or by
quantitative PCR (see, e.g., Ausubel et al., supra; PCR Technology:
Principles and Applications for DNA Amplification, H. A. Ehrlich,
Ed., Stockton Press, NY; Yap et al., Nucl. Acids. Res. 19:4294
(1991)).
Synthesis
[0177] Compounds of Formula (I) can be prepared using methods and
materials analogous to those described in the art, e.g., as
disclosed in detail in International patent applications WO
2004/080980, WO 2005/016894, WO 2006/021454, WO 2006/021457, WO
2009/143389, and WO 2009/126515. For instance, compounds of Formula
(I) in which R.sup.e is H and R.sup.d is H, Cl, CF.sub.3, or
CH.sub.3, can be synthesized from 2,4-dichloropyrimidine,
2,4,5-trichloropyrimidine,
2,4-dichloro-5-(trifluoromethyl)pyrimidine, or
2,4-dichloro-5-methylpyrimidine, respectively, as described in PCT
Publication No. WO/2009/143389.
[0178] Compounds of Formula (I) in which R.sup.d and R.sup.e,
together with the pyrimidine ring atoms to which they are attached,
form a 5- or 6-membered ring containing one or two heteroatoms can
be synthesized as described in PCT Publication No.
WO2009/126515.
[0179] Compounds of Formula (I) in which U.sup.1 and U.sup.2 are N
can be synthesized, for example, using methods analogous to those
described in Scheme A1.
##STR00033##
[0180] Compounds of Formula (I) in which U.sup.3 is N, one of
U.sup.1 and U.sup.2 is N, and the other is C--R.sup.d can be
synthesized, for example, using methods analogous to those
described in Scheme A2.
##STR00034## ##STR00035##
[0181] Further details are provided in the Examples.
Formulation
[0182] Compounds of Formula I can be Formulated into a
pharmaceutical composition that comprises a compound of Formula I
(as an active pharmaceutical ingredient) or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable
excipient. As such, the present disclosure provides a
pharmaceutical composition comprising a compound of Formula I or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable excipient.
[0183] Pharmaceutically acceptable compositions containing a
compound of Formula I suitable for administration may be Formulated
using conventional materials and methods, a wide variety of which
are well known. Suitable dosage forms include those in solution,
suspension or emulsion form, and solid oral dosage forms such as
capsules, tablets, gel caps, caplets, etc. Methods well known in
the art for making Formulations, including the foregoing unit
dosage forms, are found, for example, in "Remington: The Science
and Practice of Pharmacy" (20th ed., ed. A. R. Gennaro, 2000,
Lippincott Williams & Wilkins).
[0184] Compounds of Formula (I) can be Formulated for any route of
administration (e.g., orally, rectally, parenterally,
intracisternally, intravaginally, intraperitoneally, topically (as
by transdermal patch, powders, ointments, or drops), sublingually,
bucally, as an oral or nasal spray) effective for use in the
methods of the invention. For use in the methods of the invention,
compounds of Formula (I) are preferably Formulated in dosage unit
form for ease of administration and uniformity of dosage. For
example, a compound of Formula (I) can be Formulated for as a
capsule for oral administration containing nominally 10 mg, 50 mg,
100 mg, 150 mg, 250 mg, 500 mg, or any dosage amounts described
herein as the free base or acid addition salt of the compound
(e.g., the hydrochloride salt). The unit dosage forms of the
invention can include a compound of the invention, or a salt
thereof, Formulated with excipients, fillers, flow enhancers,
lubricants, and/or disintegrants as needed. For example, a unit
dosage form can include colloidal silicon dioxide (a flow
enhancer), lactose anhydrous (a filler), magnesium stearate (a
lubricant), microcrystalline cellulose (a filler), and/or sodium
starch glycolate (a disintegrant). The compound of the invention
and the inactive ingredients can be Formulated utilizing, for
example, conventional blending, and encapsulation processes.
Alternatively, compounds of Formula (I) are Formulated as described
in PCT Publication Nos. WO2009/143389 and WO2009/126515.
Therapy
[0185] Compounds of Formula (I) can be useful for treating
EGFR-driven cancers. In particular, the compounds can be useful for
treating EGFR-driven cancers that express EGFR mutants and for
treating EGFR-driven cancers that are refractory to TKI therapies
(e.g., erlotinib or gefitinib).
[0186] Such cancers can include, among others, non-small cell lung
cancer (NSCLS), including one or more of squamous cell carcinoma,
adenocarcinoma, adenocarcinoma, bronchioloalveolar carcinoma (BAC),
BAC with focal invasion, adenocarcinoma with BAC features, and
large cell carcinoma; neural tumors, such as glioblastomas;
pancreatic cancer; head and neck cancers (e.g., squamous cell
carcinoma); breast cancer; colorectal cancer; epithelial cancer,
including squamous cell carcinoma; ovarian cancer; prostate cancer;
adenocarcinomas; and including cancers which are EGFR mediated.
[0187] The present invention is based upon the discovery that
compounds of Formula (I) can be used to treat EGFR-driven cancers,
EGFR-driven cancers that express EGFR mutants, and for treating
EGFR-driven cancers that are refractory to TKI therapy, such as
erlotinib or gefitinib. Compounds of Formula (I) can also be used
in a maintenance role to prevent recurrence of cancer in patients
in need of such a treatment.
[0188] The effective systemic dose of a compound of Formula (I)
will typically be in the range of an average daily dose of from 10
mg to 2,000 mg of the compound per kg of patient body weight,
administered in single or multiple doses. Generally, a compound of
the invention may be administered to patients in need of such
treatment in a daily dose range of about 50 to about 2,000 mg per
patient. Administration may be once or multiple times daily, weekly
(or at some other multiple-day interval) or on an intermittent
schedule. For example, the compound may be administered one or more
times per day on a weekly basis (e.g. every Monday) indefinitely or
for a period of weeks, e.g. 4-10 weeks. Alternatively, it may be
administered daily for a period of days (e.g. 2-10 days) followed
by a period of days (e.g. 1-30 days) without administration of the
compound, with that cycle repeated indefinitely or for a given
number of repetitions, e.g. 4-10 cycles. As an example, a compound
of the invention may be administered daily for 5 days, then
discontinued for 9 days, then administered daily for another 5 day
period, then discontinued for 9 days, and so on, repeating the
cycle indefinitely, or for a total of 4-10 times.
[0189] When a TKI (e.g., erlotinib or gefitinib) is used in
combination with a compound of Formula (I), each component of the
combination therapy may be administered at their monotherapy dosing
levels and schedules. For example, erlotinib has been administered
orally for the treatment of NSCLC at 150 mg daily and of pancreatic
cancer at 100 mg daily. In another example, gefitinib has been
administered orally for the treatment of NSCLC at 250 mg daily.
[0190] The effective systemic dose of a compound of the invention
will typically be in the range of an average daily dose of from 10
mg to 2,000 mg of the compound per kg of patient body weight,
administered in single or multiple doses. Generally, a compound of
the invention may be administered to patients in need of such
treatment in a daily dose range of about 50 to about 2,000 mg per
patient. Administration may be once or multiple times daily, weekly
(or at some other multiple-day interval) or on an intermittent
schedule. For example, the compound may be administered one or more
times per day on a weekly basis (e.g. every Monday) indefinitely or
for a period of weeks, e.g. 4-10 weeks. Alternatively, it may be
administered daily for a period of days (e.g. 2-10 days) followed
by a period of days (e.g. 1-30 days) without administration of the
compound, with that cycle repeated indefinitely or for a given
number of repititions, e.g. 4-10 cycles. As an example, a compound
of the invention may be administered daily for 5 days, then
discontinued for 9 days, then administered daily for another 5 day
period, then discontinued for 9 days, and so on, repeating the
cycle indefinitely, or for a total of 4-10 times.
[0191] Alternatively, a TKI (e.g., erlotinib or gefitinib) is used
in combination with a compound of Formula (I) with a reduced dosing
level in one or both components.
[0192] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the methods and compounds claimed herein are
performed, made, and evaluated, and are intended to be purely
exemplary of the invention and are not intended to limit the scope
of what the inventors regard as their invention.
##STR00036##
[0193] Step 1: Synthesis of Compound 1
##STR00037##
[0194] To a solution of 2-iodoaniline (1.0 eq) and
dimethylphosphine oxide (1.1 eq) in DMF were added potassium
phosphate (1.1 eq) and palladium acetate/Xantphos (catalytic). The
reaction was stirred at 150.degree. C. for 3 hours and cooled to
room temperature. The solvent was evaporated and the residue was
worked up with DCM/water. The crude product was purified with a
column (EtOAc/MeOH 10:1) to give 1 as a brown solid (80%
yield).
[0195] Step 2: Synthesis of 2:
##STR00038##
[0196] 2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and
potassium carbonate (3.14 eq) in DMF were stirred at 60.degree. C.
for 5 hours and then cooled to room temperature. The mixture was
filtered and the filtrate was concentrated. The residue was
purified by column chromatography (ISCO machine) (DCM/MeOH 20:1) to
give 2 as a yellow solid (61% yield).
[0197] Step 2a: Synthesis of 8 and 3:
##STR00039##
[0198] A suspension of 10 g (59.5 mmol, 1.0 eq) of
4-methoxy-3-nitroaniline in 65 mL of dioxane and 65 mL of water was
adjusted to pH 12 with 40% NaOH, and then Boc.sub.2O (26 g, 119.1
mmol, 2.0 eq) was added in 3 portions under ice bath. The reaction
was stirred at room temperature overnight. After standing, the
mixture was filtered to give a yellow solid, 15 g, in 95%
yield.
[0199] Compound 8 (6 g, 22.4 mmol) was dissolved in 55 mL of ethyl
acetate and Pd/C (10%, wet, 0.5 g) was added. The reduction was
shaken at room temperature under H.sub.2 (30 psi) for 1 hr and
filtered. The filtrate was evaporated to a tan solid, 5.4 g, in a
quantitative yield.
[0200] Step 3: Synthesis of 4:
##STR00040##
[0201] A suspension of 2(1.27 g, 4.0 mmol),
3-Boc-amino-5-methoxyaniline (965 mg, 4.0 mmol), palladium acetate
(133 mg, 0.59 mmol), XantPhos (352 mg, 0.61 mmol) and potassium
phosphate (1.4 g, 6.6 mmol) in anhydrous DMF (35 mL) was heated at
120.degree. C. overnight. After the reaction was cooling to room
temperature, ethyl acetate was added to dilute the reaction and the
content was filtered through celite. Solvent was removed under
vacuum. The residue was purified by flash column chromatography on
silica gel to give pure product 1.3 g (yield 62%) as a tan
solid.
[0202] Step 4: Synthesis of 5:
##STR00041##
[0203] HCl/dioxane (4N, 4 mL) was added to a solution of compound 4
(440 mg, 0.85 mmol) in MeOH (4 mL). The reaction mixture was
stirred at room temp overnight. White precipitate was filtered and
dried to give the title product as a white solid (339 mg, Yield
81%).
[0204] Step 5: Synthesis of 6:
##STR00042##
[0205] Compound 5 (100 mg, 0.15 mmol) was dissolved in
CH.sub.2Cl.sub.2 (1.6 mL) and DIEA (174 .mu.L, 1 mmol). The
solution was cooled in an ice bath. Aryloyl chloride (13ul, 0.165
mmol) was added dropwise. The content was stirred at room temp for
an hour. Solvent was removed in vacuo and the residue was purified
by a prep-TLC plate (7.5% MeOH/DCM) to give final product as a tan
solid (24 mg, yield 34%).
##STR00043## ##STR00044##
[0206] Step 1: Synthesis of 10:
##STR00045##
[0207] Compound 2 (2 g, 6.3 mmol) was dissolved in NH.sub.3/MeOH
(7N, 20 mL) in a sealed tube and the content was heated at
100.degree. C. for 3 days. The volatile was evaporated and the
residue partitioned between EtOAc/H20, the organic layer was
separated and aqueous was extracted with EtOAc(2.times.). Combined
organic dried(Na.sub.2SO.sub.4). After concentration, the residue
was column purified on Silica gel(10% MeOH/DCM) to give the product
as a white solid(1.1 g, yield 57%).
[0208] Step 2: Synthesis of 11
##STR00046##
[0209] Compound 10(908 mg, 3.0 mmol) and 2-iodo-4-nitroanisole (963
mg, 4.15 mmol) were dissolved in 25 mL anhydrous DMF in a sealed
tube and was added Pd(OAc).sub.2 (86 mg, 0.38 mmol), XantPhos (227
mg, 0.30 mmol), K.sub.3PO.sub.4 (921 mg, 4.3 mmol). The content was
heated at 120.degree. C. overnight. After cooling to the room temp,
EtOAc was added and the mixture was filtered through celite, washed
with more EtOAc. Combined filtrate was conc in vacuo, and the
residue was purified by CombiFlash(MeOH/DCM). The product (476 mg,
35.5%) was obtained as a tan solid.
[0210] Step 3: Synthesis of 12
##STR00047##
[0211] Compound 11 (476 mg, 1.1 mmol) was dissolved in THF (18
mL)/H.sub.2O (13 mL) and was added Fe(300 mg) and NH.sub.4Cl(300
mL). The mixture was heated at 65.degree. C. overnight. The liquid
was decanted and the solid residue was washed with more THF.
Combined solution was conc to give a residue. The residue was
dissolved in DCM and filtered through cotton. The solution again is
conc to give crude product 480 mg.
[0212] Step 4: Synthesis of 14
##STR00048##
[0213] Compound 12 (125.4 mg, 0.3 mmol), 4-bromocrotonoic acid (49
mg, 0.3 mmol) was dissolved in 3 mL dry DCM. EDCl(63 mg, 0.33 mmol)
was then added. The mixture was stirred at room temperature for 2
hrs. Volatiles were removed in vacuo and THF (3 mL) was added,
followed by dimethylamine/H.sub.2O solution (40%, 0.5 mL, 4.0
mmol). The mixture was stirred at room temperature for another 2
hrs. Solvent was removed in vacuo and the residue was purified by
prep-TLC (10% MeOH/DCM) to give the final product as a tan solid(48
mg, yield 30.2%).
##STR00049##
[0214] General procedures: compound 5 (100 mg, 0.15 mmol) was
dissolved in CH.sub.2Cl.sub.2 (1.6 mL) at 0.degree. C. and DIEA
(174 .mu.L, 1 mmol) was added. Acid chloride (13 .mu.l, 0.165 mmol,
1.1 eq) was added dropwise. The content was stirred at room temp
for an hour. Solvent was removed in vacuo and the residue was
purified by a prep-TLC plate(10% MeOH/DCM), the corresponding bands
were collected to give final products.
##STR00050##
##STR00051##
[0215] General procedures: compound 12 (84 mg, 0.20 mmol),
respective acid (0.27 mmol, 1.35 eq.) were dissolved in dry DMF
(2.0 mL). DCC (56 mg, 0.27 mmol, 1.35 eq) was added. The content
was stirred at room temp overnight. Solvent was removed in vacuo
and the residue was purified by a prep-TLC plate (6.5% MeOH/DCM),
the corresponding bands were collected to give final products.
##STR00052##
##STR00053##
[0216] Compound 12 (200 mg, 0.48 mmol), and NEt.sub.3 (344 .mu.L)
was dissolved in 5 mL THF at room temperature,
2-chloroethylenesulfonyl chloride (115 .mu.L, 1.1 mmol) was added
and the content was stirred at room temperature for 1 hr. The
volatile was removed in vacuo and the residue was purified on
prep-TLC (2.times.) (7.5% MeOH/DCM). The product was a tan solid
(56 mg, yield 23%).
##STR00054##
[0217] Step 1: Synthesis of 17
##STR00055##
[0218] Compound 2 (158 mg, 0.50 mmol), 1,3-diaminocyclohexane (57.1
mg, 0.5 mmol) was dissolved in methoxyethanol (1.6 mL) in a sealed
tube and HCl/EtOH (200 .mu.l) was added. The content was heated at
110.degree. C. overnight. Solvent was removed in vacuo and the
residue was purified by 2 prep-TLC plate (360 mL DCM/24 mL MeOH/12
mL 7N NH.sub.3.MeOH) to give final product as a light colored solid
(134 mg, yield 68%).
[0219] Step 2: Synthesis of 18
##STR00056##
[0220] Compound 17 (70 mg, 0.177 mmol) was dissolved in
CH.sub.2Cl.sub.2 (1.6 mL) at 0.degree. C. and DIEA (174 .mu.L, 1
mmol) was added. Aryloyl chloride (15 .mu.l, 0.185 mmol) was added
dropwise. The content was stirred at room temp for an hour. Solvent
was removed in vacuo and the residue was purified by a prep-TLC
plate (10% MeOH/DCM) to give two final product as tan solids (trans
29.4 mg, yield 43.8%; cis 14.1 mg, 21.4%).
##STR00057##
[0221] Step 1: Synthesis of 21
##STR00058##
[0222] Compound 19 (154 mg, 0.54 mmol) and compound 20 (107 mg,
0.54 mmol) were dissolved in 4 mL anhydrous DMF in a sealed tube
and was added Pd(OAc).sub.2 (14 mg, 0.062 mmol), XantPhos (37 mg,
0.064 mmol), and K.sub.3PO.sub.4 (150 mg, 0.71 mmol). The content
was heated at 120.degree. C. overnight. After cooling to the room
temp, EtOAc was added and the mixture was filtered through celite,
washed with more EtOAc. Combined filtrate was conc in vacuo, and
the residue was purified by CombiFlash (MeOH/DCM). The product 21
(140 mg, yield 58%) was obtained as an orange solid.
[0223] Step 2: Synthesis of 22
##STR00059##
[0224] Compound 21 (140 mg, 0.31 mmol) was dissolved in THF/water
(3 mL/3 mL) mixture and Fe (75 mg,), NH.sub.4Cl (75 mg) was added.
The content was heated at 65.degree. C. overnight. After cooling to
room temp., the mixture was filtered through cotton. The filtrate
was concentrated and the residue was dissolved in 7.5% MeOH/DCM and
was filtered through cotton again. After solvent was removed in
vacuo, the crude product was obtained as a tan solid (126 mg, yield
96%).
[0225] Step 3: Synthesis of 23
##STR00060##
[0226] Compound 22 (163 mg, 0.15 mmol) was dissolved in
CH.sub.2Cl.sub.2(1.6 mL) at 0.degree. C. and DIEA (174 .mu.L, 1
mmol) was added. Aryloyl chloride (13 .mu.l, 0.165 mmol) was added
dropwise. The content was stirred at room temp for an hour. Solvent
was removed in vacuo and the residue was purified by a prep-TLC
plate (7.5% MeOH/DCM) to give final product as a tan solid (40 mg,
yield 56%).
##STR00061##
[0227] Procedure: compound 24 (49 mg, 0.1 mmol) was dissolved in
0.75 mL HCOOH and H.sub.2O.sub.2 (37%, 0.4 mL) was added. The
content was heated at 40.degree. C. for 1 hr. The volatiles were
removed by N.sub.2 blow and the residue was purified by prep-TLC
(7.5% MeOH/DCM) to give the product as a tan solid (13.7 mg, yield
27%).
##STR00062##
[0228] Step 1: Synthesis of 26
##STR00063##
[0229] A suspension of 5-bromo-2,4-dichloropyrimidine (2. g, 12.3
mmol, 1.0 eq), 2-dimethylphosphonylbenzeneamine (2.08 g, 12.3 mmol,
1.0 eq), K.sub.2CO.sub.3 (2.04 g, 14.8 mmol, 1.2 eq), and
nBu.sub.4HSO.sub.4 (417 mg, 1.23 mmol, 0.1 eq) in 50 mL of DMF was
stirred at 65.degree. C. for 7 hours and cooled to room
temperature. After a filtration, the filtrate was evaporated to an
oil, which was chromatographed (DCM/MeOH 20:1) to give a yellow
solid, 2.9 g, in 66% yield.
[0230] Step 2: Synthesis of 27
##STR00064##
[0231] A mixture of 7 (1.42 g, 3.938 mmol, 1.0 eq),
2-methoxy-5-nitroaniline (927 mg, 5.513 mmol, 1.4 eq), and 2.5 M
HCl/EtOH (6 mL) in 35 mL of 2-methoxyethanol was sealed and stirred
at 110.degree. C. for 5 hrs and cooled to room temperature. The
mixture was worked up with sat. Na2CO3/DCM and purified with isco
(MeOH/DCM 1:20) to give a yellow foam on oil pump, 520 mg, in 27%
yield.
[0232] Step 3: Synthesis of 28
##STR00065##
[0233] A mixture of the 27 (250 mg, 0.5 mmol), Zn (150 mg) and
NH.sub.4Cl (150 mg) in 2 mL of THF/H20 (5:1) was stirred at room
temperature for 1.5 hours and filtered. The filtrate was worked up
with saturated Na.sub.2CO.sub.3 and DCM. The crude product was
purified with preparation plates to afford a yellow solid, 143 mg,
in 61% yield.
[0234] Step 4: Synthesis of 29
##STR00066##
[0235] The aniline (280 mg, 0.606 mmol) was dissolved in 8 mL of
DCM and 0.3 mL of triethylamine was added. The mixture was cooled
to -35.degree. C. and acryloyl chloride (54.8 mg, 49 .mu.l, 0.606
mmol, 1.0 eq) was added in portions. The reaction was stirred
around -30.degree. C. for 15 min and quenched with saturated
Na.sub.2CO.sub.3. The mixture was worked up with sat.
Na.sub.2CO.sub.3/DCM and purified with preparation plates to give a
light brown solid, 205 mg, in 66% yield.
##STR00067##
[0236] Procedure: 35 mg (0.0678 mmol) of 29 was dissolved in 1.5 mL
of EtOH and Pd/C (10%, wet, 5 mg) was added. The mixture was
stirred under H.sub.2 balloon at room temperature overnight. The
mixture was filtered and purified with a preparation plate to
afford a white solid 30, 8.9 mg, in 30% yield.
##STR00068##
[0237] Step 1: Compound 31 was prepared according to the procedure
described for the synthesis of compound 1 in Example 1, using
2-iodo-3-methylaniline instead of 2-iodoaniline as the starting
material. A suspension of 31 (0.53 mmol), 2,4,5-trichloropyrimidine
(1.0 eq), potassium carbonate (1.2 eq), and tetrabutylammonium
hydrogensulfate (0.1 eq) in DMF was stirred at 65.degree. C. for 18
hrs. Upon cooling the reaction mixture was filtered and the
filtrate was concentrated. The residue was taken up into a mixture
of EtOAc and water. After extraction with EtOAc (3.times.), the
combined organic phases were concentrated to give essentially pure
material which was used directly in next step reaction.
[0238] Step 2: A solution of 32 (0.82 mmol),
2-methoxy-5-nitroaniline 33 (1 eq) and TFA (3 eq) in 2-BuOH (3 mL)
was heated at 100.degree. C. for 18 hrs. Upon cooling EtOAc and aq.
NaHCO.sub.3 were added to the reaction mixture. Extraction
(3.times.) and concentration of combined extracts gave a solid
which was purified on silica gel column (ISCO machine) with 10%
MeOH in CH.sub.2Cl.sub.2 as the eluents, furnishing 34 as a
brownish solid (55%).
[0239] Step 3: To a suspension of 34 (0.46 mmol) and zinc powder (6
eq) in acetone (9 mL) and water (1 mL) was added ammonium chloride
(10 eq) at 0.degree. C. After the mixture was stirred at room
temperature for 30 min, HPLC indicated a complete conversion.
Acetone was removed on rotavap and the residue was suspended in DCM
and water. Filtration was carried out and the filtrate was
extracted with DCM. Concentration of combined organic layers gave
crude aniline 35, which was used in the next step without
purification.
[0240] Step 4: To a solution of aniline 35 (0.43 mmol) and N,
N-diisopropylethylamine (1.1 eq) in DCM (2 mL) was added acryloyl
chloride (1.05 eq) at 0.degree. C. After the mixture was stirred at
room temperature overnight, the volatile components were removed on
rotavap. The residue was purified on silica gel column with 3% MeOH
in DCM as eluents, furnishing amide 36 as beige solid (48 mg,
21%).
##STR00069##
[0241] A solution of 12 (125 mg, 0.3 mmol), methyl
2-(bromomethyl)acrylate (1.3 eq) and N, N-diisopropylethylamine
(1.3 eq) in MeCN (5 mL) was heated at 80.degree. C. for 2 hrs.
LC-MS indicated both mono- and bis-alkylation products were formed
in almost equal amount, with small percentage of tris-alkylation
products. The mixture was subjected to a prep-HPLC (reverse phase)
purification and then a pre-TLC purification (normal phase silica
gel, 10% MeOH in DCM as eluents), furnishing the title compound as
a tan solid (15 mg, 10%).
##STR00070##
[0242] 2-(Dimethylaminomethyl)acrylic acid 39 was prepared
according to a literature procedure (Synth. Comm. 1995, 25, 641).
To a solution of 39 (65 mg, 0.5 mmol), coupling reagent TBTU (1.2
eq) and N, N-diisopropylethylamine (3.0 eq) in DMF (5 mL) and DCM
(20 mL) was added 5 (1 eq). After the mixture was stirred at room
temperature overnight, the volatile components were removed on
rotavap and the residue was purified by reverse phase prep-HPLC,
furnishing the title compound as a tan solid (23 mg, 9%).
##STR00071## ##STR00072##
[0243] Step 1: the starting material 41 was prepared from
3-fluoro-4-chlorophenol via nitration and subsequent O-methylation,
according to a published procedure (US Patent Publication No.
20080300242). The suspension of 41 (1.0 g, 4.86 mmol),
1-methylpiperzine (1 eq) and K.sub.2CO.sub.3 (1 eq) in DMF (20 mL)
was heated at 80.degree. C. for 4 hrs. DMF was removed and the
residue was partitioned between DCM and water. Extraction and
concentration followed by silica gel column chromatograph (10% MeOH
in DCM as eluents) furnished 42 (1.26 g, 91%).
[0244] Steps 2 and 3: A degassed suspension of 42 (0.96 g, 3.4
mmol), benzophenone imine (1.5 eq), palladium acetate (0.1 eq),
xantphos (0.2 eq) and cesium carbonate (1.6 eq) in DMF (20 mL) was
heated at 110.degree. C. overnight. Upon cooling the reaction
mixture was filtered and the filtrate was concentrated. The solid
residue was dissolved in dioxane and 2M aq. HCl (1:1, 40 mL) and
then heated at 70.degree. C. for 2 hrs. Upon removing dioxane on
rotavap, the water layer was washed with DCM and then basified with
aq. NaHCO.sub.3. Extraction and concentration followed by silica
gel column chromatograph (10% MeOH in DCM as eluents) furnished 43
(0.41 g, 45%).
[0245] Step 4: To a solution of 43 (0.38 g, 1.42 mmol) in THF (15
mL) was added NaH (2 eq.) under N.sub.2 at 0.degree. C. in multiple
portions. After bubbles of H.sub.2 were no longer observed,
Boc.sub.2O (4 eq.) was added. The resulting reaction mixture was
heated at 50.degree. C. and then refluxed for 2 hrs. The reaction
was quenched with MeOH. Usual workup followed by silica gel column
chromatograph (5% MeOH in DCM as eluents) furnished 44 (0.46 g,
88%).
[0246] Step 5: With EtOAc as the solvent 44 (0.46 g) was
hydrogenated under 50 psi to afford 45 (0.42 g, 99%). Upon removing
the solvent, the crude material was used directly in the next
step.
[0247] Step 6: A degassed suspension of 45 (0.42 g, 3.4 mmol), 2
(1.5 eq), palladium acetate (0.1 eq), xantphos (0.2 eq) and cesium
carbonate (1.3 eq) in DMF (10 mL) was heated at 110.degree. C. for
48 hrs. Usual workup followed by silica gel column chromatograph
(5% MeOH in DCM as eluents) furnished 46 (0.49 g, 64%).
[0248] Step 7: To a solution of 46 in DCM was added excessive TFA.
After the mixture was stirred at room temperature for 2 hrs, the
volatile components were removed on rotavap. The residue was
dissolved in EtOAC and the solution was basified with aq.
NaHCO.sub.3. Extraction and concentration gave 47 as tan solid.
[0249] Step 8: Crude 47 (100 mg) was converted to 48 by using the
procedure described in Example 14, step 4. The final product was
purified by reverse phase prep-HPLC (10.4 mg, 9%).
##STR00073##
[0250] Step 1: Under N.sub.2, to a suspension of 41 (0.5 g, 2.43
mmol) and NaH (1.5 eq) in THF (10 mL) was added dropwise a solution
of 2-(dimethylamino)ethanol (1.1 eq) in THF (2 mL) at 0.degree. C.
The resulting mixture was stirred at room temperature for 3 hrs.
Usual workup followed by silica gel column chromatograph (10% MeOH
in DCM as eluents) furnished 49 (0.53 g, 79%).
[0251] Step 2: To a degassed suspension of 49 (0.275 g, 1.0 mmol),
Pd.sub.2(dba).sub.3 (0.1 eq), 2-(di-t-butylphosphino)-N,
N-dimethylbiphenylamine (0.1 eq) and sodium t-butoxide (1.4 eq) in
dioxane (10 mL) was added a solution of NH.sub.3 in dioxane (0.5 M
in a N.sub.2-sealed bottle, 10 mL). The resulting mixture was
heated at 80.degree. C. for 3 hrs. Usual workup followed by silica
gel column chromatograph (15% MeOH in DCM as eluents) furnished 50
(0.15 g, 55%).
[0252] Steps 3 to 7: The poly-substituted aniline 50 was converted
to the title compound 51 according to the procedure described in
Example 18 by substituting 50 for 43.
##STR00074##
[0253] 2,4-Dimethoxy-5-nitroaniline 53 was prepared from
1,5-difluoro-2,4-dinitrobenzene via double S.sub.NAr substitution
to generate 52 and subsequent mono-reduction of nitro groups,
according to a published procedure (J. Org. Chem. 2005, 70, 10660).
This was converted to the title compound 54 as for Example 14 by
substituting 53 for 33 and 2 for 32.
##STR00075##
[0254] Step 1: A degassed suspension of 2-nitro-4-bromoanisole
(2.32 g, 10 mmol), N,N-dimethyl-1,3-propanediamine (1.1 eq),
Pd.sub.2(dba).sub.3 (0.02 eq), dppf (0.04 eq) and sodium t-butoxide
(1.5 eq) in dioxane (20 mL) was heated at 110.degree. C. overnight.
Upon cooling the reaction was quenched with water. The volatile
components were removed on rotavap and the residue was partitioned
between EtOAc and water. Extraction and concentration followed by
silica gel column chromatograph (15% MeOH in DCM as eluents)
furnished 55 (0.66 g, 26%).
[0255] Steps 2 to 6: The secondary amine 55 was converted to the
title compound 56 as for Example 18 by substituting 55 for 43.
##STR00076## ##STR00077##
[0256] Step 1: Acetic anhydride (7.8 mL, 82.6 mmol) was added
dropwise with vigorously stirring to a suspension of
3-fluoro-4-aminophenol (10 g, 78.6 mmol) in water (20 mL).
Insoluble amide started to precipitate as a white solid in a few
minutes. After the reaction mixture was stirred for 10 more
minutes, the white solid was collected via filtration and washed
with cold water. Silica gel column chromatograph (5% MeOH in DCM as
eluent) gave pure 57 (8.75 g, 66%).
[0257] Step 2: To a suspension of 57 (8.75 g, 51.73 mmol) and
K.sub.2CO.sub.3 (1.1 eq) in THF (30 mL) was added methyl iodide
(1.2 eq). The mixture was heated in a sealed tube at 60.degree. C.
overnight. Filtration and concentration followed by silica gel
column chromatograph (5% MeOH in DCM as eluent) furnished pure 58
(7.17 g, 89%).
[0258] Step 3: Nitric acid (70%, 3.83 mL) was added dropwise to a
solution of 58 (7 g) in DCM (70 mL) with vigorously stirring. After
stirred at room temperature for 1 hr, the reaction mixture was
refluxed for 3 hrs. DCM was removed on rotavap and the residue was
washed with cold water and then subjected to a silica gel column
chromatograph purification (5% MeOH in DCM as eluent) to afford 59
(3.26 g, 37%).
[0259] Step 4: Poly-substituted nitrobenzene 59 was reduced to
corresponding aniline 60 according to the procedure described in
Example 14, step 3.
[0260] Step 5: Poly-substituted aniline 60 (200 mg, 1 mmol) was
coupled with precursor 2 (1.5 eq) to afford 61 (320 mg, 67%) via
the procedure described in Example 18, step 6.
[0261] Step 6: N-arylacetamide 61 (320 mg) was heated at reflux in
6N HCl for 30 min. After basification, extraction and concentration
aryl amine 62 was obtained (290 mg, 98%).
[0262] Step 7: Crude 62 (150 mg) was converted to 63 by using the
procedure described in Example 14, step 4. The final product was
purified by reverse phase prep-HPLC (41 mg, 24%).
##STR00078## ##STR00079##
[0263] Step 1: 2,4-Dchloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 27
mmol) was suspended in MeCN (300 mL) and AcOH (60 mL); to this was
added selectfluor
(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate), 1.4 eq, 13.2 g) in one portion. The
reaction mixture was stirred at 60.degree. C. overnight. HPLC
monitoring indicated complete conversion. After the solvents were
evaporated to the volume of .about.100 mL, toluene (20 mL) was
added and the suspension was filtered. The filtrate was evaporated
to dryness and re-evaporated with toluene (2.times.20 mL). The
residue was then purified via a short silica pad (washing with 1/1
DCM/EtOAc) and column chromatography (ISCO machine, EtOAc/DCM,
EtOAc on a 0-100% gradient) to give the crude product. Upon
standing the pure product was seen to precipitate from the column
fractions. These were filtered and the mother liquors were combined
to precipitate a 2.sup.nd crop. Total 1.23 g of the product 64 was
obtained (22% yield, .about.90% pure, Cl-isomer was the main
impurity).
[0264] Step 2: A solution of 64 (1.22 g, 6 mmol) in THF (10 mL) was
slowly added to a suspension of NaH (1 eq) in THF (10 mL) at
0.degree. C. After the mixture was stirred for 10 min, a solution
of tosyl chloride (1 eq) in THF (5 mL) was slowly added. Stirring
was continued for 30 min at 0.degree. C. and then at room
temperature overnight. The reaction was shown to be complete via
HPLC monitoring and was quenched via the addition of aq. NH.sub.4Cl
(1-2 mL). The reaction mixture was then filtered through celite and
the filtrate was evaporated. The crude product was purified via
column chromatography (ISCO machine, EtOAc/Heptane, EtOAc on a
0-100% gradient) to give 65 (1.22 g, 56%).
[0265] Step 3: In a microwave vessel (20 mL) were placed 65 (600
mg, 1.7 mmol), 1 (282 mg, 1.7 mmol) and isopropanol (10 mL). After
HCl (1.3 mL, 4 M in dioxane) was added, the resulting mixture was
stirred in the microwave reactor at 150.degree. C. for 2 hrs. The
solvents were evaporated and the residue was purified via silica
column chromatography (ISCO machine, EtOAc/Heptane, 0-100% EtOAc to
elute impurities and then MeOH/DCM, 0-20% MeOH) to give pure 66
(900 mg, 54%).
[0266] Step 4: Intermediate 66 (493 mg, 1 mmol),
2-methoxy-5-nitroaniline 33 (168 mg, 1 mmol), K.sub.2CO.sub.3 (1.4
mmol), Pd.sub.2dba.sub.3 (5 mol %) and X-Phos (10 mol %) were
weighed into a 100 mL round bottom flask and placed under N.sub.2.
The solvents toluene (10 mL) and tert-butanol (2 mL) were added as
a mixture and the stirring solution was evacuated and backfilled
with N.sub.2 three times. The resulting mixture was then stirred
overnight at 110.degree. C. HPLC showed the reaction to be complete
and the solvents were evaporated. The residue was purified by
silica column chromatography on ISCO machine (5% MeOH in DCM as
eluents) to give coupling product 67 (570 mg, 91%).
[0267] Step 5: Poly-substituted nitrobenzene 67 was reduced to
corresponding aniline 68 according to the procedure described in
Example 14, step 3.
[0268] Step 6: Crude aniline 68 (123 mg) was converted to 69 by
using the procedure described in Example 14, step 4. The product
was purified by silica column chromatography on ISCO machine (5%
MeOH in DCM as eluents). Yield: 69 mg, 51%.
[0269] Step 7: A solution of 69 (60 mg) and TBAF (1 M in THF, 0.3
mL) in THF (10 mL) was refluxed for 5 hrs. HPLC indicated a
complete reaction. After the solvent was evaporated, the residue
was purified by silica column chromatography on ISCO machine (5%
MeOH in DCM as eluents). The product was co-eluted with TBAF; water
wash furnished pure product (10 mg, 21%).
##STR00080## ##STR00081##
[0270] Step 1: To a suspension of 5-fluoro-2-nitroanisole (50 mmol,
8.5 g) and zinc powder (3.5 eq, 11.4 g) in acetone (45 mL) and
water (5 mL) was added ammonium chloride (11 eq, 29.3 g) at
0.degree. C. in multiple portions. After the mixture was stirred at
r.t. overnight, HPLC indicated a complete conversion. Acetone was
removed on rotavap and the residue was suspended in DCM and water.
Filtration was carried out and the filtrate was extracted with DCM.
Concentration of combined organic layers gave crude aniline
(.about.7.0 g), which was used in the next step without
purification.
[0271] Step 2: To a suspension of 4-fluoro-2-methoxyaniline (5.1 g,
36.1 mmol) in concentrated sulfuric acid (55 mL) was added
guanidine nitrate (4.38 g, 36.1 mmol) in portion wise under ice
cooling over 15 min. The mixture was stirred at the same
temperature for additional 15 min. The reaction was then poured
into a saturated cold NaHCO.sub.3 solution and the precipitated
solid were collected by filtration. The residue was taken up in
EtOAc and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
stripped off to afford the B (4.72 g).
[0272] Step 3: The above compound B (0.1 g, 0.53 mmol) and 4-(ortho
dimethyl phosphinyl anilino)-5-chloro-2-chloro pyrimidine (0.17 g,
0.53 mmol) were dissolved in a mixture of 2-butanol (1.2 mL) &
trifluoroacetic acid (0.25 mL) and were heated to 100.degree. C. in
a seal tube for overnight. The reaction mixture was then cooled to
rt and poured into a saturated NaHCO.sub.3 solution while stirring
to afford an orange solid which was filtered, washed with Et.sub.2O
to remove final traces of water. The product was dried to afford C
(0.19 g) which was directly used in the next step.
[0273] Step 4: NaH (0.039 g, 0.96 mmol, 60% dispersion in oil) was
taken up in a dry capped microwave vial. To this,
1-(2-hydroxyethyl)-4-methylpiperazine (0.023 g, 0.16 mmol)
dissolved in dry tetrahydrofuran (1.6 mL) was added dropwise. The
mixture was stirred at rt for 20 min. Intermediate C (0.075 g, 0.16
mmol) was then added in one portion to this suspension and the
mixture was heated to 67.degree. C. in the closed seal tube for 25
min. The mixture was allowed to reach at rt and quenched with a few
drops of methanol. Solvent was removed under vacuum and the
resultant crude was subjected to FCC eluting with DCM-MeOH (95/5)
to furnish the desired product D (0.081 g).
[0274] Step 5Compound D (0.078 g, 0.13 mmol) was dissolved in a
mixture of acetone (1.3 mL) and water (0.3 mL). To this, zinc nano
powder (0.07 g, 1.3 mmol) was added immediately followed by
addition of NH.sub.4Cl (0.16 g, 2.6 mmol) in small portions. The
mixture was vigorously stirred at r.t for 30 min. Anhydrous Na2SO4
was then added to this stirring mixture and the resultant crude was
filtered, solvents were evaporated and the residue were taken up in
DCM and directly loaded on the silica gel cartridge and eluted with
DCM-MeOH--NH.sub.3 (90/10) to furnish the desired product E (0.044
g).
[0275] Step 6: To a solution of E (0.044 g, 0.078 mmol) in dry
tetrahydrofuran (0.52 mL) was added DIPEA (0.027 mL, 0.156 mmol) at
0.degree. C. under stirring. This was followed by the addition of
acryloyl chloride (0.007 g, 0.078 mmol). The reaction was stirred
at that temperature for additional 1 h. Solvent was stripped off
under vacuum and the crude was purified by FCC using
DCM-MeOH--NH.sub.3 (90/10) to furnish a gum which was further
triturated with Et.sub.2O to furnish a solid material F (0.02
g).
##STR00082##
[0276] Step 1: The suspension of advanced intermediate C,
(3-dimethylamino)pyrrolidine (1 eq) and K2CO3 (2 eq) in DMF was
stirred at r.t. overnight. The solid components were filtered off
and the filtrate was concentrated on rotavap and then on vacuum
pump. The residue was essentially pure by HPLC analysis and was
used directly in the next step.
[0277] Steps 2 and 3: these were carried out according to the
procedure outlined in Scheme 24, steps 5 and 6.
##STR00083##
[0278] The suspension of N-Boc-pyrrolidin-3-one, secondary amines,
sodium cyanoborohydride and magnesium sulfate in DCM was stirred at
40.degree. C. overnight. After the solid components were removed by
filtration, 2.5N HCl in MeOH was added to the filtrate and the
resulting solution was stirred at r.t. for 30 min. Volatile
components were removed on rotavap; the residue was partitioned
between DCM and aq. NaHCO3. Combined organic phases were
concentrated and the residue was purified by silica gel column
chromatography to furnish (3-dialkylamino)pyrrolidine C, which was
converted into final compounds by substituting C for
(3-dimethylamino)pyrrolidine.
##STR00084##
Secondary amines were converted into 2-(dialkylaminomethyl)acrylic
acid A according to a literature method (Synth. Comm. 1995, 25,
641). These were converted into final compounds according to the
procedure outlined in Scheme 17 by substituting A with 39.
##STR00085##
[0279] 2-Fluoro-5-nitroaniline or 2-methyl-5-nitroaniline was
converted into desired compound according to the procedure outlined
in Scheme 28.
##STR00086##
[0280] Step 1: the starting material A underwent a S.sub.NAr
reaction with intermediate 2 according to the procedure described
in step 1 of Example 14.
[0281] Step 2: To a solution of compound B (246 mg, 0.5 mmol),
coupling reagent TBTU (1.2 eq) and N, N-diisopropylethylamine (3.0
eq) in DMSO (10 mL) was added piperazine (1 eq). After the mixture
was stirred at room temperature overnight, water and DCM was added
to facilitate extraction. Combined extracts were washed with water
to remove DMSO. After drying over Na2SO4 and concentration on
rotavap the residue was purified by silica gel column
chromatography with 5% MEOH in DCM as the eluents, furnishing
compound C as a tan solid (154 mg, 54%).
[0282] Step 3: A solution of compound C (570 mg) and BH3-Me2S (2.0
M in THF, 5 eq, 0.6 mL) in THF (5 mL) was stirred at r.t.
overnight. 6N aq. HCl (15 mL) was added and the resulting solution
was stirred at r.t. for 5 hr. Solid K2CO3 was carefully added to
basify the reaction mixture. After extractions with DCM the
combined organic phases were dried, concentrated and purified by
silica gel column chromatography with 5% MeOH in DCM as the
eluents, furnishing compound D as a tan solid (300 mg, 54%).
[0283] Steps 4 and 5: Compounds C and D were converted into final
compounds E and F respectively according to the procedure described
in Example 14.
##STR00087##
[0284] Compound A was synthesized according to the procedure
outlined in Scheme 25 by substituting
3-(tert-butoxycarbonylamino)pyrrolidine for
3-(dimethylamino)pyrrolidine. Standard de-protection of Boc with
TFA-DCM followed by basification and silica gel column
chromatography (5% MeOH in DCM as the eluents) furnished title
compound.
##STR00088##
[0285] Step-1: Synthesis of 61:
[0286] To a mixture of compound 2 (420 mg) in THF (2.0 mL) was
added maleic anhydride (1.0 eq) at room temperature. The reaction
was stirred at room temperature for 1 hour. The product was
obtained by filtration and then washed with DCM (2.0 mL) to yield
the product, 61, as a yellow solid (435 mg, yield 84%).
[0287] Step-2: Synthesis of Examples 62, 63 and 64
##STR00089##
[0288] General procedures: The compound of Example 61 (77 mg, 0.15
mmol), prepared as in Step-1 (immediately above), was dissolved
with the respective amine (0.15 mmol, 1.0 eq.) in dry DMF (2.0 mL).
HBTU (80 mg) was added and followed by Et.sub.3N (30 uL). The
contents were stirred at room temp for 1 h. Solvent was removed in
vacuo and the residue was purified by a prep-TLC plate (6.5%
MeOH/DCM). The corresponding bands were collected to give the final
products:
##STR00090##
Synthesis of Example 75
##STR00091##
[0290] A solution of compound 2 (84 mg) in DCM (3.0 mL) and
Et.sub.3N (0.1 mL) was treated with Ethyl fumaroyl chloride (1.05
eq). The contents were stirred at room temp for an hour. Solvent
was removed in vacuo and the residue was purified by a prep-TLC
plate (7.5% MeOH/DCM) to give the product as a yellow solid (34 mg,
yield 31%).
##STR00092##
[0291] Step-1
##STR00093##
[0292] Example 75 (360 mg) in MeOH (1.5 mL) and water (0.5 mL) was
treated with K.sub.2CO.sub.3 (1.0 g) at 50.degree. C. for 2 h. The
reaction mixture was cooled down to room temperature. The organic
solution was transferred to a new vial and diluted with DCM (3.0
mL). The pH was adjusted to 6-7 by adding hydrochloric acid. The
resulting organic layer was evaporated and the residue was washed
with MeOH to give product as a yellow solid (304 mg, yield 89%)
[0293] Step-2
[0294] Compounds for Examples 60, 59 and 58 were made according to
the general procedure for Example 62, using the appropriate
amine:
##STR00094##
##STR00095## ##STR00096##
[0295] Step-1
##STR00097##
[0296] A mixture of 1,1-dimethylpropargylamine (4.2 g) and
Boc.sub.2O (11 g) without solvent was warmed up to 50.degree. C.
for 30 min. The resulting solid was treated with n-hexane (10 mL)
and the product was collected by filtration to give white solid
(7.6 g, yield 82%)
[0297] Step-2
##STR00098##
[0298] To a mixture of compound A (527 mg) and step-1 product (250
mg) in DMF (5.0 mL), was added (Ph.sub.3P).sub.2PdCl.sub.2 (0.1 g),
CuI (0.05 g) and Et.sub.3N (0.2 mL). The mixture was stirred at
80.degree. C. for 4 h. The reaction mixture was concentrated and
the residue was purified by a prep-TLC plate (8% MeOH/DCM) to give
final product as a yellow solid (430 mg, yield 68%).
[0299] Step-3
##STR00099##
[0300] Water was added dropwise to a mixture containing the product
of step-2 (240 mg) in acetone (1.0 mL), Zn dust (0.3 g) and
NH.sub.4Cl (0.15 g). The mixture was stirring at room temperature
for 15 min and then diluted with DCM (5 mL). After filtration, the
organic solution was evaporated and the residue was used for next
step.
[0301] Step-4
##STR00100##
[0302] The residue from Step-3 was dissolved in THF (3.0 mL) and
Et.sub.3N (0.05 mL), and the resulting solution was treated with
acroyl chloride. The reaction was monitored by HPLC until
disappearance of starting material. The reaction was then quenched
with aq.NaHCO.sub.3 and extracted with DCM (2.times.5.0 mL). The
organic solution was concentrated and the residue was purified by a
prep-TLC plate (10% MeOH/DCM) to give product as a yellow solid
(112 mg, yield 45% for two steps).
[0303] Step-5
##STR00101##
[0304] A solution of the product of Step-4 (80 mg) in MeOH (1.0 mL)
and DCM (0.5 mL) was treated with TFA (0.5 mL) at 0.degree. C. The
mixture warmed up to room temperature for 1 h. Solvent was
evaporated, the residue was neutralized with aq. NaHCO3, and the
neutralized material was subjected to prep-TLC plate (20% MeOH/DCM)
to give the desired product, 65, as a light yellow solid (42 mg,
yield 62%).
##STR00102##
[0305] Step-1
##STR00103##
[0306] To a mixture of 2,2-dimethyl-1,3-dioxan-5-one (2.6 g),
dimethyl amine HCl salt (1.8 g) in DCM (50 mL) was added
NaHB(OAc).sub.3 (6.0 g) and Et.sub.3N (3.0 mL). The reaction
mixture was stirred at room temperature overnight and then diluted
with aq.NaHCO3. The organic layer was dried and evaporated to give
colorless oil (2.5 g, yield 79%).
[0307] Step-2
##STR00104##
[0308] A solution of step-1 product (2.4 g) in MeOH (5.0 mL) was
treated with HCl (10 mL, 2N). The mixture was heated to reflux for
15 min. Solvent was evaporated and the residue was dissolved in DCM
(6.0 mL). The organic solution was dried, filtered and evaporated
to give colorless oil (1.5 g, yield 77%).
[0309] Step-3
##STR00105##
[0310] The nitro compound was synthesized by reacting compound B
and the product of step-2 according the general procedure.
[0311] Step-4
##STR00106##
[0312] Reduction of the nitro group and formation of the
corresponding acrylamide was carried out according to the procedure
in Scheme 32, step-3 and step-4.
##STR00107##
[0313] Step 1: To a solution of benzyl glycidyl ether (5.0 g) in
MeOH (5.0 mL) was added NaOMe (5.0 mL, 25% in methanol). The
mixture was warmed up to 50.degree. C. for 1 h and then heated to
reflux for 5 min. The mixture was treated with wet NaHCO.sub.3 and
filtered. Solvent was evaporated and the residue was dissolved in
DCM (20 mL). The solution was dried and evaporated to give
yellowish oil (4.8 g, yield 80%).
[0314] Step 2: A solution of step 1 product (3.0 g) in DCM (100 mL)
was treated with PDC (6.0 g) and molecular sieves (4.0 g). The
mixture was stirred at room temperature for 4 h and diluted with
Et.sub.2O (100 mL). The mixture was filtered through a Celite pad
and solvent evaporated to give yellow oil (1.7 g, yield 57%).
[0315] Step 3: The compound was synthesized according to the
following procedure: To a mixture of 2,2-dimethyl-1,3-dioxan-5-one
(2.6 g), dimethyl amine HCl salt (1.8 g) in DCM (50 mL) was added
NaHB(OAc).sub.3 (6.0 g) and Et.sub.3N (3.0 mL). The reaction
mixture was stirred at room temperature overnight and then diluted
with aq.NaHCO3. The organic layer was dried and evaporated to give
colorless oil (2.5 g, yield 79%).
[0316] Step 4: A solution of step-3 product (1.5 g) in MeOH (10 mL)
was charged with Pd--C (0.5 g, 10% wet) and hydrogenated under a
hydrogen balloon at room temperature overnight. The catalyst was
filtered off and the solvent was evaporated to give the product
(0.64 g, yield 71%) as colorless oil.
[0317] Step 5: The compound was synthesized according the general
procedure from compound B and step-4 product as a yellow solid.
[0318] Step 6: Example 37 was synthesized according to a similar
procedure to the following: To a mixture of tert-butyl
(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)
amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-2-methylbut-3-yn-2-y-
l)carbamate (240 mg) in acetone (1.0 mL) and Zn dust (0.3 g),
NH.sub.4Cl (0.15 g), was added drops of water. The mixture was
stirring at room temperature for 15 min and then diluted with DCM
(5 mL). After filtration, the organic solution was evaporated and
the residue was used for next step. The residue was dissolved in
THF (3.0 mL) and Et.sub.3N (0.05 mL) and solution was treated with
acroyl chloride. The reaction was monitored by HPLC until start
material disappear. The reaction was quenched with aq.NaHCO.sub.3
and extracted with DCM (2.times.5.0 mL). The organic solution was
concentrated and the residue was purified by a prep-TLC plate (10%
MeOH/DCM) to give the desired product.
##STR00108## ##STR00109##
[0319] Step 1: To a solution of N,N'-dimethylethylenediamine (300
mg) in DMF (2.0 mL) was added K.sub.2CO.sub.3 (1.0 g) and compound
B (466 mg). The mixture was heated at 80.degree. C. for 3 h.
Solvent was evaporated and the residue was extracted with DCM and
then purified by a prep-TLC plate (10% MeOH/DCM with 1% NH.sub.3 in
methanol) to give product as a yellow solid (400 mg, yield
75%).
[0320] Step 2: A solution of step 1 product (1 eq) in DMF (3.0 mL)
was treated with NaHCO.sub.3 (0.5 g) and the respective bromide
(2.5 eq) at 50.degree. C. for 5 h. Solvent was evaporated and the
products were purified by a prep-TLC plate (8% MeOH/DCM) to give
product as yellow solids.
[0321] Step 3: Reduction of the nitro group and formation of the
corresponding acrylamide was carried out according to the procedure
in Scheme 32, step-3 and step-4.
[0322] The methoxy- and fluoro-ompounds below were synthesized by
this method:
##STR00110##
and were converted to the corresponding acrylamides. See Example
67.
##STR00111##
[0323] Step 1: A mixture of N-(2-methoxyethyl)methylamine (1.8 g)
and ethyl bromoacetate (3.4 g) in acetonitrile (20 mL) was treated
with K.sub.2CO.sub.3 (4.0 g) and NaI (20 mmol). The mixture was
refluxed overnight. Solvent was evaporated and the residue was
extracted with DCM and then purified on Silica gel column (0-8%
MeOH/DCM) to give the product as colorless oil (3.2 g, yield
93%).
[0324] Step 2: To a solution of step-1 product (3.5 g) in THF (20
mL) was added LAH (800 mg) portion wise. The resulting mixture was
stirred at room temperature overnight and then quenched with EtOAc
and water. After filtration, the organic solution was evaporated to
give colorless oil (2.0 g, yield 75%).
[0325] Step 3: The step 3 product compound was synthesized
according the general procedure from compound B (400 mg) and step-4
product to give the title compound as a yellow solid (200 mg, yield
40%).
[0326] Step 4: Example 39 was synthesized according to a similar
procedure to that used in Step 6 of Example 37.
##STR00112##
Step-1
##STR00113##
[0328] To a mixture of 1-Boc-3-pyrrolidine (1.85 g), azetidine
(0.65 g) in DCM (10 mL) was added NaHB(OAc).sub.3 (3.5 g) and
molecular sieves (3.0 g). The reaction mixture was stirred at room
temperature for 3 h and diluted with aq.NaHCO.sub.3. The organic
layer was dried and evaporated. The residue was column purified on
Silica gel (5% MeOH/DCM) to give the product as a white solid (1.6
g, yield 71%).
[0329] Step-2
##STR00114##
[0330] To a solution of step-1 product (230 mg) in MeOH (1.0 mL)
was added HCl in dioane (3.0 mL, 4.0M solution) at room
temperature. The mixture was stirred for 1 h and solvent evaporated
to give white solid for next step.
[0331] Step-3
##STR00115##
[0332] To a mixture of compound B (450 mg), product of step-2 in
DMF (3.0 mL) was added molecular sieves (1.0 g) and K.sub.2CO.sub.3
(1.0 g). The reaction mixture was heated at 60.degree. C. for 30
min. Solvent was evaporated and the residue was purified by a
prep-TLC plate (10% MeOH/DCM) to give product as a yellow solid
(380 mg, yield 69%).
Step-4
##STR00116##
[0334] Step-4 was carried out using the procedures of Scheme 32
step-3 and step-4 to yield the desired product (Example 68) as a
yellow solid (44 mg)
[0335] B.
##STR00117## ##STR00118##
Step-1
##STR00119##
[0337] To a mixture of compound B (3.0 g) and 4-piperidinone HCl
salt in DMF (5.0 mL) was added K.sub.2CO.sub.3 (2.5 g). The mixture
was heated at 70.degree. C. for 3 h and solvent was evaporated.
[0338] The residue was extracted with DCM and purified by
CombiFlash(MeOH/DCM). The product (1.6 g, yield 46%) was obtained
as a red solid.
Step-2
[0339] General procedure of reductive amination: To a mixture of
step-1 product (275 mg), respective amines (1.5 eq) in DCM was
added NaHB(OAc).sub.3 (2 eq) and molecular sieves (0.3 g). The
resulting mixture was shaked at room temperature for 4 h and
treated with wet NaHCO.sub.3. The organic solution was separated
and purified by prep-TLC plates (7-15% MeOH/DCM) to give
products.
[0340] Compounds synthesized by this method:
##STR00120## ##STR00121##
[0341] Step-3
[0342] Reduction of the nitro group and formation of the
corresponding acrylamide was carried out according to the procedure
in Scheme 32, step-3 and step-4.
##STR00122## ##STR00123##
##STR00124## ##STR00125##
[0343] Step-1
##STR00126##
[0344] To a solution of cyclopropyl(trimethylsilyl)acetylene (13.8
g) in ether (200 mL) was added n-BuLi (40 mL, 2.5M in hexane). The
reaction mixture was stirred at room temperature overnight. The
dark-yellow solution was cooled to -78.degree. C. and a large
excess of powdered dry ice was added in portions. The reaction
mixture was allowed to warmed up to room temperature and poured
into ice-cooled water. The layer was separated, and the aqueous
layer was washed with Et.sub.2O, acidified by adding 12N aq.HCl
solution and extracted with Et.sub.2O. The organic layer was dried
and concentrated to give the title compound as a white solid (8.5
g, yield 47%).
[0345] Step-2
##STR00127##
[0346] To a solution of step-1 product (1.8 g) and DPPA (2.79 g) in
t-BuOH (30 mL) was added Et.sub.3N (2.02 g). The mixture was
refluxed for 20 h. Solvent was evaporated and the residue was
column purified on Silica gel (20% Et.sub.2O)/heptane) to give the
product as a white solid (1.3 g, yield 52%).
[0347] Step-3
##STR00128##
[0348] A solution of step-2 product (1.2 g) in THF (10 mL) was
treated with n-Bu.sub.4NF (6.0 ml, 1.0M solution in THF). The
mixture was stirred at room temperature for 1.5 h and solvent was
evaporated. The residue was column purified on Silica gel (20%
Et.sub.2O)/heptane) to give the product as a white solid (0.75 g,
yield 87%).
[0349] Step-4
##STR00129##
[0350] The product of Step-3 was then reacted with Compound A using
the procedure of Scheme 32, step-2.
[0351] Step-5
##STR00130##
[0352] To a solution of step-4 product (250 mg) in DCM was added
HCl in dioxane (1.5 mL, 4.0M solution) at -78.degree. C. The
mixture was warmed up slowly to room temperature. Solvent was
evaporated and the residue was treated with aq.K.sub.2CO.sub.3 and
then purified by a prep-TLC plate (10% MeOH/DCM) to give yellow
solid (150 mg).
[0353] The yellow solid was dissolved in DCM (3.0 mL) and treated
with formyl aldehyde (5 drops, 40% aq. solution) and MgSO4 (0.5 g,
anhydrous) for 30 min. To the mixture was added NaBH(OAc).sub.3 (2
eq). The reaction mixture was stirred for 1 h and diluted with aq.
NaHCO.sub.3. The mixture was extracted with DCM and product was and
purified by prep-TLC plates (10% MeOH/DCM) to give yellow solid (50
mg, yield 23%).
[0354] Step-6
##STR00131##
[0355] Reduction of the nitro group and formation of the
corresponding acrylamide was carried out according to the procedure
in Scheme 32, step-3 and step-4, to produce the final product
pictured above (Example 73).
##STR00132## ##STR00133##
[0356] Step 1: To a solution of 3-methoxy-4-nitrobenzyl alcohol (5
g) in DCM (100 mL) was added PDC (1.5 eq) and molecular sieves (6.0
g). The mixture was stirred at room temperature for 2 h and diluted
with Et.sub.2O (100 mL). The mixture was filtered through a Celite
pad and solvent was evaporated. The residue was washed with a small
amount MeOH to give off white solid (3.7 g, yield 74%).
[0357] Step 2: To a solution of step-1 product (0.91 g) in DCM (10
mL) was added (Ethoxycarbonylmethlene)triphenylphosphorane (2.0 g).
The mixture was stirred at room temperature for 30 min. Solvent was
evaporated and the residue was column purified on Silica gel (20%
Et.sub.2O)/heptane) to give a yellowish solid (1.1 g, yield
87%).
[0358] Step 3: A solution of step-2 product (0.52 g) in MeOH (10
mL) was charged with Pd--C (0.5 g, 10% wet) and hydrogenated under
a hydrogen balloon at room temperature overnight. The catalyst was
filtered off and solvent was evaporated to give yellow oil (0.45 g,
yield 97%).
[0359] Step 4: A vial was charged with H.sub.2SO.sub.4 (2.0 mL) and
cooled to 0.degree. C. Step-3 product (0.4 g) was carefully
introduced. Guanidine nitrate (1 eq) was added. The mixture was
stirred at 0.degree. C. for 2 h and at room temperature for 1 h.
The mixture was treated with excess wet NaHCO3 and extracted with
DCM (10 mL). The product was and purified by prep-TLC plates (8%
MeOH/DCM) to give orange solid (0.34 g, yield 71%).
[0360] Step 5: A solution of compound C (320 mg), step-4 product
(268 mg) and TFA (0.3 mL) in 2-BuOH (2 mL) was heated at
100.degree. C. for 18 hrs. Upon cooling EtOAc and aq. NaHCO.sub.3
were added to the reaction mixture. Extraction (3x) and
concentration of combined extracts gave a solid which purified by
prep-TLC plates (15% MeOH/DCM) to give orange solid (410 mg, yield
71%).
[0361] Step 6: To a suspension of step-5 product (400 mg) in MeOH
(2.0 mL) was added K.sub.2CO.sub.3 (1.0 g) and water (0.5 mL). The
reaction vial was capped and heated at 60.degree. C. for 15 min.
The mixture was cooled down to room temperature and the top layer
was transferred to a new vial and diluted with water. The pH was
adjusted to 5-6 by adding aq HCl (2N) and the product was collected
by filtration as a yellow solid (310 mg, yield 86%).
[0362] Step 7: To a mixture of step-6 product (260 mg) and
Et.sub.2NH (1.1 mmol) in DMF (2.0 mL) was added HBTU (1.3 mmol) and
Et.sub.3N (0.14 mL). The mixture was stirred at room temperature
for 2 h and diluted with DCM (5.0 mL). The mixture was washed with
aq. K.sub.2CO.sub.3 and evaporated. The residue was purified by
prep-TLC plates (15% MeOH/DCM) to give an orange solid (250 mg,
yield 87%).
[0363] Step 8: To a solution of step-7 product (250 mg) in THF (1.0
mL) was added BH.sub.3Me.sub.2S (4.0 mL, 2.0M solution in THF). The
mixture was stirred at 60.degree. C. for 2 h and solvent was
evaporated. The residue was dissolved in MeOH (2.0 ml) and treated
with wet K.sub.2CO.sub.3 in a capped vial at 70.degree. C. for 1 h.
The organic solution was evaporated and the residue was purified by
prep-TLC plates (25% MeOH/DCM) to give an orange solid (170 mg,
yield 70%).
[0364] Step 9: Reduction of the nitro group and formation of the
corresponding acrylamide was carried out according to the procedure
in Scheme 32, step-3 and step-4, to produce the final product.
##STR00134## ##STR00135##
[0365] Step 1: N,N-diethyl-2-(3-methoxy-4-nitrophenyl)acetamide was
made in accordance with the methods disclosed herein.
[0366] Step 2: To a solution of
N,N-diethyl-2-(3-methoxy-4-nitrophenyl)acetamide (1.0 g) in THF
(5.0 mL) was added BH.sub.3Me.sub.2S (20. mL, 2.0M solution in
THF). The mixture was stirred at 60C for 2 h and solvent was
evaporated. The residue was dissolved in MeOH (10 ml) and treated
with wet K.sub.2CO.sub.3 in a capped vial at 70.degree. C. for 1 h.
The organic solution was evaporated and the residue was purified on
Silica gel column (5% MeOH/DCM) to give the product as an orange
oil (0.62 g, yield 65%)
[0367] Step 3: A solution of step-2 product (600 mg) in MeOH (10
mL) was charged with Pd--C (0.5 g) and hydrogenated under a
hydrogen balloon at room temperature for 3 h. The catalyst was
filtered off and the solvent was evaporated to give a yellow oil
(430 mg, yield 81%)
[0368] Step 4: The product of step 4 was synthesized according the
procedure of step 4 of Scheme 39 as an orange oil.
[0369] Step 5: The product of step 4 was synthesized according the
procedure of step 5 of Scheme 13 to afford an orange solid.
[0370] Step 6: Reduction of the nitro group and formation of the
corresponding acrylamide was carried out according to the procedure
in Scheme 32, step-3 and step-4, to produce the final product.
##STR00136##
[0371] Step 1: A mixture of glycidyl methyl ether and aq.
methylamine (1.5 eq) was heated at 55.degree. C. for 2 hr. Removal
of volatile components gave intermediate A which was used directly
in next step.
[0372] Step 2: Intermediate A (400 mg, 3.34 mmol, 1.0 eq) in 4 ml
of dioxane and 4 ml of water was adjusted to pH 12 with 4M NaOH,
and cooled to 0.degree. C. O(Boc)2 (806 mg, 3.69 mmol, 1.1 eq) was
added in 2 portions and the mixture was stirred at R.T. overnight.
The mixture was evaporated to reduce volume by one half and then
treated with sat. NaHCO3 (3 ml). This was extracted with EtOAc
(3.times.25 ml), dried, evaporated, and chromatographed
(EtOAc/Heptane 1:2 to 1:1) to give an oil, 703 mg, in 96%
yield.
[0373] Steps 3-5: the chemistry was carried out following the
procedures described in Scheme 24.
[0374] Step 6: to a solution of intermediate B (304 mg) in DCM (5
mL) was added TFA (1.8 mL). The mixture was stirred at rt for 1 h
then quenched with saturated sodium bicarbonate solution until
pH=8.0. The organics were extracted with DCM (3.times.) and the
combined organics were dried over anhydrous sodium sulfate, and the
solvents were removed under reduced pressure to give the desired
product as a pale brownish solid (262 mg, 95%).
Example 128
##STR00137## ##STR00138##
[0376] Step-1: to a solution of compound 71 (527 mg, 1.0 mmol) and
tert-butyl(3-butynyl)carbamate (400 mg) in DMF (4.0 mL), was added
(Ph.sub.3P).sub.2PdCl.sub.2 (0.1 g), CuI (0.05 g) and Et.sub.3N
(0.2 mL). This degased mixture was stirred at 80.degree. C. for 3
h. The reaction mixture was concentrated and the residue was
purified by a prep-TLC plate (8% MeOH/DCM) to give compound 73 as a
yellow solid (280 mg, yield 46%).
[0377] Step-2: compound 73 (280 mg, 0.46 mmol) was dissolved in DCM
(2.0 mL) and treated with HCl in dioxane (1.0 mL, 4.0 M) at room
temperature for 20 min. Solvent was evaporated and the residue was
treated with aq. sodium bicarbonate and extracted with DCM.
Combined organic layers were dried and evaporated to give compound
74 (220 mg, 93%) as yellow solid.
[0378] Step-3: to a suspension of compound 74 (220 mg, 0.43 mmol)
and MgSO.sub.4 (0.5 g) in DCM (3.0 mL) was added 4 drops of
formaldehyde solution (36.5%). After the resulting mixture was
stirring for 20 min NaHB(OAc).sub.3 (250 mg) was added. The mixture
was heated at 50.degree. C. for 30 min and then quenched with aq.
NaHCO.sub.3. The product was purified by prep. TLC
(DCM:MeOH=100:15) to give compound 75 (180 mg, 78%) as yellow
solid.
[0379] Step-4: to a suspension of compound 75 (180 mg) and Zn dust
(0.3 g) in acetone (1.0 mL) was added NH.sub.4Cl (0.15 g) and drops
of water. The mixture was stirring at room temperature for 15 min
and then diluted with DCM (5 mL). After filtration, the organic
solution was evaporated and the residue (140 mg) was used for next
step.
[0380] Step-5: to a solution of compound 76 (.about.140 mg) in DCM
(3.0 mL) was added acrylic acid (0.076 mL), EDC (200 mg), Et.sub.3N
(0.2 mL). The mixture was stirring at room temperature for 3 h.
Solvent was evaporated and the residue was purified by prep TLC
(DCM: MeOH=100:15) to give title compound (40 mg, 26%) as light
yellow solid.
Example 129
##STR00139##
[0382] Using the procedure described in step 1 of Scheme 41
R-(-)-glycidyl methyl ether was converted into amino alcohol A.
Title compound was obtained from transformation of A via a 3-step
chemical sequence, as described in Scheme 24.
Example 130
[0383] Title compound was prepared in a manner similar to Example
129 using S-(+)-glycidyl methyl ether as starting material.
Example 131
[0384] Title compound was prepared in accordance with the method
described in Scheme 12 by substituting
2,4-dichloro-5-methoxypyrimidine for
5-bromo-2,4-dichloropyrimidine.
Example 132
[0385] Title compound was prepared in accordance with the method
described in Scheme 5 by reacting intermediate 5 with
2-chloroacryloyl chloride.
Example 133
[0386] Title compound was prepared in accordance with the method
described in Scheme 12 by substituting 2,4,5-trichloropyrimidine
for 5-bromo-2,4-dichloropyrimidine and
2-methoxy-4-methyl-5-nitroaniline for 2-methoxy-5-nitroaniline.
Example 134
[0387] Title compound was prepared in accordance with the method
described in Scheme 12 by substituting 2,4,5-trichloropyrimidine
for 5-bromo-2,4-dichloropyrimidine and
2-(trifluoromethoxy)-5-nitroaniline for
2-methoxy-5-nitroaniline.
Example 135
[0388] Title compound was prepared in accordance with the method
described in Scheme 12 by substituting 2,4,5-trichloropyrimidine
for 5-bromo-2,4-dichloropyrimidine and 2-ethyl-5-nitroaniline for
2-methoxy-5-nitroaniline.
Synthesis of Triazine Compound with CF.sub.3 at R.sup.a2:
[0389] Title compound was prepared in accordance with the method
described in Scheme 12 by substituting 2,4-dichloro-1,3,5-triazine
for 5-bromo-2,4-dichloropyrimidine and
2-(trifluoromethoxy)-5-nitroaniline for
2-methoxy-5-nitroaniline.
Example 136
[0390] Title compound was prepared in accordance with the method
described in Scheme 12 by substituting 2,4,5-trichloropyrimidine
for 5-bromo-2,4-dichloropyrimidine and 2-chloro-5-nitroaniline for
2-methoxy-5-nitroaniline.
Example 137
[0391] Title compound was prepared in accordance with the method
described in Scheme 5 by reacting intermediate 5 with
2-chloroacetyl chloride.
Example 138
##STR00140##
[0393] To a suspension of NaH (0.67 g, 5 eq) in THF (30 mL) was
added dropwise a solution of oxetane-3-ol (0.24 g, 1 eq) in THF (5
mL) under N2 at r.t. After the mixture was stirred at r.t. for 1
hr, 2-fluoro-5-nitroaniline (0.51 g, 1 eq) was added. The resulting
mixture was heated at 70.degree. C. for 3 hr and then quenched with
water. Concentration removed THF and the residue was taken up in
DCM. Extraction, concentration and purification on silica gel
column (0-100% EtOAc in heptane) furnished intermediate A as a
yellow oil (52%).
[0394] Intermediate A was converted into desired final compound via
a 3-step sequence outlined in Scheme 28.
Example 139
##STR00141##
[0395] Zinc cyanide (70 mg, 0.65 eq), intermediate 27 (490 mg, 1
eq), Pd2(dba)3 (46 mg, 0.05 eq), DPPF (69 mg, 0.13 eq) was placed
in a microwave tube containing DMF-H.sub.2O (3 mL). This mixture
was flushed with Ar and then heated at 130.degree. C. for 1.5 hr.
The reaction mixture was evaporated and the residue was purified on
silica gel column (0-5% MeOH in DCM) furnished intermediate A as a
yellow solid (32%).
[0396] Intermediate A was converted into desired final compound via
a 2-step sequence outlined in Scheme 12.
Example 140
[0397] Title compound was prepared in a manner similar to Example
133 by substituting 2-chloroacetyl chloride for acryloyl chloride
in last step.
Example 141
[0398] Title compound was prepared in a manner similar to Example
137 by substituting 2,4-dichloro-5-methylpyrimidine for
2,4,5-trichloropyrimidine.
Example 142
[0399] Title compound was prepared in accordance with the method
described in Scheme 43 by substituting (+)-glycidyl ethyl ether for
R-(-)-glycidyl methyl ether.
Examples 143-146
##STR00142##
[0401] The title compounds were prepared in accordance with the
method described in Scheme 24 by substituting aniline A for
2-methoxy-4-fluoroaniline and optically pure
1-(dimethylamino)-3-methoxy-2-propanol for
1-(2-hydroxyethyl)-4-methylpiperazine.
1-(dimethylamino)-3-methoxy-2-propanol was synthesized via a
procedure described in Scheme 43.
Example 147
[0402] Title compound was prepared in accordance with the method
described in Scheme 5 by reacting intermediate 5 with
2-fluoroacetyl chloride.
Example 148
[0403] Title compound was prepared in accordance with the method
described in Scheme 28 by substituting 2-chloroacetyl chloride for
acryloyl chloride in last step.
Example 149
[0404] Title compound was prepared in accordance with the method
described in Scheme 22 by substituting 2-chloroacetyl chloride for
acryloyl chloride in last step.
Example 150
[0405] Title compound was prepared in accordance with the method
described in Scheme 5 by reacting intermediate 5 with
(chloromethyl)sulfonyl chloride.
[0406] Examples 151, 152, and 156
##STR00143##
[0407] Steps 1-2: the chemistry was carried out according to the
procedure described for steps 2 and 3 in Scheme 24.
[0408] Step 3: Into a Schlenk flask was loaded intermediate C (260
mg), PdCl2(PPh3)2 (5 mol %) and Cul (10 mol %). This flask was
capped with a rubber septum and then degassed under vacuum for 1
min before N2 refill. Anhydrous DMF (4 mL) was added followed by
the addition of DIPEA (0.1 mL) and 1-(dimethylamino)-3-butyne (0.1
mL, note this alkyne was purged with dry N2 gas immediately before
use). The flask was sealed and the mixture was stirred at
80.degree. C. for 16 h. Upon cooling, the reaction mixture was
taken up in EtOAc and water. Extraction and concentration of
combined organic layers afforded crude D which was used directly in
the next step.
[0409] Steps 4-5: the chemistry was carried out according to the
procedure described for steps 3 and 4 in Scheme 12.
Example 153
[0410] Title compound was prepared in accordance with the method
described in Scheme 48 by substituting 2-(isopropylsulfonyl)aniline
for 2-(dimethylphosphoryl)aniline.
Examples 154 and 155
##STR00144##
[0412] Step 1: To a stirred mixture of diethylamine (10.3 ml, 99.6
mmol), 3-chloro-3-methylbut-1-yne (10.2 g, 99.6 mmol),
triethylamine (16.7 mL, 119 mmol), and THF (100 mL) at 0.degree. C.
was added copper (I) chloride (0.986 g, 9.96 mmol). The resulting
suspension was allowed to warm to room temperature, and stirring
continued for 4 hours. The reaction mixture was partitioned between
diethyl ether (250 mL) and a saturated aqueous solution of
NaHCO.sub.3 (100 mL). The phases were separated, and the aqueous
phase was re-extracted with diethyl ether (100 mL). The combined
organic phases were dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The brown oil was distilled (105-110.sup..degree. C)
at atmospheric pressure under N.sub.2. The product A was obtained
as an oil (1.85 g, 9%).
[0413] Steps 2-4: intermediate A was converted into desired final
compound in accordance with the method described in Scheme 48 by
substituting A for N,N-dimethylpropargylamine.
Example 160
##STR00145##
[0415] Step 1: to a solution of (N-Boc)propargylamine (3.1 g) in
DMF (20 mL) was slowly added NaH (1.1 eq) at 0.degree. C. under N2.
After the mixture was stirred at r.t. for 1 hr, methyl iodide (1.1
eq) was added at 0.degree. C. Ice bath was removed and the flask
was warmed up naturally to r.t. Water was added to quench the
reaction. After removal of solvents the residue was taken up in
EtOAc and water. Extraction and concentration of combined organic
phases gave essentially pure A (95%).
[0416] Steps 2-4: Intermediate A was converted into compound B in
accordance with the method described in steps 3-5 of Scheme 48 by
substituting A for N,N-dimethylpropargylamine.
[0417] Step 5: to a solution of compound B (189 mg) in DCM (3 mL)
was added TFA (1 mL). The mixture was stirred at rt for 1 h. The
volatile components were removed under reduced pressure to give a
cloudy residue. Trituration with MTBE followed by filtration and
wash with MTBE gave the desired product as a off-white powder (92
mg, 57%).
Example 164
[0418] Title compound was prepared in accordance with the method
described in Scheme 12 by substituting 2,4,5-trichloropyrimidine
for 5-bromo-2,4-dichloropyrimidine and
3-amino-4-(dimethylphosphoryl)-pyridine A for
2-(dimethylphosphoryl)aniline 1. Compound A was prepared in
accordance with the method described in step 1 of Scheme 1 for the
synthesis of intermediate 1 using 3-amino-4-iodopyridine instead of
2-iodoaniline as starting material.
Examples 157, 158, 159, 161,162, 165, 166, 167, 168, 177, 178, 179,
182,183, 184
##STR00146##
[0420] Step 1: a solution of appropriate secondary amine and
propargyl bromide (supplied as a solution in toluene) in ether was
stirred at 0.degree. C. then r.t. for 3 hr. The precipitate was
filtered off and the filtrate was carefully distilled to furnish
product A. Contamination of A with small amount of toluene was
unavoidable in some cases but this did not affect next step
reaction. Certain compounds A with relatively high boiling points
were purified by silica gel column chromatography (5% MeOH in DCM)
to remove residual secondary amine which was found to directly
displace the bromide in the next step.
[0421] Steps 2-4: Crude or pure A was converted into desired final
compound in accordance with the method described in Scheme 48 by
substituting A for N,N-dimethylpropargylamine.
Example 180, 181
[0422] The corresponding propargyl nitro compound was prepared as
described above, and the E and Z isomers of the reduced amino
intermediate were separately recovered. Acroylation using the
general procedure yielded the title compounds:
##STR00147##
Example 185
##STR00148##
[0424] IM1 was prepared according to a literature procedure (WO
2009143389). A solution of IM1 (284 mg, 1.12 mmol) and
dimethylamine (1.23 mmol, 1.1 mL, 40% in water) in THF-H.sub.2O
(1:1,4 mL) was stirred at 80.degree. C. overnight. HPLC showed full
conversion. The reaction mixture was concentrated under reduced
pressure followed by partition between saturated sodium bicarbonate
solution and DCM. Upon extraction the combined DCM extracts were
dried over anhydrous sodium sulfate. The solvents were removed to
give IM2 as yellow viscous oil (315 mg). No further purification
was performed.
##STR00149##
[0425] IM2 (315 mg) was reduced into IM3 using standard
Zn/NH.sub.4Cl procedure described previously; a pale yellow oil was
obtained (308 mg). This crude material was used directly in the
next step.
##STR00150##
[0426] IM4 was prepared according to a literature procedure (Nature
2009, 462, 1070). This material (400 mg) underwent a S.sub.NAr
reaction with IM3 (308 mg) under standard condition (TFA, 2-BuOH,
100.degree. C., overnight). Conventional workup followed by flash
chromatography on silica gel (eluent: 0-15% MeOH in DCM) afforded
IM5 as a white foam (89 mg, 15%).
##STR00151##
[0427] IM5 (26 mg) was converted into corresponding acrylamide
under standard acroylation procedure described previously.
Conventional workup followed by preparative TLC (eluent: 10% MeOH
in DCM) afforded the desired product as a light yellow solid (20
mg, 77%).
Compounds of the Invention
[0428] The compounds depicted below were synthesized using methods
described herein or by methods analogous thereto and can be useful
for treating EGFR-driven cancers.
[0429] Examples 1-21 were made in accordance with the methods shown
in Scheme 24 by substituting appropriate alcohols for
1-(2-hydroxyethyl)-4-methylpiperazine.
Example 1
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acrylamide
##STR00152##
[0430] Example 2
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)acrylamide
##STR00153##
[0431] Example 3
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-methylpiperidin-4-yl)methoxy)phenyl)acrylamide
##STR00154##
[0432] Example 4
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(2-morpholinoethoxyl)phenyl)acrylamide
##STR00155##
[0433] Example 5
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(3-morpholinopropoxy)phenyl)acrylamide
##STR00156##
[0434] Example 6
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-meth
oxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)acrylamide
##STR00157##
[0435] Example 7
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-methylpiperidin-2-yl)methoxy)phenyl)acrylamide
##STR00158##
[0436] Example 8
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(2-(piperidin-1-yl)ethoxy)phenyl)acrylamide
##STR00159##
[0437] Example 9
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(oxetan-3-yloxy)phenyl)acrylamide
##STR00160##
[0438] Example 10
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(pyridin-3-ylmethoxy)phenyl)acrylamide
##STR00161##
[0439] Example 11
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(pyridin-4-ylmethoxy)phenyl)acrylamide
##STR00162##
[0440] Example 12
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide
##STR00163##
[0441] Example 13
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-methylpyrrolidin-3-yl)oxy)phenyl)acrylamide
##STR00164##
[0442] Example 14
rel-(R)--N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide
##STR00165##
[0443] Example 15
N-(2-((1-(azetidin-1-yl)-3-methoxypropan-2-yl)oxy)-5-((5-chloro-4-((2-(dim-
ethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylam-
ide
##STR00166##
[0444] Example 16
rel-(R)--N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-4-methoxy-2-((1-methylpiperidin-3-yl)oxy)phenyl)acrylamide
##STR00167##
[0445] Example 17
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-methylazetidin-3-yl)oxy)phenyl)acrylamide
##STR00168##
[0446] Example 18
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)phenyl)acrylamide
##STR00169##
[0447] Example 19
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((4-methyl-1,4-oxazepan-6-yl)oxy)phenyl)acrylamide
##STR00170##
[0448] Example 20
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-methylpyrrolidin-3-yl)methoxy)phenyl)acrylamide
##STR00171##
[0449] Example 21
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-((2-(dimethylamino)cyclohexyl)oxy)-4-methoxyphenyl)acrylamide
##STR00172##
[0451] Examples 22-32 were made in accordance with the methods
shown in Scheme 25.
Example 22
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide
##STR00173##
[0452] Example 23
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(4-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide
##STR00174##
[0453] Example 24
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
##STR00175##
[0454] Example 25
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide
##STR00176##
[0455] Example 26
rac-(R)--N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamid-
e
##STR00177##
[0456]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-methoxy-2-(4-(1methylpiperidin-4yl)piperazin-1yl)acrylamide
##STR00178##
[0457] Example 28
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(3-morpholinopyrrolidin-1-yl)phenyl)acrylamide
##STR00179##
[0458] Example 29
rac-(R)--N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamid-
e
##STR00180##
[0459] Example 30
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(dimethylamino)piperidin-1-yl)-4-methoxyphenyl)acrylamide
##STR00181##
[0460] Example 31
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-yl)phenyl)acrylamide
##STR00182##
[0461] Example 32
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-hydroxypyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
##STR00183##
[0463] Examples 33-41 were made in accordance with the methods
shown in Scheme 26 by substituting secondary amines for
(3-dimethylamino)pyrrolidine.
Example 33
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)phenyl)acrylamide
##STR00184##
[0464] Example 34
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(diethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
##STR00185##
[0465] Example 35
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-hydroxy-[1,3'-bipyrrolidin]-1'-yl)-4-methoxyphenyl)acrylamide
##STR00186##
[0466] Example 36
N-(2-([1,3'-bipyrrolidin]-1'-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)ph-
enyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00187##
[0467] Example 37
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(3-(4-methylpiperazin-1yl)pyrrolidin-1-yl)phenyl)acrylamide
##STR00188##
[0468] Example 38
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-((2-(diethylamino)ethyl)(methyl)amino)pyrrolidin-1-yl)-4-methoxyph-
enyl)acrylamide
##STR00189##
[0469] Example 39
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylami-
de
##STR00190##
[0470] Example 40
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(4-(2-hydroxyethyl)piperazin-1-yl)pyrrolidin-1-yl)-4-methoxyphenyl-
)acrylamide
##STR00191##
[0471] Example 41
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(3-((2-methoxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)ac-
rylamide
##STR00192##
[0473] Examples 42-53 were made in accordance with the methods
shown in Scheme 27.
Example 42
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-(pyrrolidin-1-ylmethyl)acrylamide
##STR00193##
[0474] Example 43
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-(piperidin-1-ylmethyl)acrylamide
##STR00194##
[0475] Example 44
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)acrylamide
##STR00195##
[0476] Example 45
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)ac-
rylamide
##STR00196##
[0477] Example 46
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((1,1-dioxidothiomorpholino)methyl)acrylamide
##STR00197##
[0478] Example 47
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((3-oxopiperazin-1-yl)methyl)acrylamide
##STR00198##
[0479] Example 48
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-(morpholinomethyl)acrylamide
##STR00199##
[0480] Example 49
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((4-methylpiperazin-1-yl)methyl)acrylamide
##STR00200##
[0481] Example 50
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((4-isopropylpiperazin-1-yl)methyl)acrylamide
##STR00201##
[0482] Example 51
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((4-morpholinopiperidin-1-yl)methyl)acrylamide
##STR00202##
[0483] Example 52
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)acrylamide
##STR00203##
[0484] Example 53
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-((3-hydroxypyrrolidin-1-yl)methyl)acrylamide
##STR00204##
[0486] Example 54 was made in accordance with the methods shown in
Scheme 28.
Example 54
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-fluorophenyl)acrylamide
##STR00205##
[0488] Examples 55-57 were made in accordance with the methods
shown in Scheme 29.
Example 55
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((4-methylpiperazin-1-yl)methyl)phenyl)acrylamide
##STR00206##
[0489] Example 56
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(4-methylpiperazine-1-carbonyl)phenyl)acrylamide
##STR00207##
[0491] Example 57 was made in accordance with the methods shown in
Scheme 30.
Example 57
N-(2-(3-aminopyrrolidin-1-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)pheny-
l)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00208##
[0493] Examples 58-64 were made in accordance with the methods
shown in Scheme 31.
Example 58
N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)ami-
no)-4-methoxyphenyl)-N4-(2-(dimethylamino)ethyl)fumaramide
##STR00209##
[0494] Example 59
(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)-
amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide
##STR00210##
[0495] Example 60
N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)ami-
no)-4-methoxyphenyl)-N4,N4-dimethylfumaramide
##STR00211##
[0496] Example 61
(Z)-4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl-
)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoic acid
##STR00212##
[0497] Example 62
N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)ami-
no)-4-methoxyphenyl)-N4,N4-dimethylmaleamide
##STR00213##
[0498] Example 63
(Z)--N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl-
)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-4-oxobut-2-enamide
##STR00214##
[0499] Example 64
N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)ami-
no)-4-methoxyphenyl)-N4-(2-(dimethylamino)ethyl)maleamide
##STR00215##
[0501] Example 65 was made in accordance with the methods shown in
Scheme 32.
Example 65
N-(2-(3-amino-3-methylbut-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylphosphory-
l)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00216##
[0503] Example 66 was made in accordance with the methods shown in
Scheme 33.
Example 66
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(2-(dimethylamino)-3-hydroxypropoxy)-4-methoxyphenyl)acrylamide
##STR00217##
[0505] Example 67 was made in accordance with the methods shown in
Scheme 35.
Example 67
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-((2-((2-fluoroethyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxypheny-
l)acrylamide
##STR00218##
[0507] Examples 68-73 were made in accordance with the methods
shown in Scheme 37.
Example 68
N-(2-(3-(azetidin-1-yl)pyrrolidin-1-yl)-5-((5-chloro-4-((2-(dimethylphosph-
oryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00219##
[0508] Example 69
N-(2-([1,4'-bipiperidin]-1'-yl)-5-((5-chloro-4-((2-(dimethylphosphoryl)phe-
nyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00220##
[0509] Example 70
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(4-morpholinopiperidin-1-yl)phenyl)acrylamide
##STR00221##
[0510] Example 71
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)acryla-
mide
##STR00222##
[0511] Example 72
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)acrylamide
##STR00223##
[0513] Example 73 was made in accordance with the methods shown in
Scheme 38.
Example 73
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-((1-(dimethylamino)cyclopropyl)ethynyl)-4-methoxyphenyl)acrylamide
##STR00224##
[0515] Example 74 was made in accordance with the methods shown in
Scheme 40.
Example 74
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)acrylamide
##STR00225##
[0517] Example 75 was made in accordance with the methods shown in
Scheme 41.
Example 75
(E)-ethyl
4-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidi-
n-2-yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoate
##STR00226##
[0519] Example 76 was made in accordance with the methods shown in
Scheme 42.
Example 76
(E)-tert-butyl
(1-(3-((3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-y-
l)amino)-4-methoxyphenyl)amino)-3-oxoprop-1-en-1-yl)cyclopropyl)carbamate
##STR00227##
[0520] Example 77
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-fluoroacrylamide
##STR00228##
[0521] Example 78
(E)-3-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimi-
din-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00229##
[0522] Example 79
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)cyclohex-1-enecarboxamide
##STR00230##
[0523] Example 80
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)but-2-ynamide
##STR00231##
[0524] Example 81
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-4-(dimethylamino)but-2-ynamide
##STR00232##
[0525] Example 82
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-(trifluoromethyl)acrylamide
##STR00233##
[0526] Example 83
N-(3-((5-chloro-2-((4-(dimethylphosphoryl)-2-methoxyphenyl)amino)pyrimidin-
-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-ynamide
##STR00234##
[0527] Example 84
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-1-methyl-1,2,5,6-tetrahydropyridine-3-carboxamide
##STR00235##
[0528] Example 85
(E)-3-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimi-
din-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide
##STR00236##
[0529] Example 86
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-methoxyethoxyl)phenyl)amin-
o)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00237##
[0530] Example 87
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-ynamide
##STR00238##
[0531] Example 88
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-fluoro-4-methoxyphenyl)-5-(piperidin-1-yl)pent-2-ynamide
##STR00239##
[0532] Example 89
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-fluoro-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-ynamide
##STR00240##
[0533] Example 90
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-fluoro-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-ynamide
##STR00241##
[0534] Example 91
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-ynamide
##STR00242##
[0535] Example 92
(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)-
amino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide
##STR00243##
[0536] Example 93
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-3-phenylpropiolamide
##STR00244##
[0537] Example 94
(E)-3-(1-aminocyclopropyl)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)pheny-
l)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00245##
[0538] Example 95
(E)-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)-
amino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-enamide
##STR00246##
[0539] Example 96
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(diethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide
##STR00247##
[0540] Example 97
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-4-methoxybut-2-ynamide
##STR00248##
[0541] Example 98
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-(pyrrolidin-1-yl)ethoxy)ph-
enyl)amino)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide
##STR00249##
[0542] Example 99
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-((tetrahydrofuran-3-yl)oxy)ph-
enyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00250##
[0543] Example 100
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-((tetrahydro-2H-pyran-4-yl)me-
thoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00251##
[0544] Example 101
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-morpholinophenyl)-5-(piperidin-1-yl)pent-2-ynamide
##STR00252##
[0545] Example 102
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)but-2-ynamide
##STR00253##
[0546] Example 103
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(oxetan-3-yloxy)phenyl)but-2-ynamide
##STR00254##
[0547] Example 104
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-morpholinophenyl)-4-(dimethylamino)but-2-ynamide
##STR00255##
[0548] Example 105
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-morpholinophenyl)-4-methoxybut-2-ynamide
##STR00256##
[0549] Example 106
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)but-2-ynam-
ide
##STR00257##
[0550] Example 107
N-(4-((5-chloro-4-((2-(dimethylphosphoryl)-3-(2-(piperidin-1-yl)ethoxy)phe-
nyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)acrylamide
##STR00258##
[0551] Example 108
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2-(piperidin-1-yl)ethoxy)phe-
nyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00259##
[0552] Example 109
N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)ami-
no)-4-methoxyphenyl)-N4-methylfumaramide
##STR00260##
[0553] Example 110
N1-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)ami-
no)-4-methoxyphenyl)-N4-methylmaleamide
##STR00261##
[0554] Example 111
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)-4-methoxybut-2-yn-
amide
##STR00262##
[0555] Example 112
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)but-2-ynamide
##STR00263##
[0556] Example 113
rac-(R)--N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)methacryl-
amide
##STR00264##
[0557] Example 114
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-morpholinophenyl)-5-(dimethylamino)pent-2-ynamide
##STR00265##
[0558] Example 115
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-morpholinophenyl)-5-methoxypent-2ynamide
##STR00266##
[0559] Example 116
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(3-methyl-3-(pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)acrylamid-
e
##STR00267##
[0560] Example 117
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-(2-(dimethylamino)ethoxy)phenyl)acrylamide
##STR00268##
[0561] Example 118
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-morpholinophenyl)-5-(4-methylpiperazin-1-yl)pent-2-ynamide
##STR00269##
[0562] Example 119
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-(pyrrolidin-1-yl)phenyl)-5-(4-methylpiperazin-1-yl)pent-2-y-
namide
##STR00270##
[0563] Example 120
N-(5-((5-cyclopropyl-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl-
)amino)-2-((2-(diethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamid-
e
##STR00271##
[0564] Example 121
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-((1-(diethylamino)-3-fluoropropan-2-yl)oxy)-4-methoxyphenyl)acrylamid-
e
##STR00272##
[0565] Example 122
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-morpholinophenyl)-5-(2-(methoxymethyl)pyrrolidin-1-yl)pent--
2-ynamide
##STR00273##
[0566] Example 123
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-((1-(2-methoxyethyl)piperidin-3-yl)oxy)phenyl)acrylamide
##STR00274##
[0567] Example 124
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide
##STR00275##
[0568] Example 125
N-(3-((5-chloro-4-((4-(2-(dimethylamino)ethoxy)-2-(dimethylphosphoryl)phen-
yl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00276##
[0569] Example 126
N-(3-((5-chloro-4-((4-(3-(dimethylamino)propoxy)-2-(dimethylphosphoryl)phe-
nyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00277##
[0570] Example 127
1-(6-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-5-methoxyindolin-1-yl)prop-2-en-1-one
##STR00278##
[0571] Example 128
##STR00279##
[0572]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2--
yl)amino)-2-(4-dimethylamino)but-1-yn-1-yl)-4-methoxyphenyl)acrylamide
Example 129
##STR00280##
[0573]
(R)--N-(5((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidi-
n-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphe-
nyl)acrylamide
##STR00281##
[0574] Example 130
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-2-((1-dimethylamino)-3
methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide
Example 131
##STR00282##
[0575]
N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methoxypyrimidin-2-
-yl)amino)-4-methoxyphenyl)acrylamide
##STR00283##
[0576] Example 132
2-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-4-methoxyphenyl)acrylamide
##STR00284##
[0577] Example 133
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxy-2-methylphenyl)acrylamide
Example 134
##STR00285##
[0578]
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide
Example 135
##STR00286##
[0579]
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2--
yl)amino)-4-ethylphenyl)acrylamide
Example 136
##STR00287##
[0580]
N-(4-chloro-3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pry-
imidin-2-yl)amino)phenyl)acrylamide
Example 137
##STR00288##
[0581]
2-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyr-
imidin-2-yl)amino)-4-methoxyphenyl)acetamide
Example 138
##STR00289##
[0582]
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-(oxetan-3-yloxy)phenyl)acrylamide
Example 139
##STR00290##
[0583]
N-(3-((5-cyano-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-y-
l)amino)-4-methoxyphenyl)acrylamide
Example 140
##STR00291##
[0584]
2-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyr-
imidin-2-yl)amino)-4-methoxy-2-methylphenyl)acetamide
Example 141
##STR00292##
[0585]
2-chloro-N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyr-
imidin-2-yl)amino)-4-methoxyphenyl)acetamide
Example 142
##STR00293##
[0586]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pryimidin-2--
yl)amino)-2-((1-(dimethylamino)-3-ethoxypropan-2-yl)oxy)-4-methoxyphenyl)a-
crylamide
Example 143
##STR00294##
[0587]
N-5-((5-cloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl-
)amino)-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-meth-
ylphenyl)acrylamide
Example 144
##STR00295##
[0588]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methylphenyl)a-
crylamide
##STR00296##
[0589]
N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyr-
imidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)a-
crylamide
Example 146
##STR00297##
[0590]
N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyr-
imidin-2-yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-yl)oxy)phenyl)a-
crylamide
##STR00298##
[0591] Example 147
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amin-
o)-4-methoxyphenyl)-2-fluoroacetamide
##STR00299##
[0592] Example 148
2-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-4-methylphenyl)acetamide
Example 149
2-chloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-2-fluoro-4-methoxyphenyl)acetamide
##STR00300##
[0593] Example 150
1-chloro-N-(3-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin--
2-yl)amino)-4-methoxyphenyl)methanesulfonamide
##STR00301##
[0594] Example 151
##STR00302##
[0595]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-methylphenyl)acrylamide
Example 152
##STR00303##
[0596]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-ethylphenyl)acrylamide
Example 153
##STR00304##
[0597]
N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-y-
l)amino)-2-(3-(dimethylamino)prop-1-yn
1-yl)-4-methoxyphenyl)acrylamide
Example 154
##STR00305##
[0598]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(diethylamino)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acryl-
amide
Example 155
##STR00306##
[0599]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(dimethylamio)-3-methylbut-1-yn-1-yl)-4-methoxyphenyl)acryl-
amide
Example 156
##STR00307##
[0600]
N-(4-chloro-5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyr-
imidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)acrylamide
Example 157
##STR00308##
[0601]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-methyoxy-2-(3-(pyrrolidin-1-yl)prop-1-yn-1-yl)phenyl)
acrylamide
Example 158
##STR00309##
[0602]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(diisopropylamino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamid-
e
Example 159
##STR00310##
[0603]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)phenyl)acr-
ylamide
Example 160
##STR00311##
[0604]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-methoxy-2-(3-(methylamino)prop-1-yn-1-yl)phenyl)acrylamide
Example 161
##STR00312##
[0605]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-methoxy-2-(3-((2-methoxyethyl)(methyl)amino)prop-1-yn-1-yl)phe-
nyl)acrylamide
Example 162
##STR00313##
[0606]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(ethyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acrylam-
ide
Example 163
##STR00314##
[0607]
N-(3-((6-((3-(dimethylphosphoryl)pyridin-2-yl)amino)pyrimidin-4-yl)-
amino)-4-methoxyphenyl)acrylamide
Example 164
##STR00315##
[0608]
N-(3-((5-chloro-4-((4-(dimethylphosphoryl)pyridin-3-yl)amino)pyrimi-
din-2-yl)amino)-4-methoxyphenyl)acrylamide
Example 165
##STR00316##
[0609]
N-(2-(3-(azepan-1-yl)prop-1-yn-1-yl)-5-((5-chloro-4-((2-(dimethylph-
osphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide
Example 166
##STR00317##
[0610]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(isopropyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)acr-
ylamide
Example 167
##STR00318##
[0611]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-4-methyoxy-2-(3-(piperidin-1-yl)prop-1-yn-1-yl)phenyl)acrylamide
Example 168
##STR00319##
[0612]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)amino)-2-(3-(cyclopentyl(methyl)amino)prop-1-yn-1-yl)-4-methoxyphenyl)a-
crylamide
##STR00320##
[0613] Example 169
N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-1,3,5-triazin-2-yl)amino)-4-
-methoxyphenyl)acrylamide
Example 170
##STR00321##
[0614]
N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-1,3,5-triazin-2-yl)a-
mino)-4-(trifluoromethoxy)phenyl) acrylamide
Example 171
##STR00322##
[0615]
N-(3-((6-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-4-yl)amino)-
-4-methoxyphenyl)acrylamide
Example 172
##STR00323##
[0616] (1
S,2R,3S,4R)-3-((2-((5-acrylamido-2-methoxyphenyl)amino)-5-chloro-
pyrimidin-4-yl)amino)bicyclo[2.2.1]heptane-2-carboxamide
Example 173
##STR00324##
[0617]
2-((2-((5-acrylamido-4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-
phenyl)amino)-5-chloropyrimidin-4-yl)amino)benzamide
Example 174
##STR00325##
[0618]
N-(5-((5-chloro-4-((2-cyanophenyl)amino)pyrimidin-2-yl)amino)-2-(3--
(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
Example 175
##STR00326##
[0619]
N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-y-
l)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide
Example 176
##STR00327##
[0620]
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2--
yl)methyl)-4-methoxy-2-(3-(4-methylpiperidin-1-yl)prop-1-yn-1-yl)phenyl)ac-
rylamide
Example 177
##STR00328##
[0622]
N-(2-(3-(tert-butyl(methyl)amino)prop-1-yn-1-yl)-5-((5-chloro-4-((2-
-(dimethylphosphoryl) phenyl)amino)pyrimidin-2-yl)
methyl)-4-methoxyphenyl)acrylamide
Example 178
##STR00329##
[0624] N-(5-((5-chloro-4-((2-(dimethylphosphoryl)
phenyl)amino)pyrimidin-2-yl)
methyl)-2-(3-(2-(dimethylamino)pyrrolidin-1-yl)
prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide
Example 179
##STR00330##
[0626] N-(5-((5-chloro-4-((2-(dimethylphosphoryl)
phenyl)amino)pyrimidin-2-yl)
methyl)-4-methoxy-2-(3-(2-methylpiperidin-1-yl)
prop-1-yn-1-1-yl)phenyl)acrylamide
Example 180
##STR00331##
[0628] (Z)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)
phenyl)amino)pyrimidin-2-yl)
methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)
4-methoxyphenyl)acrylamide
Example 181
##STR00332##
[0630] (E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)
phenyl)amino)pyrimidin-2-yl)
methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)
4-methoxyphenyl)acrylamide
Example 182
##STR00333##
[0632] N-(5-((5-chloro-4-((2-(dimethylphosphoryl)
phenyl)amino)pyrimidin-2-yl)
methyl)-2-(3-(4-fluoropiperidin-1-yl)prop-1-yn-1-yl)-4-methoxyphenyl)
acrylamide
Example 183
##STR00334##
[0634] N-(5-((5-chloro-4-((2-(dimethylphosphoryl)
phenyl)amino)pyrimidin-2-yl)
methyl)-4-methoxy-2-(3-(methyl(tetrahydro-2H-pyran-4-yl)
amino)prop-1-yn-1-yl)phenyl)acrylamide
Example 184
##STR00335##
[0636] N-(5-((5-chloro-4-((2-(dimethylphosphoryl)
phenyl)amino)pyrimidin-2-yl)
methyl)-4-methoxy-2-(3-(dimethylamino)prop-1-yn-1-yl)
4-methoxyphenyl)but-2-ynamide
Example 185
##STR00336##
[0638]
N-(3-((5-chloro-2-(2-methoxy-4-(1-methyl-4-oxido-1,4-azaphosphinan--
4-yl) benzyl)pyrimidin-4-yl)oxy)phenyl)acrylamide
Example 186
Additional Compounds of the Invention
[0639] The compounds depicted below can be synthesized using
methods analogous to those described herein and can be useful for
treating EGFR-driven cancers.
##STR00337## ##STR00338## ##STR00339## ##STR00340##
##STR00341##
Biological Assays.
[0640] Kinase inhibitory activity of the compounds was measured
against human EGFR (native sequence) and against EGFR bearing the
L858R mution and the L858R/T790M double mutation (EGFR, L858R, and
L858R/T790M, respectively in Table 1). Additional assays can be
conducted with EGFR deletion mutants such as delE746-A750 with or
without the additional T790M mutation. Assay conditions included 10
pt curves with 3 .mu.M top concentration (singlicates) and 10 .mu.M
ATP.
[0641] We also assessed the antiproliferative activity of compounds
of Formula (I) against BaF3 cells expressing the target EGFR
mutations or control (i.e., cell lines expressing wildtype EGFR).
Assays were conducted using MTT.
TABLE-US-00001 TABLE 1 IC50 for kinase inhibition (nM).sup.1 BAF3
BAF3 EGFR EGFR DEL L858R- EGFR T790M T790M Example Chemical Name
LC-MS EGFR L858R BAF3 PURO PURO # (ChemDraw Ultra 12.0 (M + H) EGFR
L858R T790M PARENTAL POOL POOL 1 N-(5-((5-chloro-4-((2- 585.2 A A A
D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(2-(pyrrolidin-1- yl)ethoxy)phenyl)acrylamide
2 N-(5-((5-chloro-4-((2- 614.2 C A A D D N/A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-
yl)ethoxy)phenyl)acrylamide 3 N-(5-((5-chloro-4-((2- 599.2 B A A D
C D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpiperidin-4-
yl)methoxy)phenyl)acrylamide 4 N-(5-((5-chloro-4-((2- 601.2 A A A D
B C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(2- morpholinoethoxy)phenyl)acrylamide 5
N-(5-((5-chloro-4-((2- 615.2 C A A D C C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3- morpholinopropoxy)phenyl)acrylamide 6
N-(5-((5-chloro-4-((2- 586.2 D A B D B C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-
yl)methoxy)phenyl)acrylamide 7 N-(5-((5-chloro-4-((2- 599.2 A A A D
A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpiperidin-2-
yl)methoxy)phenyl)acrylamide 8 N-(5-((5-chloro-4-((2- 599.2 A A A D
A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(2-(piperidin-1- yl)ethoxy)phenyl)acrylamide
9 N-(5-((5-chloro-4-((2- 544.1 D A A D A B
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(oxetan-3- yloxy)phenyl)acrylamide 10
N-(5-((5-chloro-4-((2- 579.2 B A A D B C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(pyridin-3- ylmethoxy)phenyl)acrylamide 11
N-(5-((5-chloro-4-((2- 579.1 A A A D A C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(pyridin-4- ylmethoxy)phenyl)acrylamide 12
N-(5-((5-chloro-4-((2- 585.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpiperidin-3-
yl)oxy)phenyl)acrylamide 13 N-(5-((5-chloro-4-((2- 571.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-
yl)oxy)phenyl)acrylamide 14 rel-(R)-N-(5-((5-chloro-4-((2- 585.2 A
A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpiperidin-3-
yl)oxy)phenyl)acrylamide 15
N-(2-((1-(azetidin-1-yl)-3-methoxypropan-2-yl)oxy)-5-((5- 615.2 A A
A D A A chloro-4-((2- (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 16
rel-(R)-N-(5-((5-chloro-4-((2- 585.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpiperidin-3-
yl)oxy)phenyl)acrylamide 17 N-(5-((5-chloro-4-((2- 557.2 N/A N/A
N/A D B C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylazetidin-3-
yl)oxy)phenyl)acrylamide 18 N-(5-((5-chloro-4-((2- 585.2 N/A N/A
N/A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpyrrolidin-2-
yl)methoxy)phenyl)acrylamide 19 N-(5-((5-chloro-4-((2- 601.2 N/A
N/A N/A N/A N/A N/A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((4-methyl-1,4-oxazepan-6-
yl)oxy)phenyl)acrylamide 20 N-(5-((5-chloro-4-((2- 585.2 N/A N/A
N/A N/A N/A N/A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-methylpyrrolidin-3-
yl)methoxy)phenyl)acrylamide 21 N-(5-((5-chloro-4-((2- 613.2 N/A
N/A N/A N/A N/A N/A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((2-(dimethylamino)cyclohexyl)oxy)-4-
methoxyphenyl)acrylamide 22 N-(5-((5-chloro-4-((2- 653.2 A A A D B
B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-
yl)piperidin-1-yl)phenyl)acrylamide 23 N-(5-((5-chloro-4-((2- 598.2
A A A D A C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(4-(dimethylamino)piperidin-1-yl)-4-
methoxyphenyl)acrylamide 24 N-(5-((5-chloro-4-((2- 584.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-
methoxyphenyl)acrylamide 25 N-(5-((5-chloro-4-((2- 584.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-
yl)phenyl)acrylamide 26 rac-(R)-N-(5-((5-chloro-4-((2- 584.2 A A A
D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-
methoxyphenyl)acrylamide 27 N-(5-((5-chloro-4-((2- 653.3 A A A D B
C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-(1-methylpiperidin-4-
yl)piperazin-1-yl)phenyl)acrylamide 28 N-(5-((5-chloro-4-((2- 626.2
A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-morpholinopyrrolidin-1-
yl)phenyl)acrylamide 29 rac-(R)-N-(5-((5-chloro-4-((2- 584.2 A A A
D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-
methoxyphenyl)acrylamide 30 N-(5-((5-chloro-4-((2- 598.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)piperidin-1-yl)-4-
methoxyphenyl)acrylamide 31 N-(5-((5-chloro-4-((2- 596.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)azetidin-1-
yl)phenyl)acrylamide 32 N-(5-((5-chloro-4-((2- 557.2 A A A D B C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-hydroxypyrrolidin-1-yl)-4- methoxyphenyl)acrylamide
33 N-(5-((5-chloro-4-((2- 624.3 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-
yl)phenyl)acrylamide 34 N-(5-((5-chloro-4-((2- 612.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(diethylamino)pyrrolidin-1-yl)-4-
methoxyphenyl)acrylamide 35 N-(5-((5-chloro-4-((2- 626.2 A A A D C
D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-hydroxy-[1,3'-bipyrrolidin]-1'-yl)-4-
methoxyphenyl)acrylamide 36
N-(2-([1,3'-bipyrrolidin]-1'-yl)-5-((5-chloro-4-((2- 610.2 A A A D
A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 37 N-(5-((5-chloro-4-((2-
639.3 A A A D B C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-
yl)pyrrolidin-1-yl)phenyl)acrylamide 38 N-(5-((5-chloro-4-((2-
669.3 A A A D A C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-((2-
(diethylamino)ethyl)(methyl)amino)pyrrolidin-1-yl)-4-
methoxyphenyl)acrylamide 39 N-(5-((5-chloro-4-((2- 640.3 A A A D C
D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(4-hydroxypiperidin-1-yl)pyrrolidin-1-yl)-4-
methoxyphenyl)acrylamide 40 N-(5-((5-chloro-4-((2- 669.2 A A A D D
D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(4-(2-hydroxyethyl)piperazin-1-
yl)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide 41
N-(5-((5-chloro-4-((2- 628.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-((2-
methoxyethyl)(methyl)amino)pyrrolidin-1- yl)phenyl)acrylamide 42
N-(3-((5-chloro-4-((2- 555.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-(pyrrolidin-1- ylmethyl)acrylamide 43
N-(3-((5-chloro-4-((2- 569.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-(piperidin-1- ylmethyl)acrylamide 44
N-(3-((5-chloro-4-((2- 648.1 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((4-
(methylsulfonyl)piperazin-1-yl)methyl)acrylamide 45
N-(3-((5-chloro-4-((2- 667.3 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((4-(4-methylpiperazin-1-
yl)piperidin-1-yl)methyl)acrylamide 46 N-(3-((5-chloro-4-((2- 619.1
D B A D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((1,1-
dioxidothiomorpholino)methyl)acrylamide 47 N-(3-((5-chloro-4-((2-
584.2 A A A D C D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((3-oxopiperazin-1-
yl)methyl)acrylamide 48 N-(3-((5-chloro-4-((2- 571.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2- (morpholinomethyl)acrylamide 49
N-(3-((5-chloro-4-((2- 584.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((4-methylpiperazin-1-
yl)methyl)acrylamide 50 N-(3-((5-chloro-4-((2- 612.2 B A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((4-isopropylpiperazin-1-
yl)methyl)acrylamide 51 N-(3-((5-chloro-4-((2- 654.3 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((4-morpholinopiperidin-
1-yl)methyl)acrylamide 52 N-(3-((5-chloro-4-((2- 614.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((4-(2-
hydroxyethyl)piperazin-1-yl)methyl)acrylamide 53
N-(3-((5-chloro-4-((2- 571.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-((3-hydroxypyrrolidin-1-
yl)methyl)acrylamide 54 N-(3-((5-chloro-4-((2- 460.1 N/A N/A N/A D
A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-fluorophenyl)acrylamide 55 N-(5-((5-chloro-4-((2- 584.2
A A A D A B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((4-methylpiperazin-1-
yl)methyl)phenyl)acrylamide 56 N-(5-((5-chloro-4-((2- 598.2 C A A D
D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-methylpiperazine-1-
carbonyl)phenyl)acrylamide 57
N-(2-(3-aminopyrrolidin-1-yl)-5-((5-chloro-4-((2- 556.2 A A A D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 58 N1-(3-((5-chloro-4-((2-
586.2 A A A D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-N4-(2- (dimethylamino)ethyl)fumaramide
59 (E)-N-(3-((5-chloro-4-((2- 598.2 A A A D C D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-
4-oxobut-2-enamide 60 N1-(3-((5-chloro-4-((2- 543.2 D B C D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-N4,N4-dimethylfumaramide
61 (Z)-4-((3-((5-chloro-4-((2- 516.1 D D C D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoic acid 62
N1-(3-((5-chloro-4-((2- 543.2 D D D D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-N4,N4-dimethylmaleamide 63
(Z)-N-(3-((5-chloro-4-((2- 598.2 D C D D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)-
4-oxobut-2-enamide 64 N1-(3-((5-chloro-4-((2- 586.2 D A A D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-N4-(2- (dimethylamino)ethyl)maleamide 65
N-(2-(3-amino-3-methylbut-1-yn-1-yl)-5-((5-chloro-4-((2- 553.2 A A
A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 66 N-(5-((5-chloro-4-((2-
589.2 N/A N/A N/A D C D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(2-(dimethylamino)-3-hydroxypropoxy)-4-
methoxyphenyl)acrylamide 67 N-(5-((5-chloro-4-((2- 604.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((2-((2-
fluoroethyl)(methyl)amino)ethyl)(methyl)amino)-4-
methoxyphenyl)acrylamide 68
N-(2-(3-(azetidin-1-yl)pyrrolidin-1-yl)-5-((5-chloro-4-((2- 596.2 A
A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 69
N-(2-([1,4'-bipiperidin]-1'-yl)-5-((5-chloro-4-((2- 638.3 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 70 N-(5-((5-chloro-4-((2-
640.3 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-morpholinopiperidin-1-
yl)phenyl)acrylamide 71 N-(5-((5-chloro-4-((2- 667.3 A A A D B c
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-(4-methyl-1,4-diazepan-1-
yl)piperidin-1-yl)phenyl)acrylamide 72 N-(5-((5-chloro-4-((2- 624.2
B A A D A C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-(pyrrolidin-1-yl)piperidin-1-
yl)phenyl)acrylamide 73 N-(5-((5-chloro-4-((2- 579.2 D A A D C C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)cyclopropyl)ethynyl)-4-
methoxyphenyl)acrylamide 74 N-(5-((5-chloro-4-((2- 598.3 A A A D C
D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(2-(4-methylpiperazin-1-
yl)ethyl)phenyl)acrylamide 75 (E)-ethyl 4-((3-((5-chloro-4-((2-
544.1 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)amino)-4-oxobut-2-enoate 76
(E)-tert-butyl(1-(3-((3-((5-chloro-4-((2- 627.2 D D D D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)amino)-3-oxoprop-1-en-1-
yl)cyclopropyl)carbamate 77 N-(3-((5-chloro-4-((2- 490.1 D A B D A
B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-fluoroacrylamide 78
(E)-3-chloro-N-(3-((5-chloro-4-((2- 506 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 79 N-(3-((5-chloro-4-((2-
526.2 D D D D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)cyclohex-1-enecarboxamide 80
N-(5-((5-chloro-4-((2- 597.2 D A A D A C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(2-(pyrrolidin-1-
yl)ethoxy)phenyl)but-2-ynamide 81 N-(3-((5-chloro-4-((2- 527.2 A A
A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2- ynamide 82
N-(3-((5-chloro-4-((2- 540.1 A A A D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2- (trifluoromethyl)acrylamide 83
N-(3-((5-chloro-2-((4-(dimethylphosphoryl)-2- 528.2 A A A D C D
methoxyphenyl)amino)pyrimidin-4-yl)oxy)phenyl)-4-
(dimethylamino)but-2-ynamide 84 N-(3-((5-chloro-4-((2- 541.2 D A A
D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-1-methyl-1,2,5,6-
tetrahydropyridine-3-carboxamide 85
(E)-3-chloro-N-(5-((5-chloro-4-((2- 524 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide 86
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2- 546.1 B A A D A B
methoxyethoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-
methoxyphenyl)acrylamide 87 N-(5-((5-chloro-4-((2- 545.1 A A A C A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-fluoro-4-methoxyphenyl)-4- (dimethylamino)but-2-ynamide
88 N-(5-((5-chloro-4-((2- 599.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-fluoro-4-methoxyphenyl)-5-(piperidin-1-
yl)pent-2-ynamide 89 N-(5-((5-chloro-4-((2- 571.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-fluoro-4-methoxyphenyl)-4-(pyrrolidin-1-
yl)but-2-ynamide 90 N-(5-((5-chloro-4-((2- 599.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-fluoro-4-methoxyphenyl)-4-methyl-4-
(pyrrolidin-1-yl)pent-2-ynamide 91 N-(3-((5-chloro-4-((2- 581.2 A A
A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-4-methyl-4-(pyrrolidin-1-
yl)pent-2-ynamide 92 (E)-N-(3-((5-chloro-4-((2- 569.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2- enamide 93
N-(3-((5-chloro-4-((2- 546.1 D A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-3-phenylpropiolamide 94
(E)-3-(1-aminocyclopropyl)-N-(3-((5-chloro-4-((2- 527.1 C A A D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 95 (E)-N-(3-((5-chloro-4-((2-
555.2 D A A D B D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2- enamide 96
N-(5-((5-chloro-4-((2- 581.2 D A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(diethylamino)prop-1-yn-1-yl)-4-
methoxyphenyl)acrylamide 97 N-(3-((5-chloro-4-((2- 514.1 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-4-methoxybut-2-ynamide 98
N-(5-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2- 603.2 A A A D A A
(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-
yl)amino)-2-fluoro-4-methoxyphenyl)acrylamide 99
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4- 558.2 A A A D A B
((tetrahydrofuran-3-yl)oxy)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 100
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4- 584.2 B A A D A A
((tetrahydro-2H-pyran-4-
yl)methoxy)phenyl)amino)pyrimidin-2-yl)amino)-4-
methoxyphenyl)acrylamide 101 N-(5-((5-chloro-4-((2- 666.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-morpholinophenyl)-5-(piperidin-
1-yl)pent-2-ynamide 102 N-(5-((5-chloro-4-((2- 598.2 D C D D A B
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((tetrahydro-2H-pyran-4-
yl)methoxy)phenyl)but-2-ynamide 103 N-(5-((5-chloro-4-((2- 556.1 D
A B D A B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(oxetan-3-yloxy)phenyl)but-2- ynamide 104
N-(5-((5-chloro-4-((2- 612.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-morpholinophenyl)-4-
(dimethylamino)but-2-ynamide 105 N-(5-((5-chloro-4-((2- 599.2 A A A
D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-morpholinophenyl)-4- methoxybut-2-ynamide 106
N-(5-((5-chloro-4-((2- 665.2 B A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-
yl)piperidin-1-yl)phenyl)but-2-ynamide 107
N-(4-((5-chloro-4-((2-(dimethylphosphoryl)-3-(2- 599.2 C A A D A C
(piperidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-
yl)amino)-3-methoxyphenyl)acrylamide 108
N-(3-((5-chloro-4-((2-(dimethylphosphoryl)-4-(2- 599.2 A A A D A A
(piperidin-1-yl)ethoxy)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 109 N1-(3-((5-chloro-4-((2-
529.1 D A A D B C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-N4-methylfumaramide 110
N1-(3-((5-chloro-4-((2- 529.1 D A A D A C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-N4-methylmaleamide 111
N-(5-((5-chloro-4-((2- 626.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-
methoxyphenyl)-4-methoxybut-2-ynamide 112 N-(5-((5-chloro-4-((2-
596.2 A A A D A B (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-
methoxyphenyl)but-2-ynamide 113 rac-(R)-N-(5-((5-chloro-4-((2-
598.2 C A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-
methoxyphenyl)methacrylamide 114 N-(5-((5-chloro-4-((2- 626.2 A A A
D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-morpholinophenyl)-5-
(dimethylamino)pent-2-ynamide 115 N-(5-((5-chloro-4-((2- 613.2 A A
A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-morpholinophenyl)-5- methoxypent-2-ynamide
116 N-(5-((5-chloro-4-((2- 607.2 B A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-methyl-3-(pyrrolidin-1-yl)but-
1-yn-1-yl)phenyl)acrylamide 117 N-(3-((5-chloro-4-((2- 529.2 D D D
D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2- yl)amino)-4-(2-
(dimethylamino)ethoxy)phenyl)acrylamide 118 N-(5-((5-chloro-4-((2-
681.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-morpholinophenyl)-5-(4-
methylpiperazin-1-yl)pent-2-ynamide 119 N-(5-((5-chloro-4-((2-
665.2 A A A D C C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(pyrrolidin-1-yl)phenyl)-5-(4-
methylpiperazin-1-yl)pent-2-ynamide 120 N-(5-((5-cyclopropyl-4-((2-
606.3 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((2-(diethylamino)ethyl)(methyl)amino)-4-
methoxyphenyl)acrylamide 121 N-(5-((5-chloro-4-((2- 619.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(diethylamino)-3-fluoropropan-2-yl)oxy)-
4-methoxyphenyl)acrylamide 122 N-(5-((5-chloro-4-((2- 696.3 A A A D
A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-morpholinophenyl)-5-(2-
(methoxymethyl)pyrrolidin-1-yl)pent-2-ynamide 123
N-(5-((5-chloro-4-((2- 629.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-((1-(2-methoxyethyl)piperidin-3-
yl)oxy)phenyl)acrylamide 124 N-(5-((5-chloro-4-((2- 553.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-
methoxyphenyl)acrylamide 125
N-(3-((5-chloro-4-((4-(2-(dimethylamino)ethoxy)-2- 559.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 126
N-(3-((5-chloro-4-((4-(3-(dimethylamino)propoxy)-2- 573.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 127 1-(6-((5-chloro-4-((2-
498.1 N/A N/A N/A D C D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-5-methoxyindolin-1-yl)prop-2-en-1-one 128
N-(5-((5-chloro-4-((2- 567.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(4-(dimethylamino)but-1-yn-1-yl)-4-
methoxyphenyl)acrylamide 129 (R)-N-(5-((5-chloro-4-((2- 603.2 A A A
D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-
yl)oxy)-4-methoxyphenyl)acrylamide 130 N-(5-((5-chloro-4-((2- 603.2
A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-
yl)oxy)-4-methoxyphenyl)acrylamide 131
N-(3-((4-((2-(dimethylphosphoryl)phenyl)amino)-5- 468.1 B A A D A B
methoxypyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide 132
2-chloro-N-(3-((5-chloro-4-((2- 506.1 A A A D A C
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 133 N-(5-((5-chloro-4-((2-
486.1 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-methylphenyl)acrylamide 134
N-(3-((5-chloro-4-((2- 526.1 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-(trifluoromethoxy)phenyl)acrylamide 135
N-(3-((5-chloro-4-((2- 470.1 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-ethylphenyl)acrylamide 136
N-(4-chloro-3-((5-chloro-4-((2- 476 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)phenyl)acrylamide 137 2-chloro-N-(3-((5-chloro-4-((2-
514.1 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acetamide 138 N-(3-((5-chloro-4-((2-
463.1 D D D D D D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-(oxetan-3-yloxy)phenyl)acrylamide 139
N-(3-((5-cyano-4-((2- 508.1 A A A D C D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 140
2-chloro-N-(5-((5-chloro-4-((2- 474.1 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-methylphenyl)acetamide 141
2-chloro-N-(3-((4-((2- 617.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-
2-yl)amino)-4-methoxyphenyl)acetamide 142 N-(5-((5-chloro-4-((2-
587.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)-3-ethoxypropan-2-
yl)oxy)-4-methoxyphenyl)acrylamide 143 N-(5-((5-chloro-4-((2- 587.2
A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-
yl)oxy)-4-methylphenyl)acrylamide 144 N-(5-((5-chloro-4-((2- 607.1
A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-
yl)oxy)-4-methylphenyl)acrylamide 145
N-(4-chloro-5-((5-chloro-4-((2- 606.7 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-
yl)oxy)phenyl)acrylamide 146 N-(4-chloro-5-((5-chloro-4-((2- 514.1
A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-((1-(dimethylamino)-3-methoxypropan-2-
yl)oxy)phenyl)acrylamide 147 N-(3-((5-chloro-4-((2- 478.1 D B C D D
D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)-2-fluoroacetamide 148
2-chloro-N-(3-((5-chloro-4-((2- 478.1 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methylphenyl)acetamide 149
2-chloro-N-(5-((5-chloro-4-((2- 512.1 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-fluoro-4-methoxyphenyl)acetamide 150
1-chloro-N-(3-((5-chloro-4-((2- 530.0 D D D D D D
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)methanesulfonamide 151
N-(5-((5-chloro-4-((2- 537.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-
methylphenyl)acrylamide 152 N-(5-((5-chloro-4-((2- 551.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-
ethylphenyl)acrylamide 153 N-(5-((5-chloro-4-((2- 583.2 A A A D A A
(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-2-
(3-(dimethylamino)prop-1-yn-1-yl)-4- methoxyphenyl)acrylamide 154
N-(5-((5-chloro-4-((2- 536.1 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(diethylamino)-3-methylbut-1-yn-1-yl)-4-
methoxyphenyl)acrylamide 155 N-(5-((5-chloro-4-((2- 581.2 A A A D A
A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-
4-methoxyphenyl)acrylamide 156 N-(4-chloro-5-((5-chloro-4-((2-
557.1 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(dimethylamino)prop-1-yn-1- yl)phenyl)acrylamide 157
N-(5-((5-chloro-4-((2- 579.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-(pyrrolidin-1-yl)prop-1-yn-1-
yl)phenyl)acrylamide 158 N-(5-((5-chloro-4-((2- 609.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(diisopropylamino)prop-1-yn-1-yl)-4-
methoxyphenyl)acrylamide 159 N-(5-((5-chloro-4-((2- 608.2 A A A D A
C (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-(4-methylpiperazin-1-yl)prop-
1-yn-1-yl)phenyl)acrylamide 160 N-(5-((5-chloro-4-((2- 539.1 A A A
D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-(methylamino)prop-1-yn-1-
yl)phenyl)acrylamide 161 N-(5-((5-chloro-4-((2- 597.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-((2-
methoxyethyl)(methyl)amino)prop-1-yn-1- yl)phenyl)acrylamide 162
N-(5-((5-chloro-4-((2- 567.2 A A A D A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(ethyl(methyl)amino)prop-1-yn-1-yl)-4-
methoxyphenyl)acrylamide 163
N-(3-((6-((3-(dimethylphosphoryl)pyridin-2- 439.1 B A C D D D
yl)amino)pyrimidin-4-yl)amino)-4- methoxyphenyl)acrylamide 164
N-(3-((5-chloro-4-((4-(dimethylphosphoryl)pyridin-3- 473.1 D A A D
C D yl)amino)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide 165
N-(2-(3-(azepan-1-yl)prop-1-yn-1-yl)-5-((5-chloro-4-((2- 607.2 A A
A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxyphenyl)acrylamide 166 N-(5-((5-chloro-4-((2-
581.2 A A A D A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(isopropyl(methyl)amino)prop-1-yn-1-yl)-
4-methoxyphenyl)acrylamide 167 N-(5-((5-chloro-4-((2- 593.2 A A A A
A A (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-4-methoxy-2-(3-(piperidin-1-yl)prop-1-yn-1-
yl)phenyl)acrylamide 168 N-(5-((5-chloro-4-((2- 607.2 A A A A A A
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)amino)-2-(3-(cyclopentyl(methyl)amino)prop-1-yn-1-
yl)-4-methoxyphenyl)acrylamide 176 N-(5-((5-chloro-4-((2- 607.2 A A
A D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-4-methoxy-2-(3-(4-methylpiperidin-1-yl)prop-
1-yn-1-yl)phenyl)acrylamide 177
N-(2-(3-(ferf-butyl(methyl)amino)prop-1-yn-1-yl)-5- 595.2 A A A D
((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-4-methoxyphenyl)acrylamide 178 N-(5-((5-chloro-4-((2-
622.2 B A A D (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-2-(3-(2-(dimethylamino)pyrrolidin-1-
yl)prop-1-yn-1-yl)-4-methoxyphenyl)acrylamide 179
N-(5-((5-chloro-4-((2- 607.2
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-4-methoxy-2-(3-(2-methylpiperidin-1-
yl)prop-1-yn-1-yl)phenyl)acrylamide 180 (Z)-N-(5-((5-chloro-4-((2-
555.2 (dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)-4-
methoxyphenyl)acrylamide 181 (E)-N-(5-((5-chloro-4-((2- 555.2
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-2-(3-(dimethylamino)prop-1-en-1-yl)-4-
methoxyphenyl)acrylamide 182 N-(5-((5-chloro-4-((2- 611.2
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-2-(3-(4-fluoropiperidin-1-yl)prop-1-yn-1-
yl)-4-methoxyphenyl)acrylamide 183 N-(5-((5-chloro-4-((2- 623.2
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-4-methoxy-2-(3-(methyl(tetrahydro-2H-
pyran-4-yl)amino)prop-1-yn-1-yl)phenyl)acrylamide 184
N-(5-((5-chloro-4-((2- 565.2
(dimethylphosphoryl)phenyl)amino)pyrimidin-2-
yl)methyl)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4-
methoxyphenyl)but-2-ynamide 185
N-(3-((5-chloro-2-(2-methoxy-4-(1-methyl-4-oxido- 528.1
1,4-azaphosphinan-4-yl)benzyl)pyrimidin-4- yl)oxy)phenyl)acrylamide
.sup.1A = <50 nM; B = 50 .fwdarw. 100 nM; C = 101 nM .fwdarw.
<250 nM; D = .gtoreq.250 nM
OTHER EMBODIMENTS
[0642] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each independent publication or patent
application was specifically and individually indicated to be
incorporated by reference.
[0643] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure that come
within known or customary practice within the art to which the
invention pertains and may be applied to the essential features
hereinbefore set forth, and follows in the scope of the claims.
[0644] Other embodiments are within the claims.
* * * * *