U.S. patent application number 16/872279 was filed with the patent office on 2020-10-15 for macrocyclic mcl-1 inhibitors and methods of use.
The applicant listed for this patent is AbbVie Deutschland GmbH & Co. KG, AbbVie Inc.. Invention is credited to Wilfried Braje, George A. Doherty, Katja Jantos, Cheng Ji, Andrew S. Judd, Andreas Kling, Aaron R. Kunzer, Chunqiu Lai, Anthony Mastracchio, Thomas D. Penning, Frauke Pohlki, Xiaohong Song, Andrew J. Souers, Gerard M. Sullivan, Zhi-Fu Tao, Jesse A. Teske, Xilu Wang, Michael D. Wendt.
Application Number | 20200325153 16/872279 |
Document ID | / |
Family ID | 1000004916779 |
Filed Date | 2020-10-15 |
View All Diagrams
United States Patent
Application |
20200325153 |
Kind Code |
A1 |
Judd; Andrew S. ; et
al. |
October 15, 2020 |
Macrocyclic MCL-1 Inhibitors and Methods of Use
Abstract
The present disclosure provides for compounds of formula (I)
##STR00001## wherein A.sup.2, A.sup.3, A.sup.4, A.sup.6, A.sup.7,
A.sup.8, A.sup.15, R.sup.A, R.sup.5, R.sup.9, R.sup.10A, R.sup.10B,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.16, W, X, and Y have
any of the values defined in the specification, and
pharmaceutically acceptable salts thereof, that are useful as
agents in the treatment of diseases and conditions, including
cancer. Also provided are pharmaceutical compositions comprising
compounds of formula (I).
Inventors: |
Judd; Andrew S.; (Grayslake,
IL) ; Kunzer; Aaron R.; (Arlington Heights, IL)
; Lai; Chunqiu; (Libertyville, IL) ; Souers;
Andrew J.; (Libertyville, IL) ; Sullivan; Gerard
M.; (Libertyville, IL) ; Tao; Zhi-Fu; (Vernon
Hills, IL) ; Teske; Jesse A.; (Lake Bluff, IL)
; Mastracchio; Anthony; (Vernon Hills, IL) ; Wang;
Xilu; (Libertyville, IL) ; Ji; Cheng; (Buffalo
Grove, IL) ; Wendt; Michael D.; (Vernon Hills,
IL) ; Song; Xiaohong; (Grayslake, IL) ;
Doherty; George A.; (Libertyville, IL) ; Jantos;
Katja; (Wiesbaden, DE) ; Braje; Wilfried;
(Wiesbaden, DE) ; Kling; Andreas; (Wiesbaden,
DE) ; Pohlki; Frauke; (Wiesbaden, DE) ;
Penning; Thomas D.; (Elmhurst, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc.
AbbVie Deutschland GmbH & Co. KG |
North Chicago
Wiesbaden |
IL |
US
DE |
|
|
Family ID: |
1000004916779 |
Appl. No.: |
16/872279 |
Filed: |
May 11, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15998789 |
Aug 15, 2018 |
10676485 |
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16872279 |
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62545853 |
Aug 15, 2017 |
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62555475 |
Sep 7, 2017 |
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62692663 |
Jun 30, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 35/00 20180101; C07D 491/22 20130101; C07D 495/16 20130101;
C07D 495/18 20130101; A61P 35/02 20180101; C07D 491/18 20130101;
A61K 31/519 20130101; C07D 495/22 20130101 |
International
Class: |
C07D 495/16 20060101
C07D495/16; C07D 495/18 20060101 C07D495/18; A61K 45/06 20060101
A61K045/06; C07D 495/22 20060101 C07D495/22; C07D 491/18 20060101
C07D491/18; A61K 31/519 20060101 A61K031/519; C07D 491/22 20060101
C07D491/22; A61P 35/00 20060101 A61P035/00; A61P 35/02 20060101
A61P035/02 |
Claims
1. A compound of formula (I) or a pharmaceutically acceptable salt
thereof, ##STR00087## wherein A.sup.2 is CR.sup.2, A.sup.3 is N,
A.sup.4 is CR.sup.4a, and A.sup.6 is C; or A.sup.2 is CR.sup.2,
A.sup.3 is N, A.sup.4 is O or S, and A.sup.6 is C; or A.sup.2 is
CR.sup.2, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is C; A.sup.2
is N, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is C; or A.sup.2
is N, A.sup.3 is C, A.sup.4 is CR.sup.4a, and A.sup.6 is N; R.sup.A
is hydrogen, CH.sub.3, halogen, CN, CH.sub.2F, CHF.sub.2, or
CF.sub.3; X is O, or N(R.sup.x2); wherein R.sup.x2 is hydrogen,
C.sub.1-C.sub.3 alkyl, or unsubstituted cyclopropyl; Y is
(CH.sub.2).sub.m, --CH.dbd.CH--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.p--CH.dbd.CH--, or
--(CH.sub.2).sub.qCH.dbd.CH--(CH.sub.2).sub.r; wherein 0, 1, 2, or
3 CH.sub.2 groups are each independently replaced by O,
N(R.sup.ya), C(R.sup.ya)(R.sup.yb), C(O), NC(O)R.sup.ya, or
S(O).sub.2; m is 2, 3, 4, or 5; n is 1,2, or 3; p is 1,2, or 3; q
is 1 or 2; and r is 1 or 2; wherein the sum of q and r is 2 or 3;
R.sup.ya, at each occurrence, is independently hydrogen,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, G.sup.1,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; wherein the
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkyl, and C.sub.1-C.sub.6 haloalkyl are optionally substituted
with 1 or 2 substituents independently selected from the group
consisting of oxo, --N(R.sup.yd)(R.sup.ye), G.sup.1, --OR.sup.yf,
--SR.sup.yg, --S(O).sub.2N(R.sup.yd)(R.sup.ye), and
--S(O).sub.2-G.sup.1; and R.sup.yb is C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, G.sup.1, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; wherein the C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6
haloalkyl are optionally substituted with 1 or 2 substituents
independently selected from the group consisting of oxo,
--N(R.sup.yd)(R.sup.ye), G.sup.1, --OR.sup.yf, --SR.sup.yg,
--S(O).sub.2N(R.sup.yd)(R.sup.ye), and --S(O).sub.2-G.sup.1; or
R.sup.ya and R.sup.yb, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.7 monocyclic cycloalkyl,
C.sub.4-C.sub.7 monocyclic cycloalkenyl, or a 4-7 membered
monocyclic heterocycle; wherein the C.sub.3-C.sub.7 monocyclic
cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, and the 4-7
membered monocyclic heterocycle are each optionally substituted
with 1 --OR.sup.m and 0, 1, 2, or 3 independently selected R.sup.s
groups; R.sup.yd, R.sup.ye, R.sup.yf, and R.sup.yg, at each
occurrence, are each independently hydrogen, G.sup.1,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; wherein the
C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.6 haloalkyl are
optionally substituted with one substituent selected from the group
consisting of G, --OR.sup.yh, --SR.sup.yh, --SO.sub.2R.sup.yh, and
--N(R.sup.yi)(R.sup.yk); G.sup.1, at each occurrence, is
piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl,
tetrahydropyranyl, morpholinyl, oxetanyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
wherein each G.sup.1 is optionally substituted with 1 --OR.sup.m
and 0, 1, 2, or 3 substituents independently selected from the
group consisting of G.sup.2, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.2,
and R.sup.s; G.sup.2, at each occurrence, is a C.sub.3-C.sub.7
monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl,
oxetanyl, morpholinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each G.sup.2 is
optionally substituted with 1 --OR.sup.m and 0, 1, or 2
independently selected R.sup.t groups; R.sup.2 is independently
hydrogen, halogen, CH.sub.3, or CN; R.sup.4a, at each occurrence,
is independently hydrogen, halogen, CN, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, G.sup.A, C.sub.1-C.sub.4 alkyl-G.sup.A, or
C.sub.1-C.sub.4 alkyl-O-G.sup.A; wherein each G.sup.A is
independently C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.7 monocyclic
cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, or 4-7
membered heterocycle; wherein each G.sup.A is optionally
substituted with 1, 2, or 3 R.sup.u groups; R.sup.5 is
independently hydrogen, halogen, G.sup.3, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; wherein the
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are each optionally substituted with one G.sup.3; G.sup.3,
at each occurrence, is independently C.sub.6-C.sub.10 aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, oxetanyl, 2-oxaspiro[3.3]heptanyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl,
2,3-dihydro-1,4-dioxinyl, or 1,4-dioxepanyl; wherein each G.sup.3
is optionally substituted with 1, 2, or 3 R.sup.v groups; A.sup.7
is N or CR.sup.7; A.sup.8 is N or CR.sup.8; A.sup.15 is N or
CR.sup.15; R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, --CN, --OR.sup.7a, --SR.sup.7a, or
--N(R.sup.7b)(R.sup.7c); R.sup.8, R.sup.13, R.sup.14, and R.sup.15,
are each independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
--N(R.sup.8b)(R.sup.8c), or C.sub.3-C.sub.4 monocyclic cycloalkyl;
wherein the C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.3 alkyl, and
C.sub.1-C.sub.3 haloalkyl; or R.sup.8 and R.sup.13 are each
independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
--N(R.sup.8b)(R.sup.8c), or C.sub.3-C.sub.4 monocyclic cycloalkyl;
wherein the C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.3 alkyl, and
C.sub.1-C.sub.3 haloalkyl; and R.sup.14 and R.sup.15, together with
the carbon atoms to which they are attached, form a monocyclic ring
selected from the group consisting of benzene, cyclobutane,
cyclopentane, and pyridine; wherein the monocyclic ring is
optionally substituted with 1, 2, or 3 substituents independently
selected from the group consisting of halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
and --N(R.sup.8b)(R.sup.8c); R.sup.9 is --OH, --O--C.sub.1-C.sub.4
alkyl, --O--CH.sub.2--OC(O)(C.sub.1-C.sub.6 alkyl), --NHOH,
##STR00088## or --N(H)S(O).sub.2--(C.sub.1-C.sub.6 alkyl);
R.sup.10A and R.sup.10B, are each independently hydrogen,
C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl; or R.sup.10A
and R.sup.10B, together with the carbon atom to which they are
attached, form a cyclopropyl; wherein the cyclopropyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen and CH.sub.3; W is
--CH.dbd.CH--, C.sub.1-C.sub.4 alkyl, --O--CHF--,
-L.sup.1-CH.sub.2--, or --CH.sub.2-L.sup.1-; wherein L.sup.1 at
each occurrence, is independently O, S, S(O), S(O).sub.2,
S(O).sub.2N(H), N(H), or N(C.sub.1-C.sub.3 alkyl); R.sup.11 is a
C.sub.6-C.sub.10 aryl or a 5-11 membered heteroaryl; wherein each
R.sup.11 is optionally substituted with 1, 2, or 3 independently
selected R.sup.w groups; R.sup.w, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN,
NO.sub.2, --OR.sup.11a, --SR.sup.11b, --S(O).sub.2R.sup.11b,
--S(O).sub.2N(R.sup.11c).sub.2, --C(O)R.sup.11a,
--C(O)N(R.sup.11c).sub.2, --N(R.sup.11c).sub.2,
--N(R.sup.11c)C(O)R.sup.11b, --N(R.sup.11c)S(O).sub.2R.sup.11b,
--N(R.sup.11c)C(O)O(R.sup.11b), --N(R.sup.11)C(O)N(R.sup.1c).sub.2,
G.sup.4, --(C.sub.1-C.sub.6 alkylenyl)-OR.sup.11a,
--(C.sub.1-C.sub.6 alkylenyl)-OC(O)N(R.sup.11c).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-SR.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)S(O).sub.2R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)O(R.sup.11b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-CN, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.4; R.sup.11a
and R.sup.11c, at each occurrence, are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
haloalkyl, G.sup.4, --(C.sub.2-C.sub.6 alkylenyl)-OR.sup.11d,
--(C.sub.2-C.sub.6 alkylenyl)-N(R.sup.11e).sub.2, or
--(C.sub.2-C.sub.6 alkylenyl)-G.sup.4; R.sup.11b, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.1-C.sub.6 haloalkyl, G.sup.4, --(C.sub.2-C.sub.6
alkylenyl)-OR.sup.11d, --(C.sub.2-C.sub.6
alkylenyl)-N(R.sup.11e).sub.2, or --(C.sub.2-C.sub.6
alkylenyl)-G.sup.4; G.sup.4, at each occurrence, is independently
phenyl, monocyclic heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, 2,6-dioxa-9-azaspiro[4.5]decanyl,
2-oxa-5-azabicyclo[2.2.1]heptanyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, piperidinyl, piperazinyl,
azetidinyl, morpholinyl, dihydropyranyl, tetrahydropyridinyl,
dihydropyrrolyl, pyrrolidinyl, 2,3-dihydrodioxinyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
wherein each G.sup.4 is optionally substituted with 1 --OR.sup.m
and 0, 1, 2, or 3 substituents independently selected from the
group consisting of G.sup.5, R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.5, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O,
C(O), N(H), N(C.sub.1-C.sub.6 alkyl), NHC(O), C(O)O, S, S(O), or
S(O).sub.2; s is 0 or 1; G.sup.5, at each occurrence, is
independently phenyl, monocyclic heteroaryl, C.sub.3-C.sub.7
monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl,
piperazine, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each G.sup.5 is
optionally substituted with 1 independently selected --OR.sup.m or
0, 1, 2, or 3 R.sup.z groups; R.sup.s, R.sup.t, R.sup.u, R.sup.v,
R.sup.y, and R.sup.z, at each occurrence, are each independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, oxo, NO.sub.2,
P(O)(R.sup.k).sub.2, --OC(O)R.sup.k, --OC(O)N(R').sub.2,
--SR.sup.j, --S(O).sub.2R.sup.k, --S(O).sub.2N(R.sup.j).sub.2,
--C(O)R.sup.j, --C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2,
--N(R.sup.j)C(O)R.sup.k, --N(R.sup.j)S(O).sub.2R,
--N(R.sup.j)C(O)O(R.sup.k), --N(R.sup.j)C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.j, (C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-C(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R)C(O)R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)O(R.sup.k), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)N(R.sup.j).sub.2, or --(C.sub.1-C.sub.6
alkylenyl)-CN; R.sup.m is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --(C.sub.2-C.sub.6 alkylenyl)-OR.sup.j,
or --(C.sub.2-C.sub.6 alkylenyl)-N(R.sup.j).sub.2; R.sup.yh,
R.sup.yi, R.sup.yk, R.sup.7a, R.sup.7b, R.sup.7c, R.sup.8a,
R.sup.8b, R.sup.8c, R.sup.11d, R.sup.11e, and R.sup.j, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
or C.sub.1-C.sub.6 haloalkyl; and R.sup.k, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl;
wherein at least one of G.sup.1, G.sup.2, G.sup.3, G.sup.4, and
G.sup.5 is 2,2-dimethyl-1,3-dioxolanyl, 2,3-dihydro-1,4-dioxinyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or
1,4-dioxepanyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.A is hydrogen.
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.9 is --OH.
4. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.10A and R.sup.10B, are each independently
hydrogen.
5. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.7, R.sup.12 and R.sup.16 are each
independently hydrogen.
6. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein X is O.
7. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.A is hydrogen; X is O; R.sup.9 is --OH;
R.sup.10A and R.sup.10B, are each independently hydrogen; and
R.sup.7, R.sup.12 and R.sup.16 are each independently hydrogen.
8. The compound of claim 7, or a pharmaceutically acceptable salt
thereof, wherein A.sup.2 is CH; A.sup.3 is N; A.sup.4 is CH; and
A.sup.6 is C.
9. The compound of claim 7, or a pharmaceutically acceptable salt
thereof, wherein A.sup.2 is N; A.sup.3 is C; A.sup.4 is O; and
A.sup.6 is C.
10. The compound of claim 7 or a pharmaceutically acceptable salt
thereof, wherein A.sup.2 is N; A.sup.3 is C; A.sup.4 is S; and
A.sup.6 is C.
11. The compound of claim 10, or a pharmaceutically acceptable salt
thereof, wherein Y is (CH.sub.2).sub.m; wherein 1 CH.sub.2 group is
independently replaced by N(R.sup.ya); and m is 3.
12. The compound of claim 10 or a pharmaceutically acceptable salt
thereof, wherein Y is (CH.sub.2).sub.m; wherein 2 CH.sub.2 groups
are each independently replaced by O and 1 CH.sub.2 group is
replaced by C(R.sup.ya)(R.sup.yb); and m is 4.
13. The compound of claim 11, or a pharmaceutically acceptable salt
thereof, wherein G.sup.1 is piperazinyl substituted with 1
R.sup.s.
14. The compound of claim 12, or a pharmaceutically acceptable salt
thereof, wherein G.sup.1 is piperazinyl substituted with 1
R.sup.s.
15. The compound of claim 13 or a pharmaceutically acceptable salt
thereof, wherein W is -L.sup.1-CH.sub.2--; and L.sup.1 is
independently O.
16. The compound of claim 14 or a pharmaceutically acceptable salt
thereof, wherein W is -L.sup.1-CH.sub.2--; and L.sup.1 is
independently O.
17. The compound of claim 16 or a pharmaceutically acceptable salt
thereof, wherein W is --O--CH.sub.2--, and R.sup.11 is pyrimidinyl,
optionally substituted with 1, 2, or 3 independently selected
R.sup.w groups.
18. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein the compound is selected from the group consisting
of Example 1-Example 53 of Table 1.
19. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of formula (I) according to claim 1,
or a pharmaceutically acceptable salt thereof, in combination with
a pharmaceutically acceptable carrier.
20. A method for treating multiple myeloma in a subject comprising
administering a therapeutically effective amount of a compound of
formula (I) according to claim 1 or a pharmaceutically acceptable
salt thereof, to a subject in need thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 15/998,789, filed on Aug. 15, 2018, which claims priority
to U.S. Provisional Application No. 62/692,663, filed Jun. 30,
2018, U.S. Provisional Application No. 62/555,475, filed Sep. 7,
2017, and U.S. Provisional Application No. 62/545,853, filed Aug.
15, 2017, the entire contents of which are incorporated herein by
reference.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted electronically in ASCII format and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Feb. 4, 2019, is named ABV12392USO1_SEQUENCE_LISTING and is 728
bytes in size.
BACKGROUND
Technical Field
[0003] This disclosure relates to inhibitors of induced myeloid
leukemia cell differentiation protein (MCL-1), compositions
containing compounds described herein, and methods of treatment
thereof.
Description of Related Technology
[0004] Apoptosis, a type of programmed cell death, is critical for
normal development and for preservation of cellular homeostasis.
Dysregulation of apoptosis is recognized to play an important role
in the development of various diseases. For example, blocks in
apoptotic signaling are a common requirement for oncogenesis, tumor
maintenance and chemoresistance (Hanahan, D. et al. Cell 2000, 100,
57). Apoptotic pathways can be divided into two categories,
intrinsic and extrinsic, depending on the origin of the death
signal. The intrinsic pathway, or mitochondrial apoptotic pathway,
is initiated by intracellular signals that ultimately lead to
mitochondrial outer membrane permeabilization (MOMP), caspase
activation and cell death.
[0005] The intrinsic mitochondrial apoptotic pathway is highly
regulated, and the dynamic binding interactions between the
pro-apoptotic (e.g. BAX, BAK, BAD, BIM, NOXA) and anti-apoptotic
(e.g. BCL-2, BCL-XL, MCL-1) BCL-2 family members control commitment
to cell death (Youle, R. J. et al. Nat. Rev. Mol. Cell Biol. 2008,
9, 47). BAK and BAX are essential mediators that upon
conformational activation cause MOMP, an irreversible event that
subsequently leads to cytochrome c release, caspase activation and
cell death. Anti-apoptotic BCL-2 family members such as BCL-2,
BCL-XL and MCL-1 can bind and sequester their pro-apoptotic
counterparts, thus preventing BAX/BAK activation and promoting cell
survival.
[0006] BCL-2 plays a dominant role in the survival of several
hematological malignancies where it is frequently overexpressed,
whereas BCL-XL is a key survival protein in some hematological and
solid tumors. The related anti-apoptotic protein MCL-1 is
implicated in mediating malignant cell survival in a number of
primary tumor types (Ashkenazi, A. et al. Nature Rev Drug Discovery
2017, 16, 273). MCL-1 gene amplifications are frequently found in
human cancers, including breast cancer and non-small cell lung
cancer (Beroukhim, R. et al. Nature 2010, 463, 899), and the MCL-1
protein has been shown to mediate survival in models of multiple
myeloma (Derenn, S. et al. Blood 2002, 100, 194), acute myeloid
leukemia (Glaser, S. et al. Genes Dev 2012, 26, 120) and MYC-driven
lymphomas (Kelly, G. et al. Genes Dev 2014, 28, 58). Specific
compounds that broadly inhibit gene transcription (e.g., CDK9
inhibitors) exert their cytotoxic effects on tumor cells, at least
in part, by down-regulating MCL-1 (Kotschy, A. et al. Nature 2016,
538, 477); alvocidib (Kim, W. et al. Blood 2015, 126, 1343) and
dinaciclib (Gregory, G. et al. Leukemia 2015, 29, 1437) are two
examples that have demonstrated clinical proof-of-concept in
patients with hematological malignancies. Literature data supports
a role for MCL-1 as a resistance factor to anticancer therapies
such gemcitabine, vincristine and taxol (Wertz, I. E. et al. Nature
2011, 471, 110). Accordingly, there is a need in the therapeutic
arts for compounds which inhibit the activity of the MCL-1
protein.
SUMMARY
[0007] In embodiments the present disclosure provides for compounds
of formula (I) or a pharmaceutically acceptable salt thereof,
##STR00002##
wherein [0008] A.sup.2 is CR.sup.2, A.sup.3 is N, A.sup.4 is
CR.sup.4a, and A.sup.6 is C; or [0009] A.sup.2 is CR.sup.2, A.sup.3
is N, A.sup.4 is O or S, and A.sup.6 is C; or [0010] A.sup.2 is
CR.sup.2, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is C; or
[0011] A.sup.2 is N, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is
C; or [0012] A.sup.2 is N, A.sup.3 is C, A.sup.4 is CR.sup.4a, and
A.sup.6 is N; [0013] R.sup.A is hydrogen, CH.sub.3, halogen, CN,
CH.sub.2F, CHF.sub.2, or CF.sub.3; [0014] X is O, or N(R.sup.x2);
wherein R.sup.x2 is hydrogen, C.sub.1-C.sub.3 alkyl, or
unsubstituted cyclopropyl; [0015] Y is (CH.sub.2).sub.m,
--CH.dbd.CH--(CH.sub.2).sub.n--, --(CH.sub.2).sub.p--CH.dbd.CH--,
or --(CH.sub.2).sub.qCH.dbd.CH--(CH.sub.2).sub.r--; wherein 0, 1,
2, or 3 CH.sub.2 groups are each independently replaced by O,
N(R.sup.ya), C(R.sup.ya)(R.sup.yb), C(O), NC(O)R.sup.ya, or
S(O).sub.2; [0016] m is 2, 3, 4, or 5; [0017] n is 1, 2, or 3;
[0018] p is 1, 2, or 3; [0019] q is 1 or 2; and [0020] r is 1 or 2;
wherein the sum of q and r is 2 or 3; [0021] R.sup.ya, at each
occurrence, is independently hydrogen, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, G.sup.1, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; wherein the C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6
haloalkyl are optionally substituted with 1 or 2 substituents
independently selected from the group consisting of oxo,
--N(R.sup.yd)(R.sup.ye), G.sup.1, --OR.sup.yf, --SR.sup.yg,
--S(O).sub.2N(R.sup.yd)(R.sup.ye), and --S(O).sub.2-G.sup.1; and
[0022] R.sup.yb is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, G, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl;
wherein the C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 haloalkyl are optionally
substituted with 1 or 2 substituents independently selected from
the group consisting of oxo, --N(R.sup.yd)(R.sup.ye), G.sup.1,
--OR.sup.yf, --SR.sup.yg, --S(O).sub.2N(R.sup.yd)(R.sup.ye), and
--S(O).sub.2-G.sup.1; or [0023] R.sup.ya and R.sup.yb, together
with the carbon atom to which they are attached, form a
C.sub.3-C.sub.7 monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic
cycloalkenyl, or a 4-7 membered monocyclic heterocycle; wherein the
C.sub.3-C.sub.7 monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic
cycloalkenyl, and the 4-7 membered monocyclic heterocycle are each
optionally substituted with 1 --OR.sup.m and 0, 1, 2, or 3
independently selected R.sup.s groups; R.sup.yd, R.sup.ye,
R.sup.yf, and R.sup.yg, at each occurrence, are each independently
hydrogen, G.sup.1, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; wherein the C.sub.1-C.sub.6 alkyl and the
C.sub.1-C.sub.6 haloalkyl are optionally substituted with one
substituent selected from the group consisting of G.sup.1,
--OR.sup.yh, --SR.sup.yh, --SO.sub.2R.sup.yh, and
--N(R.sup.yi)(R.sup.yk); [0024] G.sup.1, at each occurrence, is
piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl,
tetrahydropyranyl, morpholinyl, oxetanyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
wherein each G.sup.1 is optionally substituted with 1 --OR.sup.m
and 0, 1, 2, or 3 substituents independently selected from the
group consisting of G.sup.2, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.2,
and R.sup.s; [0025] G.sup.2, at each occurrence, is a
C.sub.3-C.sub.7 monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic
cycloalkenyl, oxetanyl, morpholinyl, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each
G.sup.2 is optionally substituted with 1 --OR.sup.m and 0, 1, or 2
independently selected R.sup.1 groups; [0026] R.sup.2 is
independently hydrogen, halogen, CH.sub.3, or CN; [0027] R.sup.4a,
at each occurrence, is independently hydrogen, halogen, CN,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, G.sup.A, C.sub.1-C.sub.4
alkyl-G.sup.A, or C.sub.1-C.sub.4 alkyl-O-G.sup.A; wherein each
G.sup.A is independently C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.7
monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, or
4-7 membered heterocycle; wherein each G.sup.A is optionally
substituted with 1, 2, or 3 R.sup.u groups; [0028] R.sup.5 is
independently hydrogen, halogen, G.sup.3, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; wherein the
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are each optionally substituted with one G.sup.3; [0029]
G.sup.3, at each occurrence, is independently C.sub.6-C.sub.10
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, oxetanyl, 2-oxaspiro[3.3]heptanyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl,
2,3-dihydro-1,4-dioxinyl, or 1,4-dioxepanyl; wherein each G.sup.3
is optionally substituted with 1, 2, or 3 R.sup.v groups; [0030]
A.sup.7 is N or CR.sup.7; [0031] A.sup.8 is N or CR.sup.8; [0032]
A.sup.15 is N or CR.sup.15; [0033] R.sup.7, R.sup.12 and R.sup.16
are each independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.7a, --SR.sup.7a, or
--N(R.sup.7b)(R.sup.7c); [0034] R.sup.8, R.sup.13, R.sup.14, and
R.sup.15, are each independently hydrogen, halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
--N(R.sup.8b)(R.sup.8c), or C.sub.3-C.sub.4 monocyclic cycloalkyl;
wherein the C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.3 alkyl, and
C.sub.1-C.sub.3 haloalkyl; or [0035] R.sup.8 and R.sup.13 are each
independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
--N(R.sup.8b)(R.sup.8c), or C.sub.3-C.sub.4 monocyclic cycloalkyl;
wherein the C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.3 alkyl, and
C.sub.1-C.sub.3 haloalkyl; and [0036] R.sup.14 and R.sup.15,
together with the carbon atoms to which they are attached, form a
monocyclic ring selected from the group consisting of benzene,
cyclobutane, cyclopentane, and pyridine; wherein the monocyclic
ring is optionally substituted with 1, 2, or 3 substituents
independently selected from the group consisting of halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, --CN,
--OR.sup.8a, --SR.sup.8a, and --N(R.sup.8b)(R.sup.8c); [0037]
R.sup.9 is --OH, --O--C.sub.1-C.sub.4 alkyl,
--O--CH.sub.2--OC(O)(C.sub.1-C.sub.6 alkyl), --NHOH,
##STR00003##
[0037] or --N(H)S(O).sub.2--(C.sub.1-C.sub.6 alkyl); [0038]
R.sup.10A and R.sup.10B, are each independently hydrogen,
C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl; or R.sup.10A
and R.sup.10B, together with the carbon atom to which they are
attached, form a cyclopropyl; wherein the cyclopropyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen and CH.sub.3; [0039] W is
--CH.dbd.CH--, C.sub.1-C.sub.4 alkyl, --O--CHF--,
-L.sup.1-CH.sub.2--, or --CH.sub.2-L.sup.1-; wherein L.sup.1 at
each occurrence, is independently O, S, S(O), S(O).sub.2,
S(O).sub.2N(H), N(H), or N(C.sub.1-C.sub.3 alkyl); [0040] R.sup.11
is a C.sub.6-C.sub.10 aryl or a 5-11 membered heteroaryl; wherein
each R.sup.11 is optionally substituted with 1, 2, or 3
independently selected R.sup.w groups; [0041] R.sup.w, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6
haloalkyl, --CN, NO.sub.2, --OR.sup.11a, --SR.sup.11b,
--S(O).sub.2R.sup.11b, --S(O).sub.2N(R.sup.11c).sub.2,
--C(O)R.sup.11a, --C(O)N(R.sup.11c).sub.2, --N(R.sup.11c).sub.2,
--N(R.sup.11c)C(O)R.sup.11b, --N(R.sup.11c)S(O).sub.2R.sup.11b,
--N(R.sup.11c)C(O)O(R.sup.11b),
--N(R.sup.11c)C(O)N(R.sup.11c).sub.2, G.sup.4, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)S(O).sub.2R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)O(R.sup.11b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-CN, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.4; [0042]
R.sup.11a and R.sup.11c, at each occurrence, are each independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.4, --(C.sub.2-C.sub.6
alkylenyl)-OR.sup.11d, --(C.sub.2-C.sub.6
alkylenyl)-N(R.sup.11e).sub.2, or --(C.sub.2-C.sub.6
alkylenyl)-G.sup.4; [0043] R.sup.11b, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.4, --(C.sub.2-C.sub.6
alkylenyl)-OR.sup.11d, --(C.sub.2-C.sub.6
alkylenyl)-N(R.sup.11e).sub.2, or --(C.sub.2-C.sub.6
alkylenyl)-G.sup.4; [0044] G.sup.4, at each occurrence, is
independently phenyl, monocyclic heteroaryl, C.sub.3-C.sub.1
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl,
2,6-dioxa-9-azaspiro[4.5]decanyl,
2-oxa-5-azabicyclo[2.2.1]heptanyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, piperidinyl, piperazinyl,
azetidinyl, morpholinyl, dihydropyranyl, tetrahydropyridinyl,
dihydropyrrolyl, pyrrolidinyl, 2,3-dihydrodioxinyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
wherein each G.sup.4 is optionally substituted with 1 --OR.sup.m
and 0, 1, 2, or 3 substituents independently selected from the
group consisting of G.sup.5, R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.5, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G; [0045] L.sup.2 is O,
C(O), N(H), N(C.sub.1-C.sub.6 alkyl), NHC(O), C(O)O, S, S(O), or
S(O).sub.2; [0046] s is 0 or 1; [0047] G.sup.5, at each occurrence,
is independently phenyl, monocyclic heteroaryl, C.sub.3-C.sub.7
monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl,
piperazine, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each G.sup.5 is
optionally substituted with 1 independently selected --OR.sup.m or
0, 1, 2, or 3 R.sup.z groups; [0048] R.sup.s, R.sup.t, R.sup.u,
R.sup.v, R.sup.y, and R.sup.z, at each occurrence, are each
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN,
oxo, NO.sub.2, P(O)(R.sup.k).sub.2, --OC(O)R.sup.k,
--OC(O)N(R.sup.j).sub.2, --SR.sup.j, --S(O).sub.2R.sup.k,
--S(O).sub.2N(R.sup.j).sub.2, --C(O)R.sup.j,
--C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2,
--N(R.sup.j)C(O)R.sup.k, --N(R.sup.j)S(O).sub.2R.sup.k,
--N(R.sup.j)C(O)O(R.sup.k), --N(R.sup.j)C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.j, (C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R, --(C.sub.1-C.sub.6 alkylenyl)-C(O)N(R).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R)C(O)R, --(C.sub.1-C.sub.6
alkylenyl)-N(R)S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)O(R.sup.k), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)N(R.sup.j).sub.2, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [0049] R.sup.m is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --(C.sub.2-C.sub.6 alkylenyl)-OR.sup.j,
or --(C.sub.2-C.sub.6 alkylenyl)-N(R.sup.j).sub.2; [0050] R.sup.yh,
R.sup.yi, R.sup.yk, R.sup.7a, R.sup.7b, R.sup.7c, R.sup.8a,
R.sup.8b, R.sup.8c, R.sup.11d, R.sup.11e, and R.sup.j, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
or C.sub.1-C.sub.6 haloalkyl; and [0051] R.sup.k, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 haloalkyl; [0052] wherein at least one of G.sup.1,
G.sup.2, G.sup.3, G.sup.4, and G.sup.5 is
2,2-dimethyl-1,3-dioxolanyl, 2,3-dihydro-1,4-dioxinyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or
1,4-dioxepanyl.
[0053] In embodiments, the present disclosure provides for methods
of treating or preventing disorders that are amenable to inhibition
of MCL-1. Such methods comprise administering to the subject a
therapeutically effective amount of a compound of formula (I),
alone, or in combination with a pharmaceutically acceptable
carrier.
[0054] In embodiments, some methods are directed to treating or
preventing cancer. That is, in embodiments, the present disclosure
provides for methods for treating or preventing cancer, wherein
such methods comprise administering to the subject a
therapeutically effective amount of a compound of formula (I),
alone, or in combination with a pharmaceutically acceptable
carrier.
[0055] In embodiments, the present disclosure relates to methods of
treating cancer in a subject comprising administering a
therapeutically effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, to a subject in need
thereof. In certain embodiments, the cancer is multiple myeloma. In
certain embodiments, the methods further comprise administering a
therapeutically effective amount of at least one additional
therapeutic agent.
[0056] In embodiments, the present disclosure provides the use of a
compound of formula (I), alone or in combination with at least one
additional therapeutic agent, in the manufacture of a medicament
for treating or preventing conditions and disorders disclosed
herein, with or without a pharmaceutically acceptable carrier.
[0057] Pharmaceutical compositions comprising a compound of formula
(I), or a pharmaceutically acceptable salt, alone or in combination
with at least one additional therapeutic agent, are also
provided.
DETAILED DESCRIPTION
[0058] In embodiments, the present disclosure provides for
compounds of Formula (I), or a pharmaceutically acceptable salt
thereof,
##STR00004##
wherein A.sup.2, A.sup.3, A.sup.4, A.sup.6, A.sup.7, A.sup.8,
A.sup.15, R.sup.A, R.sup.5, R.sup.9, R.sup.10A, R.sup.10B,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.16, W, X, and Y are
defined above in the Summary and below in the Detailed Description.
Further, compositions comprising such compounds and methods for
treating conditions and disorders using such compounds and
compositions are also included.
[0059] Compounds included herein may contain one or more
variable(s) that occur more than one time in any substituent or in
the formulae herein. Definition of a variable on each occurrence is
independent of its definition at another occurrence. Further,
combinations of substituents are permissible only if such
combinations result in stable compounds. Stable compounds are
compounds which can be isolated from a reaction mixture.
Definitions
[0060] It is noted that, as used in this specification and the
intended claims, the singular form "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes a single
compound as well as one or more of the same or different compounds,
reference to "a pharmaceutically acceptable carrier" means a single
pharmaceutically acceptable carrier as well as one or more
pharmaceutically acceptable carriers, and the like.
[0061] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0062] The term "alkenyl" as used herein, means a straight or
branched hydrocarbon chain containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond. The term
"C.sub.2-C.sub.6 alkenyl" and "C.sub.2-C.sub.4 alkenyl" means an
alkenyl group containing 2-6 carbon atoms and 2-4 carbon atoms
respectively. Non-limiting examples of alkenyl include
buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl,
3-butenyl, 4-pentenyl, and 5-hexenyl. The terms "alkenyl,"
"C.sub.2-C.sub.6 alkenyl," and "C.sub.2-C.sub.4 alkenyl" used
herein are unsubstituted, unless otherwise indicated.
[0063] The term "alkyl" as used herein, means a saturated, straight
or branched hydrocarbon chain radical. In some instances, the
number of carbon atoms in an alkyl moiety is indicated by the
prefix "C.sub.x-C.sub.y", wherein x is the minimum and y is the
maximum number of carbon atoms in the substituent. Thus, for
example, "C.sub.1-C.sub.6 alkyl" means an alkyl substituent
containing from 1 to 6 carbon atoms, "C.sub.1-C.sub.4 alkyl" means
an alkyl substituent containing from 1 to 4 carbon atoms, and
"C.sub.1-C.sub.3 alkyl" means an alkyl substituent containing from
1 to 3 carbon atoms. Representative examples of alkyl include, but
are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,
n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,
2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl,
and 1,2,2-trimethylpropyl. The terms "alkyl," "C.sub.1-C.sub.6
alkyl," "C.sub.1-C.sub.4 alkyl," and "C.sub.1-C.sub.3 alkyl" used
herein are unsubstituted, unless otherwise indicated.
[0064] The term "alkylene" or "alkylenyl" means a divalent radical
derived from a straight or branched, saturated hydrocarbon chain,
for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms
(C.sub.1-C.sub.6 alkylenyl) or of 1 to 4 carbon atoms
(C.sub.1-C.sub.4 alkylenyl) or of 1 to 3 carbon atoms
(C.sub.1-C.sub.3 alkylenyl) or of 2 to 6 carbon atoms
(C.sub.2-C.sub.6 alkylenyl). Examples of alkylenyl include, but are
not limited to, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--C((CH.sub.3).sub.2)--CH.sub.2CH.sub.2CH.sub.2--,
--C((CH.sub.3).sub.2)--CH.sub.2CH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0065] The term "C.sub.2-C.sub.6 alkynyl" and "C.sub.2-C.sub.4
alkynyl" as used herein, means a straight or branched chain
hydrocarbon radical containing from 2 to 6 carbon atoms and 2 to 4
carbon atoms respectively, and containing at least one
carbon-carbon triple bond. Representative examples of
C.sub.2-C.sub.6 alkynyl and C.sub.2-C.sub.4 alkynyl include, but
are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,
2-pentynyl, and 1-butynyl. The terms "alkynyl," "C.sub.2-C.sub.6
alkynyl," and "C.sub.2-C.sub.4 alkynyl" used herein are
unsubstituted, unless otherwise indicated.
[0066] The term "C.sub.6-C.sub.10 aryl" as used herein, means
phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, or a
phenyl fused to a C.sub.3-C.sub.6 monocyclic cycloalkyl, or a
phenyl fused to a C.sub.4-C.sub.6 monocyclic cycloalkenyl.
Non-limiting examples of the aryl groups include dihydroindenyl,
indenyl, naphthyl, dihydronaphthalenyl, and
tetrahydronaphthalenyl.
[0067] The term "C.sub.3-C.sub.11 cycloalkyl" as used herein, means
a hydrocarbon ring radical containing 3-11 carbon atoms, zero
heteroatom, and zero double bond. The C.sub.3-C.sub.11 cycloalkyl
group may be a single-ring (monocyclic) or have two or more rings
(polycyclic or bicyclic). Monocyclic cycloalkyl groups typically
contain from 3 to 8 carbon ring atoms (C.sub.3-C.sub.8 monocyclic
cycloalkyl) or 3 to 7 carbon ring atoms (C.sub.3-C.sub.7 monocyclic
cycloalkyl), and even more typically 3-6 carbon ring atoms
(C.sub.3-C.sub.6 monocyclic cycloalkyl). Examples of monocyclic
cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl
groups contain two or more rings, and bicyclic cycloalkyls contain
two rings. In certain embodiments, the polycyclic cycloalkyl groups
contain 2 or 3 rings. The rings within the polycyclic and the
bicyclic cycloalkyl groups may be in a bridged, fused, or spiro
orientation, or combinations thereof. In a spirocyclic cycloalkyl,
one atom is common to two different rings. An example of a
spirocyclic cycloalkyl is spiro[4.5]decane. In a bridged
cycloalkyl, the rings share at least two non-adjacent atoms.
Examples of bridged cycloalkyls include, but are not limited to,
bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl,
bicyclo[3.2.1]octanyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl,
bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl,
tricyclo[3.3.1.0.sup.37]nonyl (octahydro-2,5-methanopentalenyl or
noradamantyl), tricyclo[3.3.1.1.sup.3,7]decyl (adamantyl), and
tricyclo[4.3.1.1.sup.3,8]undecyl (homoadamantyl). In a fused ring
cycloalkyl, the rings share one common bond. Example of fused-ring
cycloalkyl include, but not limited to, decalin
(decahydronaphthyl).
[0068] The term "C.sub.3-C.sub.7 monocyclic cycloalkyl" as used
herein, means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0069] The term "C.sub.4-C.sub.11 cycloalkenyl" as used herein,
refers to a monocyclic or a bicyclic hydrocarbon ring radical. The
monocyclic cycloalkenyl has four-, five-, six-, seven- or eight
carbon atoms and zero heteroatoms. The four-membered ring systems
have one double bond, the five- or six-membered ring systems have
one or two double bonds, and the seven- or eight-membered ring
systems have one, two, or three double bonds. Representative
examples of monocyclic cycloalkenyl groups include, but are not
limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is a
monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or
a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.
The monocyclic and bicyclic cycloalkenyl ring may contain one or
two alkylene bridges, each consisting of one, two, or three carbon
atoms, and each linking two non-adjacent carbon atoms of the ring
system. Representative examples of the bicyclic cycloalkenyl groups
include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene,
octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic
and the bicyclic cycloalkenyls, including exemplary rings, are
optionally substituted unless otherwise indicated. The monocyclic
cycloalkenyl and bicyclic cycloalkenyl are attached to the parent
molecular moiety through any substitutable atom contained within
the ring systems.
[0070] The term "C.sub.3-C.sub.6 monocyclic cycloalkyl" as used
herein, means cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl.
[0071] The term "C.sub.3-C.sub.4 monocyclic cycloalkyl" as used
herein, means cyclopropyl and cyclobutyl.
[0072] The term "C.sub.4-C.sub.6 monocyclic cycloalkenyl" as used
herein, means cyclobutenyl, cyclopentenyl, and cyclohexenyl.
[0073] The term "halo" or "halogen" as used herein, means Cl, Br,
I, and F.
[0074] The term "haloalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five, or six
hydrogen atoms are replaced by halogen. The term "C.sub.1-C.sub.6
haloalkyl" means a C.sub.1-C.sub.6 alkyl group, as defined herein,
in which one, two, three, four, five, or six hydrogen atoms are
replaced by halogen. The term "C.sub.1-C.sub.4 haloalkyl" means a
C.sub.1-C.sub.4 alkyl group, as defined herein, in which one, two,
three, four, or five hydrogen atoms are replaced by halogen. The
term "C.sub.1-C.sub.3 haloalkyl" means a C.sub.1-C.sub.3 alkyl
group, as defined herein, in which one, two, three, four, or five
hydrogen atoms are replaced by halogen. Representative examples of
haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl,
2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl,
pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and
trifluoropropyl. The terms "haloalkyl," "C.sub.1-C.sub.6
haloalkyl," "C.sub.1-C.sub.4 haloalkyl," and "C.sub.1-C.sub.3
haloalkyl," as used herein are unsubstituted, unless otherwise
indicated.
[0075] The term "5-11 membered heteroaryl" as used herein, means a
monocyclic heteroaryl and a bicyclic heteroaryl. The monocyclic
heteroaryl is a five- or six-membered hydrocarbon ring wherein at
least one carbon ring atom is replaced by heteroatom independently
selected from the group consisting of O, N, and S. The
five-membered ring contains two double bonds. The five membered
ring may have one heteroatom selected from O or S; or one, two,
three, or four nitrogen atoms and optionally one oxygen or one
sulfur atom. The six-membered ring contains three double bonds and
one, two, three or four nitrogen atoms. Examples of monocyclic
heteroaryl include, but are not limited to, furanyl, imidazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl,
tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and
triazinyl. The bicyclic heteroaryl consists of a monocyclic
heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a
monocyclic C.sub.3-C.sub.6 cycloalkyl, or a monocyclic heteroaryl
fused to C.sub.4-C.sub.6 monocyclic cycloalkenyl, or a monocyclic
heteroaryl fused to a monocyclic heteroaryl, or a monocyclic
heteroaryl fused to a 4-7 membered monocyclic heterocycle.
Representative examples of bicyclic heteroaryl groups include, but
are not limited to, benzofuranyl, benzothienyl, benzoxazolyl,
benzimidazolyl, benzoxadiazolyl, phthalazinyl,
2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,
6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,
6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,
indolyl, isoindolyl, isoquinolinyl, naphthyridinyl,
pyridoimidazolyl, quinolinyl,
2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,
thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and
5,6,7,8-tetrahydroquinolin-5-yl.
[0076] The term "4-11 membered heterocycle" as used herein, means a
hydrocarbon ring radical of 4-11 carbon ring atoms wherein at least
one carbon ring atom is replaced by atoms independently selected
from the group consisting of O, N, S, P(.dbd.O), and Si. The 4-11
membered heterocycle ring may be a single ring (monocyclic) or have
two or more rings (bicyclic or polycyclic). In certain embodiments,
the monocyclic heterocycle is a four-, five-, six-, or seven-,
membered hydrocarbon ring wherein at least one carbon ring atom is
replaced by atoms independently selected from the group consisting
of O, N, S, P(.dbd.O), and Si. In certain embodiments, the
monocyclic heterocycle is a 4-6 membered hydrocarbon ring wherein
at least one carbon ring atom is replaced by atoms independently
selected from the group consisting of O, N, S, P(.dbd.O), and Si. A
four-membered monocyclic heterocycle contains zero or one double
bond, and one carbon ring atom replaced by an atom selected from
the group consisting of O, N, and S. A five-membered monocyclic
heterocycle contains zero or one double bond and one, two, or three
carbon ring atoms replaced by atoms selected from the group
consisting of O, N, S, P(.dbd.O), and Si. Examples of five-membered
monocyclic heterocycles include those containing in the ring: 10; 1
S; 1 N; 1 P(.dbd.O); 1 Si; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 10
and 1 N; or 10 and 2 N. Non-limiting examples of 5-membered
monocyclic heterocyclic groups include 1,3-dioxolanyl,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,
dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl,
isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, pyrazolinyl,
pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, and
thiazolidinyl. A six-membered monocyclic heterocycle contains zero,
one, or two double bonds and one, two, or three carbon ring atoms
replaced by heteroatoms selected from the group consisting of O, N,
S, P(.dbd.O), and Si. Examples of six-membered monocyclic
heterocycles include those containing in the ring: 1 P(.dbd.O); 1
Si; 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1
N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and
2 N. Examples of six-membered monocyclic heterocycles include
1,3-oxazinanyl, tetrahydropyranyl, dihydropyranyl,
1,6-dihydropyridazinyl, 1,2-dihydropyrimidinyl,
1,6-dihydropyrimidinyl, dioxanyl, 1,4-dithianyl,
hexahydropyrimidinyl, morpholinyl, piperazinyl, piperidinyl,
1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl,
thiomorpholinyl, thioxanyl, and trithianyl. Seven- and
eight-membered monocyclic heterocycles contains zero, one, two, or
three double bonds and one, two, or three carbon ring atoms
replaced by heteroatoms selected from the group consisting of O, N,
and S. Examples of monocyclic heterocycles include, but are not
limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,
1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,
1,6-dihydropyridazinyl, 1,2-dihydropyrimidinyl,
1,6-dihydropyrimidinyl, hexahydropyrimidinyl, imidazolinyl,
imidazolidinyl, isoindolinyl, isothiazolinyl, isothiazolidinyl,
isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,
oxadiazolidinyl, 1,3-oxazinanyl, oxazolinyl, 1,3-oxazolidinyl,
oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,
pyrazolidinyl, pyrrolinyl, pyrrolidinyl, 1,2-dihydropyridinyl,
tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,
tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
thiopyranyl, and trithianyl. Polycyclic heterocycle groups contain
two or more rings, and bicyclic heterocycles contain two rings. In
certain embodiments, the polycyclic heterocycle groups contain 2 or
3 rings. The rings within the polycyclic and the bicyclic
heterocycle groups are in a bridged, fused, or spiro orientation,
or combinations thereof. In a spirocyclic heterocycle, one atom is
common to two different rings. Non limiting examples of spirocyclic
heterocycles include 4,6-diazaspiro[2.4]heptanyl,
6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octan-6-yl, and
2,7-diazaspiro[4.4]nonane. In a fused ring heterocycle, the rings
share one common bond. Examples of fused bicyclic heterocycles are
a 4-6 membered monocyclic heterocycle fused to a phenyl group, or a
4-6 membered monocyclic heterocycle fused to a monocyclic
C.sub.3-C.sub.6 cycloalkyl, or a 4-6 membered monocyclic
heterocycle fused to a C.sub.4-C.sub.6 monocyclic cycloalkenyl, or
a 4-6 membered monocyclic heterocycle fused to a 4-6 membered
monocyclic heterocycle. Examples of fused bicyclic heterocycles
include, but are not limited to
hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl,
hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,
hexahydro-1H-imidazo[5,1-c][1,4]oxazinyl,
hexahydro-1H-pyrrolo[1,2-c]imidazolyl,
hexahydrocyclopenta[c]pyrrol-3a(1H)-yl, and
3-azabicyclo[3.1.0]hexanyl. In abridged heterocycle, the rings
share at least two non-adjacent atoms. Examples of such bridged
heterocycles include, but are not limited to,
azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),
8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene,
hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane
(1-azatricyclo[3.3.1.1.sup.3,7]decane), and oxa-adamantane
(2-oxatricyclo[3.3.1.1.sup.3,7]decane).
[0077] The term "4-7 membered monocyclic heterocycle" as used
herein, means a four-, five-, six-, or seven-membered monocyclic
heterocycle, as defined herein above.
[0078] The phenyl, the aryls, the cycloalkyls, the cycloalkenyls,
the heteroaryls, and the heterocycles, including the exemplary
rings, are optionally substituted unless otherwise indicated; and
are attached to the parent molecular moiety through any
substitutable atom contained within the ring system.
[0079] The term "heteroatom" as used herein, means a nitrogen,
oxygen, and sulfur.
[0080] The term "oxo" as used herein, means a .dbd.O group.
[0081] The term "radiolabel" means a compound of the present
disclosure in which at least one of the atoms is a radioactive atom
or a radioactive isotope, wherein the radioactive atom or isotope
spontaneously emits gamma rays or energetic particles, for example
alpha particles or beta particles, or positrons. Examples of such
radioactive atoms include, but are not limited to, .sup.3H
(tritium), .sup.14C, C, .sup.15O, .sup.18F, .sup.35S, .sup.123I,
and .sup.125I.
[0082] A moiety is described as "substituted" when a non-hydrogen
radical is in the place of hydrogen radical of any substitutable
atom of the moiety. Thus, for example, a substituted heterocycle
moiety is a heterocycle moiety in which at least one non-hydrogen
radical is in the place of a hydrogen radical on the heterocycle.
It should be recognized that if there are more than one
substitution on a moiety, each non-hydrogen radical may be
identical or different (unless otherwise stated).
[0083] If a moiety is described as being "optionally substituted,"
the moiety may be either (1) not substituted or (2) substituted. If
a moiety is described as being optionally substituted with up to a
particular number of non-hydrogen radicals, that moiety may be
either (1) not substituted; or (2) substituted by up to that
particular number of non-hydrogen radicals or by up to the maximum
number of substitutable positions on the moiety, whichever is less.
Thus, for example, if a moiety is described as a heteroaryl
optionally substituted with up to 3 non-hydrogen radicals, then any
heteroaryl with less than 3 substitutable positions would be
optionally substituted by up to only as many non-hydrogen radicals
as the heteroaryl has substitutable positions. To illustrate,
tetrazolyl (which has only one substitutable position) would be
optionally substituted with up to one non-hydrogen radical. To
illustrate further, if an amino nitrogen is described as being
optionally substituted with up to 2 non-hydrogen radicals, then a
primary amino nitrogen will be optionally substituted with up to 2
non-hydrogen radicals, whereas a secondary amino nitrogen will be
optionally substituted with up to only 1 non-hydrogen radical.
[0084] The terms "treat", "treating", and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms. In certain embodiments, "treat," "treating," and
"treatment" refer to ameliorating at least one physical parameter,
which may not be discernible by the subject. In yet another
embodiment, "treat", "treating", and "treatment" refer to
modulating the disease or disorder, either physically (for example,
stabilization of a discernible symptom), physiologically (for
example, stabilization of a physical parameter), or both. In a
further embodiment, "treat", "treating", and "treatment" refer to
slowing the progression of the disease or disorder.
[0085] The terms "prevent", "preventing", and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring or developing a disease or
disorder.
[0086] The phrase "therapeutically effective amount" means an
amount of a compound, or a pharmaceutically acceptable salt
thereof, sufficient to prevent the development of or to alleviate
to some extent one or more of the symptoms of the condition or
disorder being treated when administered alone or in conjunction
with another therapeutic agent for treatment in a particular
subject or subject population. The "therapeutically effective
amount" may vary depending on the compound, the disease and its
severity, and the age, weight, health, etc., of the subject to be
treated. For example in a human or other mammal, a therapeutically
effective amount may be determined experimentally in a laboratory
or clinical setting, or may be the amount required by the
guidelines of the United States Food and Drug Administration, or
equivalent foreign agency, for the particular disease and subject
being treated.
[0087] The term "subject" is defined herein to refer to animals
such as mammals, including, but not limited to, primates (e.g.,
humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits,
rats, mice and the like. In one embodiment, the subject is a human.
The terms "human," "patient," and "subject" are used
interchangeably herein.
Compounds
[0088] Compounds of the present disclosure have the general Formula
(I) as described above.
[0089] Particular values of variable groups are as follows. Such
values may be used where appropriate with any of the other values,
definitions, claims or embodiments defined hereinbefore or
hereinafter.
Formula (I)
[0090] In embodiments, the present disclosure pertains to compounds
of Formula (I), or pharmaceutically acceptable salts thereof,
##STR00005##
wherein [0091] A.sup.2 is CR.sup.2, A.sup.3 is N, A.sup.4 is
CR.sup.4a, and A.sup.6 is C; or [0092] A.sup.2 is CR.sup.2, A.sup.3
is N, A.sup.4 is O or S, and A.sup.6 is C; or [0093] A.sup.2 is
CR.sup.2, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is C; or
[0094] A.sup.2 is N, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is
C; or [0095] A.sup.2 is N, A.sup.3 is C, A.sup.4 is CR.sup.4a, and
A.sup.6 is N; [0096] R.sup.A is hydrogen, CH.sub.3, halogen, CN,
CH.sub.2F, CHF.sub.2, or CF.sub.3; [0097] X is O, or N(R.sup.x2);
wherein R.sup.x2 is hydrogen, C.sub.1-C.sub.3 alkyl, or
unsubstituted cyclopropyl; Y is (CH.sub.2).sub.m,
--CH.dbd.CH--(CH.sub.2).sub.n--, --(CH.sub.2).sub.p--CH.dbd.CH--,
or --(CH.sub.2).sub.q--CH.dbd.CH--(CH.sub.2).sub.r--; wherein 0, 1,
2, or 3 CH.sub.2 groups are each independently replaced by O,
N(R.sup.ya), C(R.sup.ya)(R.sup.yb), C(O), NC(O)R.sup.ya, or
S(O).sub.2; [0098] m is 2, 3, 4, or 5; [0099] n is 1, 2, or 3;
[0100] p is 1, 2, or 3; [0101] q is 1 or 2; and [0102] r is 1 or 2;
wherein the sum of q and r is 2 or 3; [0103] R.sup.ya, at each
occurrence, is independently hydrogen, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, G.sup.1, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; wherein the C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6
haloalkyl are optionally substituted with 1 or 2 substituents
independently selected from the group consisting of oxo,
--N(R.sup.yd)(R.sup.ye), G.sup.1, --OR.sup.yf, --SR.sup.y,
--S(O).sub.2N(R.sup.yd)(R.sup.ye), and --S(O).sub.2-G.sup.1; and
[0104] R.sup.yb is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, G.sup.1, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6
haloalkyl; wherein the C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 haloalkyl are
optionally substituted with 1 or 2 substituents independently
selected from the group consisting of oxo, --N(R.sup.yd)(R.sup.ye),
G.sup.1, --OR.sup.yf, --SR.sup.yg,
--S(O).sub.2N(R.sup.yd)(R.sup.ye), and --S(O).sub.2-G.sup.1; or
[0105] R.sup.ya and R.sup.yb, together with the carbon atom to
which they are attached, form a C.sub.3-C.sub.7 monocyclic
cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, or a 4-7
membered monocyclic heterocycle; wherein the C.sub.3-C.sub.7
monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, and
the 4-7 membered monocyclic heterocycle are each optionally
substituted with 1 --OR.sup.m and 0, 1, 2, or 3 independently
selected R.sup.s groups; [0106] R.sup.yd, R.sup.ye, R.sup.yf, and
R.sup.yg, at each occurrence, are each independently hydrogen,
G.sup.1, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl;
wherein the C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.6 haloalkyl
are optionally substituted with one substituent selected from the
group consisting of G.sup.1, --OR.sup.yh, --SR.sup.yh,
--SO.sub.2R.sup.yh, and --N(R.sup.yi)(R.sup.yk); [0107] G.sup.1, at
each occurrence, is piperazinyl, piperidinyl, pyrrolidinyl,
thiomorpholinyl, tetrahydropyranyl, morpholinyl, oxetanyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or
1,4-dioxepanyl; wherein each G.sup.1 is optionally substituted with
1 --OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of G.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2, and R.sup.s; [0108] G.sup.2, at each
occurrence, is a C.sub.3-C.sub.7 monocyclic cycloalkyl,
C.sub.4-C.sub.7 monocyclic cycloalkenyl, oxetanyl, morpholinyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or
1,4-dioxepanyl; wherein each G.sup.2 is optionally substituted with
1 --OR.sup.m and 0, 1, or 2 independently selected R.sup.t groups;
[0109] R.sup.2 is independently hydrogen, halogen, CH.sub.3, or CN;
[0110] R.sup.4a, at each occurrence, is independently hydrogen,
halogen, CN, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, G.sup.A,
C.sub.1-C.sub.4 alkyl-G.sup.A, or C.sub.1-C.sub.4 alkyl-O-G.sup.A;
wherein each G.sup.A is independently C.sub.6-C.sub.10 aryl,
C.sub.3-C.sub.7 monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic
cycloalkenyl, or 4-7 membered heterocycle; wherein each G.sup.A is
optionally substituted with 1, 2, or 3 R.sup.u groups; [0111]
R.sup.5 is independently hydrogen, halogen, G.sup.3,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl; wherein the C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl are each optionally
substituted with one G.sup.3, [0112] G.sup.3, at each occurrence,
is independently C.sub.6-C.sub.10 aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl,
oxetanyl, 2-oxaspiro[3.3]heptanyl, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-dioxepanyl, 2,3-dihydro-1,4-dioxinyl, or
1,4-dioxepanyl; wherein each G.sup.3 is optionally substituted with
1, 2, or 3 R.sup.v groups; [0113] A.sup.7 is N or CR.sup.7; [0114]
A.sup.8 is N or CR; [0115] A.sup.15 is N or CR.sup.15; [0116]
R.sup.7, R.sup.12 and R.sup.16 are each independently hydrogen,
halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, --CN,
--OR.sup.7a, --SR.sup.7a, or --N(R.sup.7b)(R.sup.7c); [0117]
R.sup.8, R.sup.13, R.sup.14, and R.sup.15, are each independently
hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a, --N(R.sup.8b)(R.sup.8c),
or C.sub.3-C.sub.4 monocyclic cycloalkyl; wherein the
C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally substituted
with one or two substituents independently selected from the group
consisting of halogen, C.sub.1-C.sub.3 alkyl, and C.sub.1-C.sub.3
haloalkyl; or [0118] R.sup.8 and R.sup.13 are each independently
hydrogen, halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a, --N(R.sup.8b)(R.sup.8c),
or C.sub.3-C.sub.4 monocyclic cycloalkyl; wherein the
C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally substituted
with one or two substituents independently selected from the group
consisting of halogen, C.sub.1-C.sub.3 alkyl, and C.sub.1-C.sub.3
haloalkyl; and [0119] R.sup.14 and R.sup.15, together with the
carbon atoms to which they are attached, form a monocyclic ring
selected from the group consisting of benzene, cyclobutane,
cyclopentane, and pyridine; wherein the monocyclic ring is
optionally substituted with 1, 2, or 3 substituents independently
selected from the group consisting of halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
and --N(R.sup.8b)(R.sup.8c); [0120] R.sup.9 is-OH,
--O--C.sub.1-C.sub.4 alkyl, --O--CH.sub.2--OC(O)(C.sub.1-C.sub.6
alkyl), --NHOH,
##STR00006##
[0120] or --N(H)S(O).sub.2--(C.sub.1-C.sub.6 alkyl); [0121]
R.sup.10A and R.sup.10B, are each independently hydrogen,
C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 haloalkyl; or R.sup.10A
and R.sup.10B, together with the carbon atom to which they are
attached, form a cyclopropyl; wherein the cyclopropyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen and CH.sub.3; [0122] W is
--CH.dbd.CH--, C.sub.1-C.sub.4 alkyl, --O--CHF--,
-L.sup.1-CH.sub.2--, or --CH.sub.2-L.sup.1-; wherein L.sup.1 at
each occurrence, is independently O, S, S(O), S(O).sub.2,
S(O).sub.2N(H), N(H), or N(C.sub.1-C.sub.3 alkyl); [0123] R.sup.11
is a C.sub.6-C.sub.10 aryl or a 5-11 membered heteroaryl; wherein
each R.sup.11 is optionally substituted with 1, 2, or 3
independently selected R.sup.w groups; R.sup.w, at each occurrence,
is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN,
NO.sub.2, --OR.sup.11a, --SR.sup.11b, --S(O).sub.2R.sup.11b,
--S(O).sub.2N(R.sup.11c).sub.2, --C(O)R.sup.11a,
--C(O)N(R.sup.11c).sub.2, --N(R.sup.11c).sub.2,
--N(R.sup.11c)C(O)R.sup.11b, --N(R.sup.11c)S(O).sub.2R.sup.11b,
--N(R.sup.11c)C(O)O(R.sup.11b),
--N(R.sup.11c)C(O)N(R.sup.11c).sub.2, G.sup.4, --(C.sub.1-C.sub.6
alkylenyl)-OR.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R.sup.11a, --(C.sub.1-C.sub.6
alkylenyl)-C(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)S(O).sub.2R.sup.11b, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)O(R.sup.11b), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.11c)C(O)N(R.sup.11c).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-CN, or --(C.sub.1-C.sub.6 alkylenyl)-G.sup.4; [0124]
R.sup.11a and R.sup.11c, at each occurrence, are each independently
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.4, --(C.sub.2-C.sub.6
alkylenyl)-OR.sup.11d, --(C.sub.2-C.sub.6
alkylenyl)-N(R.sup.11e).sub.2, or --(C.sub.2-C.sub.6
alkylenyl)-G.sup.4; [0125] R.sup.11b, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 haloalkyl, G.sup.4, --(C.sub.2-C.sub.6
alkylenyl)-OR.sup.11d, --(C.sub.2-C.sub.6
alkylenyl)-N(R.sup.11e).sub.2, or --(C.sub.2-C.sub.6
alkylenyl)-G.sup.4; [0126] G.sup.4, at each occurrence, is
independently phenyl, monocyclic heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl,
2,6-dioxa-9-azaspiro[4.5]decanyl,
2-oxa-5-azabicyclo[2.2.1]heptanyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, piperidinyl, piperazinyl,
azetidinyl, morpholinyl, dihydropyranyl, tetrahydropyridinyl,
dihydropyrrolyl, pyrrolidinyl, 2,3-dihydrodioxinyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
wherein each G.sup.4 is optionally substituted with 1 --OR.sup.m
and 0, 1, 2, or 3 substituents independently selected from the
group consisting of G.sup.5, R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.5, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; [0127] L.sup.2
is O, C(O), N(H), N(C.sub.1-C.sub.6 alkyl), NHC(O), C(O)O, S, S(O),
or S(O).sub.2; [0128] s is 0 or 1; [0129] G.sup.5, at each
occurrence, is independently phenyl, monocyclic heteroaryl,
C.sub.3-C.sub.7 monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic
cycloalkenyl, piperazine, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each
G.sup.5 is optionally substituted with 1 independently selected
--OR.sup.m or 0, 1, 2, or 3 R.sup.z groups; [0130] R.sup.s, R, R,
Y, R.sup.y, and R.sup.z, at each occurrence, are each independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, halogen, C.sub.1-C.sub.6 haloalkyl, --CN, oxo, NO.sub.2,
P(O)(R.sup.k).sub.2, --OC(O)R.sup.k, --OC(O)N(R.sup.j).sub.2,
--SR.sup.j, --S(O).sub.2R.sup.k, --S(O).sub.2N(R.sup.j).sub.2,
--C(O)R.sup.j, --C(O)N(R.sup.j).sub.2, --N(R.sup.j).sub.2,
--N(R.sup.j)C(O)R.sup.k, --N(R.sup.j)S(O).sub.2R.sup.k,
--N(R)C(O)O(R.sup.k), --N(R.sup.j)C(O)N(R.sup.j).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-OR.sup.j, (C.sub.1-C.sub.6
alkylenyl)-OC(O)N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-SR.sup.j, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-S(O).sub.2N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-C(O)R, --(C.sub.1-C.sub.6 alkylenyl)-C(O)N(R).sub.2,
--(C.sub.1-C.sub.6 alkylenyl)-N(R.sup.j).sub.2, --(C.sub.1-C.sub.6
alkylenyl)-N(R)C(O)R, --(C.sub.1-C.sub.6
alkylenyl)-N(R)S(O).sub.2R.sup.k, --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)O(R.sup.k), --(C.sub.1-C.sub.6
alkylenyl)-N(R.sup.j)C(O)N(R.sup.j).sub.2, or --(C.sub.1-C.sub.6
alkylenyl)-CN; [0131] R.sup.m is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, --(C.sub.2-C.sub.6 alkylenyl)-OR.sup.j,
or --(C.sub.2-C.sub.6 alkylenyl)-N(R.sup.j).sub.2; [0132] R.sup.yh,
R.sup.yi, R.sup.yk, R.sup.7a, R.sup.7b, R.sup.7c, R.sup.8a,
R.sup.8b, R.sup.8c, R.sup.11d, R.sup.11e, and R.sup.j, at each
occurrence, are each independently hydrogen, C.sub.1-C.sub.6 alkyl,
or C.sub.1-C.sub.6 haloalkyl; and [0133] R.sup.k, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 haloalkyl; wherein at least one of G.sup.1,
G.sup.2, G.sup.3, G.sup.4, and G is 2,2-dimethyl-1,3-dioxolanyl,
2,3-dihydro-1,4-dioxinyl, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl.
[0134] In one embodiment of Formula (I), A.sup.2 is CR.sup.2,
A.sup.3 is N, A.sup.4 is CR.sup.4a, and A.sup.6 is C; or A.sup.2 is
CR.sup.2, A.sup.3 is N, A.sup.4 is O or S, and A.sup.6 is C; or
A.sup.2 is N, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is C; or
A.sup.2 is CR.sup.2, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is
C; or A.sup.2 is N, A.sup.3 is C, A.sup.4 is CR.sup.4a, and A.sup.6
is N. In another embodiment of Formula (I), A.sup.2 is CR.sup.2,
A.sup.3 is N, A.sup.4 is CR.sup.4a, and A.sup.6 is C. In another
embodiment of Formula (I), A.sup.2 is CH, A.sup.3 is N, A.sup.4 is
CH, and A.sup.6 is C. In another embodiment of Formula (I), A.sup.2
is CR.sup.2, A.sup.3 is N, A.sup.4 is CR.sup.4a, A.sup.6 is C,
R.sup.2 is H, and R.sup.4a is halogen. In another embodiment of
Formula (I), A.sup.2 is CR.sup.2, A.sup.3 is N, A.sup.4 is
CR.sup.4a, A.sup.6 is C, R.sup.2 is H, and R.sup.4a is Cl. In
another embodiment of Formula (I), A.sup.2 is CR.sup.2, A.sup.3 is
N, A.sup.4 is O or S, and A.sup.6 is C. In another embodiment of
Formula (I), A.sup.2 is N, A.sup.3 is C, A.sup.4 is O, and A.sup.6
is C. In another embodiment of Formula (I), A.sup.2 is N, A.sup.3
is C, A.sup.4 is S, and A.sup.6 is C. In another embodiment of
Formula (I), A.sup.2 is N, A.sup.3 is C, A.sup.4 is CR.sup.4a, and
A.sup.6 is N. In another embodiment of Formula (I), A.sup.2 is
CR.sup.2, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is C.
[0135] In one embodiment of Formula (I), R.sup.A is hydrogen,
CH.sub.3, halogen, CN, CH.sub.2F, CHF.sub.2, or CF.sub.3. In
another embodiment of Formula (I), R.sup.A is hydrogen.
[0136] In one embodiment of Formula (I), X is O, or N(R.sup.x2);
wherein R.sup.x2 is hydrogen, C.sub.1-C.sub.3 alkyl, or
unsubstituted cyclopropyl. In another embodiment of Formula (I), X
is O.
[0137] In one embodiment of Formula (I), Y is (CH.sub.2).sub.m,
--CH.dbd.CH--(CH.sub.2).sub.n--, --(CH.sub.2).sub.p--CH.dbd.CH--,
or --(CH.sub.2).sub.qCH.dbd.CH--(CH.sub.2).sub.r; wherein 0, 1, 2,
or 3 CH.sub.2 groups are each independently replaced by O,
N(R.sup.ya), C(R.sup.ya)(R.sup.yb), C(O), NC(O)R.sup.ya, or
S(O).sub.2; and m is 2, 3, 4, or 5. In another embodiment of
Formula (I), Y is (CH.sub.2).sub.m; wherein 1, 2, or 3 CH.sub.2
groups are each independently replaced by O, N(R.sup.ya),
C(R.sup.ya)(R.sup.yb), C(O), or NC(O)R.sup.ya; and m is 3 or 4. In
another embodiment of Formula (I), Y is (CH.sub.2).sub.m; wherein 1
CH.sub.2 group is independently replaced by N(R.sup.ya); and m is
3. In another embodiment of Formula (I), Y is (CH.sub.2).sub.m;
wherein 2 CH.sub.2 groups are each independently replaced by O and
1 CH.sub.2 group is replaced by C(R.sup.ya)(R.sup.yb); and m is 4.
In another embodiment of Formula (I), Y is
##STR00007##
In another embodiment of Formula (I), Y is
##STR00008##
In another embodiment of Formula (I), Y is
##STR00009##
[0138] In one embodiment of Formula (I), R.sup.ya, at each
occurrence, is independently hydrogen, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, G.sup.1, C.sub.1-C.sub.6 alkyl, or
C.sub.1-C.sub.6 haloalkyl; wherein the C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6
haloalkyl are optionally substituted with 1 or 2 substituents
independently selected from the group consisting of oxo,
--N(R.sup.yd)(R.sup.ye), G.sup.1, --OR.sup.yf, --SR.sup.yg,
--S(O).sub.2N(R.sup.yd)(R.sup.ye), and --S(O).sub.2-G.sup.1; and
R.sup.yb is C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
G.sup.1, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl;
wherein the C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 haloalkyl are optionally
substituted with 1 or 2 substituents independently selected from
the group consisting of oxo, --N(R(R.sup.ye), G.sup.1, --OR.sup.yf,
--SR.sup.y, --S(O).sub.2N(R.sup.yd)(R.sup.ye), and
--S(O).sub.2-G.sup.1; or R.sup.ya and R.sup.yb, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, or
a 4-7 membered monocyclic heterocycle; wherein the C.sub.3-C.sub.7
monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, and
the 4-7 membered monocyclic heterocycle are each optionally
substituted with 1 --OR.sup.m and 0, 1, 2, or 3 independently
selected R.sup.s groups; and R.sup.yd, R.sup.ye, R.sup.yf, and
R.sup.yg, at each occurrence, are each independently hydrogen,
G.sup.1, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl;
wherein the C.sub.1-C.sub.6 alkyl and the C.sub.1-C.sub.6 haloalkyl
are optionally substituted with one substituent selected from the
group consisting of G.sup.1, --OR.sup.h, --SR.sup.h,
--SO.sub.2R.sup.yh, and --N(R.sup.yi)(R.sup.yk). In another
embodiment of Formula (I), R.sup.ya, at each occurrence, is
independently hydrogen, or C.sub.1-C.sub.6 alkyl; wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1 or 2
substituents independently selected from the group consisting of
--N(R.sup.yd)(R.sup.ye), G.sup.1, --OR.sup.yf, or C.sub.1-C.sub.6
alkyl; and R.sup.yb is C.sub.1-C.sub.6 alkyl; wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with 1 or 2
substituents independently selected from the group consisting of
--N(R.sup.yd)(R.sup.ye), G.sup.1, and --OR.sup.yf; and R.sup.yd,
R.sup.ye, and R.sup.yf, at each occurrence, are each independently
hydrogen, or C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with one substituent selected from
the group consisting of G.sup.1, --OR.sup.yh, and SO.sub.2R.sup.yh.
In another embodiment of Formula (I), R.sup.ya, at each occurrence,
is independently hydrogen; and R.sup.yb is C.sub.1-C.sub.6 alkyl;
wherein the C.sub.1-C.sub.6 alkyl is substituted with 1
G.sup.1.
[0139] In one embodiment of Formula (I), G.sup.1, at each
occurrence, is piperazinyl, piperidinyl, pyrrolidinyl,
thiomorpholinyl, tetrahydropyranyl, morpholinyl, oxetanyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or
1,4-dioxepanyl; wherein each G.sup.1 is optionally substituted with
1 --OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of G.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2, and R.sup.s. In another embodiment of Formula
(I), G.sup.1 is piperazinyl optionally substituted with 1
--OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of G.sup.2, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.2, and R.sup.s. In another embodiment of Formula
(I), G.sup.1 is piperazinyl substituted with 1 R.sup.s. In another
embodiment of Formula (I), G.sup.1 is piperazinyl substituted with
1 R.sup.s; and R.sup.s is C.sub.1-C.sub.6 alkyl. In another
embodiment of Formula (I), G.sup.1 is piperazinyl substituted with
1 R.sup.s; and R.sup.s is CH.sub.3.
[0140] In one embodiment of Formula (I), G.sup.2, at each
occurrence, is a C.sub.3-C.sub.7 monocyclic cycloalkyl,
C.sub.4-C.sub.7 monocyclic cycloalkenyl, oxetanyl, morpholinyl,
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or
1,4-dioxepanyl; wherein each G.sup.2 is optionally substituted with
1 independently selected R groups. In another embodiment of Formula
(I), G.sup.2, at each occurrence, is a C.sub.3-C.sub.7 monocyclic
cycloalkyl. In another embodiment of Formula (I), G.sup.2, at each
occurrence, is morpholinyl.
[0141] In one embodiment of Formula (I), R.sup.2 is independently
hydrogen, halogen, CH.sub.3, or CN. In another embodiment of
Formula (I), R.sup.2 is independently hydrogen.
[0142] In one embodiment of Formula (I), R.sup.4a, at each
occurrence, is independently hydrogen, halogen, CN, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, G.sup.A, C.sub.1-C.sub.4 alkyl-G.sup.A,
or C.sub.1-C.sub.4 alkyl-O-G.sup.A; wherein each G.sup.A is
independently C.sub.6-C.sub.10 aryl, C.sub.3-C.sub.7 monocyclic
cycloalkyl, C.sub.4-C.sub.7 monocyclic cycloalkenyl, or 4-7
membered heterocycle; wherein each G.sup.A is optionally
substituted with 1, 2, or 3 R.sup.u groups. In another embodiment
of Formula (I), R.sup.4a, at each occurrence, is independently
halogen.
[0143] In one embodiment of Formula (I), R.sup.5 is independently
hydrogen, halogen, G.sup.3, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl; wherein the C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl are
each optionally substituted with one G.sup.3; and G.sup.3, at each
occurrence, is independently C.sub.6-C.sub.10 aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, oxetanyl, 2-oxaspiro[3.3]heptanyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl,
2,3-dihydro-1,4-dioxinyl, or 1,4-dioxepanyl; wherein each G.sup.3
is optionally substituted with 1, 2, or 3 R.sup.v groups. In
another embodiment of Formula (I), R.sup.5 is independently
hydrogen, G.sup.3, or C.sub.2-C.sub.6 alkynyl; and G.sup.3, at each
occurrence, is independently C.sub.6-C.sub.10 aryl, or
C.sub.3-C.sub.11 cycloalkyl; wherein each G.sup.3 is optionally
substituted with 1, 2, or 3 R.sup.v groups. In another embodiment
of Formula (I), R.sup.5 is independently C.sub.1-C.sub.6 alkyl;
wherein the C.sub.1-C.sub.6 alkyl is optionally substituted with
one G.sup.3; and G.sup.3, at each occurrence, is independently
C.sub.6-C.sub.10 aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, oxetanyl,
2-oxaspiro[3.3]heptanyl, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-dioxepanyl, 2,3-dihydro-1,4-dioxinyl, or
1,4-dioxepanyl; wherein each G.sup.3 is optionally substituted with
1, 2, or 3 R.sup.v groups. In another embodiment of Formula (I),
R.sup.5 is independently C.sub.1-C.sub.6 alkyl; wherein the
C.sub.1-C.sub.6 alkyl is optionally substituted with one G.sup.3;
and G.sup.3, at each occurrence, is independently 1,4-dioxanyl. In
another embodiment of Formula (I), R.sup.5 is independently
G.sup.3; and G.sup.3, at each occurrence, is independently
C.sub.3-C.sub.11 cycloalkyl; wherein each G.sup.3 is optionally
substituted with 1, 2, or 3 R.sup.v groups. In another embodiment
of Formula (I), R.sup.5 is independently G.sup.3; and G.sup.3, at
each occurrence, is independently C.sub.4-C.sub.11 cycloalkenyl;
wherein each G.sup.3 is optionally substituted with 1, 2, or 3
R.sup.v groups. In another embodiment of Formula (I), R.sup.5 is
independently G.sup.3; and G.sup.3, at each occurrence, is
independently 2,3-dihydro-1,4-dioxinyl; wherein each G.sup.3 is
optionally substituted with 1, 2, or 3 R.sup.v groups.
[0144] In another embodiment of Formula (I), R.sup.4 is
independently G.sup.3; and G.sup.3, at each occurrence, is
independently C.sub.6-C.sub.10 aryl; wherein each G.sup.3 is
optionally substituted with 1 R.sup.v groups. In another embodiment
of Formula (I), R.sup.5 is independently G.sup.3; and G.sup.3, at
each occurrence, is independently phenyl; wherein each G.sup.3 is
optionally substituted with 1 R.sup.v groups; and R.sup.v is
halogen. In another embodiment of Formula (I), R.sup.5 is
independently G.sup.3; and G.sup.3, at each occurrence, is
independently phenyl; wherein G.sup.3 is optionally substituted
with 1 R.sup.v groups; and R.sup.v is F.
[0145] In one embodiment of Formula (I), A.sup.7 is N or CR.sup.7;
A.sup.8 is N or CR.sup.8; and A.sup.15 is N or CR.sup.15. In
another embodiment of Formula (I), R.sup.7, R.sup.12 and R.sup.16
are each independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.7a, --SR.sup.7a, or
--N(R.sup.7b)(R.sup.7c); and R.sup.8, R.sup.13, R.sup.14, and
R.sup.15, are each independently hydrogen, halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
--N(R.sup.8b)(R.sup.8c), or C.sub.3-C.sub.4 monocyclic cycloalkyl;
wherein the C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.3 alkyl, and
C.sub.1-C.sub.3 haloalkyl. In another embodiment of Formula (I),
R.sup.7, R.sup.12 and R.sup.16 are each independently hydrogen. In
another embodiment of Formula (I), A.sup.7 is CH; A.sup.8 is
CR.sup.8; A.sup.15 is CR.sup.15; and R.sup.8 and R.sup.15 are each
independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl, or
--OR.sup.8a. In another embodiment of Formula (I), A.sup.7 is CH;
A.sup.8 is CR.sup.8; A.sup.15 is CR.sup.15; and R.sup.8 and
R.sup.15 are each independently hydrogen, halogen, or
C.sub.1-C.sub.4 alkyl. In another embodiment of Formula (I),
A.sup.7 is CH; A.sup.8 is CR.sup.8; A.sup.15 is CR.sup.15; and
R.sup.8 and R.sup.15 are each independently hydrogen, Cl, or
CH.sub.3.
[0146] In one embodiment of Formula (I), R.sup.8 and R.sup.13 are
each independently hydrogen, halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
--N(R.sup.8b)(R.sup.8c), or C.sub.3-C.sub.4 monocyclic cycloalkyl;
wherein the C.sub.3-C.sub.4 monocyclic cycloalkyl is optionally
substituted with one or two substituents independently selected
from the group consisting of halogen, C.sub.1-C.sub.3 alkyl, and
C.sub.1-C.sub.3 haloalkyl; and R.sup.14 and R.sup.15, together with
the carbon atoms to which they are attached, form a monocyclic ring
selected from the group consisting of benzene, cyclobutane,
cyclopentane, and pyridine; wherein the monocyclic ring is
optionally substituted with 1, 2, or 3 substituents independently
selected from the group consisting of halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, --CN, --OR.sup.8a, --SR.sup.8a,
and --N(R.sup.8b)(R.sup.8c). In another embodiment of Formula (I),
R.sup.8 and R.sup.13 are each independently hydrogen, and R.sup.14
and R.sup.15, together with the carbon atoms to which they are
attached form benzene.
[0147] In one embodiment of Formula (I), R.sup.9 is --OH,
--O--C.sub.1-C.sub.4 alkyl, --O--CH.sub.2--OC(O)(C.sub.1-C.sub.6
alkyl), --NHOH,
##STR00010##
or --N(H)S(O).sub.2--(C.sub.1-C.sub.6 alkyl). In another embodiment
of Formula (I), R.sup.9 is --OH.
[0148] In one embodiment of Formula (I), R.sup.10A and R.sup.10B,
are each independently hydrogen, C.sub.1-C.sub.3 alkyl, or
C.sub.1-C.sub.3 haloalkyl; or R.sup.10A and R.sup.1B, together with
the carbon atom to which they are attached, form a cyclopropyl;
wherein the cyclopropyl is optionally substituted with one or two
substituents independently selected from the group consisting of
halogen and CH.sub.3. In another embodiment of Formula (I),
R.sup.10A and R.sup.10B are each independently hydrogen.
[0149] In one embodiment of Formula (I),
[0150] R.sup.A is hydrogen;
[0151] R.sup.9 is --OH;
[0152] R.sup.10A and R.sup.10B, are each independently hydrogen;
and
[0153] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen.
[0154] In one embodiment of Formula (I), W is --CH.dbd.CH--,
C.sub.1-C.sub.4 alkyl, --O--CHF--, -L.sup.1-CH.sub.2--, or
--CH.sub.2-L.sup.1-; wherein L.sup.1 at each occurrence, is
independently O, S, S(O), S(O).sub.2, S(O).sub.2N(H), N(H), or
N(C.sub.1-C.sub.3 alkyl). In another embodiment of Formula (I), W
is --O--CHF--, or -L.sup.1-CH.sub.2--; wherein L.sup.1 at each
occurrence, is independently O. In another embodiment of Formula
(I), W is -L.sup.1-CH.sub.2--; wherein L.sup.1 at each occurrence,
is independently O.
[0155] In one embodiment of Formula (I), R.sup.11 is a
C.sub.6-C.sub.10 aryl or a 5-11 membered heteroaryl; wherein each
R.sup.11 is optionally substituted with 1, 2, or 3 independently
selected R.sup.w groups. In another embodiment of Formula (I),
R.sup.11 is a C.sub.6-C.sub.10 aryl or a 5-11 membered heteroaryl;
wherein each R.sup.11 is optionally substituted with 1 or 2
independently selected R.sup.w groups. In another embodiment of
Formula (I), W is --O--CH.sub.2--, and R.sup.11 is pyrimidinyl,
optionally substituted with 1, 2, or 3 independently selected
R.sup.w groups. In another embodiment of Formula (I), W is
--O--CH.sub.2--; and R.sup.11 is pyrimidinyl, optionally
substituted with 1, 2, or 3 independently selected R.sup.w groups;
and R.sup.w, at each occurrence, is independently C.sub.1-C.sub.6
alkyl, --OR.sup.11a or G.sup.4. In another embodiment of Formula
(I), W is --O--CH.sub.2--; and R.sup.11 is pyrimidinyl, optionally
substituted with 1, 2, or 3 independently selected R.sup.w groups;
and R.sup.w, at each occurrence, is independently --OR.sup.11a or
G.sup.4.
[0156] In one embodiment of Formula (I), R.sup.11a and R.sup.11c,
at each occurrence, are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
haloalkyl, G.sup.4, --(C.sub.2-C.sub.6 alkylenyl)-OR.sup.11d,
--(C.sub.2-C.sub.6 alkylenyl)-N(R.sup.11e).sub.2, or
--(C.sub.2-C.sub.6 alkylenyl)-G.sup.4; and R.sup.11b, at each
occurrence, is independently C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.1-C.sub.6 haloalkyl, G.sup.4, --(C.sub.2-C.sub.6
alkylenyl)-OR.sup.11d, --(C.sub.2-C.sub.6
alkylenyl)-N(R.sup.11e).sub.2, or --(C.sub.2-C.sub.6
alkylenyl)-G.sup.4. In another embodiment of Formula (I), R.sup.11a
is C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 haloalkyl. In another
embodiment of Formula (I), R.sup.11a is --(C.sub.2-C.sub.6
alkylenyl)-G.sup.4.
[0157] In one embodiment of Formula (I), G.sup.4, at each
occurrence, is independently phenyl, monocyclic heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
2,6-dioxa-9-azaspiro[4.5]decanyl,
2-oxa-5-azabicyclo[2.2.1]heptanyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, piperidinyl, piperazinyl,
azetidinyl, morpholinyl, dihydropyranyl, tetrahydropyridinyl,
dihydropyrrolyl, pyrrolidinyl, 2,3-dihydrodioxinyl, 1,3-dioxolanyl,
1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl;
wherein each G.sup.4 is optionally substituted with 1 --OR.sup.m
and 0, 1, 2, or 3 substituents independently selected from the
group consisting of G.sup.5, R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-G.sup.1, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O,
C(O), N(H), N(C.sub.1-C.sub.6 alkyl), NHC(O), C(O)O, S, S(O), or
S(O).sub.2; and s is 0 or 1.
[0158] In embodiments of Formula (I), G.sup.4, at each occurrence,
is independently phenyl, monocyclic heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,
2,6-dioxa-9-azaspiro[4.5]decanyl,
2-oxa-5-azabicyclo[2.2.1]heptanyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, piperidinyl, azetidinyl,
dihydropyranyl, tetrahydropyridinyl, dihydropyrrolyl, pyrrolidinyl,
2,3-dihydrodioxinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each G.sup.4 is
optionally substituted with 1 --OR.sup.m and 0, 1, 2, 3, or 4
substituents independently selected from the group consisting of
G.sup.5, R.sup.y, --(C.sub.1-C.sub.6 alkylenyl)-G.sup.5,
--(C.sub.1-C.sub.6 alkylenyl)-L.sup.2-(C.sub.1-C.sub.6
alkylenyl)-G.sup.5, and -L.sup.2-(C.sub.1-C.sub.6
akylenyl).sub.s-G.sup.5; and L.sup.2 is O, C(O), N(H),
N(C.sub.1-C.sub.6 alkyl), NHC(O), C(O)O, S, S(O), or S(O).sub.2;
and s is 0 or 1. In another embodiment of Formula (I), G.sup.4, at
each occurrence, is independently phenyl, monocyclic heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, morpholinyl, 2,6-dioxa-9-azaspiro[4.5]decanyl,
2-oxa-5-azabicyclo[2.2.1]heptanyl,
3-oxa-8-azabicyclo[3.2.1]octanyl, pyrrolidinyl,
2,3-dihydrodioxinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each G.sup.4 is
optionally substituted with 1 --OR.sup.m and 0, 1, 2, 3, or 4
substituents independently selected from the group consisting of
R.sup.y, --(C.sub.1-C.sub.6 alkylenyl)-L.sup.2-(C.sub.1-C.sub.6
alkylenyl)-G.sup.5, and -L.sup.2-(C.sub.1-C.sub.6
akylenyl).sub.s-G.sup.5; L.sup.2 is O or C(O)O; and s is 0 or 1. In
another embodiment of Formula (I), G.sup.4, at each occurrence, is
independently phenyl optionally substituted with 1 --OR.sup.m and
0, 1, 2, 3, or 4 substituents independently selected from the group
consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O or
C(O)O; and s is 0 or 1. In another embodiment of Formula (I),
G.sup.4, at each occurrence, is independently phenyl optionally
substituted with -L.sup.2-(C.sub.1-C.sub.6
alkylenyl).sub.s-G.sup.5. In another embodiment of Formula (I),
G.sup.4, at each occurrence, is independently phenyl optionally
substituted with -L.sup.2-(C.sub.1-C.sub.6
alkylenyl).sub.s-G.sup.5; L.sup.2 is O; and s is 1. In another
embodiment of Formula (I), G.sup.4, at each occurrence, is
independently phenyl, monocyclic heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, piperidinyl,
piperazinyl, azetidinyl, morpholinyl, 1,4-dioxanyl, or
1,4-dioxepanyl; wherein each G.sup.4 is optionally substituted with
1 --OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O,
or S(O).sub.2; and s is 0 or 1. In another embodiment of Formula
(I), G.sup.4, at each occurrence, is independently phenyl; wherein
each G.sup.4 is optionally substituted with 1 --OR.sup.m and 0, 1,
2, or 3 substituents independently selected from the group
consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O,
or S(O).sub.2; and s is 0 or 1. In another embodiment of Formula
(I), G.sup.4, at each occurrence, is independently monocyclic
heteroaryl; wherein each G.sup.4 is optionally substituted with 1
--OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O,
or S(O).sub.2; and s is 0 or 1. In another embodiment of Formula
(I), G.sup.4, at each occurrence, is independently C.sub.3-C.sub.11
cycloalkyl; wherein each G.sup.4 is optionally substituted with 1
--OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O,
or S(O).sub.2; and s is 0 or 1. In another embodiment of Formula
(I), G.sup.4, at each occurrence, is independently C.sub.4-C.sub.u
cycloalkenyl; wherein each G.sup.4 is optionally substituted with 1
--OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G; L.sup.2 is O, or
S(O).sub.2; and s is 0 or 1. In another embodiment of Formula (I),
G.sup.4, at each occurrence, is independently piperidinyl,
piperazinyl, azetidinyl, morpholinyl, 1,4-dioxanyl, or
1,4-dioxepanyl; wherein each G.sup.4 is optionally substituted with
1 --OR.sup.m and 0, 1, 2, or 3 substituents independently selected
from the group consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; L.sup.2 is O,
or S(O).sub.2; and s is 0 or 1.
[0159] In one embodiment of Formula (I), G.sup.5, at each
occurrence, is independently phenyl, monocyclic heteroaryl,
C.sub.3-C.sub.7 monocyclic cycloalkyl, C.sub.4-C.sub.7 monocyclic
cycloalkenyl, piperazine, 1,3-dioxolanyl, 1,3-dioxanyl,
1,4-dioxanyl, 1,3-dioxepanyl, or 1,4-dioxepanyl; wherein each G is
optionally substituted with 1 independently selected --OR.sup.m or
0, 1, 2, or 3 R.sup.z groups. In another embodiment of Formula (I),
G.sup.5, at each occurrence, is independently 1,3-dioxolanyl
optionally substituted with 2 independently selected R.sup.z
groups. In another embodiment of Formula (I), G.sup.5, at each
occurrence, is independently 1,4-dioxanyl optionally substituted
with 2 independently selected R.sup.z groups.
[0160] In one embodiment of Formula (I), [0161] A.sup.2 is CH;
[0162] A.sup.3 is N; [0163] A.sup.4 is CH; [0164] A.sup.6 is C;
[0165] R.sup.A is hydrogen; [0166] X is O; [0167] R.sup.9 is --OH;
[0168] R.sup.10A and R.sup.10B, are each independently hydrogen;
and [0169] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen.
[0170] In one embodiment of Formula (I), [0171] A.sup.2 is N;
[0172] A.sup.3 is C; [0173] A.sup.4 is O; [0174] A.sup.6 is C;
[0175] R.sup.A is hydrogen; [0176] X is O; [0177] R.sup.9 is --OH;
[0178] R.sup.10A and R.sup.10B, are each independently hydrogen;
and [0179] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen.
[0180] In one embodiment of Formula (I), [0181] A.sup.2 is N;
[0182] A.sup.3 is C; [0183] A.sup.4 is S; [0184] A.sup.6 is C;
[0185] R.sup.A is hydrogen; [0186] X is O; [0187] R.sup.9 is --OH;
[0188] R.sup.10A and R.sup.10B, are each independently hydrogen;
and [0189] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen.
[0190] In one embodiment of Formula (I), [0191] A.sup.2 is N;
[0192] A.sup.3 is C; [0193] A.sup.4 is S; [0194] A.sup.6 is C;
[0195] R.sup.A is hydrogen; [0196] X is O; [0197] R.sup.9 is --OH;
[0198] R.sup.10A and R.sup.10B, are each independently hydrogen;
[0199] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0200] Y is (CH.sub.2).sub.m; wherein 1 CH.sub.2 group is
independently replaced by N(R.sup.ya); and [0201] m is 3.
[0202] In one embodiment of Formula (I), [0203] A.sup.2 is N;
[0204] A.sup.3 is C; [0205] A.sup.4 is S; [0206] A.sup.6 is C;
[0207] R.sup.A is hydrogen; [0208] X is O; [0209] R.sup.9 is --OH;
[0210] R.sup.10A and R.sup.10B, are each independently hydrogen;
[0211] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0212] Y is (CH.sub.2).sub.m; wherein 2 CH.sub.2 groups
are each independently replaced by O and 1 CH.sub.2 group is
replaced by C(R.sup.ya)(R.sup.yb); and [0213] m is 4.
[0214] In one embodiment of Formula (I), [0215] A.sup.2 is CH;
[0216] A.sup.3 is N; [0217] A.sup.4 is CH; [0218] A.sup.6 is C;
[0219] R.sup.A is hydrogen; [0220] X is O; [0221] R.sup.9 is --OH;
[0222] R.sup.10A and R.sup.10B, are each independently hydrogen;
[0223] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0224] Y is (CH.sub.2).sub.m; wherein 1 CH.sub.2 group is
independently replaced by N(R.sup.ya); [0225] m is 3; and [0226]
G.sup.1 is piperazinyl substituted with 1 R.sup.s.
[0227] In one embodiment of Formula (I), [0228] A.sup.2 is CH;
[0229] A.sup.3 is N; [0230] A.sup.4 is CH; [0231] A.sup.6 is C;
[0232] R.sup.A is hydrogen; [0233] X is O; [0234] R.sup.9 is --OH;
[0235] R.sup.10A and R.sup.10B, are each independently hydrogen;
[0236] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0237] Y is (CH.sub.2).sub.m; wherein 2 CH.sub.2 groups
are each independently replaced by O and 1 CH.sub.2 group is
replaced by C(R.sup.ya)(R.sup.yb); [0238] m is 4; and [0239]
G.sup.1 is piperazinyl substituted with 1 R.sup.s.
[0240] In one embodiment of Formula (I), [0241] A.sup.2 is CH;
[0242] A.sup.3 is N; [0243] A.sup.4 is CH; [0244] A.sup.6 is C;
[0245] R.sup.A is hydrogen; [0246] X is O; [0247] R.sup.9 is --OH;
[0248] R.sup.10A and R.sup.10B, are each independently hydrogen;
[0249] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0250] Y is (CH.sub.2).sub.m; wherein 1 CH.sub.2 group is
independently replaced by N(R.sup.ya); [0251] m is 3; [0252]
G.sup.1 is piperazinyl substituted with 1 R.sup.s; [0253] W is
-L.sup.1-CH.sub.2--; and [0254] L.sup.1 is independently O.
[0255] In one embodiment of Formula (I), [0256] A.sup.2 is CH;
[0257] A.sup.3 is N; [0258] A.sup.4 is CH; [0259] A.sup.6 is C;
[0260] R.sup.A is hydrogen; [0261] X is O; [0262] R.sup.9 is --OH;
[0263] R.sup.10A and R.sup.10B, are each independently hydrogen;
[0264] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0265] Y is (CH.sub.2).sub.m; wherein 2 CH.sub.2 groups
are each independently replaced by O and 1 CH.sub.2 group is
replaced by C(R.sup.ya)(R.sup.yb); [0266] m is 4; [0267] G.sup.1 is
piperazinyl substituted with 1 R.sup.s; [0268] W is
-L.sup.1-CH.sub.2--; and [0269] L.sup.1 is independently O.
[0270] In one embodiment of Formula (I), [0271] A.sup.2 is CH;
[0272] A.sup.3 is N; [0273] A.sup.4 is CH; [0274] A.sup.6 is C;
[0275] R.sup.A is hydrogen; [0276] X is O; [0277] R.sup.9 is --OH;
[0278] R.sup.10A and R.sup.10B, are each independently hydrogen;
[0279] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0280] Y is (CH.sub.2).sub.m; wherein 1 CH.sub.2 group is
independently replaced by N(R.sup.ya); [0281] m is 3; [0282]
G.sup.1 is piperazinyl substituted with 1 R.sup.s; [0283] W is
-L.sup.1-CH.sub.2--; [0284] L.sup.1 is independently O; [0285] W is
--O--CH.sub.2--, and [0286] R.sup.11 is pyrimidinyl, optionally
substituted with 1, 2, or 3 independently selected R.sup.w
groups.
[0287] One embodiment pertains to compounds of Formula (I), or
pharmaceutically acceptable salts thereof,
wherein [0288] A.sup.2 is N, A.sup.3 is C, A.sup.4 is S and A.sup.6
is C; [0289] R.sup.A is hydrogen; [0290] X is O; [0291] Y is
(CH.sub.2).sub.m; wherein 3 CH.sub.2 groups are each independently
replaced by O, or C(R.sup.ya)(R.sup.yb); [0292] m is 4; [0293]
R.sup.ya, at each occurrence, is independently hydrogen; [0294]
R.sup.yb is C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with 1 G.sup.1; [0295] G.sup.1, at
each occurrence, is piperazinyl; wherein each G.sup.1 is optionally
substituted with R.sup.s; [0296] R.sup.5 is independently G.sup.3;
[0297] G.sup.3, at each occurrence, is independently
C.sub.6-C.sub.10 aryl optionally substituted with 1 R.sup.v group;
[0298] A.sup.7 is CR.sup.7; [0299] A.sup.8 is CR.sup.8; [0300]
A.sup.15 is CR.sup.15; [0301] R.sup.7, R.sup.12 and R.sup.16 are
each independently hydrogen; [0302] R.sup.8, R.sup.13, R.sup.14,
and R.sup.15, are each independently hydrogen, halogen,
C.sub.1-C.sub.4 alkyl; [0303] R.sup.9 is --OH; [0304] R.sup.10A and
R.sup.10B, are each independently hydrogen; [0305] W is
-L.sup.1-CH.sub.2--; wherein L.sup.1 is independently O; [0306]
R.sup.11 is a 5-11 membered heteroaryl; wherein each R.sup.11 is
optionally substituted with 1, 2, or 3 independently selected
R.sup.w groups; [0307] R.sup.w at each occurrence, is independently
G.sup.4; [0308] G.sup.4, at each occurrence, is independently
phenyl substituted with -L.sup.2-(C.sub.1-C.sub.6
alkylenyl).sub.s-G.sup.5; [0309] L.sup.2 is O; [0310] s is 1;
[0311] G.sup.5, at each occurrence, is independently
1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxepanyl, or
1,4-dioxepanyl; wherein each G.sup.5 is optionally substituted with
1 independently selected --OR.sup.m or 0, 1, 2, or 3 R.sup.z
groups; [0312] R.sup.s, R.sup.v, and R.sup.z, at each occurrence,
are each independently C.sub.1-C.sub.6 alkyl; and [0313] R.sup.m is
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
--(C.sub.2-C.sub.6 alkylenyl)-OR.sup.j, or --(C.sub.2-C.sub.6
alkylenyl)-N(R.sup.j).sub.2.
[0314] One embodiment pertains to compounds of Formula (I), or
pharmaceutically acceptable salts thereof,
wherein [0315] A.sup.2 is N, A.sup.3 is C, A.sup.4 is S and A.sup.6
is C; [0316] R.sup.A is hydrogen; [0317] X is O; [0318] Y is
(CH.sub.2).sub.m; wherein 3 CH.sub.2 groups are each independently
replaced by O or C(R.sup.ya)(R.sup.yb; [0319] m is 4; [0320]
R.sup.ya, at each occurrence, is independently hydrogen; [0321]
R.sup.yb is C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with G.sup.1; [0322] G.sup.1 is
piperazinyl; wherein each G.sup.1 is optionally substituted with
R.sup.s; [0323] R.sup.5 is independently G.sup.3; [0324] G.sup.3,
at each occurrence, is independently C.sub.6-C.sub.10 aryl; wherein
each G.sup.3 is optionally substituted with 1 R.sup.v groups;
[0325] A.sup.7 is CR.sup.7; [0326] A.sup.8 is CR.sup.8; [0327]
A.sup.15 is CR.sup.15; [0328] R.sup.7, R.sup.12 and R.sup.16 are
each independently hydrogen; [0329] R.sup.8, R.sup.13, R.sup.14,
and R.sup.15, are each independently halogen or C.sub.1-C.sub.4
alkyl; [0330] R.sup.9 is --OH; [0331] R.sup.10A and R.sup.10B, are
each independently hydrogen; [0332] W is -L.sup.1-CH.sub.2; wherein
L.sup.1 at each occurrence, is independently O; [0333] R.sup.11 is
5-11 membered heteroaryl; wherein each R.sup.11 is optionally
substituted with 1 independently selected R.sup.w group; [0334]
R.sup.w, at each occurrence, is independently G.sup.4; [0335]
G.sup.4, at each occurrence, is independently phenyl or
C.sub.3-C.sub.11 cycloalkyl; wherein each G.sup.4 is optionally
substituted with 1 substituent independently selected from the
group consisting of (C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; [0336] L.sup.2
is O; [0337] s is 1; [0338] G.sup.1, at each occurrence, is
independently 1,4-dioxanyl; and [0339] R.sup.s and R.sup.v, at each
occurrence, are each independently C.sub.1-C.sub.6 alkyl or
halogen.
[0340] One embodiment pertains to compounds of Formula (I), or
pharmaceutically acceptable salts thereof,
wherein [0341] A.sup.2 is N, A.sup.3 is C, A.sup.4 is S and A.sup.6
is C; [0342] R.sup.A is hydrogen; [0343] X is O; [0344] Y is
(CH.sub.2).sub.m; wherein 3 CH.sub.2 groups are each independently
replaced by O or C(R.sup.ya)(R.sup.yb; [0345] m is 4; [0346]
R.sup.ya, at each occurrence, is independently hydrogen; [0347]
R.sup.yb is C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with G.sup.1; [0348] G.sup.1 is
piperazinyl; wherein each G.sup.1 is optionally substituted with
R.sup.s; [0349] R.sup.5 is independently G.sup.3; [0350] G.sup.3,
at each occurrence, is independently C.sub.6-C.sub.10 aryl; wherein
each G.sup.3 is optionally substituted with 1 R.sup.v groups;
[0351] A.sup.7 is CR.sup.7; [0352] A.sup.8 is CR.sup.8; [0353]
A.sup.15 is CR.sup.15; [0354] R.sup.7, R.sup.12 and R.sup.16 are
each independently hydrogen; [0355] R.sup.8, R.sup.13, R.sup.14,
and R.sup.15, are each independently halogen or C.sub.1-C.sub.4
alkyl; [0356] R.sup.9 is --OH; [0357] R.sup.10A and R.sup.10B, are
each independently hydrogen; [0358] W is -L.sup.1-CH.sub.2; wherein
L.sup.1 at each occurrence, is independently O; [0359] R.sup.11 is
5-11 membered heteroaryl; wherein each R.sup.11 is optionally
substituted with 1 independently selected R.sup.w group; [0360]
R.sup.w, at each occurrence, is independently G.sup.4; [0361]
G.sup.4, at each occurrence, is independently phenyl; wherein each
G.sup.4 is optionally substituted with L.sup.2-(C.sub.1-C.sub.6
alkylenyl).sub.s-G.sup.5; [0362] L.sup.2 is O; [0363] s is 1;
[0364] G.sup.5, at each occurrence, is independently 1,4-dioxanyl;
and [0365] R.sup.s and R.sup.v, at each occurrence, are each
independently C.sub.1-C.sub.6 alkyl or halogen. [0366] One
embodiment pertains to compounds of Formula (I), or
pharmaceutically acceptable salts thereof, wherein [0367] A.sup.2
is N, A.sup.3 is C, A.sup.4 is S and A.sup.6 is C; [0368] R.sup.A
is hydrogen; [0369] X is O; [0370] Y is (CH.sub.2).sub.m; wherein 3
CH.sub.2 groups are each independently replaced by O or
C(R.sup.ya)(R.sup.yb; [0371] m is 4; [0372] R.sup.ya, at each
occurrence, is independently hydrogen; [0373] R.sup.yb is
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with G.sup.1; [0374] G.sup.1 is piperazinyl;
wherein each G.sup.1 is optionally substituted with R.sup.s; [0375]
R.sup.5 is independently G.sup.3; [0376] G.sup.3, at each
occurrence, is independently C.sub.6-C.sub.10 aryl; wherein each
G.sup.3 is optionally substituted with 1 R.sup.v groups; [0377]
A.sup.7 is CR.sup.7; [0378] A.sup.8 is CR.sup.8; [0379] A.sup.15 is
CR.sup.15; [0380] R.sup.7, R.sup.12 and R.sup.16 are each
independently hydrogen; [0381] R.sup.8, R.sup.13, R.sup.14, and
R.sup.15, are each independently halogen or C.sub.1-C.sub.4 alkyl;
[0382] R.sup.9 is --OH; [0383] R.sup.10A and R.sup.10B, are each
independently hydrogen; [0384] W is -L.sup.1-CH.sub.2; wherein
L.sup.1 at each occurrence, is independently O; [0385] R.sup.11 is
5-11 membered heteroaryl; wherein each R.sup.11 is optionally
substituted with 1 independently selected R.sup.w group; [0386]
R.sup.w, at each occurrence, is independently G.sup.4; [0387]
G.sup.4, at each occurrence, is independently C.sub.3-C.sub.1
cycloalkyl; wherein each G.sup.4 is optionally substituted with
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; [0388] L.sup.2
is O; [0389] s is 1; [0390] G.sup.5, at each occurrence, is
independently 1,4-dioxanyl; and [0391] R.sup.s and R.sup.v, at each
occurrence, are each independently C.sub.1-C.sub.6 alkyl or
halogen.
[0392] One embodiment pertains to compounds of Formula (I), or
pharmaceutically acceptable salts thereof,
wherein [0393] A.sup.2 is N, A.sup.3 is C, A.sup.4 is S and A.sup.6
is C; [0394] R.sup.A is hydrogen; [0395] X is O; [0396] Y is
(CH.sub.2).sub.m; wherein 3 CH.sub.2 groups are each independently
replaced by O or C(R.sup.ya)(R.sup.yb; [0397] m is 4; [0398]
R.sup.ya, at each occurrence, is independently hydrogen; [0399]
R.sup.yb is C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6
alkyl is optionally substituted with G.sup.1; [0400] G.sup.1 is
piperazinyl; wherein each G.sup.1 is optionally substituted with
R.sup.s; [0401] R.sup.5 is independently G.sup.3; [0402] G.sup.3,
at each occurrence, is independently C.sub.6-C.sub.10 aryl; wherein
each G.sup.3 is optionally substituted with 1 R.sup.v groups;
[0403] A.sup.7 is CR.sup.7; [0404] A.sup.8 is CR.sup.8; [0405]
A.sup.15 is CR.sup.15; [0406] R.sup.7, R.sup.12 and R.sup.16 are
each independently hydrogen; [0407] R.sup.8, R.sup.13, R.sup.14,
and R.sup.15, are each independently halogen or C.sub.1-C.sub.4
alkyl; [0408] R.sup.9 is --OH; [0409] R.sup.10A and R.sup.10B, are
each independently hydrogen; [0410] W is -L.sup.1-CH.sub.2; wherein
L.sup.1 at each occurrence, is independently O; [0411] R.sup.11 is
5-11 membered heteroaryl; wherein each R.sup.11 is optionally
substituted with 1 independently selected R.sup.w group; [0412]
R.sup.w, at each occurrence, is independently G.sup.4; [0413]
G.sup.4, at each occurrence, is independently C.sub.3-C.sub.11
cycloalkyl; wherein each G.sup.4 is optionally substituted with
--(C.sub.1-C.sub.6 alkylenyl)-L.sup.2-(C.sub.1-C.sub.6
alkylenyl)-G.sup.5; [0414] L.sup.2 is O; [0415] s is 1; [0416]
G.sup.5, at each occurrence, is independently 1,4-dioxanyl; and
[0417] R.sup.s and R.sup.v at each occurrence, are each
independently C.sub.1-C.sub.6 alkyl or halogen. [0418] One
embodiment pertains to compounds of Formula (I), or
pharmaceutically acceptable salts thereof, wherein [0419] A.sup.2
is N, A.sup.3 is C, A.sup.4 is O or S and A.sup.6 is C; [0420]
R.sup.A is hydrogen; [0421] X is O; [0422] Y is (CH.sub.2).sub.m;
wherein 3 CH.sub.2 groups are each independently replaced by O, or
C(R.sup.ya)(R.sup.yb); [0423] m is 4; [0424] R.sup.ya, at each
occurrence, is independently hydrogen; [0425] R.sup.yb is
C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with G.sup.1; [0426] G.sup.1, at each
occurrence, is piperazinyl; wherein each G.sup.1 is optionally
substituted with 1 R.sup.s; [0427] R.sup.5 is independently G.sup.3
and C.sub.1-C.sub.6 alkyl; wherein the C.sub.1-C.sub.6 alkyl is
optionally substituted with one G.sup.3; [0428] G.sup.3, at each
occurrence, is independently C.sub.6-C.sub.10 aryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl,
1,4-dioxanyl, or 2,3-dihydro-1,4-dioxinyl; wherein each G.sup.3 is
optionally substituted with 13 R.sup.v groups; [0429] A.sup.7 is
CR.sup.7; [0430] A.sup.8 is CR.sup.8; [0431] A.sup.15 is CR.sup.15;
[0432] R.sup.7, R.sup.12 and R.sup.16 are each independently
hydrogen; [0433] R.sup.8, R.sup.13, R.sup.14, and R.sup.15, are
each independently hydrogen, halogen, or C.sub.1-C.sub.4 alkyl;
[0434] R.sup.9 is --OH; [0435] R.sup.10A and R.sup.10B, are each
independently hydrogen; [0436] W is -L.sup.1-CH.sub.2--; wherein
L.sup.1 at each occurrence, is independently O; [0437] R.sup.11 is
5-11 membered heteroaryl; wherein each R.sup.11 is optionally
substituted with 1 or 2 independently selected R.sup.w groups;
[0438] R.sup.w, at each occurrence, is independently --OR.sup.11a
or G.sup.4; [0439] R.sup.11a, at each occurrence, are each
independently --(C.sub.2-C.sub.6 alkylenyl)-G.sup.4; [0440]
G.sup.4, at each occurrence, is independently phenyl, monocyclic
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl,
1,4-dioxanyl, or 1,4-dioxepanyl; wherein each G.sup.4 is optionally
substituted with 1 --OR.sup.m and 1 or 2 substituents independently
selected from the group consisting of R.sup.y, --(C.sub.1-C.sub.6
alkylenyl)-L.sup.2-(C.sub.1-C.sub.6 alkylenyl)-G.sup.5, and
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.1; [0441] L.sup.2
is O, or S(O).sub.2; [0442] s is 1; [0443] G.sup.5, at each
occurrence, is independently 1,3-dioxolanyl, or 1,4-dioxanyl;
wherein each G.sup.1 is substituted with 0, 1, or 2 R.sup.z groups;
[0444] R.sup.s, R.sup.v, R.sup.y, and R.sup.z, at each occurrence,
are each independently C.sub.1-C.sub.6 alkyl, or halogen; and
[0445] R.sup.m is C.sub.1-C.sub.6 alkyl; [0446] wherein at least
one of G.sup.3, G.sup.4, and G.sup.5 is 2,3-dihydro-1,4-dioxinyl,
1,3-dioxolanyl, 1,4-dioxanyl, or 1,4-dioxepanyl.
[0447] Exemplary compounds of Formula (I) include, but are not
limited to: [0448]
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(4S)-2,2-dimethyl-1,3-dioxolan-
-4-yl]methoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylic acid; [0449]
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)p-
yrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0450]
(7R,16R)-19,23-dichloro-10-{[2-(2-{[(4R)-2,2-dimethyl-1,3-dioxolan-
-4-yl]methoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylic acid; [0451]
(7R,16R,21S)-19-chloro-10-{[2-(1,4-dioxan-2-yl)pyrimidin-4-yl]methoxy}-1--
(4-fluorophenyl)-20-methyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-t-
etrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclo-
nonadeca[1,2,3-cd]indene-7-carboxylic acid; [0452]
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin--
3-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-meth-
ylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)--
6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0453]
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin--
3-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-meth-
ylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)--
6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0454]
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2S)-1,4-dioxan-2-yl]methoxy}phenyl)p-
yrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0455]
(7R,16R)-19,23-dichloro-10-({2-[4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluoropiperidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)--
20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18-
,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2-
,3-cd]indene-7-carboxylic acid; [0456]
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan-2-yl]methoxy}-
cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylic acid; [0457]
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}piperidi-
n-1-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-me-
thylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno-
)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxyli-
c acid; [0458]
(7R,16R)-19,23-dichloro-10-({2-[1-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)-
cyclobutyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylic acid; [0459]
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)-
azetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-
-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(-
metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-ca-
rboxylic acid; [0460]
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2R)-1,4-dioxan-2-yl]methoxy}methyl)-
azetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-
-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(-
metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-ca-
rboxylic acid; [0461]
(7R,16R)-19,23-dichloro-10-[(2-{(1r,4r)-4-[(1,3-dioxolan-4-yl)methoxy]cyc-
lohexyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-m-
ethylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methen-
o)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxyl-
ic acid; [0462]
(7R,16R)-19,23-dichloro-10-[(2-{(1s,4s)-4-[(1,4-dioxan-2-yl)methoxy]cyclo-
hexyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-met-
hylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-
-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0463]
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)p-
yrazin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipera-
zin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17--
trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0464]
(7R,16R)-19,23-dichloro-1-cyclohexyl-10-{[2-(4-{[(2S)-1,4-dioxan-2-
-yl]methoxy}phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpip-
erazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,-
17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0465]
(7R,16R)-19,23-dichloro-1-{[(2R)-1,4-dioxan-2-yl]methyl}-10-{[2-(2-
-methoxyphenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperaz-
in-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-t-
rioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0466]
(7R,16R)-19,23-dichloro-1-{[(2S)-1,4-dioxan-2-yl]methyl}-10-{[2-(2-
-methoxyphenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperaz-
in-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-t-
rioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0467]
(7R,16R)-19,23-dichloro-10-({2-[(2R)-2-{[(1,4-dioxan-2-yl)methoxy]-
methyl}morpholin-4-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dim-
ethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-ethen-
o-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]ind-
ene-7-carboxylic acid; [0468]
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)p-
yrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0469]
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}p-
henyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-met-
hylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-
-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0470]
(7R,16R)-19,23-dichloro-10-{[4-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)p-
yrimidin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0471]
(7R,16R)-19,23-dichloro-10-[(2-{[(2S)-1,4-dioxan-2-yl]methoxy}pyri-
midin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperaz-
in-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-t-
rioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0472]
(7R,16R)-19,23-dichloro-10-[(2-{[(2R)-1,4-dioxan-2-yl]methoxy}pyri-
midin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperaz-
in-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-t-
rioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0473]
(7R,16R)-19,23-dichloro-10-[(2-{4-[(1,4-dioxan-2-yl)methanesulfony-
l]piperazin-1-yl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-
-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,-
9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-
-carboxylic acid; [0474]
(7R,16R)-19,23-dichloro-1-(5,6-dihydro-1,4-dioxin-2-yl)-10-{[2-(2-methoxy-
phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic acid;
[0475]
(7R,16R)-19,23-dichloro-10-({2-[(1R,4s)-4-({[(2S)-1,4-dioxan-2-yl]methoxy-
}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,-
22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-
-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3--
cd]indene-7-carboxylic acid; [0476]
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-[(2-{(1r,4r)-4-[(1,4-dioxan-2-yl)-
methoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dimethyl-16-[(4-methylpip-
erazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,-
17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0477]
(7R,16R)-19,23-dichloro-10-{[2-(1,4-dioxepan-6-yl)pyrimidin-4-yl]m-
ethoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)meth-
yl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-
-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic acid; [0478]
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)p-
yrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0479]
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-[(2-{(1r,4r)-4--
[(1,4-dioxan-2-yl)methoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dimethy-
l-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13-
,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene--
7-carboxylic acid; [0480]
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1R,4s)-4-({[(2S)-
-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy-
)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro--
18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1-
,2,3-cd]indene-7-carboxylic acid; [0481]
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4-({[(2R)-1,-
4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}me-
thoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylic acid; [0482]
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4-({[(2S)-1,-
4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}me-
thoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylic acid; [0483]
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2S)-1,4-dioxan-2-yl]methyl}amino)py-
ridin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylic acid; [0484]
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1S,4r)-4-({[(2S)-
-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy-
)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro--
18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1-
,2,3-cd]indene-7-carboxylic acid; [0485]
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4-({[(2S)-1,-
4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}me-
thoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylic acid; [0486]
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2R)-1,4-dioxan-2-yl]methoxy-
}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,-
22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-
-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3--
cd]indene-7-carboxylic acid; [0487]
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}me-
thyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl-
)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro--
18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1-
,2,3-cd]indene-7-carboxylic acid; [0488]
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2R)-1,4-dioxan-2-yl]methyl}amino)py-
ridin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylic acid; [0489]
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}me-
thyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl-
)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro--
18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1-
,2,3-cd]indene-7-carboxylic acid; [0490]
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}me-
thyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl-
)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro--
18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1-
,2,3-cd]indene-7-carboxylic acid; [0491]
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-{[(2S)-1,4-dioxan-2-yl]methoxy}-
cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylic acid; [0492]
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}me-
thyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl-
)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro--
18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1-
,2,3-cd]indene-7-carboxylic acid; [0493]
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2S)-1,4-dioxan-2-yl]methoxy-
}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,-
22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-
-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3--
cd]indene-7-carboxylic acid; [0494]
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2R)-1,4-dioxan-2-yl]methoxy-
}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,-
22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-
-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3--
cd]indene-7-carboxylic acid; [0495]
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4-({[(2R)-1,-
4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}me-
thoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylic acid;
[0496]
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2R)-1,4-dioxan-2-yl]-
methoxy}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-
-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-e-
theno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd-
]indene-7-carboxylic acid; [0497]
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2S)-1,4-dioxan-2-yl]methoxy-
}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimeth-
yl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-1-
3,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-
-7-carboxylic acid; [0498]
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2S)-1,4-dioxan-2-yl]methoxy-
}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimeth-
yl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-1-
3,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-
-7-carboxylic acid; [0499]
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan--
2-yl]methoxy}cyclohexyl]pyrimidin-4-yl}methoxy)-20,22-dimethyl-16-[(4-meth-
ylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)--
6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid; [0500]
(7R,16R)-19,23-dichloro-10-{[3-{[(2S)-1,4-dioxan-2-yl]methoxy}-6-(2-metho-
xyphenyl)pyridin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-me-
thylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno-
)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxyli-
c acid; and pharmaceutically acceptable salts thereof.
Formula (II)
[0501] One embodiment pertains to compounds of Formula (IIa),
(IIb), (IIc), (IId), or pharmaceutically acceptable salts
thereof,
##STR00011##
wherein A.sup.7, A.sup.8, A.sup.15, R.sup.5, R.sup.9, R.sup.10A,
R.sup.10B, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.16, W, X,
and Y are as described in embodiments of Formula (I) herein.
[0502] Exemplary compounds of Formula (IIa), (IIb), (IIc), and
(IId) include, but are not limited to: Examples 1-53; and
pharmaceutically acceptable salts thereof.
Formula (III)
[0503] One embodiment pertains to compounds of Formula (IIIa),
(IlIb), (IIIc), (IId), or pharmaceutically acceptable salts
thereof,
##STR00012##
wherein A.sup.8, A.sup.15, R.sup.5, R.sup.11, R.sup.13, R.sup.14,
W, and Y are as described in embodiments of Formula (I) herein.
[0504] Exemplary compounds of Formula IIIa), (IIIb), (IIIc), and
(IIId) include, but are not limited to: Examples 1-53; and
pharmaceutically acceptable salts thereof.
Formula (IV)
[0505] One embodiment pertains to compounds of Formula (IVa),
(IVb), (IVc), (IVd), or pharmaceutically acceptable salts
thereof,
##STR00013##
wherein A.sup.8, A.sup.15, R.sup.5, R.sup.13, R.sup.14, R.sup.w,
and Y are as described in embodiments of Formula (I) herein.
[0506] One embodiment pertains to compounds of Formula (IVa),
(IVb), (IVc), and (IVd) wherein R is tetrahydrofuranyl,
tetrahydropyranyl, or phenyl, substituted with one
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5.
[0507] One embodiment pertains to compounds of Formula (IVa),
(IVb), (IVc), and (IVd) wherein R is phenyl, substituted with one
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5.
[0508] One embodiment pertains to compounds of Formula (IVa),
(IVb), (IVc), and (IVd) wherein R is phenyl, substituted with one
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; and R.sup.s is
4-fluorophenyl or cyclopropyl.
[0509] Exemplary compounds of Formula (IVa), (IVb), (IVc), (IVd)
include, but are not limited to: Examples 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 24, 25, 26, 27,
28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,
46, 47, 48, 49, 50, 51, 52, and pharmaceutically acceptable salts
thereof.
Formula (V)
[0510] One embodiment pertains to compounds of Formula (Va), (Vb),
(Vc), (Vd), or pharmaceutically acceptable salts thereof,
##STR00014##
wherein A.sup.8, A.sup.15, R.sup.5, R.sup.13, R.sup.14, R.sup.w,
and Y are as described in embodiments of Formula (I) herein.
[0511] One embodiment pertains to compounds of Formula (Va), (Vb),
(Vc), and (Vd) wherein R.sup.w is tetrahydrofuranyl,
tetrahydropyranyl, or phenyl, substituted with one
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5.
[0512] One embodiment pertains to compounds of Formula (Va), (Vb),
(Vc), and (Vd) wherein R.sup.w is phenyl, substituted with one
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5.
[0513] One embodiment pertains to compounds of Formula (Va), (Vb),
(Vc), and (Vd) wherein R.sup.w is phenyl, substituted with one
-L.sup.2-(C.sub.1-C.sub.6 alkylenyl).sub.s-G.sup.5; and R.sup.s is
4-fluorophenyl or cyclopropyl.
[0514] Exemplary compounds of Formula (Va), (Vb), (Vc), (Vd),
include, but are not limited to: Example 4, and pharmaceutically
acceptable salts thereof.
[0515] Compound names are assigned by using Name 2016.1.1 (File
Version N30E41, Build 86668) or Name 2017.2.1 (File Version N40E41,
Build 96719) naming algorithm by Advanced Chemical Development or
Struct=Name naming algorithm as part of CHEMDRAW.RTM. ULTRA v.
12.0.2.1076 or Professional Version 15.0.0.106.
[0516] Compounds of the disclosure may exist as atropisomers,
resulting from hindered rotation about a single bond, when energy
differences due to steric strain or other contributors create a
barrier to rotation that is high enough to allow for isolation of
individual conformers. See, e.g., Bringmann, G. et al.,
Atroposelective Synthesis of Axially Chiral Biaryl Compounds.
Angew. Chem., Int. Ed., 2005, 44: 5384-5428. In some instances, the
barrier of rotation is high enough that the different atropisomers
may be separated and isolated, such as by chromatography on a
chiral stationary phase. It is to be understood that the
stereochemistry of the atropisomers is included in the compound
names only when compounds are assayed as being pure (at least 95%)
or are predominantly (at least 80%) one isomer. Where there is no
atropisomer stereochemistry noted for a compound, then it is to be
understood that either the stereochemistry is undetermined, or it
was determined to be a near-equal mixture of atropisomers. In
addition, where there is a discrepancy between the name of the
compound and the structure found in Table 1, the structure depicted
in Table 1 shall prevail.
[0517] Compounds of the present disclosure may exist as
stereoisomers wherein asymmetric or chiral centers are present.
These stereoisomers are "R" or "S" depending on the configuration
of substituents around the chiral carbon atom. The terms "R" and
"S" used herein are configurations as defined in IUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, in Pure
Appl. Chem., 1976, 45: 13-30. The present disclosure contemplates
various stereoisomers and mixtures thereof and these are
specifically included within the scope of this disclosure.
Stereoisomers include enantiomers and diastereomers, and mixtures
of enantiomers or diastereomers. Individual stereoisomers of
compounds of the present disclosure may be prepared synthetically
from commercially available starting materials which contain
asymmetric or chiral centers or by preparation of racemic mixtures
followed by methods of resolution well-known to those of ordinary
skill in the art. These methods of resolution are exemplified by
(1) attachment of a mixture of enantiomers to a chiral auxiliary,
separation of the resulting mixture of diastereomers by
precipitation or chromatography and optional liberation of the
optically pure product from the auxiliary as described in Furniss,
Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical
Organic Chemistry", 5th edition (1989), Longman Scientific &
Technical, Essex CM20 2JE, England, or (2) direct separation of the
mixture of optical enantiomers on chiral chromatographic columns or
(3) fractional recrystallization methods. It is to be understood
that an asterisk (*) at a particular stereocenter in a structure of
a chiral compound, indicates an arbitrary assignment of
stereochemical configuration at that stereocenter. Moreover, an
asterisk (*) following a stereochemical descriptor in the name of
such a compound designates an arbitrary assignment of
stereochemical configuration at that stereocenter.
[0518] Compounds of the present disclosure may exist as cis or
trans isomers, wherein substituents on a ring may attached in such
a manner that they are on the same side of the ring (cis) relative
to each other, or on opposite sides of the ring relative to each
other (trans). For example, cyclobutane may be present in the cis
or trans configuration, and may be present as a single isomer or a
mixture of the cis and trans isomers. Individual cis or trans
isomers of compounds of the present disclosure may be prepared
synthetically from commercially available starting materials using
selective organic transformations, or prepared in single isomeric
form by purification of mixtures of the cis and trans isomers. Such
methods are well-known to those of ordinary skill in the art, and
may include separation of isomers by precipitation or
chromatography.
[0519] It should be understood that the compounds of the present
disclosure may possess tautomeric forms, as well as geometric
isomers, and that these also constitute an aspect of the
disclosure.
[0520] The present disclosure includes all pharmaceutically
acceptable isotopically-labeled compounds of formula (I) wherein
one or more atoms are replaced by atoms having the same atomic
number, but an atomic mass or mass number different from the atomic
mass or mass number which predominates in nature. Examples of
isotopes suitable for inclusion in the compounds of the disclosure
include isotopes of hydrogen, such as .sup.2H and .sup.3H, carbon,
such as .sup.11C, .sup.13C and .sup.14C, chlorine, such as
.sup.36Cl, fluorine, such as .sup.18F, iodine, such as .sup.123I
and .sup.125I, nitrogen, such as .sup.13N and .sup.15N, oxygen,
such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such as
.sup.32P, and sulphur, such as .sup.35S. Certain
isotopically-labeled compounds of formula (I), for example, those
incorporating a radioactive isotope, are useful in drug and/or
substrate tissue distribution studies. The radioactive isotopes
tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection. Substitution with
heavier isotopes such as deuterium, i.e. 2H, may afford certain
therapeutic advantages resulting from greater metabolic stability,
for example, increased in vivo half-life or reduced dosage
requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as .sup.11C,
.sup.18F, .sup.15O and .sup.13N, can be useful in Positron Emission
Topography (PET) studies for examining substrate receptor
occupancy. Isotopically-labeled compounds of formula (I) may
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples using an appropriate isotopically-labeled
reagents in place of the non-labeled reagent previously
employed.
[0521] Thus, the formula drawings within this specification can
represent only one of the possible tautomeric, geometric, or
stereoisomeric forms. It is to be understood that the present
disclosure encompasses any tautomeric, geometric, or stereoisomeric
form, and mixtures thereof, and is not to be limited merely to any
one tautomeric, geometric, or stereoisomeric form utilized within
the formula drawings.
[0522] Exemplary compounds of formula (I) include, but are not
limited to, the compounds shown in Table 1 below. It is to be
understood that when there is a discrepancy between the name of the
compound found herein and the structure found in Table 1, the
structure in Table 1 shall prevail. In addition, it is to be
understood that an asterisk (*), at a particular stereocenter in a
structure, indicates an arbitrary assignment of stereochemical
configuration at that stereocenter.
TABLE-US-00001 TABLE 1 EXAMPLE STRUCTURE 1 ##STR00015## 2
##STR00016## 3 ##STR00017## 4 ##STR00018## 5 ##STR00019## 6
##STR00020## 7 ##STR00021## 8 ##STR00022## 9 ##STR00023## 10
##STR00024## 11 ##STR00025## 12 ##STR00026## 13 ##STR00027## 14
##STR00028## 15 ##STR00029## 16 ##STR00030## 17 ##STR00031## 18
##STR00032## 19 ##STR00033## 20 ##STR00034## 21 ##STR00035## 22
##STR00036## 23 ##STR00037## 24 ##STR00038## 25 ##STR00039## 26
##STR00040## 27 ##STR00041## 28 ##STR00042## 29 ##STR00043## 30
##STR00044## 31 ##STR00045## 32 ##STR00046## 33 ##STR00047## 34
##STR00048## 35 ##STR00049## 36 ##STR00050## 37 ##STR00051## 38
##STR00052## 39 ##STR00053## 40 ##STR00054## 41 ##STR00055## 42
##STR00056## 43 ##STR00057## 44 ##STR00058## 45 ##STR00059## 46
##STR00060## 47 ##STR00061## 48 ##STR00062## 49 ##STR00063## 50
##STR00064## 51 ##STR00065## 52 ##STR00066## 53 ##STR00067##
[0523] One embodiment pertains to Example 2, and pharmaceutically
acceptable salts thereof:
##STR00068##
That is, in embodiments, the compound of Formula (I) is
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)p-
yrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid, or pharmaceutically acceptable salts thereof.
[0524] One embodiment pertains to Example 9, and pharmaceutically
acceptable salts thereof:
##STR00069##
That is, in embodiments, the compound of Formula (I) is
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan-2-yl]methoxy}-
cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylic acid, or pharmaceutically acceptable salts thereof.
[0525] One embodiment pertains to Example 28, and pharmaceutically
acceptable salts thereof:
##STR00070##
That is, in embodiments, the compound of Formula (I) is
(7R,16R)-19,23-dichloro-10-({2-[(1R,4s)-4-({[(2S)-1,4-dioxan-2-yl]methoxy-
}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,-
22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-
-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3--
cd]indene-7-carboxylic acid, or pharmaceutically acceptable salts
thereof.
[0526] One embodiment pertains to Example 39, and pharmaceutically
acceptable salts thereof:
##STR00071##
That is, in embodiments, the compound of Formula (I) is
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2R)-1,4-dioxan-2-yl]methoxy-
}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,-
22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-
-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3--
cd]indene-7-carboxylic acid, or pharmaceutically acceptable salts
thereof.
[0527] One embodiment pertains to Example 44, and pharmaceutically
acceptable salts thereof:
##STR00072##
That is, in embodiments, the compound of Formula (I) is
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-{[(2S)-1,4-dioxan-2-yl]methoxy}-
cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylic acid, or pharmaceutically acceptable salts thereof.
[0528] One embodiment pertains to Example 49, and pharmaceutically
acceptable salts thereof:
##STR00073##
That is, in embodiments, the compound of Formula (I) is
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2R)-1,4-dioxan-2-yl]methoxy-
}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimeth-
yl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-1-
3,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-
-7-carboxylic acid, or pharmaceutically acceptable salts
thereof.
[0529] One embodiment pertains to Example 51, and pharmaceutically
acceptable salts thereof:
##STR00074##
That is, in embodiments, the compound of Formula (I) is
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2$)-1,4-dioxan-2-yl]methoxy-
}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimeth-
yl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-1-
3,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-
-7-carboxylic acid, or pharmaceutically acceptable salts
thereof.
[0530] Compounds of formula (I) may be used in the form of
pharmaceutically acceptable salts. The phrase "pharmaceutically
acceptable salt" means those salts which are, within the scope of
sound medical judgement, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity,
irritation, allergic response and the like and are commensurate
with a reasonable benefit/risk ratio.
[0531] Pharmaceutically acceptable salts have been described in S.
M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.
[0532] Compounds of formula (I) may contain either a basic or an
acidic functionality, or both, and may be converted to a
pharmaceutically acceptable salt, when desired, by using a suitable
acid or base. The salts may be prepared in situ during the final
isolation and purification of the compounds of the present
disclosure.
[0533] Examples of acid addition salts include, but are not limited
to acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
malate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Examples of acids which may be
employed to form pharmaceutically acceptable acid addition salts
include such inorganic acids as hydrochloric acid, hydrobromic
acid, sulfuric acid, and phosphoric acid and such organic acids as
acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic
acid, succinic acid and citric acid.
[0534] Basic addition salts may be prepared in situ during the
final isolation and purification of compounds of this disclosure by
reacting a carboxylic acid-containing moiety with a suitable base
such as, but not limited to, the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to,
cations based on alkali metals or alkaline earth metals such as,
but not limited to, lithium, sodium, potassium, calcium, magnesium
and aluminum salts and the like and nontoxic quaternary ammonia and
amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine and the like. Other
examples of organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
Synthesis
[0535] The compounds described herein, including compounds of
general formula (I) and specific examples, may be prepared, for
example, through the reaction routes depicted in schemes 1-9. The
variables A.sup.2, A.sup.3, A.sup.4, A.sup.6, A.sup.7, A.sup.8,
A.sup.15, R.sup.A, R.sup.5, R.sup.9, R.sup.10A, R.sup.10B,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, W, X,
and Y used in the following schemes have the meanings as set forth
in the Summary and Detailed Description sections unless otherwise
noted.
[0536] Abbreviations that may be used in the descriptions of the
schemes and the specific examples have the meanings listed in the
table below.
TABLE-US-00002 Abbreviation Definition .mu.L microliter Boc
tert-butoxycarbonyl br s broad singlet d duplet DCI desorption
chemical ionization DCM dichloromethane dd double duplet DIEA
N,N-Diisopropylethylamine DMAP dimethylaminopyridine DMF
N,N-dimethylformamide DMSO dimethyl sulfoxide eq or equiv
equivalents ESI electrospray ionization Et ethyl g gram h hours
HATU 1-[bis(dimethylamino)methyene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HOBt
1-hydroxybenzotriazole hydrate HPLC high performance liquid
chromatography or high pressure liquid chromatography kg kilogram
LC/MS or LCMS liquid chromatography-mass spectrometry m multiplet
Me methyl MeOH methanol mg milligram min minute mL milliliter mmol
millimoles MPLC medium pressure liquid chromatography MS mass
spectrum NMP N-methylpyrrolidone NMR nuclear magnetic resonance Ph
phenyl ppm parts per million psi pounds per square inch s singlet
SFC supercritical fluid chromatography tBuOH or t-BuOH tert-butanol
TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer
chromatography XPhos 2-dicyclohexylphosphino-2',4',6'-
triisopropylbiphenyl
##STR00075##
[0537] The synthesis of thienopyrimidine intermediates of formula
(5) is described in Scheme 1. Thieno[2,3-d]pyrimidine-4(3H)-ones of
formula (1), wherein R.sup.A is as described herein, can be treated
with periodic acid and iodine to provide
6-iodothieno[2,3-d]pyrimidin-4(3H)-ones of formula (2). The
reaction is typically performed at an elevated temperature, for
example from 60.degree. C. to 70.degree. C., in a solvent system
such as, but not limited to, acetic acid, sulfuric acid and water.
4-Chloro-6-iodothieno[2,3-d]pyrimidines of formula (3) can be
prepared by treating 6-iodothieno[2,3-d]pyrimidin-4(3H)-ones of
formula (2) with phosphorous oxychloride. The reaction is typically
carried out in a solvent such as, but not limited to,
N,N-dimethylaniline at an elevated temperature.
5-Bromo-4-chloro-6-iodothieno[2,3-d]pyrimidines of formula (4) can
be prepared by the treatment of
4-chloro-6-iodothieno[2,3-d]pyrimidines of formula (3) with
N-bromosuccinimide in the presence of tetrafluoroboric
acid-dimethyl ether complex. The reaction is typically performed at
ambient temperature in a solvent such as, but not limited to,
acetonitrile. Compounds of formula (5) can be prepared by reacting
5-bromo-4-chloro-6-iodothieno[2,3-d]pyrimidines of formula (4) with
a boronic acid (or the equivalent boronate ester) of formula (6),
wherein R.sup.5 is G.sup.3 as described herein, under Suzuki
Coupling conditions described herein, known to those skilled in the
art, or widely available in the literature.
##STR00076##
[0538] The synthesis of thienopyrimidine intermediates of formula
(9) is described in Scheme 2. Thieno[2,3-d]pyrimidine-4(3H)-ones of
formula (1), wherein R.sup.A is as described herein, can be treated
with periodic acid and iodine to provide
5,6-diiodothieno[2,3-d]pyrimidin-4(3H)-ones of formula (7). The
reaction is typically performed at an elevated temperature, for
example from 60.degree. C. to 100.degree. C., in a solvent system
such as, but not limited to, acetic acid, sulfuric acid and water.
4-Chloro-5,6-diiodothieno[2,3-d]pyrimidines of formula (8) can be
prepared by treating 5,6-diiodothieno[2,3-d]pyrimidin-4(3H)-ones of
formula (7) with phosphorous oxychloride. The reaction is typically
carried out in a solvent such as, but not limited to,
N,N-dimethylaniline at an elevated temperature.
4-Chloro-5,6-diiodothieno[2,3-d]pyrimidines of formula (8) can be
treated with tert-butylmagnesium chloride to provide compounds of
formula (9). The reaction is typically performed at a low
temperature in a solvent, such as, but not limited to,
tetrahydrofuran.
##STR00077##
[0539] Scheme 3 describes the synthesis of furanopyrimidine
intermediates of formula (13). 4-Chlorofuro[2,3-d]pyrimidines (10),
wherein R.sup.A is as described herein, can be treated with lithium
diisopropylamide followed by iodine, in a solvent such as, but not
limited to, tetrahydrofuran, to provide
4-chloro-6-iodofuro[2,3-d]pyrimidines of formula (11). The reaction
is typically performed by first incubating a compound of formula
(10) with lithium diisopropylamide at a low temperature, such as
-78.degree. C., followed by the addition of iodine and subsequent
warming to ambient temperature. Compounds of formula (12) can be
prepared by reacting 4-chloro-6-iodofuro[2,3-d]pyrimidines of
formula (11) with a boronic acid (or the equivalent boronate ester)
of formula (6) under Suzuki Coupling conditions described herein,
known to those skilled in the art, or widely available in the
literature. Compounds of formula (12) can be treated with
N-bromosuccinimide to provide compounds of formula (13). The
reaction is typically performed at ambient temperature in a
solvent, such as, but not limited to, N,N-dimethylformamide.
##STR00078##
[0540] Scheme 4 describes the synthesis of pyrrolopyrazine
intermediates of the formula (22), wherein R.sup.A and R.sup.5 are
as described herein. Compounds of the formula (15) can be prepared
by reacting methyl 4-bromo-1H-pyrrole-2-carboxylate (14) with a
boronic acid (or the equivalent boronate ester) of formula (6)
under Suzuki Coupling conditions described herein, known to those
skilled in the art, or widely available in the literature.
Compounds of formula (15) can be heated in the presence of an
aqueous ammonium hydroxide solution to provide compounds of formula
(16). Compounds of the formula (17) can be prepared by treatment of
pyrroles of formula (16) with 2-bromo-1,1-dimethoxyethane in the
presence of a base such as, but not limited to, cesium carbonate.
The reaction is typically performed in a solvent such as, but not
limited to, N,N-dimethylformamide at elevated temperatures ranging
from 80.degree. C. to 90.degree. C. Compounds of formula (17) can
be treated with hydrogen chloride in a solvent such as, but not
limited to, dichloromethane to provide compounds of the formula
(18). Compounds of the formula (19) can be prepared by reacting
intermediates (18) with phosphorous oxychloride in the presence of
a base such as, but not limited to, N,N-diisopropylethylamine. The
reaction is typically performed at elevated temperatures such as
ranging from 100.degree. C. to 115.degree. C. Compounds of formula
(19) can be treated with N-chlorosuccinimide in a solvent system
such as, but not limited to, tetrahydrofuran to provide compounds
of formula (20). The reaction is typically performed at an elevated
temperature. Compounds of formula (21) can be prepared by reacting
compounds of formula (20) with N-iodosuccinimide at an elevated
temperature in a solvent such as, but not limited to,
N,N-dimethylformamide. Compounds of formula (21) can be treated
with tetramethylammonium fluoride to provide compounds of formula
(22). The reaction is typically performed at ambient temperature in
a solvent such as, but not limited to, N,N-dimethylformamide.
##STR00079## ##STR00080##
[0541] Scheme 5 describes the synthesis of propanoate intermediates
of formula (30). 2,5-Dihydroxybenzaldehyde (23) can be treated with
tert-butylchlorodimethylsilane to provide mono-silylated
intermediate (24). The reaction is typically conducted at ambient
temperature in the presence of a base such as, but not limited to,
imidazole in a solvent such as, but not limited to,
dichloromethane. The mono-silylated intermediate can be reacted
with benzyl bromide to provide
2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)benzaldehyde (25).
The reaction is typically performed in the presence of a base such
as, but not limited to, potassium carbonate, and in a solvent such
as, but not limited to acetone, N,N-dimethylformamide, or mixtures
thereof. The reaction is typically initiated at room temperature
followed by heating to an elevated temperature.
2-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)benzaldehyde (25) can
be treated with ethyl 2-acetoxy-2-(diethoxyphosphoryl)acetate to
provide (E)/(Z)-ethyl
2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acrylat-
es (26). The reaction is typically run in the presence a base such
as, but not limited to, cesium carbonate in a solvent such as, but
not limited to, tetrahydrofuran, toluene, or mixtures thereof.
(E)/(Z)-Ethyl
2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acrylat-
es (26) can be reacted with the catalyst (R,R)--Rh EtDuPhos
(1,2-bis[(2R,5R)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodiu-
m(I) trifluoromethanesulfonate) under an atmosphere of hydrogen gas
in a solvent such as, but not limited to, methanol, to provide
(R)-ethyl
2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propano-
ate (27). The reaction is typically performed at 35.degree. C.
under 50 psi of hydrogen gas. Ethyl
(R)-2-acetoxy-3-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)propano-
ate (28) can be provided by reacting (R)-ethyl
2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propano-
ate (27) under hydrogenolysis conditions, such as in the presence
of 5% palladium on carbon under 50 psi of hydrogen gas in a solvent
such as, but not limited to, ethanol at an elevated temperature,
such as, but not limited to, 35.degree. C. Ethyl
(R)-2-acetoxy-3-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)propano-
ate (28) can be reacted with compounds of formula (31), wherein
R.sup.11 is as described herein, under Mitsunobu conditions
described herein, known to those skilled in the art, or widely
available in the literature, to provide compounds of formula (29).
Compounds of the formula (29) can be treated with ethanol in the
presence of a base such as, but not limited to, potassium carbonate
or sodium ethoxide, to provide compounds of the formula (30).
##STR00081##
[0542] Scheme 6 describes the synthesis of propanoate intermediates
of formula (35). (R)-Ethyl 2-acetoxy-3-(2-hydroxyphenyl)propanoate
(32), which can be prepared using methods similar to those
described for compounds of formula (28) in Scheme 5 or using
methods described herein, can be treated with a brominating agent
such as N-bromosuccinimide to provide (R)-ethyl
2-acetoxy-3-(5-bromo-2-hydroxyphenyl)propanoate (33). The reaction
is typically performed in a solvent such as, but not limited to,
tetrahydrofuran, at a low temperature, such as -30.degree. C. to
0.degree. C., before warming to ambient temperature. (R)-Ethyl
2-acetoxy-3-(5-bromo-2-hydroxyphenyl)propanoate (33) can be reacted
with compounds of formula (31), wherein R.sup.11 is as described
herein, under Mitsunobu conditions described herein or in the
literature to provide compounds of formula (34). Compounds of
formula (34) can be treated with ethanol in the presence of a base
such as, but not limited to, potassium carbonate or sodium ethoxide
at ambient temperature to provide compounds of formula (35).
##STR00082## ##STR00083##
[0543] Scheme 7 describes the synthesis of macrocyclic compounds of
the formula (46), which are representative of compounds of formula
(I). Intermediates of the formula (5) can be reacted with compounds
of the formula (36), wherein A.sup.7, R.sup.11, R.sup.12, R.sup.16
are as described herein and R.sup.E is alkyl, in the presence of
base such as, but not limited to, cesium carbonate, to provide
compounds of the formula (37). The reaction is typically conducted
at an elevated temperature, such as, but not limited to 65.degree.
C., in a solvent such as but not limited to tert-butanol,
N,N-dimethylformamide, or mixtures thereof. Compounds of formula
(39) can be prepared by reacting compounds of formula (37) with a
boronate ester (or the equivalent boronic acid) of formula (38)
under Suzuki Coupling conditions described herein or in the
literature. Compounds of formula (39) can be treated with
tetrabutylammonium fluoride in a solvent system such as
dichloromethane, tetrahydrofuran or mixtures thereof to provide
compounds of formula (40). Treatment of compounds of formula (40)
with a base such as, but not limited to, cesium carbonate in a
solvent such as, but not limited to, N,N-dimethylformamide, will
provide compounds of formula (41). The reaction is typically
performed at an elevated temperature, or more preferably at ambient
temperature. Compounds of the formula (41) can be deprotected to
give compounds of the formula (42) using procedures described
herein or available in the literature. For example, compounds of
formula (41) can be treated with formic acid at ambient temperature
in a solvent system such as, but not limited to, dichloromethane
and methanol, to provide compounds of the formula (42). Compounds
of the formula (42) can be treated with para-toluenesulfonyl
chloride in the presence of a base such as, but not limited to,
triethylamine or DABCO (1,4-diazabicyclo[2.2.2]octane) to provide
compounds of formula (43). The reaction is typically performed at
low temperature before warming to room temperature in a solvent
such as, but not limited to, dichloromethane. Compounds of formula
(43) can be reacted with amine nucleophiles of formula (44),
wherein two R.sup.x, together with the nitrogen to which they are
attached, optionally form a heterocycle, to provide intermediates
of formula (45). The reaction is typically performed in a solvent
such as, but not limited to, N,N-dimethylformamide, at ambient
temperature before heating to 35.degree. C. to 40.degree. C.
Compounds of formula (46) can be prepared by treating compounds of
formula (45) with lithium hydroxide. The reaction is typically
performed at ambient temperature in a solvent such as, but not
limited to, tetrahydrofuran, methanol, water, or mixtures
thereof.
##STR00084##
[0544] Scheme 8 describes an alternative synthesis of intermediates
of the formula (39). Compounds of formula (48) can be prepared by
reacting compounds of formula (37) with a boronate ester (or the
equivalent boronic acid) of formula (47) under Suzuki Coupling
conditions described herein or available in the literature.
Compounds of the formula (48) can be reacted with compounds of
formula (49) under Mitsunobu conditions described herein or
available in the literature to provide compounds of the formula
(39). Compounds of the formula (39) can be further treated as
described in Scheme 7 or using methods described herein to provide
macrocyclic compounds of the formula (46), which are representative
of compounds of formula (I).
##STR00085## ##STR00086##
[0545] Scheme 9 describes the synthesis of compounds of formula
(56). Compounds of formula (50) can be prepared by reacting
compounds of formula (9) with a boronate ester (or the equivalent
boronic acid) of formula (49) under Suzuki Coupling conditions
described herein or available in the literature. Compounds of
formula (50) can be treated with a strong base such as, but not
limited to lithium diisopropylamide, followed by the addition of
iodine to provide compounds of the formula (51). The reaction is
typically performed in a solvent such as, but not limited to,
tetrahydrofuran, at a reduced temperature before warming to ambient
temperature. Compounds of formula (52) can be prepared by reacting
compounds of formula (51) with a boronate ester (or the equivalent
boronic acid) of formula (6) under Suzuki Coupling conditions
described herein or known in the literature. Compounds of formula
(52) can be treated with aluminum trichloride to provide compounds
of formula (53). The reaction is typically performed at an elevated
temperature, for example from 60.degree. C. to 70.degree. C., in a
solvent, such as but not limited to, 1,2-dichloroethane. Compounds
of formula (53) can be treated with compounds of formula (54) under
Mitsunobu conditions described herein or available in the
literature to provide compounds of the formula (55). Compounds of
formula (55) can be reacted with compounds of formula (36) in the
presence of a base such as, but not limited to, cesium carbonate to
provide compounds of formula (56). The reaction is typically
performed at an elevated temperature in a solvent such as
tert-butanol, N,N-dimethylformamide, or mixtures thereof. Compounds
of formula (56) can be used as described in subsequent steps herein
to provide compounds of formula (I).
[0546] It should be appreciated that the synthetic schemes and
specific examples as illustrated in the synthetic examples section
are illustrative and are not to be read as limiting the scope of
the present disclosure as it is defined in the appended claims. All
alternatives, modifications, and equivalents of the synthetic
methods and specific examples are included within the scope of the
claims.
[0547] Optimum reaction conditions and reaction times for each
individual step can vary depending on the particular reactants
employed and substituents present in the reactants used. Specific
procedures are provided in the Synthetic Examples section.
Reactions can be worked up in the conventional manner, e.g. by
eliminating the solvent from the residue and further purified
according to methodologies generally known in the art such as, but
not limited to, crystallization, distillation, extraction,
trituration and chromatography. Unless otherwise described, the
starting materials and reagents are either commercially available
or can be prepared by one skilled in the art from commercially
available materials using methods described in the chemical
literature.
[0548] Manipulation of the reaction conditions, reagents and
sequence of the synthetic route, protection of any chemical
functionality that can not be compatible with the reaction
conditions, and deprotection at a suitable point in the reaction
sequence of the method are included in the scope of the present
disclosure. Suitable protecting groups and the methods for
protecting and deprotecting different substituents using such
suitable protecting groups are well known to those skilled in the
art; examples of which can be found in T. Greene and P. Wuts,
Protecting Groups in Organic Synthesis (3.sup.rd ed.), John Wiley
& Sons, NY (1999), which is incorporated herein by reference in
its entirety. Synthesis of the compounds of the present disclosure
can be accomplished by methods analogous to those described in the
synthetic schemes described hereinabove and in specific
examples.
[0549] Starting materials, if not commercially available, can be
prepared by procedures selected from standard organic chemical
techniques, techniques that are analogous to the synthesis of
known, structurally similar compounds, or techniques that are
analogous to the above described schemes or the procedures
described in the synthetic examples section.
[0550] When an optically active form of a compound is required, it
can be obtained by carrying out one of the procedures described
herein using an optically active starting material (prepared, for
example, by asymmetric induction of a suitable reaction step), or
by resolution of a mixture of the stereoisomers of the compound or
intermediates using a standard procedure (such as chromatographic
separation, recrystallization or enzymatic resolution).
[0551] Similarly, when a pure geometric isomer of a compound is
required, it can be prepared by carrying out one of the above
procedures using a pure geometric isomer as a starting material, or
by resolution of a mixture of the geometric isomers of the compound
or intermediates using a standard procedure such as chromatographic
separation.
Pharmaceutical Compositions
[0552] When employed as a pharmaceutical, a compound of the present
disclosure is typically administered in the form of a
pharmaceutical composition. One embodiment pertains to a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula (I) according to claim 1, or a
pharmaceutically acceptable salt thereof, in combination with a
pharmaceutically acceptable carrier. The phrase "pharmaceutical
composition" refers to a composition suitable for administration in
medical or veterinary use.
[0553] The term "pharmaceutically acceptable carrier" as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation
auxiliary.
Methods of Use
[0554] The compounds of formula (I), or pharmaceutically acceptable
salts thereof, and pharmaceutical compositions comprising a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, may be administered to a subject suffering from a disorder
or condition associated with MCL-1 overexpression or up-regulation.
The term "administering" refers to the method of contacting a
compound with a subject. Disorders or conditions associated with
MCL-1 overexpression or up-regulation may be treated
prophylactically, acutely, and chronically using compounds of
formula (I), depending on the nature of the disorder or condition.
Typically, the host or subject in each of these methods is human,
although other mammals may also benefit from the administration of
a compound of formula (I).
[0555] A "MCL-1-mediated disorder or condition" is characterized by
the participation of MCL-1 in the inception, manifestation of one
or more symptoms or disease markers, maintenance, severity, or
progression of a disorder or condition. In embodiments, the present
disclosure provides a method for treating multiple myeloma. The
method comprises the step of administering to a subject in need
thereof a therapeutically effective amount of a compound of formula
(I) or a preferred embodiment thereof, with or without a
pharmaceutically acceptable carrier.
[0556] In embodiments, the present disclosure provides compounds of
the disclosure, or pharmaceutical compositions comprising a
compound of the disclosure, for use in medicine. In embodiments,
the present disclosure provides compounds of the disclosure, or
pharmaceutical compositions comprising a compound of the
disclosure, for use in the treatment of diseases or disorders as
described herein above.
[0557] One embodiment is directed to the use of a compound
according to formula (I), or a pharmaceutically acceptable salt
thereof in the preparation of a medicament. The medicament
optionally can comprise at least one additional therapeutic agent.
In some embodiments the medicament is for use in the treatment of
diseases and disorders as described herein above.
[0558] This disclosure is also directed to the use of a compound
according to formula (I), or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of the
diseases and disorders as described herein above. The medicament
optionally can comprise at least one additional therapeutic
agent.
[0559] The compounds of formula (I) may be administered as the sole
active agent or may be co-administered with other therapeutic
agents, including other compounds that demonstrate the same or a
similar therapeutic activity and that are determined to be safe and
efficacious for such combined administration. The term
"co-administered" means the administration of two or more different
therapeutic agents or treatments (e.g., radiation treatment) that
are administered to a subject in a single pharmaceutical
composition or in separate pharmaceutical compositions. Thus
co-administration involves administration at the same time of a
single pharmaceutical composition comprising two or more different
therapeutic agents or administration of two or more different
compositions to the same subject at the same or different
times.
EXAMPLES
[0560] The following Examples may be used for illustrative purposes
and should not be deemed to narrow the scope of the present
disclosure.
[0561] All reagents were of commercial grade and were used as
received without further purification, unless otherwise stated.
Commercially available anhydrous solvents were used for reactions
conducted under inert atmosphere. Reagent grade solvents were used
in all other cases, unless otherwise specified. Chemical shifts
(.delta.) for .sup.1H NMR spectra were reported in parts per
million (ppm) relative to tetramethylsilane (.delta. 0.00) or the
appropriate residual solvent peak, i.e. CHCl.sub.3 (.delta. 7.27),
as internal reference. Multiplicities were given as singlet (s),
doublet (d), triplet (t), quartet (q), quintuplet (quin), multiplet
(m) and broad (br).
Example 1
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]me-
thoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
Example 1A
Thieno[2,3-d]pyrimidin-4(3H)-one
[0562] A mixture of 2-amino-3-cyanothiophene (50 g) in formic acid
(100 mL) and H.sub.2SO.sub.4 (22 mL) was heated in a sealed tube
for 2 hours at 100.degree. C. The mixture was cooled to 20.degree.
C. and was diluted with water (1 L). The resulting precipitate was
collected by filtration, washed with water twice (2.times.1 L) and
dried under reduced pressure to provide the title compound. .sup.1H
NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.16 (br s,
1H), 8.09 (s, 1H), 7.54 (d, 1H), 7.35 (d, 1H).
Example 1B
5,6-diiodothieno[2,3-d]pyrimidin-4(3H)-one
[0563] To an ice-cooled 4-neck 2 L flask fit with a mechanical
stirrer, reflux condenser and thermocouple/JKEM was added acetic
acid (160 mL), sulfuric acid (8 mL) and water (80 mL) with
stirring. Example 1A (40.0 g), periodic acid (30.0 g) and iodine
(133 g) were added sequentially and the mixture became slightly
endothermic. The ice bucket was removed and a heating mantle was
added. The reaction mixture was ramped up to 60.degree. C. and was
stirred for 20 minutes. The temperature climbed to 95.degree. C.
The heating mantle was removed and reaction mixture was allowed to
cool to room temperature. The resulting suspension was poured into
saturated aqueous sodium sulfite solution, filtered, and washed
with water. The organic layer was dried under vacuum to provide the
title compound.
Example 1C
4-chloro-5,6-diiodothieno[2,3-d]pyrimidine
[0564] A 250 mL flask equipped with magnetic stirring, heating
mantle, temperature probe and reflux condenser to a nitrogen
bubbler was charged with phosphorus oxychloride (57.3 mL) and
N,N-dimethylaniline (17.64 mL). To the mixture was added Example 1B
(56.22 g) over 5 minutes. The resulting suspension was heated at
105.degree. C. for 30 minutes. After cooling, the resulting
material was broken up and transferred to a funnel with heptane.
The material was washed with heptane to remove most of the
phosphorus oxychloride. The material was slowly scooped into
rapidly stirring ice water (600 mL) and stirred for 30 minutes. The
material was collected by filtration, washed with water and ether
(200 mL), dried over Na.sub.2SO.sub.4, and filtered to provide the
title compound which was used in the next step without further
purification.
Example 1D
4-chloro-5-iodothieno[2,3-d]pyrimidine
[0565] A 500 mL 3-neck jacketed flask with magnetic stirring under
nitrogen was charged with Example 1C (23 g) and tetrahydrofuran
(200 mL). The resulting suspension was cooled to -16.degree. C.
using a Huber chiller set to -17.degree. C. To the mixture was
added tert-butylmagnesium chloride (40.8 mL, 2 M in ether) dropwise
over 40 minutes, keeping the temperature between -15.degree. C. and
-16.degree. C. The temperature was slowly raised to 0.degree. C.
and was stirred for 30 minutes. The reaction mixture was cooled to
-20.degree. C. and was quenched by the very slow dropwise addition
(initially about 1 drop/minute) of water (23 mL) over 35 minutes,
maintaining the temperature at about -20.degree. C., and then
slowly warmed to ambient temperature over 1 hour. The stirring was
stopped and the supernatant was decanted from the remaining
residue. To the residue was added tetrahydrofuran (200 mL). The
mixture was stirred briefly, and after standing, the supernatant
was decanted from the remaining residue. This was repeated two
times. The combined organics were concentrated. The crude material
was purified by chromatography on silica gel eluting with isocratic
methylene chloride. The title compound was precipitated from a
minimum of hot heptanes.
Example 1E
4-chloro-5-(4-methoxy-2,6-dimethylphenyl)thieno[2,3-d]pyrimidine
[0566] To a suspension of Example 1D (5 g),
(4-methoxy-2,6-dimethylphenyl)boronic acid (6.07 g) and cesium
carbonate (10.99 g) in degassed toluene (50.0 mL) and water (12.5
mL) was added
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)
(597 mg). The mixture was heated to 100.degree. C. overnight. After
cooling to room temperature, the mixture was diluted with ethyl
acetate (200 mL). The organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, filtered and
concentrated under vacuum. The residue was purified by silica gel
chromatography on a CombiFlash.RTM. Teledyne Isco system eluting
with 0-20% ethyl acetate in heptanes to provide the title compound.
.sup.1H NMR (501 MHz, CDCl.sub.3) .delta. ppm 8.88 (s, 1H), 7.35
(s, 1H), 6.70 (s, 2H), 3.85 (s, 3H), 1.99 (s, 6H). MS (ESI) m/z
305.1 (M+H).sup.+.
Example 1F
4-chloro-6-iodo-5-(4-methoxy-2,6-dimethylphenyl)thieno[2,3-d]pyrimidine
[0567] To a mixture of diisopropylamine (4.15 mL) in
tetrahydrofuran (50 mL) cooled to -78.degree. C. was added
n-butyllithium (9.71 mL, 2.5 M in hexanes) dropwise. The mixture
was stirred for 1 minute before Example 1E (3.7 g) was added as a
mixture in tetrahydrofuran (50 mL). The resulting mixture was
stirred at -78.degree. C. for 15 minutes. Iodine (6.16 g) was added
in one portion and the mixture was warmed to room temperature. The
reaction mixture was quenched with saturated aqueous ammonium
chloride mixture (100 mL) and was extracted with ethyl acetate (50
mL.times.3). The combined organic layers were washed sequentially
with a sodium thiosulfate mixture and brine, dried over anhydrous
sodium sulfate, filtered and concentrated onto silica gel.
Purification by flash chromatography on a silica gel column eluting
with 0-20% ethyl acetate in heptanes provided crude product, which
was triturated with heptanes to obtain the title compound. .sup.1H
NMR (501 MHz, CDCl.sub.3) .delta. ppm 8.82 (s, 1H), 6.72 (s, 2H),
3.87 (s, 3H), 1.94 (s, 6H). MS (ESI) m/z 431.1 (M+H).sup.+.
Example 1G
4-chloro-6-(4-fluorophenyl)-5-(4-methoxy-2,6-dimethylphenyl)thieno[2,3-d]p-
yrimidine
[0568] To a mixture of Example 1F (3.3 g), (4-fluorophenyl)boronic
acid (2.144 g)
di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosph-
ine (0.179 g) and potassium phosphate tribasic (3.25 g) in degassed
tetrahydrofuran (60 mL) and water (15 mL) was added
tris(dibenzylideneacetone)dipalladium(0) (0.175 g). The mixture was
heated to 60.degree. C. overnight. After cooling to room
temperature, the mixture was diluted with ethyl acetate (100 mL).
The organic layer was washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated under vacuum. The residue
was purified by flash chromatography on a silica gel column eluting
with 0-20% ethyl acetate in heptanes to give crude product, which
was triturated with heptanes to obtain the title compound. .sup.1H
NMR (501 MHz, CDCl.sub.3) .delta. ppm 8.84 (s, 1H), 7.31-7.23 (m,
2H), 7.02-6.93 (m, 2H), 6.65 (d, 2H), 3.83 (s, 3H), 1.92 (d, 6H).
MS (ESI) m/z 399.1 (M+H).sup.+.
Example 1H
4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)-6-(4-fluorophenyl)t-
hieno[2,3-d]pyrimidine
[0569] To a suspension of Example 1G (2.13 g) in acetonitrile (50
mL) was added N-chlorosuccinimide (2.85 g). The mixture was heated
to reflux for 1 hour. The mixture was concentrated under vacuum and
the residue was redissolved in ethyl acetate (50 mL). The mixture
was washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated under vacuum. The residue was purified by
silica gel chromatography on a CombiFlash.RTM. Teledyne Isco system
eluting with 0-10% ethyl acetate in heptanes to provide the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.89 (s,
1H), 7.28-7.18 (m, 2H), 7.08-6.97 (m, 2H), 3.96 (s, 3H), 2.02 (s,
6H). MS (ESI) m/z 469.1 (M+H).sup.+.
Example 1I
2,6-dichloro-4-(4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl)-3,-
5-dimethylphenol
[0570] To Example 1H (5 g) in 1,2-dichloroethane (200 mL) was added
aluminum trichloride (4.28 g), and the mixture was heated to
68.degree. C. for 6 hours and was cooled to room temperature.
Saturated aqueous NaHCO.sub.3 (3 mL) was added and the mixture was
stirred for 2 minutes. Saturated aqueous NH.sub.4Cl (15 mL) was
added. The mixture was diluted with ethyl acetate and the layers
were separated. The aqueous layer was extracted once with ethyl
acetate. The organic layers were combined and washed with water and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated to
provide the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 10.10 (br s, 1H), 9.00 (s,
1H), 7.35 (m, 2H), 7.28 (m, 2H), 1.96 (s, 6H). MS (ESI) m/z 452.9
(M-H).sup.-.
Example 1J
(R)-3-(allyloxy)propane-1,2-diol
[0571] To a 250 mL round bottom containing
(S)-4-((allyloxy)methyl)-2,2-dimethyl-1,3-dioxolane (7.08 g) was
added methanol (100 mL) and p-toluenesulfonic acid monohydrate
(0.782 g). The mixture was heated to 50.degree. C. for 18 hours,
and at 60.degree. C. for 4 hours. The mixture was cooled to room
temperature, and potassium carbonate (1.704 g) and MgSO.sub.4 (5 g)
were added. The material was filtered and washed with ethyl
acetate. The mixture was concentrated, and the residue was
chromatographed on silica gel using 20-80% ethyl acetate in
heptanes as the eluent, to provide the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) 6 ppm 5.87 (tdd, 1H), 5.25
(dd, 1H), 5.13 (dd, 1H), 4.62 (d, 1H), 4.46 (t, 1H), 3.94 (ddd,
2H), 3.58 (m, 1H), 3.39 (m, 1H), 3.30 (m, 3H).
Example 1K
(S)-1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propan-2-ol
[0572] To a mixture of Example 1J (2.25 g) and
4,4'-(chloro(phenyl)methylene)bis(methoxybenzene) (DMTrCl) (6.06 g)
in dichloromethane (68.1 mL) cooled to 0.degree. C., was added
N,N-diisopropylethylamine (3.27 mL). The mixture was allowed to
warm to room temperature and was stirred for 30 minutes. The
reaction mixture was quenched with saturated aqueous ammonium
chloride mixture (50 mL). The organic layer was washed with brine,
dried over anhydrous sodium sulfate, filtered and concentrated
under vacuum. The residue was purified by silica gel chromatography
on a CombiFlash.RTM. Teledyne Isco system, eluting with 0-50% ethyl
acetate in heptanes to provide the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.45-7.40 (m, 2H), 7.35-7.24 (m, 6H),
7.24-7.17 (m, 1H), 6.86-6.77 (m, 4H), 5.95-5.79 (m, 1H), 5.24 (dq,
1H), 5.17 (dq, 1H), 4.00 (dt, 2H), 3.98-3.91 (m, 1H), 3.78 (s, 6H),
3.55 (dd, 1H), 3.49 (dd, 1H), 3.24-3.16 (m, 2H), 2.40 (bs, 1H). MS
(ESI) m/z 457.1 (M+Na)*.
Example 1L
(R)-5-(4-((1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propan-2-yl-
)oxy)-3,5-dichloro-2,6-dimethylphenyl)-4-chloro-6-(4-fluorophenyl)thieno[2-
,3-d]pyrimidine
[0573] Triphenylphosphine (1.561 g), Example 11 (1.5 g), and
Example 1K (1.580 g) were taken up in 18 mL tetrahydrofuran and
di-tert-butylazodicarboxylate (1.370 g) was added and the reaction
was stirred overnight. The material was filtered off and rinsed
with 1:1 ether/ethyl acetate, and the organics were concentrated.
The crude material was chromatographed on silica gel using 1-40%
ethyl acetate in heptanes as eluent to provide the title compound.
MS (ESI) m/z 891.1 (M+Na).sup.+.
Example 1M
2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)benzaldehyde
[0574] A 2 L round bottom flask was charged with
2,5-dihydroxybenzaldehyde (30 g), imidazole (29.6 g) and
dichloromethane (543 mL). The flask was placed in a water bath and
solid tert-butylchlorodimethylsilane (32.7 g) was added. The
reaction mixture was stirred at ambient temperature for 15 minutes
at which point thin-layer chromatography indicated complete
consumption of starting material. The reaction mixture was poured
into a separatory funnel with 200 mL water. The biphasic mixture
was shaken and the layers were separated. The aqueous layer was
washed with 100 mL dichloromethane and the organic layers were
combined. The organic layer was dried over sodium sulfate,
filtered, and concentrated and the material was used in the next
step. A 1 L three-necked round bottom flask equipped with an
internal temperature probe, a reflux condenser, and a stir bar was
charged with 5-((tert-butyldimethylsilyl)oxy)-2-hydroxybenzaldehyde
(45 g, 178 mmol) in acetone (297 mL). Solid K.sub.2CO.sub.3 (27.1
g) was added followed by dropwise addition of neat benzyl bromide
(21.21 mL). The mixture was stirred at ambient temperature for 10
minutes and heated to 55.degree. C. The reaction mixture was
stirred overnight. The reaction mixture was cooled to ambient
temperature then poured over cold water (200 mL). The mixture was
then transferred to a 1 L separatory funnel. The crude product was
extracted with ethyl acetate (3.times.250 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated.
The crude material was purified by silica gel chromatography over a
330 g column on a Grace Reveleris system (0-5% ethyl
acetate/heptanes elution gradient). Fractions containing the
desired product were combined, concentrated and dried under vacuum
to obtain the title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 10.35 (s, 1H), 7.51-7.47 (m, 2H),
7.42-7.37 (m, 2H), 7.35-7.31 (m, 1H), 7.22 (d, 1H), 7.15 (dd, 1H),
7.11 (d, 1H), 5.21 (s, 2H), 0.93 (s, 9H), 0.16 (s, 6H).
Example 1N
tert-butyl 2-acetoxy-2-(diethoxyphosphoryl)acetate
[0575] A 3 L jacketed round bottom flask equipped with an overhead
stirrer was charged with glyoxylic acid monohydrate (15 g) and
diethyl phosphite (20.82 mL) and was heated to a 60.degree. C.
jacket temperature with stirring. The flask headspace was
continuously purged with a nitrogen sweep. After stirring
overnight, dichloromethane (250 mL) was added, the reaction was
cooled to an internal temperature of 5.degree. C., and pyridine
(13.05 mL) was added dropwise. After stirring for 1 hour at the
same temperature, acetyl chloride (11.47 mL) was added dropwise
over 20 minutes. The reaction was warmed to 20.degree. C., stirred
for 1.5 hours, and cooled to 5.degree. C. internal temperature.
Pyridine (19.57 mL) was added slowly. Tert-butanol (15.43 mL) was
added in one portion followed by dropwise addition of
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(144 mL, 50% by weight in ethyl acetate) over 20 minutes. After
stirring for 1 hour, the reaction was warmed to 20.degree. C. and
was stirred overnight. The reactor was then cooled to 5.degree. C.
and 1 N aqueous hydrochloric acid (200 mL) was added slowly. The
biphasic mixture was stirred for 30 minutes at 20.degree. C., and
was poured into a separatory funnel. Dichloromethane (400 mL) and
1N aqueous hydrochloric acid (250 mL) were added and the mixture
was separated. The aqueous layer was extracted with dichloromethane
(400 mL), and the combined organic layers were washed with a
mixture of water (300 mL) and saturated aqueous sodium chloride
solution (300 mL). The combined organics were dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The crude material was purified by plug filtration on
silica gel eluting with 1:1 ethyl acetate/heptanes to give the
title compound after concentration under reduced pressure. .sup.1H
NMR (400 MHz, Chloroform-d) .delta. ppm 5.32 (d, 1H), 4.29-4.18 (m,
4H), 2.21 (s, 3H), 1.37 (tdd, 6H). MS (ESI) m/z 255.0
(M-tert-butyl+2H)*.
Example 10
(E)-tert-butyl
2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acrylat-
e
[0576] An oven dried 2 L 3-neck round bottomed flask equipped with
overhead stirring was charged with anhydrous lithium chloride (5.55
g). The flask was purged with a sweep of argon for 10 minutes and
anhydrous tetrahydrofuran (350 mL) was added. A solution of Example
1N (40.6 g) in tetrahydrofuran (50 mL) was added. A solution of
1,8-diazabicyclo[5.4.0]undec-7-ene) (19.72 mL) in tetrahydrofuran
(50 mL) was added dropwise. The stirring mixture became cloudy and
was cooled in an ice-water bath to an internal temperature of
15.degree. C. A mixture of Example 1M (32 g) in tetrahydrofuran (50
mL) was added over 30 minutes. The reaction was stirred overnight,
cooled to an internal temperature of 5.degree. C., and quenched by
addition of 1% by weight aqueous citric acid (700 mL). Ethyl
acetate (400 mL) was added and the layers were separated. The
combined organic layers were washed with saturated aqueous sodium
chloride solution (400 mL), dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The crude
material was purified by flash column chromatography on a Grace
Reveleris system using a Teledyne Isco RediSep Gold 330 g column,
eluting with a 0-25% ethyl acetate/heptanes gradient to give the
title compound in a 9:1 mixture of E- and Z-isomers. E-isomer
.sup.1H NMR (501 MHz, Chloroform-d) .delta. ppm 7.39 (ddt, 2H),
7.36 (ddd, 2H), 7.32-7.27 (m, 1H), 6.88 (dd, 1H), 6.85 (d, 1H),
6.76 (d, 1H), 6.71 (ddd, 1H), 5.01 (s, 2H), 2.22 (s, 3H), 1.34 (s,
9H), 0.97 (s, 9H), 0.17 (s, 6H). MS (ESI) m/z 515.9 (M+NH.sub.4)*.
This isomer was assigned E by 2D NOE experiments. Z-isomer: .sup.1H
NMR (501 MHz, Chloroform-d) .delta. ppm 7.74 (s, 1H), 7.45 (ddt,
2H), 7.38 (ddd, 2H), 7.35-7.30 (m, 1H), 7.29-7.26 (m, 1H), 6.83 (d,
1H), 6.79 (dd, 1H), 5.06 (s, 2H), 2.30 (d, 3H), 1.53 (s, 9H), 0.99
(s, 9H), 0.18 (s, 6H). MS (ESI) m/z 515.9 (M+NH.sub.4)*. This
isomer was assigned Z by 2D NMR experiments.
Example 1P
(R)-tert-butyl
2-acetoxy-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propano-
ate
[0577] A 600 mL stainless steel reactor was charged with
(1,2-bis[(2R,5R)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodiu-
m(I) trifluoromethanesulfonate (1.88 g), followed by a solution of
Example 10 (34.86 g) in methanol (350 mL). The reactor was purged
with nitrogen 3 times and 2 times with hydrogen. The mixture was
stirred at 1200 RPM under 120 psi of hydrogen with no external
heating for 24 hours. The mixture was concentrated under reduced
pressure, suspended in 5:1 heptanes/dichloromethane (70 mL) and
filtered through a pad of diatomaceous earth. The filtrate was
concentrated under reduced pressure and purified on a Grace
Reveleris system using a 750 g Teledyne Isco Redisep gold column
eluting with an ethyl acetate/heptanes gradient (0-25%). The title
compound was concentrated under reduced pressure. .sup.1H NMR (500
MHz, Chloroform-d) .delta. ppm 7.45 (d, 2H), 7.42-7.34 (m, 2H),
7.34-7.28 (m, 1H), 6.77 (d, 1H), 6.70 (d, 1H), 6.67 (dd, 1H), 5.19
(dd, 1H), 5.05 (d, 1H), 5.01 (d, 1H), 3.29 (dd, 1H), 2.92 (dd, 1H),
2.03 (s, 3H), 1.40 (s, 9H), 0.97 (s, 9H), 0.16 (s, 6H). MS (DCI)
m/z 518.2 (M+NH.sub.4).sup.+.
Example 1Q
(R)-tert-butyl
3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-2-hydroxypropano-
ate
[0578] An oven dried 250 mL 3-neck flask was charged with Example
1P (27.46 g). The flask was equipped with a magnetic star bar and
rubber septa, and vacuum purged with nitrogen gas twice. Anhydrous
ethanol (274 mL) was added, and the mixture was stirred. To the
stirring solution was added dropwise sodium ethoxide (21% wt in
ethanol, 1.024 mL). The reaction was stirred for three hours at
ambient temperature and was quenched by addition of acetic acid
(0.3 mL). The bulk of the solvents were removed by rotary
evaporation, and the material was diluted with ethyl acetate (300
mL). Saturated aqueous sodium bicarbonate was added (300 mL). The
layers were separated and the aqueous layer was extracted with
ethyl acetate (300 mL). The combined organic layers were washed
with saturated aqueous sodium chloride, dried over MgSO.sub.4,
treated with activated charcoal (0.5 g) and stirred for 1 hour
before filtering through diatomaceous earth to give the title
compound after concentration under reduced pressure. .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 7.48-7.42 (m, 2H), 7.42-7.36
(m, 2H), 7.36-7.29 (m, 1H), 6.79 (d, 1H), 6.75 (d, 1H), 6.67 (dd,
1H), 5.10-4.99 (m, 2fH), 4.39 (ddd, 1H), 3.16 (dd, 1H), 2.91 (d,
1H), 2.86 (dd, 1H), 1.41 (s, 9H), 0.99 (s, 9H), 0.18 (s, 6H). MS
(DCI) m/z 476.2 (M+NH.sub.4).
Example 1R
tert-butyl
(R)-2-((5-(4-(((R)-1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)-
methoxy)propan-2-yl)oxy)-3,5-dichloro-2,6-dimethylphenyl)-6-(4-fluoropheny-
l)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(benzyloxy)-5-((tert-butyldimethyl-
silyl)oxy)phenyl)propanoate
[0579] Example 1L (14.7 g), Example 1Q (8.52 g), and cesium
carbonate (11.01 g) were added to a three-necked flask equipped
with an overhead stirrer and 2.2 g of 4 mm glass beads.
Tert-butanol (145 mL) was added and the mixture was heated to
65.degree. C. for 3 hours. Additional cesium carbonate (5.50 g) was
added the reaction was stirred at 65.degree. C. overnight. The
reaction mixture was cooled and was diluted with ethyl acetate (300
mL). The resulting solution was filtered through diatomaceous
earth, and washed through with 200 mL ethyl acetate. The mixture
was concentrated, taken up in toluene and purified by silica gel
chromatography using 10-30% ethyl acetate in heptanes as eluent to
give the title compound. MS (ESI) m/z 1293.3 (M+H).sup.+.
Example 1S
tert-butyl
(R)-2-((5-(4-(((S)-1-(allyloxy)-3-hydroxypropan-2-yl)oxy)-3,5-d-
ichloro-2,6-dimethylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)-
oxy)-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propanoate
[0580] Example 1R (17.11 g) in dichloromethane (65 mL) and methanol
(65 mL) was cooled to 0.degree. C. Formic acid (38 mL) was added
and the solution was stirred for 15 minutes at 0.degree. C. The
mixture was slowly added to 1 L of vigorously stirred saturated
aqueous sodium bicarbonate. The resulting mixture was extracted
with ethyl acetate (2.times.500 mL). The combined organics were
washed with brine (100 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The crude material was purified by silica gel
chromatography using 10-30% ethyl acetate in heptanes as eluent to
give the title compound. MS (ESI) m/z 988.9 (M+H).sup.+.
Example 1T
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(-
benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propanoate
[0581] Example 1S (13.04 g) was dissolved in dichloromethane (125
mL) and cooled to 0.degree. C. para-Toluenesulfonyl chloride (3.77
g), and 1,4-diazabicyclo[2.2.2]octane (2.95 g) were added, and the
reaction was stirred at 0.degree. C. for 30 minutes. The mixture
was diluted with 55 mL dichloromethane, and quenched with 55 mL
saturated aqueous NH.sub.4Cl. The layers were separated and the
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude material was purified by
silica gel chromatography using 10-25% ethyl acetate in heptanes to
provide the title compound. MS (ESI) m/z 1145.1 (M+H).sup.+.
Example 1U
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(-
benzyloxy)-5-hydroxyphenyl)propanoate
[0582] To Example 1T (14.15 g) in tetrahydrofuran (120 mL) was
added acetic acid (0.779 mL), and tetrabutylammonium fluoride
(13.60 mL, 1M in tetrahydrofuran). The reaction mixture was stirred
for 20 minutes. The mixture was quenched with 20 mL saturated
aqueous sodium bicarbonate solution. The mixture was diluted with
20% ethyl acetate/heptanes (150 mL). The layers were separated and
the organic layer was washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude material
was purified by silica gel chromatography using 10-50% ethyl
acetate in heptanes to provide the title compound. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.90 (s, 1H), 8.64 (s,
1H), 7.70 (d, 2H), 7.40 (d, 2H), 7.30 (m, 7H), 7.21 (m, 2H), 7.05
(t, 1H), 6.81 (d, 1H), 6.57 (m, 1H), 6.17 (d, 1H), 5.65 (m, 1H),
5.20 (t, 1H), 5.00 (m, 2H), 4.50 (m, 1H), 4.25 (m, 2H), 3.72 (m,
2H), 3.56 (m, 2H), 2.66 (m, 1H), 2.39 (s, 3H), 2.14 (s, 3H), 1.82
(s, 3H), 1.21 (s, 9H). MS (ESI) m/z 1030.7 (M+H).sup.+.
Example 1V
tert-butyl
(7R,16R)-10-(benzyloxy)-19,23-dichloro-1-(4-fluorophenyl)-20,22-
-dimethyl-16-{[(prop-2-en-1-yl)oxy]methyl}-7,8,15,16-tetrahydro-18,21-ethe-
no-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]in-
dene-7-carboxylate
[0583] To Example 1U (11.88 g) in N,N-dimethylformamide (1160 mL)
was added cesium carbonate (18.79 g) and the reaction was stirred
for 2 hours. The solution was poured into water (3600 mL), and the
aqueous solution was extracted with ethyl acetate (4.times.300 mL).
The combined organics were washed with water (2.times.800 mL), and
brine (500 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude material was purified by silica gel
chromatography using 10-50% ethyl acetate in heptanes to provide
the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.75 (s, 1H), 7.40 (m, 5H),
7.20 (m, 4H), 6.90 (m, 2H), 5.98 (m, 1H), 5.92 (m, 1H), 5.68 (s,
1H), 5.30 (d, 1H), 5.19 (d, 1H), 5.02 (q, 2H), 4.81 (m, 1H), 4.51
(dd, 1H), 4.36 (d, 1H), 4.03 (m, 2H), 3.75 (m, 2H), 3.58 (m, 1H),
2.81 (m, 1H), 2.05 (s, 3H), 1.91 (s, 3H), 1.09 (s, 9H). MS (ESI)
m/z 857.0 (M+H).sup.+.
Example 1W
tert-butyl
(7R,16R)-10-(benzyloxy)-19,23-dichloro-1-(4-fluorophenyl)-16-(h-
ydroxymethyl)-20,22-dimethyl-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
late
[0584] A solution of Example 1V (8.75 g) in tetrahydrofuran (120
mL) and methanol (80 mL) was degassed and flushed with nitrogen
three times. Tetrakis(triphenylphosphine)palladium (0) (1.179 g),
and then 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (3.98 g)
were added, and the solution was degassed and flushed with nitrogen
once. The reaction mixture was stirred overnight.
Pyrrolidine-1-carbodithioic acid, ammonia salt (0.251 g) was added
as a palladium scavenger, and the reaction was stirred for 30
minutes. Ethyl acetate (100 mL) was added and the mixture was
filtered through diatomaceous earth, washing with more ethyl
acetate. The crude material was concentrated and used without
further purification. MS (ESI) m/z 819.2 (M+H).sup.+.
Example 1X
tert-butyl
(7R,16S)-10-(benzyloxy)-19,23-dichloro-1-(4-fluorophenyl)-20,22-
-dimethyl-16-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}-7,8,15,16-tetrahydr-
o-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca-
[1,2,3-cd]indene-7-carboxylate
[0585] Example 1W (8.09 g) in dichloromethane (95 mL) was cooled to
0.degree. C. To the mixture was added p-toluenesulfonyl chloride
(4.9 g), and 1,4-diazabicyclo[2.2.2]octane (3.9 g). The reaction
was stirred at 0.degree. C. for 1 hour. The mixture was diluted
with 50 mL dichloromethane, and quenched with 50 mL saturated
aqueous NH.sub.4Cl. Water (50 mL) was added and the layers were
separated. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude material
was purified by silica gel chromatography using 10-35% ethyl
acetate in heptanes to provide the title compound. MS (ESI) m/z
971.2 (M+H).sup.+.
Example 1Y
tert-butyl
(7R,16R)-10-(benzyloxy)-19,23-dichloro-1-(4-fluorophenyl)-20,22-
-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-e-
theno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd-
]indene-7-carboxylate
[0586] To an ambient solution of Example 1X (2.98 g) in
N,N-dimethylformamide (10 mL) was added 1-methylpiperazine (10.20
mL). The reaction was heated to 40.degree. C. for 24 hours. Another
2 mL 1-methyl-piperazine was added and the reaction was heated at
35.degree. C. overnight. The reaction was cooled to room
temperature, and the solvents were removed by rotary evaporation.
The crude material was cooled in an ice bath, stirred, and diluted
sequentially with ethyl acetate (100 mL) and water (100 mL). The
layers were separated, and the aqueous layer was extracted with
additional ethyl acetate (2.times.100 mL). The combined organics
were washed with brine (2.times.100 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was diluted with toluene (5 mL) and was purified by
normal phase MPLC (Biotage.RTM. Isolera, 100 g Biotage.RTM. Ultra
SiO.sub.2 column), eluting with a gradient of 0-6% methanol in
dichloromethane to provide the title compound. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.74 (s, 1H), 7.41 (m,
2H), 7.39 (m, 2H), 7.35 (m, 1H), 7.20 (m, 4H), 6.90 (m, 1H), 6.81
(m, 1H), 6.00 (m, 1H), 5.67 (s, 1H), 5.02 (q, 2H), 4.75 (m, 1H),
4.44 (m, 2H), 3.60 (m, 1H), 3.58 (m, 1H), 2.80 (m, 1H), 2.48 (m,
3H), 2.40 (m, 4H), 2.30 (m, 4H), 2.15 (s, 3H), 2.08 (s, 3H), 1.89
(s, 3H), 1.09 (s, 9H). MS (ESI) m/z 899.4 (M+H).sup.+.
Example 1Z
tert-butyl
(7R,16R)-19,23-dichloro-1-(4-fluorophenyl)-10-hydroxy-20,22-dim-
ethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-ethen-
o-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]ind-
ene-7-carboxylate
[0587] Example 1Y (1.943 g) in tetrahydrofuran (11 mL) was added to
5% Pd/C (1.801 g) in a 20 mL Barnstead Hast C pressure reactor. The
reactor was purged with argon gas. The mixture was stirred at 1600
rpm under 50 psi of hydrogen at 25.degree. C. After 17.3 hours, the
reaction was vented. The mixture was filtered through a filter
funnel with a polyethylene frit packed with diatomaceous earth. The
mixture was concentrated, and the crude material was taken up in
ether and a small amount of dichloromethane. The mixture was
filtered through diatomaceous earth, washing with
ether/dichloromethane. The solvent was removed on a rotovap, and
the material was placed on high vacuum overnight to provide the
title compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 9.11 (s, 1H), 8.72 (s, 1H), 7.20 (m, 4H), 6.67 (m, 2H),
5.96 (m, 1H), 5.50 (s, 1H), 4.69 (m, 1H), 4.41 (m, 1H), 4.37 (m,
1H), 3.54 (dd, 1H), 3.58 (m, 1H), 2.62 (m, 2H), 2.22-2.50 (m, 9H),
2.18 (s, 6H), 1.88 (s, 3H), 1.09 (s, 9H). MS (ESI) mz 811.2
(M+H).sup.+.
Example 1AA
methyl
2-(4-((tert-butyldimethylsilyl)oxy)phenyl)pyrimidine-4-carboxylate
[0588] A mixture of methyl 2-chloropyrimidine-4-carboxylate (3.57
g) and 4-(tert-butyldimethylsilyloxy)phenylboronic acid (15.7 g)
were suspended in previously degassed 1,4-dioxane, (140 mL).
Potassium carbonate (10.75 g) was solubilized in previously
degassed water (21.5 mL), and was added to the reaction mixture.
1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (2.050 g) was then added and the reaction
mixture was placed under an argon atmosphere, then heated at
80.degree. C. for 7 hours. The reaction mixture was diluted with
250 mL of dichloromethane and 200 mL of water and the layers were
separated. The aqueous layer was extracted with 3.times.150 mL of
dichloromethane. The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated to provide the crude
material. Purification was performed by flash chromatography on a
Biotage.RTM. silica gel cartridge (KPSil 340 g), eluting from 5-20%
ethyl acetate in cyclohexane to afford the title compound. LCMS
(APCI) m/z 345.0 (M+H).sup.+.
Example 1AB
(2-(4-((tert-butyldimethylsilyl)oxy)phenyl)pyrimidin-4-yl)methanol
[0589] To a solution of Example 1AA (14.06 g) in tetrahydrofuran
(100 mL) and methanol (200 mL) was added at -10.degree. C., sodium
borohydride (5.40 g) and the reaction was stirred at 0.degree. C.
for 30 minutes. The reaction was quenched at 0.degree. C. with 400
mL saturated aqueous NH.sub.4Cl and the organic solvents were
evaporated. The remaining mixture was diluted with 300 mL
dichloromethane. The organic layer was collected and the aqueous
phase was extracted with 3.times.200 mL dichloromethane. The
organic layers were combined, dried with MgSO.sub.4, filtered and
concentrated. The crude material was purified on a silica gel
column eluting with 5-20% ethyl acetate in cyclohexane to afford
the title compound. LCMS (APCI) m/z 317.0 (M+H).sup.+.
Example 1AC
4-(4-(hydroxymethyl)pyrimidin-2-yl)phenol
[0590] To an ambient solution of Example 1AB (1.5 g) in
tetrahydrofuran (60 mL) was added tetrabutylammonium fluoride (5.21
mL, 1.0 M in tetrahydrofuran) via syringe. The reaction was stirred
overnight and was quenched by the addition of methanol (30 mL). The
mixture was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (50 g), eluting with a
gradient of 0-5% methanol in dichloromethane to give the title
compound. .sup.1H NMR (300 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 9.92 (s, 1H), 8.78 (d, 1H), 8.23 (d, 2H), 7.37 (d, 1H), 6.86
(d, 2H), 5.62 (t, 1H), 4.59 (d, 2H).
Example 1AD
(S)-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)pyrimidin-4-yl)m-
ethanol
[0591] To a solution of Example 1AC (238 mg) in
N,N-dimethylformamide (3.5 mL) was added
(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate
(371 mg) and cesium carbonate (460 mg). The mixture was stirred at
50.degree. C. for 24 hours. Ethyl acetate was added and the
solution was washed with water, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The crude residue was purified by
silica gel flash chromatography (Biotage.RTM. 25 g silica gel
column, eluting with 30-80% ethyl acetate in hexanes) to give the
title compound.
Example 1AE
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(4S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]methoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-d-
imethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-eth-
eno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]i-
ndene-7-carboxylate
[0592] A 4 mL vial, equipped with stir bar, was charged with
Example 1Z (100 mg), Example 1AD (78 mg), triphenylphosphine (68.0
mg) and di-tert-butylazodicarboxylate (56.9 mg). The vial was
capped with a septum, then evacuated and backfilled with nitrogen
gas. Toluene (1.2 mL) was added, and the vial was evacuated and
backfilled with nitrogen gas again. The reaction mixture was
stirred overnight. The mixture was concentrated and purification by
flash chromatography on an AnaLogix IntelliFlash.sup.280 system (10
g silica gel cartridge (eluting with 0-8%
methanol/dichloromethane)) afforded the title compound. MS (ESI)
m/z 1107.4 (M+H).sup.+.
Example 1AF
(7R,16R)-19,23-dichloro-10-[(2-{4-[(2R)-2,3-dihydroxypropoxy]phenyl}pyrimi-
din-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-
-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-tri-
oxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0593] To a solution of Example 1AE (120 mg) in dichloromethane
(0.7 mL) was added trifluoroacetic acid (TFA) (0.700 mL). The
mixture was stirred for 4 hours, concentrated in vacuo, and
dissolved in acetonitrile. The solution was made basic with
saturated aqueous NaHCO.sub.3, and was filtered to remove solids.
The filtrate was purified by reverse phase preparative LC using a
Gilson 2020 system (Luna C-18, 250.times.50 mm column, mobile phase
A: 0.1% TFA in water; B: acetonitrile; 20-75% B to A gradient at 70
mL/minute) to afford the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.85 (s, 1H), 8.76 (s, 1H),
8.35 (d, 2H), 7.42 (d, 1H), 7.19 (m, 4H), 7.05 (d, 2H), 6.90 (d,
1H), 6.81 (m, 1H), 6.24 (m, 1H), 5.80 (s, 1H), 5.21 (q, 2H), 4.92
(m, 1H), 4.41 (m, 2H), 4.08 (dd, 1H), 3.95 (dd, 1H), 3.81 (m, 1H),
3.48 (m, 1H), 3.40 (m, 2H), 3.21 (m, 1H), 2.92-3.08 (m, 8H), 2.82
(m, 2H), 2.80 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H). MS (ESI) m/z
1011.4 (M+H).sup.+.
Example 1AG
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]me-
thoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
[0594] To a solution of Example 1AF (36 mg) and
2,2-dimethoxypropane (30.2 mg) in dichloromethane (1.2 mL) was
added p-toluenesulfonic acid monohydrate (5.52 mg). The mixture was
stirred for 1 hour. The mixture was purified by reverse phase
preparatory LC using a Gilson 2020 system (Luna C-18, 250.times.50
mm column, mobile phase A: 0.1% TFA in water; B: acetonitrile;
20-75% B to A gradient at 70 mL/minute) to afford the title
compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 8.82 (s, 1H), 8.76 (s, 1H), 8.35 (d, 2H), 7.42 (d, 1H), 7.19
(m, 4H), 7.06 (d, 2H), 6.88 (d, 1H), 6.80 (m, 1H), 6.25 (m, 1H),
5.78 (s, 1H), 5.20 (q, 2H), 4.90 (m, 1H), 4.41 (m, 2H), 4.08 (dd,
2H), 3.79 (dd, 1H), 3.62 (m, 1H), 3.21 (m, 1H), 2.88-3.12 (m, 10H),
2.82 (m, 2H), 2.80 (s, 3H), 1.95 (s, 3H), 1.95 (s, 3H), 1.37 (s,
3H), 1.30 (s, 3H). MS (ESI) m/z 1051.3 (M+H).sup.+.
Example 2
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 2A
(R)-2-(4-((1,4-dioxan-2-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane
[0595] (S)-(1,4-dioxan-2-yl)methanol (160 mg) was dissolved in
dichloromethane (6 mL). The mixture was cooled to 0.degree. C.
Triethylamine (0.217 mL) was added. Methanesulfonyl chloride (0.116
mL) was then added dropwise. The mixture was allowed to warm to
room temperature. After two hours, saturated aqueous sodium
bicarbonate (3 mL) was added. The layers were separated and the
organic portion was washed with brine (5 mL). The aqueous portions
were combined and back-extracted with dichloromethane (10 mL). The
organic portions were combined and dried over anhydrous sodium
sulfate, and filtered. The solvent was removed under vacuum. To
this material was added
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (200 mg) and
N,N-dimethylformamide (5 mL). Cesium carbonate (592 mg) was added,
and the mixture was heated to 90.degree. C. for 16 hours. The
mixture was cooled and saturated aqueous ammonium chloride (2 mL)
was added. The mixture was diluted with ethyl acetate (20 mL) and
washed with water (10 mL) twice. The organic portion was washed
with brine (10 mL) and dried on anhydrous sodium sulfate. After
filtration, the mixture was concentrated under vacuum and was
purified by flash column chromatography on silica gel using a
30-60% gradient of ethyl acetate in heptanes to provide the title
compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 7.60 (d, 2H), 6.94 (d, 2H), 3.98 (d, 2H), 3.88-3.74 (m, 3H),
3.68-3.59 (m, 2H), 3.52-3.46 (m, 1H), 3.42-3.37 (m, 1H), 1.27 (s,
12H). MS (ESI) m/z 221.3 (M-tert-butyl carboxylate)*.
Example 2B
(R)-(2-(4-((1,4-dioxan-2-yl)methoxy)phenyl)pyrimidin-4-yl)methanol
[0596] Example 2A (138 mg) and (2-bromopyrimidin-4-yl)methanol (94
mg) were dissolved in 1,4-dioxane (2 mL). Aqueous sodium carbonate
(2 M, 0.65 mL) was added. The mixture was degassed and flushed with
nitrogen three times.
Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct (35 mg) was added, and the mixture was
degassed and flushed with nitrogen once. The mixture was stirred at
75.degree. C. for 16 hours. The mixture was cooled, diluted with
ethyl acetate (10 mL), washed with water (10 mL), washed with brine
(10 mL), and dried over anhydrous sodium sulfate. The mixture was
concentrated and purified by flash column chromatography on silica
gel using a 30-60% gradient of ethyl acetate in heptanes to provide
the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.81 (d, 1H), 8.33 (d, 2H),
7.42 (d, 1H), 7.07 (d, 2H), 5.65 (t, 1H), 4.61 (d, 2H), 4.04 (d,
2H), 3.92-3.76 (m, 3H), 3.69-3.61 (m, 2H), 3.54-3.48 (m, 1H),
3.45-3.40 (m, 1H). MS (ESI) m/z 303.2 (M+H).sup.+.
Example 2C
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methox-
y}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
late
[0597] The title compound was prepared by substituting Example 2B
for Example 1AD in Example 1AE. MS (ESI) m/z 1093.1
(M+H).sup.+.
Example 2D
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0598] The title compound was prepared by substituting Example 2C
for Example 1AE in Example 1AF. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 9.42 (bs, 1H), 8.84 (d, 1H),
8.76 (s, 1H), 8.32 (d, 2H), 7.44 (d, 1H), 7.21-7.15 (m, 4H), 7.08
(d, 2H), 6.91 (d, 1H), 6.83 (dd, 1H), 6.28 (m, 1H), 5.79 (d, 1H),
5.21 (q, 2H), 4.93 (m, 1H), 4.51-4.42 (m, 2H), 4.05 (m, 2H),
3.92-3.88 (m, 1H), 3.87 (dd, 1H), 3.78 (dd, 1H), 3.71-3.62 (m, 3H),
3.53 (m, 1H), 3.24 (m, 4H), 3.12-2.91 (m, 6H), 2.89-2.81 (m, 2H),
2.80 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H). MS (ESI) m/z 1037.1
(M+H).sup.+.
Example 3
(7R,16R)-19,23-dichloro-10-{[2-(2-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]me-
thoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
Example 3A
(S)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4,4,5,5-tetramet-
hyl-1,3,2-dioxaborolane
[0599] To a solution of
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1000 mg) in
N,N-dimethylformamide (10 mL) was added
(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate
(1431 mg) and cesium carbonate (1777 mg). The mixture was stirred
at 120.degree. C. for 24 hours, cooled, and diluted with ethyl
acetate and washed with water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by silica gel flash chromatography (Biotage.RTM. 25 g
silica gel column, eluting with 30-80% ethyl acetate in hexanes) to
give the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 7.39 (m, 2H), 6.95 (m, 2H),
4.31 (m, 1H), 4.00 (m, 4H), 1.34 (s, 6H), 1.24 (s, 6H), 1.21 (s,
6H).
Example 3B
(S)-(2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)pyrimidin-4-yl)m-
ethanol
[0600] To a solution of (2-chloropyrimidin-4-yl)methanol (143 mg)
and Example 3A (330 mg) in a mixture of tetrahydrofuran (5.712 mL)
and saturated aqueous sodium bicarbonate solution (3.26 mL) was
added Pd(PPh.sub.3).sub.4 (114 mg). The reaction was heated to
75.degree. C. overnight. The reaction was then cooled to room
temperature and was diluted with water (20 mL) and dichloromethane
(20 mL). The layers were separated, and the aqueous layer was
extracted with additional dichloromethane (2.times.25 mL). The
combined organics were dried with anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. The crude product
was purified by MPLC (Biotage.RTM. Isolera, 10 g silica column, 37
mL/min flow), eluting with a gradient of 0-50% ethyl acetate in
heptane over 20 minutes to give the title compound. MS (ESI) m/z
317.2 (M+H).sup.+.
Example 3C
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(2-{[(4S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]methoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-d-
imethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-eth-
eno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]i-
ndene-7-carboxylate
[0601] A solution of Example 1Z (100 mg), Example 3B (117 mg),
triphenylphosphine (97.0 mg) and di-tert-butylazodicarboxylate (85
mg) in toluene (2 mL) was stirred overnight. The solution was
directly purified by MPLC (Biotage.RTM. Isolera, 10 g silica, 36
mL/min flow), eluting with a gradient of 0-6% CH.sub.3OH in
dichloromethane over 25 minutes to give the title compound. MS
(ESI) m/z 1107.5 (M+H).sup.+.
Example 3D
(7R,16R)-19,23-dichloro-10-[(2-{2-[(2R)-2,3-dihydroxypropoxy]phenyl}pyrimi-
din-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-
-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-tri-
oxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0602] The title compound was prepared by substituting Example 3C
for Example 1AE in Example 1AF. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 9.43 (s, 1H), 8.87 (d, 1H),
8.77 (s, 1H), 7.67 (dd, 1H), 7.54 (d, 1H), 7.51-7.45 (m, 1H),
7.24-7.13 (m, 6H), 7.09 (t, 1H), 6.88 (d, 1H), 6.84 (dd, 1H), 6.28
(dd, 1H), 5.79 (d, 1H), 5.23 (d, 1H), 5.17 (d, 1H), 4.98-4.85 (m,
1H), 4.55-4.39 (m, 2H), 4.12 (dd, 1H), 4.01 (dd, 1H), 3.77 (p, 1H),
3.67 (dd, 1H), 3.27-3.16 (m, 2H), 3.13-2.94 (m, 8H), 2.85 (qd, 2H),
2.80 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H). MS (ESI) m/z 1011.3
(M+H).sup.+.
Example 3E
(7R,16R)-19,23-dichloro-10-{[2-(2-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]me-
thoxy}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
[0603] The title compound was prepared by substituting Example 3D
for Example 1AF in Example 1AG. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 9.44 (s, 1H), 8.88 (d, 1H),
8.77 (s, 1H), 7.59 (dd, 1H), 7.52 (d, 1H), 7.49-7.41 (m, 1H),
7.24-7.12 (m, 6H), 7.08 (t, 1H), 6.89 (d, 1H), 6.83 (dd, 1H), 6.28
(dd, 1H), 5.80 (d, 1H), 5.24-5.11 (m, 2H), 4.98-4.90 (m, 1H),
4.53-4.39 (m, 2H), 4.35-4.27 (m, 1H), 4.10 (dd, 1H), 4.04 (dd, 1H),
4.00 (dd, 1H), 3.86 (dd, 1H), 3.64 (dd, 1H), 3.13-2.94 (m, 8H),
2.91-2.82 (m, 2H), 2.80 (s, 3H), 1.99 (s, 3H), 1.97 (s, 3H), 1.23
(s, 3H), 1.15 (s, 3H). MS (ESI) m/z 1051.4 (M+H).sup.+.
Example 4
(7R,16R,21S)-19-chloro-10-{[2-(1,4-dioxan-2-yl)pyrimidin-4-yl]methoxy}-1-(-
4-fluorophenyl)-20-methyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-te-
trahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclon-
onadeca[1,2,3-cd]indene-7-carboxylic Acid
Example 4A
6-iodothieno[2,3-d]pyrimidin-4(3H)-one
[0604] Acetic acid (312 mL), sulfuric acid (9.37 mL) and water (63
mL) were combined with stirring. Thieno[2,3-d]pyrimidin-4(3H)-one
(50 g), periodic acid (37.4 g) and iodine (75 g) were added
sequentially, and the mixture became slightly endothermic. A
heating mantle was added and the reaction mixture was ramped up to
60.degree. C. Midway through, the temperature climbed to
68-69.degree. C. The heating mantle was removed and the temperature
was maintained at 70.degree. C. by self-heating for about 45
minutes. The reaction mixture was cooled to room temperature. The
resulting suspension was filtered, washed with 5:1 acetic
acid:water (three times), and washed with diethyl ether (five
times) to provide the title compound which was used in the next
step without further purification. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 12.80-12.41 (m, 1H), 8.10
(s, 1H), 7.66 (s, 1H). MS (ESI) m/z 277.9 (M-H).sup.-.
Example 4B
4-chloro-6-iodothieno[2,3-d]pyrimidine
[0605] Phosphorous oxychloride (37 mL) and N,N-dimethylaniline
(11.5 mL) were combined, and Example 4A (25 g) was added over a few
minutes. The reaction mixture was stirred at 105.degree. C. for 1.5
hours. The suspension was cooled to 5-10.degree. C., filtered, and
washed with heptanes. The crude filter cake was dumped into ice
water with rapid stirring. The mixture was stirred for about 30
minutes, filtered, and washed with three times with water and three
times with diethyl ether. The material was dried on the filter bed
overnight to provide the title compound which was used in the next
step without further purification. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.89 (s, 1H), 7.95 (s,
1H).
Example 4C
5-bromo-4-chloro-6-iodothieno[2,3-d]pyrimidine
[0606] Example 4B (20.5 g) was taken up in acetonitrile (173 mL)
and N-bromosuccinimide (13.54 g) was added followed by
tetrafluoroboric acid-dimethyl ether complex (2 mL). While the
reaction mixture was stirring, the temperature slowly climbed,
reaching 25.5.degree. C. after 30 minutes. The reaction mixture was
allowed to stir overnight at room temperature. An additional 0.4
equivalents of N-bromosuccinimide was added followed by
tetrafluoroboric acid-dimethyl ether complex (2 mL), and the
reaction mixture was stirred for an additional 5 hours. The
reaction mixture was cooled in an ice bath to about 5.degree. C.
(internal) and was filtered. The material was washed with
acetonitrile (twice) and dried on the filter bed overnight. The
title compound was used in the next step without further
purification. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.93 (s, 1H).
Example 4D
5-bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine
[0607] (Tris(dibenzylideneacetone)dipalladium(0)) (7.32 g),
di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(7.47 g), tripotassium phosphate (181 g), (4-fluorophenyl)boronic
acid (89 g), and Example 4C (200 g) were combined in a three neck,
5 L round bottom flask, fitted with a water condenser,
thermocouple/JKEM, overhead stirring and an argon gas inlet. The
material was flushed with argon for 40 minutes. Tetrahydrofuran
(1705 mL) and water (426 mL) were combined into a 3 L round bottom
flask. The contents were sparged with argon for 30 minutes. The
solvent mixture was cannulated into the flask containing the
solids. A sharp temperature increase to 37.degree. C. was observed.
The temperature was set to 64.degree. C. (internal), and the
reaction mixture was stirred overnight (16 hours) at 64.degree. C.
under a light positive flow of argon. The reaction mixture was
cooled to 38.degree. C., and 200 mL water was added with stirring
(overhead). Stirring was continued for 2 hours, and the material
was filtered and washed with water. A second crop was obtained from
the filtrate and was combined with the first crop. The combined
material was taken up in hot tetrahydrofuran (2 L), stirred with 20
g thiosilica gel and 20 g charcoal for 30 minutes, and filtered
through a pad of diatomaceous earth. The filtrate was concentrated
to provide the title compound. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 8.86 (s, 1H), 7.75-7.58 (m, 2H), 7.22 (t, 2H). MS (ESI)
m/z 344.8 (M+H).sup.+.
Example 4E
(R)-tert-butyl
3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-2-((5-bromo-6-(4-
-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)propanoate
[0608] A 1 L flask containing Example 1Q (24.03 g) and Example 4D
(19.08 g) was equipped with a stir bar, thermocouple for internal
temperature monitoring and sealed with a rubber septum. The flask
was flushed with argon, and warm tert-butanol (262 mL) was added
via cannula. Cesium carbonate (51.2 g) was added in one portion.
The reaction was heated to an internal temperature of 65.degree. C.
After four hours at 65.degree. C., the reaction was allowed to cool
to ambient temperature, diluted with methyl tert-butyl ether (100
mL) and filtered through a pad of diatomaceous earth. The filter
pad was washed with ethyl acetate (2.times.100 mL). The solvents
were evaporated, and the crude material was dissolved in ethyl
acetate (500 mL). The mixture was washed with water (300 mL) and
saturated aqueous sodium chloride solution (300 mL), dried over
anhydrous magnesium sulfate, filtered, and concentrated. The crude
residue was purified on a Grace Reveleris instrument using a
Teledyne Isco Redisep.RTM. Gold 750 g column, eluting with a 0-30%
ethyl acetate/heptanes gradient. The desired fractions were
combined and concentrated to give the title compound. .sup.1H NMR
(501 MHz, chloroform-d) .delta. ppm 8.49 (s, 1H), 7.68-7.59 (m,
2H), 7.48-7.44 (m, 2H), 7.39-7.32 (m, 2H), 7.32-7.27 (m, 1H),
7.21-7.13 (m, 2H), 6.91 (d 1H), 6.77 (d, 1H), 6.65 (dd, 1H), 5.76
(dd, 1H), 5.07 (d, 1H), 5.04 (d, 1H), 3.49 (dd, 1H), 3.26 (dd, 1H),
1.40 (s, 9H), 0.93 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H). MS (ESI)
m/z 765.2 (M+H).sup.+.
Example 4F
(3-chloro-4-hydroxy-2-methylphenyl)boronic acid
[0609] A 5 L 3 neck jacketed flask equipped with overhead stirring
and thermocouple for internal temperature monitoring was charged
with Example 1R (50 g),
chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)
(5.78 g), tetrahydroxydiboron (60.7 g), and potassium acetate (55.4
g) which had been dried overnight under vacuum at 50.degree. C. The
flask was flow purged with a N.sub.2 gas sweep for 2 hours, and
cooled until the internal temperature of the material reached
-6.degree. C. An oven dried 2 L round bottomed flask was charged
with anhydrous methanol (1129 mL) and anhydrous ethylene glycol
(376 mL). The stirring solvents were degassed by subsurface
sparging with nitrogen gas for two hours and were cooled to
-8.degree. C. in an ice/ethanol bath. The solvent mixture was
transferred to the reaction flask via cannula over 10 minutes. The
reaction was stirred at -7.degree. C. for 2.5 hours, quenched by
addition of water (1 L), and allowed to stir at 0.degree. C. for 1
hour. The mixture was filtered through a large pad of diatomaceous
earth and the filter pad was washed with 1:1 water/methanol
(2.times.500 mL). The filtrate was concentrated on a rotary
evaporator until approximately 1.5 L of solvent had been removed.
The mixture was extracted with ethyl acetate (2.times.1 L). The
combined organic extracts were washed with brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The crude material was treated with
dichloromethane (200 mL), and the title compound was collected by
filtration. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6/deuterium oxide) 6 ppm 7.19 (d, 1H), 6.75
(dlH), 2.38 (s, 3H). MS (ESI) m/z 412.9 (M-H).sup.-.
Example 4G
(R)-tert-butyl
3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)-2-(((1S)-5-(3-ch-
loro-4-hydroxy-2-methylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4--
yl)oxy)propanoate
[0610] A 1 L 3 neck flask equipped with overhead stirring was
charged with Example 4E (30.2 g),
4-(di-tert-butylphosphino)-N,N-dimethylaniline (1.15 g),
(tris(dibenzylideneacetone)dipalladium(0)) (1.806 g), and Example
4F (14.70 g). The flask was sealed with a rubber septa and was
flushed with argon for 15 minutes. A separate 500 mL round bottomed
flask equipped with a magnetic stir bar was charged with cesium
carbonate (25.7 g) and was sealed with a septum. The flask was
flushed with argon for 10 minutes and water (46.9 mL) and
1,4-dioxane (235 mL) were added. The flask was degassed by
subsurface sparging with stirring for 30 minutes and the contents
were transferred to the reaction flask via cannula. The reaction
was stirred for 60 hours and was quenched by addition of ammonium
pyrrolidine-1-carbodithioate (1.296 g). The reaction was stirred
for 1 hour at which point ethyl acetate (200 mL) and water (100 mL)
were added. The biphasic mixture was filtered through a pad of
diatomaceous earth, washing with ethyl acetate (100 mL) and water
(50 mL). The layers were separated and the aqueous layer was
extracted with ethyl acetate (200 mL). The combined organic layers
were washed with a solution of saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The crude material was purified by flash
column chromatography using a Grace Reveleris system using a
Teledyne Isco Redisep.RTM. Gold 750 g column eluting with a 0-30%
ethyl acetate/heptanes gradient. The pure fractions were collected
and concentrated under reduced pressure to give the title compound.
.sup.1H NMR (501 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 10.10
(s, 1H), 8.61 (s, 1H), 7.43-7.38 (m, 2H), 7.36-7.24 (m, 5H),
7.24-7.18 (m, 2H), 6.92 (d, 1H), 6.89 (d, 1H), 6.80 (d, Hz, 1H),
6.68 (dd, 1H), 6.43 (d, 1H), 5.34 (t, 1H), 5.03 (s, 2H), 2.70-2.60
(m, 2H), 1.91 (s, 3H), 1.17 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H),
0.08 (s, 3H). MS (ESI) m/z 827.1 (M+H).sup.+.
Example 4H
(S)-3-(allyloxy)-2-hydroxypropyl 4-methylbenzenesulfonate
[0611] A 1 L 3 necked round bottomed flask equipped with a magnetic
stir bar was charged with a solution of Example 1J (45.8 g) in
dichloromethane (500 mL). 4-Dimethylaminopyridine (0.572 g) and
N-ethyl-N-isopropylpropan-2-amine (60.3 mL) were added
sequentially. Solid 4-methylbenzene-1-sulfonyl chloride (33 g) was
added portionwise and the reaction was heated to an internal
temperature of 40.degree. C. overnight. Upon cooling to ambient
temperature, a solution of saturated aqueous ammonium chloride was
added (300 mL). The layers were separated, and the organic layer
was washed with a solution of saturated sodium chloride (200 mL),
dried over anhydrous magnesium sulfate, filtered and concentrated
under reduced pressure. The crude material was purified by flash
column chromatography on a Grace Reveleris System using a Teledyne
Isco Redisep.RTM. Gold 750 g column eluting with a 0-40% ethyl
acetate/heptanes gradient to give the title compound. .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 7.79 (d, 2H), 7.35 (d, 2H),
5.82 (ddt, 1H), 5.22 (dq), 5.16 (dq, 1H), 4.10 (dd, 1H), 4.04 (dd,
1H), 3.98 (dd, 1H), 3.94 (dt, 2H), 3.47 (dd, 1H), 3.43 (dd, 1H),
2.87 (d, 1H), 2.44 (s, 3H). MS (ESI) m/z 304.0
(M+NH.sub.4).sup.+.
Example 41
(R)-tert-butyl
2-(((1S)-5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3-chloro-2--
methylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(ben-
zyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propanoate
[0612] An oven dried 250 mL 3-necked flask was charged with Example
4H (3.11 g) and Example 4G (5.0 g). The flask was equipped with a
magnetic stir bar, sealed with rubber septa, and purged with an
argon sweep for 15 minutes. Toluene (30 mL) was added and upon
dissolution, the flask was cooled in an ice bath to an internal
temperature of 5.degree. C. Triphenylphosphine (3.17 g) was added
and the reaction mixture was stirred for 5 minutes at which point
di-tert-butyl azodicarboxylate (2.78 g) was added. After 30
minutes, the cooling bath was removed and the flask was allowed to
warm to ambient temperature and was stirred overnight. The reaction
mixture was loaded onto a 400 mL Buchner funnel packed with silica
gel which had been equilibrated with heptanes. The silica gel plug
was eluted with a mixture of 1:3 ethyl acetate/heptanes (600 mL),
which was concentrated. The crude product was purified by flash
column chromatography on a Teledyne Isco Combiflash.RTM. Rf
instrument using a Teledyne Isco RediSep.RTM. Gold 220 g column.
The pure fractions were combined and concentrated to give the title
compound. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 8.62 (s, 1H), 7.75 (d, 1H), 7.46-7.33 (m, 5H), 7.33-7.25 (m,
3H), 7.22 (t, 2H), 7.09 (d, 1H), 6.96 (d, 1H), 6.91 (d, 1H), 6.67
(dd, 1H), 6.39 (d, 1H), 5.62 (ddt, 1H), 5.31 (dd, 1H), 5.06-4.99
(m, 3H), 4.97 (dq, 1H), 4.69 (dt, 1H), 4.28 (dd, 1H), 4.18 (dd,
1H), 3.73 (dq, 2H), 3.45 (d, 2H), 2.58 (qd, 2H), 2.38 (s, 3H), 1.94
(s, 3H), 1.15 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.08 (s, 3H). MS
(ESI) m/z 1095.3 (M+H).sup.+.
Example 4J
(R)-tert-butyl
2-(((1S)-5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3-chloro-2--
methylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(ben-
zyloxy)-5-hydroxyphenyl)propanoate
[0613] A 100 mL round bottomed flask was charged with Example
41(3.58 g), sealed with a septum and purged with nitrogen gas for
10 minutes. Tetrahydrofuran (23 mL) was added followed by acetic
acid (0.3 mL). The stirring homogeneous solution was cooled in an
ice bath to 5.degree. C. internal temperature and a solution of
tetra-N-butylammonium fluoride (4.75 mL, 1M) in tetrahydrofuran was
added dropwise. After 1 hour, the reaction was quenched by addition
of saturated aqueous sodium bicarbonate (40 mL), and diluted with
methyl tert-butyl ether (160 mL). The layers were separated and the
organic layer was washed sequentially with water and brine, then
dried over magnesium sulfate, filtered and concentrated. The crude
residue was purified by flash column chromatography on a Teledyne
Isco Combiflash.RTM. Rf instrument using a Teledyne Isco
RediSep.RTM. Gold 80 g column eluting with a 0-60% ethyl
acetate/heptanes gradient. The desired fractions were collected,
combined and concentrated to give the title compound. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.78 (s, 1H), 8.61
(s, 1H), 7.80-7.70 (m, 2H), 7.45-7.40 (m, 2H), 7.40-7.33 (m, 4H),
7.32-7.24 (m, 3H), 7.24-7.19 (m, 2H), 7.13 (d, 1H), 7.01 (d, 1H),
6.83 (d, 1H), 6.57 (dd, 1H), 6.17 (d, 1H), 5.63 (ddt, 1H), 5.21
(dd, 1H), 5.04 (dq, 1H), 4.98 (ddt, 3H), 4.73 (dt, 1H), 4.29 (dd,
1H), 4.19 (dd, Hz, 1H), 3.75 (q, 1H), 3.74 (q, 1H), 3.48 (d, 2H),
2.59 (dd, 1H), 2.50 (d, 1H), 2.38 (s, 3H), 1.93 (s, 3H), 1.17 (s,
9H). MS (ESI) m/z 981.1 (M+H).sup.+.
Example 4K
tert-butyl
(7R,16R,21S)-10-(benzyloxy)-19-chloro-1-(4-fluorophenyl)-16-(al-
lyloxymethyl)-20-methyl-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6-
,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0614] An oven dried 3 neck 500 mL round bottomed flask was charged
with Example 4J (3.13 g), and equipped with a magnetic stir bar and
sealed with rubber septa. The flask was purged with an argon flow
for 10 minutes. N,N-Dimethylformamide (319 mL) was added and the
material was dissolved with stirring at ambient temperature. Cesium
carbonate (5.19 g) was added and the suspension was stirred at
ambient temperature for 3 hours. Ethyl acetate (100 mL) was added
and the mixture was filtered through a pad of diatomaceous earth.
The solvents were concentrated under vacuum, and the crude residue
was treated with ethyl acetate (200 mL) and water (100 mL). A 1 M
aqueous solution of lithium chloride was added (50 mL), and the
layers were separated. The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography on a Teledyne Isco Combiflash.RTM. Rf instrument
using a Teledyne Isco RediSep.RTM. Gold 120 g column eluting with a
0-50% ethyl acetate/heptanes gradient. The desired fractions were
collected, combined and concentrated to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.70
(s, 1H), 7.49-7.43 (m, 3H), 7.43-7.36 (m, 3H), 7.37-7.29 (m, 1H),
7.26-7.14 (m, 6H), 6.97-6.91 (m, 3H), 6.88 (dd, 1H), 5.97 (dd, 1H),
5.89 (ddt, 1H), 5.52 (d, 1H), 5.27 (dq, 1H), 5.16 (dq, 1H), 5.04
(d, 1H), 4.97 (d, 1H), 4.50 (hept, 1H), 4.46-4.41 (m, 1H),
4.41-4.37 (m, 1H), 4.06-3.97 (m, 1H), 4.01-3.92 (m, 1H), 3.76 (dd,
1H), 3.68 (dd, 1H), 3.62 (dd, 1H), 2.71 (d, 1H), 2.23 (s, 3H), 1.01
(s, 9H). MS (ESI) m/z 809.1 (M+H).sup.+.
Example 4L
tert-butyl
(7R,16R,21S)-10-(benzyloxy)-19-chloro-1-(4-fluorophenyl)-16-(hy-
droxymethyl)-20-methyl-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,-
14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0615] An oven dried 100 mL round bottomed flask was charged with
Example 4K (2.23 g), tetrakis(triphenylphosphine)palladium(0)
(0.318 g), 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.946 g),
and a magnetic stir bar, and sealed with a septum. The flask was
purged with a flow of argon for 15 minutes. A mixture of
tetrahydrofuran (18 mL) and methanol (9 mL), which was degassed by
subsurface sparging with argon for 30 minutes, was added via
cannula. The reaction was stirred at ambient temperature for 40
hours at which point ammonium pyrrolidine-1-carbodithioate (0.181
g) was added and the stirring was continued for 1 hour. The
reaction mixture was filtered through a plug of diatomaceous earth,
and the filter pad was washed with ethyl acetate (25 mL) and water
(25 mL). The filtrate layers were separated and the aqueous layer
was extracted once with ethyl acetate (25 mL). The combined organic
layers were washed with a solution of saturated aqueous sodium
chloride (50 mL), dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The crude residue was purified
by flash column chromatography on a Teledyne Isco Combiflash.RTM.
Rf instrument using a Teledyne Isco RediSep.RTM. Gold 80 g column
eluting with a 0-50% ethyl acetate/heptanes gradient. The pure
fractions were collected, combined and concentrated to give the
title compound. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.70 (s, 1H), 7.50-7.43 (m, 2H), 7.44-7.36 (m, 2H),
7.37-7.30 (m, 1H), 7.26-7.14 (m, 5H), 6.98-6.90 (m, 2H), 6.86 (dd,
1H), 5.96 (dd, 1H), 5.52 (d, 1H), 5.04 (d, 1H), 4.98 (q, 2H),
4.48-4.31 (m, 3H), 3.76 (dd, 1H), 3.69 (ddd, 1H), 3.56 (dt, 1H),
2.77-2.66 (m, 1H), 2.23 (s, 3H), 1.02 (s, 9H). MS (ESI) m/z 769.2
(M+H).sup.+.
Example 4M
tert-butyl
(7R,16R,21S)-10-(benzyloxy)-19-chloro-1-(4-fluorophenyl)-20-met-
hyl-16-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}-7,8,15,16-tetrahydro-18,2-
1-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-
-cd]indene-7-carboxylate
[0616] A 50 mL round bottomed flask was charged with Example 4L
(1.81 g), and a magnetic stir bar. Dichloromethane was added (16
mL), and the mixture was stirred to dissolution.
1,4-Diazabicyclo[2.2.2]octane (0.660 g) andp-toluenesulfonyl
chloride (0.673 g) were added sequentially. The reaction was
stirred at ambient temperature for 1 hour and quenched by addition
of ethylenediamine (0.079 mL). The reaction mixture was stirred for
10 minutes and was diluted with dichloromethane (20 mL). A solution
of 1.0 M sodium dihydrogen phosphate NaH.sub.2PO.sub.4 (30 mL) was
added. The layers were separated and the aqueous layer was
extracted with dichloromethane (20 mL). The combined organic layers
were dried over anhydrous magnesium sulfate, filtered and
concentrated to give the title compound which was used without
further purification. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.70 (s, 1H), 7.84-7.77 (m,
2H), 7.46 (ddd, 4H), 7.44-7.37 (m, 2H), 7.37-7.31 (m, 1H), 7.20 (d,
3H), 7.11-7.04 (m, 1H), 6.94 (d, 1H), 6.92 (d, 1H), 6.87 (dd, 1H),
5.97 (dd, 1H), 5.48 (d, 1H), 5.06 (d, 1H), 4.99 (d, 1H), 4.61-4.49
(m, 1H), 4.39-4.32 (m, 3H), 4.29 (dd, 1H), 3.75 (dd, 1H), 2.75-2.64
(m, 1H), 2.40 (s, 3H), 2.21 (s, 3H), 1.01 (s, 9H). MS (ESI) m/z
923.0 (M+H).sup.+.
Example 4N
tert-butyl
(7R,16R,21S)-10-(benzyloxy)-19-chloro-1-(4-fluorophenyl)-20-met-
hyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno--
13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inden-
e-7-carboxylate
[0617] An oven dried 100 mL round bottomed flask was charged with
Example 4M (2.17 g) and a magnetic stir bar then sealed with a
rubber septum. The flask was purged with a nitrogen gas sweep for
10 minutes. Dimethylformamide (8 mL) and 1-methylpiperazine (8 mL)
were added sequentially. The reaction was stirred for 60 hours at
ambient temperature and 16 hours at 30.degree. C. The reaction was
cooled in an ice bath, and diluted with ethyl acetate (20 mL) and
water (20 mL). The reaction was allowed to warm to ambient
temperature and was further diluted with water (80 mL) and ethyl
acetate (80 mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were washed sequentially with water and a 0.5 M
aqueous solution of lithium chloride, dried over anhydrous
magnesium sulfate, and concentrated. The crude residue was purified
by flash column chromatography on a Teledyne Isco Combiflash.RTM.
Rf instrument using a Teledyne Isco RediSep.RTM. Gold 80 g column
eluting with a 0-10% methanol/dichlormethane gradient to yield the
title compound. .sup.1H NMR (501 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.71 (s, 1H), 7.47-7.43 (m, 3H), 7.43-7.37 (m, 3H),
7.37-7.29 (m, 2H), 7.26-7.13 (m, 5H), 6.93 (d, J=2.9 Hz, 1H), 6.91
(d, J=3.7 Hz, 1H), 6.82 (dd, J=9.0, 2.9 Hz, 2H), 6.01 (dd, J=5.9,
2.3 Hz, 2H), 5.53 (d, J=2.7 Hz, 1H), 5.06 (d, J=12.1 Hz, 1H), 4.98
(d, J=12.1 Hz, 1H), 4.48 (d, J=13.2 Hz, 1H), 4.44 (dd, J=8.2, 5.5
Hz, 1H), 4.32 (dd, J=13.0, 8.4 Hz, 1H), 3.78 (dd, J=16.7, 5.9 Hz,
1H), 2.75-2.68 (m, 1H), 2.60-2.55 (m, 1H), 2.54 (dd, J=13.0, 7.8
Hz, 1H), 2.31 (d, J=29.0 Hz, 8H), 2.24 (s, 3H), 2.15 (s, 3H), 1.01
(s, 9H). MS (ESI) m/z 851.0 (M+H).sup.+.
Example 40
tert-butyl
(7R,16R,21S)-19-chloro-1-(4-fluorophenyl)-10-hydroxy-20-methyl--
16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-
-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7--
carboxylate
[0618] A 20 mL Barnstead Hastelloy C reactor was charged with
palladium on carbon (0.55 g, 5% weight palladium, wet). A solution
of Example 4N in tetrahydrofuran (2.5 mL) was added and the reactor
was purged with argon. The mixture was stirred under 50 psi of
hydrogen at 25.degree. C. for 48 hours. The mixture was filtered,
concentrated under reduced pressure and purified by flash column
chromatography on a Teledyne Isco Combiflash.RTM. Rf instrument
using a Teledyne Isco RediSep.RTM. Gold 40 g column eluting with a
0-10% methanol/dichlormethane gradient to yield the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 9.03
(s, 1H), 8.67 (s, 1H), 7.32-7.04 (m, 7H), 6.88 (d, 1H), 6.78-6.51
(m, 2H), 5.91 (dd, 1H), 5.33 (d, 1H), 4.43-4.32 (m, 2H), 4.24 (dd,
1H), 3.65 (dd, 1H), 2.57 (d, 1H), 2.53-2.47 (m, 3H), 2.36-2.25 (m,
8H), 2.24 (s, 3H), 2.10 (s, 3H), 1.01 (s, 9H). MS (ESI+) m/z 761.5
(M+H).sup.+.
Example 4P
1,4-dioxane-2-carboxamide
[0619] In a 1 L recovery flask, 1,4-dioxane-2-carboxylic acid (11.0
g) in tetrahydrofuran (200 mL) was cooled to 3.degree. C., and
di(1H-imidazol-1-yl)methanone (16 g) was added all at once. The
mixture was stirred cold for 5 minutes, and stirred at room
temperature for 2 hours. The mixture was then cooled in an
ice-water bath for 15 minutes, concentrated ammonium hydroxide (16
mL) was added, and the reaction was stirred for 1 hour. The cold
bath was removed and the reaction was stirred another 1 hour. The
mixture was concentrated and left under high vacuum overnight. The
material was taken up in 150 mL ethyl acetate and 40 mL 6N aqueous
HCl. The layers were separated, and the aqueous layer was extracted
with 4.times.200 mL ethyl acetate. The combined organic layers were
dried over sodium sulfate, filtered, and concentrated. The crude
product was carried on without further purification.
Example 4Q
methyl 1,4-dioxane-2-carbimidate
[0620] Example 4P (12.0 g) was added to dichloromethane (225 mL),
and the mixture was cooled using an ice-water bath for 15 minutes.
Trimethyloxonium tetrafluoroborate (12.0 g) was added all at once.
The reaction was allowed to come to room temperature overnight.
Saturated aqueous sodium bicarbonate (240 mL) was added and the
layers were separated. The aqueous layer was extracted with ethyl
acetate (3.times.180 mL). The combined ethyl acetate layers were
dried over sodium sulfate, filtered, and concentrated. The crude
product was carried on without further purification.
Example 4R
1,4-dioxane-2-carboximidamide, hydrochloride salt
[0621] Example 4Q (7.8 g) was dissolved in methanol (115 mL), and
cooled using an ice-water bath for 15 minutes. Ammonium
hydrochloride (4.5 g) was added. The reaction was stirred cold for
five minutes, at room temperature for 30 minutes, and finally at
70.degree. C. overnight. The reaction was cooled and concentrated,
and the residue was stirred in dichloromethane (50 mL) for 45
minutes, and filtered through diatomaceous earth. The filtrate was
concentrated to give the title compound which was used in the next
step without further purification. MS (DCI) m/z 131.0
(M+H).sup.+.
Example 4S
(4-(dimethoxymethyl)-2-(1,4-dioxane-2-yl)pyrimidine
[0622] To a mixture of Example 4R (4.6 g) in ethanol (115 mL) was
added (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (5.4 g) and
sodium ethoxide (21 wt. %, 21 mL), and the mixture was stirred at
70.degree. C. for 18 hours. The mixture was cooled to room
temperature and was concentrated under reduced pressure. The
residue was diluted with ethyl acetate (150 mL) and saturated
aqueous ammonium chloride (70 mL), the layers were separated, and
the aqueous layer was extracted with ethyl acetate. The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure to provide the title compound,
which was chromatographed on silica gel using 15% ethyl acetate in
heptanes as the eluent to give the title compound. .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 8.81 (d, 1H), 7.47 (d, 1H), 5.29 (d,
1H), 4.92 (dd, 1H), 4.20 (dd, 1H), 4.05 (d, 1H), 3.95 (m, 1H), 3.79
(m, 2H), 3.74 (d, 1H), 3.42 (s, 6H).
Example 4T
(2-(1,4-dioxan-2-yl)pyrimidin-4-yl)methanol
[0623] A mixture of Example 4S (2.4 g) in 2M HCl/in 1,4-dioxane
(1:1, 80 mL) was heated to 50.degree. C. for 16 hours. The reaction
mixture was cooled to 0.degree. C., and concentrated sodium
hydroxide (4.5 mL) was added to adjust the pH to 8. Sodium
borohydride (0.75 g) was added. The mixture was stirred for one
hour at 0.degree. C. The mixture was extracted with three times
with ethyl acetate. The combined organic phases were dried over
sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel,
eluting with 0.5-10% methanol in dichloromethane to provide the
title compound. .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm
8.72 (d, 1H), 7.32 (d, 1H), 4.89 (dd, 1H), 4.78 (d, 2H), 4.19 (dd,
1H), 4.05 (dd, 1H), 3.93 (m, 1H), 3.84-3.71 (m, 3H), 3.48 (dd,
1H).
Example 4U
(2-(1,4-dioxan-2-yl)pyrimidin-4-yl)methyl methanesulfonate
[0624] To Example 4T (65 mg) in dichloromethane (1.6 mL) was added
triethylamine (60 .mu.L), and the mixture was cooled in an
ice-water bath for 15 minutes. Methanesulfonyl chloride (33 .mu.L)
was added dropwise. The reaction mixture was stirred cold for 5
minutes, and at room temperature for 2 hours. Saturated aqueous
sodium bicarbonate solution was added, and the solution was
extracted twice with dichloromethane. The extracts were washed with
brine, dried over sodium sulfate, filtered, and concentrated. The
crude product was carried on without further purification.
Example 4V
tert-butyl
(7R,16R,21S)-19-chloro-10-{[2-(1,4-dioxan-2-yl)pyrimidin-4-yl]m-
ethoxy}-1-(4-fluorophenyl)-20-methyl-16-[(4-methylpiperazin-1-yl)methyl]-7-
,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5--
diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0625] To Example 4U (59 mg) in dimethylformamide (0.5 mL) was
added Example 40 (120 mg), followed by cesium carbonate (103 mg),
and the reaction was stirred overnight. The crude mixture was
chromatographed on a Reveleris prep LC with a 250.times.50 mm
Luna.TM. column using 10-80% acetonitrile in 0.1% aqueous TFA over
30 minutes to give the title compound as a mix of diastereomers. MS
(ESI) m/z 939.5 (M+H).sup.+.
Example 4W
(7R,16R,21S)-19-chloro-10-{[2-(1,4-dioxan-2-yl)pyrimidin-4-yl]methoxy}-1-(-
4-fluorophenyl)-20-methyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-te-
trahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclon-
onadeca[1,2,3-cd]indene-7-carboxylic Acid
[0626] To Example 4V (68 mg) in dichloromethane (700 .mu.L) was
added trifluoroacetic acid (700 .mu.L). The reaction was stirred
for 5 hours. The solution was concentrated, dissolved in 1 mL
dimethylformamide and 0.5 mL water, and purified by prep liquid
chromatography on a Luna.TM. 250.times.50 mm column, using 5-75%
acetonitrile in 0.1% aqueous TFA over 30 minutes, to give the title
compound as a mixture of two diastereomers. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.88 (d, 1H), 8.79 (s, 1H),
7.60 (d, 1H), 7.21 (m, 5H), 7.00 (d, 1H), 6.89 (m, 2H), 6.19 (dd,
1H), 5.70 (d, 1H), 5.20 (dd, 2H), 4.75 (d, 1H), 4.61 (dd, 1H), 4.50
(d, 1H), 4.40 (dd, 1H), 4.02 (d, 1H), 3.98-3.75 (m, 6H), 3.61 (m,
1H), 3.41 (m, 2H), 3.12 (m, 4H), 2.90 (d, 1H), 2.82 (s, 3H), 2.80
(m, 1H), 2.48 (m, 2H), 2.21 (s, 3H). MS (ESI+) m/z 883.3
(M+H).sup.+.
Example 5
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-3-
-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methy-
lpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6-
,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 5A
2-((1,4-dioxan-2-yl)methoxy)-5-bromopyridine
[0627] To a solution of (1, 4-dioxan-2-yl) methanol (2.4 g) in
dimethylsulfoxide (24 mL) was added 5-bromo-2-chloropyridine (3.91
g) and sodium hydride (0.81 g) at 20.degree. C. under nitrogen
flow. The reaction mixture was stirred at 60.degree. C. for 10
hours under nitrogen atmosphere. The reaction was diluted with
water (40 mL) at 25.degree. C. and extracted with ethyl acetate
(3.times.40 mL). The combined organic layers were washed with brine
(5.times.20 mL) and dried over sodium sulfate. After filtration,
the filtrate was concentrated to give a residue which was purified
by column chromatography on silica gel (eluted with petroleum
ether:ethyl acetate=100:1 to 20:1) to give the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.15 (d, 1H), 7.63
(dd, 1H), 6.70 (d, 1H) 4.38-4.49 (m, 2H), 3.78-3.85 (m, 2H),
3.59-3.71 (m, 6H), 3.52 (dd, 2H), 3.35 (s, 3H).
Example 5B
(6-((1,4-dioxan-2-yl)methoxy)pyridin-3-yl)boronic acid
[0628] To a solution of Example 5A (4 g) in 1,4-dioxane (200 mL)
was added potassium acetate (2.58 g), 1,1'-bis(diphenylphosphino)
ferrocenedichloro palladium(II) dichloromethane (2.15 g) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (5 g)
at 20.degree. C. under nitrogen flow. The reaction mixture was
stirred at 100.degree. C. for 12 hours under nitrogen atmosphere.
The reaction mixture was cooled and filtered through diatomaceous
earth. The filtration was concentrated to provide the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.51 (br s,
1H), 7.92 (br d, 1H), 6.77 (br d, 1H), 4.35 (br s, 2H), 4.06-3.76
(m, 5H), 3.62-3.45 (m, 2H).
Example 5C
2-(6-((1,4-dioxan-2-yl)methoxy)pyridin-3-yl)pyrimidine-4-carboxylic
Acid
[0629] To a solution of 2-chloropyrimidine-4-carboxylic acid (0.81
g) in 1,4-dioxane (120 mL) and water (60 mL) was added sodium
bicarbonate (0.85 g), tetrakis (triphenylphosphine) palladium(0)
(0.58 g) and Example 5B (8.1 g) at 20.degree. C. The reaction
mixture was stirred at 80.degree. C. for 12 hours, cooled down to
20.degree. C. and filtered. The filtrate was concentrated to
provide the title compound. .sup.1H NMR (400 MHz, D.sub.2O) .delta.
ppm 8.39 (br s, 1H), 7.70-7.43 (m, 2H), 6.85 (br s, 1H), 4.36-3.38
(m, 9H).
Example 5D
methyl
2-(6-((1,4-dioxan-2-yl)methoxy)pyridin-3-yl)pyrimidine-4-carboxylat-
e
[0630] To a solution of Example 5C (2.8 g) in methanol (84 mL) was
added H.sub.2SO4 (0.7 mL) at 20.degree. C. The reaction was stirred
at 80.degree. C. for 2 hours under nitrogen atmosphere, cooled,
diluted with water (150 mL) and extracted with ethyl acetate
(3.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated. The residue was purified
by column chromatography on silica gel (eluted with petroleum
ether:ethyl acetate=100:1 to 10:1) to provide the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 9.27 (d, 1H), 8.99
(d, 1H), 8.65 (dd, 1H), 7.82 (d, 1H), 6.89 (d, 1H), 4.43 (m, 1H),
4.06-3.96 (m, 4H), 3.94-3.63 (m, 5H), 3.55 (dd, 1H).
Example 5E
(R)-(2-(6-((1,4-dioxan-2-yl)methoxy)pyridin-3-yl)pyrimidin-4-yl)methanol
[0631] To a solution of Example 5D (1.8 g) in dimethyl formamide
(27 mL)/methanol (27 mL)/water (2.7 mL) was added sodium
borohydride (0.14 g) at 0.degree. C. under nitrogen flow. The
reaction mixture was stirred at 25.degree. C. for 10 hours under
nitrogen atmosphere. The reaction was quenched by addition of water
(30 mL) and extracted with ethyl acetate (3.times.50 mL). The
combined organic layers were dried over sodium sulfate, filtered
and concentrated. The residue was purified by column chromatography
on silica gel (eluted with petroleum ether:ethyl acetate=100:1 to
100:13) to provide a mixture of two enantiomers. The enantiomeric
mixture was separated on a Thar SFC80 preparative SFC instrument
(Column: Chiralpak AD-H 250*30 mm i.d. 5 .mu.m, Mobile phase: A for
CO.sub.2 and B for ethanol (0.1% ammonium hydroxide); Gradient: B
%=45%; Flow rate: 85 g/minute; Wavelength: 220 nm; Column
temperature: 40.degree. C.; System back pressure: 100 bar; Cycle
time: 20 minutes; Injection amount: 25 mg per injection) to provide
the title compound. The stereochemistry of the title compound was
arbitrarily assigned. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
9.23 (d, 1H), 8.73 (d, 1H), 8.61 (dd, 1H), 7.17 (d, 1H), 6.91 (d,
1H), 4.81 (br s, 2H), 4.47-4.37 (m, 2H), 4.05 (dtd, 1H), 3.94-3.64
(m, 5H), 3.61-3.54 (m, 2H).
Example 5F
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2R)-1,4-dioxan-2-yl]methox-
y}pyridin-3-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-1-
6-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9--
(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-c-
arboxylate
[0632] A mixture of Example 1Z (40 mg), Example 5E (30 mg) and
Ph.sub.3P (38.9 mg) in a 4-mL vial was purged with nitrogen gas for
20 minutes. Tetrahydrofuran (1 mL) was added. The suspension was
stirred for 2 minutes and sonicated for 2 minutes. Toluene (1 mL)
was added. The mixture was stirred for 3 minutes and
(E)-N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethyldiazene-1,2-dicarboxamide
(29.8 mg) was added. The reaction mixture was heated at 50.degree.
C. overnight, cooled, diluted with dichloromethane, loaded to a
silica gel column, and eluted with 0-10% methanol in
dichloromethane to provide the title compound.
Example 5G
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2R)-1,4-dioxan-2-yl]methoxy}pyridin-3-
-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methy-
lpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6-
,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0633] Example 5F (48 mg) in dichloromethane (4.5 mL) was treated
with trifluoroacetic acid (1.5 mL) overnight and concentrated. The
residue was dissolved in ethyl acetate and washed with sodium
bicarbonate water solution, and brine/water. The organic layer was
dried over sodium sulfate and concentrated. The residue was
purified by reverse phase HPLC on a ACCQPrep HP125 system (Column:
Luna.TM. 10 .mu.m C18(2) 100 .ANG., 250.times.50 mm), eluting with
40-70% acetonitrile in 5 mM ammonium acetate to provide the title
compound. .sup.1H NMR (501 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 9.11 (d, 1H), 8.86 (d, 1H), 8.72 (s, 1H), 8.58 (dd, 1H), 7.54
(d, 1H), 7.25-7.08 (m, 3H), 6.98 (d, 1H), 6.87 (d, 1H), 6.73 (dd,
1H), 6.19 (t, 1H), 5.84 (d, 1H), 5.30-5.13 (m, 2H), 4.88 (d, 1H),
4.49-4.26 (m, 4H), 3.90 (ddt, 1H), 3.82 (dd, 1H), 3.77 (dd, 1H),
3.70-3.58 (m, 3H), 3.56-3.46 (m, 2H), 3.55-3.40 (m, 5H), 3.02-2.90
(m, 1H), 2.74-2.59 (m, 2H), 2.47-2.24 (m, 3H), 2.16 (s, 2H), 1.97
(d, 5H). MS (ESI) m/z 1036.0 (M-H).sup.-.
Example 6
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2)-1,4-dioxan-2-yl]methoxy}pyridin-3--
yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methyl-
piperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,-
14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 6A
(S)-(2-(6-((1,4-dioxan-2-yl)methoxy)pyridin-3-yl)pyrimidin-4-yl)methanol
[0634] To a solution of Example 5D (1.8 g) in dimethylformamide (27
mL)/methanol (27 mL)/water (2.7 mL) was added sodium borohydride
(0.14 g) at 0.degree. C. under nitrogen flow. The reaction mixture
was stirred at 25.degree. C. for 10 hours under nitrogen
atmosphere. The reaction was quenched by addition of water (30 mL)
and extracted with ethyl acetate (3.times.50 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated. The residue was purified by column chromatography on
silica gel (eluted with petroleum ether:ethyl acetate=100:1 to
100:13) to provide a mixture of two enantiomers. The enantiomeric
mixture was separated on a Thar SFC80 preparative SFC instrument
(Column: Chiralpak AD-H 250*30 mm i.d. 5 .mu.m; Mobile phase: A for
CO.sub.2 and B for ethyl acetate (0.1% ammonium hydroxide);
Gradient: B %=45%; Flow rate: 85 g/minute; Wavelength: 220 nm;
Column temperature: 40.degree. C.; System back pressure: 100 bar;
Cycle time: 20 minutes; Injection amount: 25 mg per injection) to
provide the title compound. The stereochemistry of the title
compound was arbitrarily assigned. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 9.23 (d, 1H), 8.73 (d, 1H), 8.61 (dd, 1H),
7.17 (d, 1H), 6.91 (d, 1H), 4.81 (s, 2H), 4.49-4.37 (m, 2H), 4.05
(dtd, 1H), 3.95-3.63 (m, 5H), 3.61-3.54 (m, 2H).
Example 6B
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2$)-1,4-dioxan-2-yl]methox-
y}pyridin-3-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-1-
6-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9--
(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-c-
arboxylate
[0635] The title compound was prepared as described in Example 5F
by replacing Example 5E with Example 6A.
Example 6C
(7R,16R)-19,23-dichloro-10-{[2-(6-{[(2S)-1,4-dioxan-2-yl]methoxy}pyridin-3-
-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methy-
lpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6-
,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0636] The title compound was prepared as described in Example 5G
by replacing Example 5F with Example 6B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 9.03 (d, 1H), 8.78 (d, 1H),
8.66 (s, 1H), 8.50 (dd, 1H), 7.46 (d, 1H), 7.16-7.08 (m, 2H), 7.06
(ddd, 2H), 6.90 (d, 1H), 6.80 (d, 1H), 6.66 (dd, 1H), 6.15 (dd,
1H), 5.77 (d, 1H), 5.18 (d, 1H), 5.11 (d, 1H), 4.79 (p, 1H), 4.37
(d, 2H), 4.24 (qd, 2H), 3.83 (dddd, 1H), 3.75 (dd, 1H), 3.69 (dd,
1H), 3.63-3.51 (m, 3H), 3.47-3.39 (m, 1H), 3.34 (dd, 1H), 2.93-2.85
(m, 1H), 2.62 (dd, 1H), 2.56 (dd, 1H), 2.37 (s, 7H), 2.14 (s, 3H),
1.90 (d, 6H).
Example 7
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2S)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 7A
(S)-2-(4-((1,4-dioxan-2-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane
[0637] The title compound was prepared by substituting
(R)-(1,4-dioxan-2-yl)methanol for (S)-(1,4-dioxan-2-yl)methanol in
Example 2A. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 7.59 (d, 2H), 6.92 (d, 2H), 3.96 (d, 2H), 3.87-3.73 (m,
3H), 3.67-3.58 (m, 2H), 3.51-3.46 (m, 1H), 3.41-3.35 (m, 1H), 1.26
(s, 12H). MS (ESI) m/z 338.1 (M+NH.sub.4).sup.+.
Example 7B
(S)-(2-(4-((1,4-dioxan-2-yl)methoxy)phenyl)pyrimidin-4-yl)methanol
[0638] The title compound was prepared by substituting Example 7A
for Example 2A in Example 2B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.81 (d, 1H), 8.33 (d, 2H),
7.41 (d, 1H), 7.07 (d, 2H), 5.65 (t, 1H), 4.61 (d, 2H), 4.04 (d,
2H), 3.92-3.76 (m, 3H), 3.69-3.61 (m, 2H), 3.54-3.48 (m, 1H),
3.45-3.40 (m, 1H). MS (ESI) m/z 303.2 (M+H).sup.+.
Example 7C
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2S)-1,4-dioxan-2-yl]methox-
y}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
late
[0639] Example 1Z (50 mg), Example 7B (37 mg), and
triphenylphosphine (49 mg) were dissolved in toluene (0.3 mL) and
tetrahydrofuran (0.3 mL).
(E)-N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethyldiazene-1,2-dicarboxamide
(32 mg) was added, and the solution was stirred and heated at
50.degree. C. for 90 minutes. The solution was cooled, and the
solvent was removed under vacuum. The material was carried on to
the next step without further purification. MS (ESI) m/z 1093.5
(M+H).sup.+.
Example 7D
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2S)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0640] Example 7C (66 mg) was dissolved in dichloromethane (0.3
mL). Trifluoroacetic acid was added (0.35 mL), and the solution was
stirred overnight. The solvent was removed under vacuum. The
material was taken up in dimethylformamide (1 mL) and water (1 mL).
The solution was neutralized with minimal 1 M aqueous NaOH and was
purified by reverse phase using 30-100% acetonitrile in water (w/10
mM ammonium acetate) over 40 min on a Grace Reveleris equipped with
a Luna.TM. column: C18(2), 100 A, 250.times.50 mm. Product
fractions were pooled, frozen, and placed on a lyophilizer. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.81 (d, 1H),
8.69 (s, 1H), 8.33 (d, 2H), 7.47 (d, 1H), 7.20-7.17 (m, 2H),
7.13-7.10 (m, 2H), 7.06 (d, 2H), 6.84 (d, 1H), 6.69 (dd, 1H), 6.20
(m, 1H), 5.92 (s, 1H), 5.19 (q, 2H), 4.92 (m, 1H) 4.48-4.38 (m,
2H), 4.04 (d, 2H), 3.92-3.86 (m, 1H), 3.84 (d, 1H), 3.80-3.74 (m,
1H), 3.70-3.57 (m, 3H), 3.53-3.45 (m, 2H), 2.96 (d, 2H), 2.71-2.62
(m, 3H), 2.46 (m, 2H) 2.36 (m, 4H) 2.15 (s, 3H), 1.94 (s, 3H), 1.92
(s, 3H). MS (ESI) m/z 1037.6 (M+H).sup.+.
Example 8
(7R,16R)-19,23-dichloro-10-({2-[4-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)--
4-fluoropiperidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-di-
methyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-ethe-
no-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]in-
dene-7-carboxylic Acid
Example 8A
(S)-tert-butyl
4-(((1,4-dioxan-2-yl)methoxy)methyl)-4-fluoropiperidine-1-carboxylate
[0641] To a solution of tert-butyl
4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (200 mg) in
dimethylformamide (2.8 mL) at 0.degree. C. was added sodium hydride
(43 mg, 60% oil dispersion), and the reaction was allowed to stir
for 15 minutes. (S)-(1,4-dioxan-2-yl)methyl
4-methylbenzenesulfonate (410 mg) was added, and the reaction was
allowed to warm to room temperature overnight. The reaction was
diluted with saturated aqueous ammonium chloride and extracted
three times with ethyl acetate. The combined organic layers were
washed with water and brine, dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by normal phase
MPLC on a Teledyne Isco Combiflash.RTM. Rf+24 g gold silica gel
column eluting with 0-45% ethyl acetate in heptanes to give the
title compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 3.82-3.36 (m, 12H), 3.26 (dd, 1H), 2.99 (br s, 2H),
1.78-1.66 (m, 2H), 1.63-1.46 (m, 2H), 1.39 (s, 9H).
Example 8B
(S)-4-(((1,4-dioxan-2-yl)methoxy)methyl)-4-fluoropiperidine
[0642] To a solution of Example 8A (90 mg) in dichloromethane (500
.mu.L) was added trifluoroacetic acid (260 .mu.L), and the reaction
was allowed to stand for 2 hours. The reaction was concentrated to
give the title compound which was used in the next step without
further purification.
Example 8C
(S)-(2-(4-(((1,4-dioxan-2-yl)methoxy)methyl)-4-fluoropiperidin-1-yl)pyrimi-
din-4-yl)methanol
[0643] A solution of Example 8B (89 mg),
(2-chloropyrimidin-4-yl)methanol (30 mg) and
N,N-diisopropylethylamine (190 .mu.L) in acetonitrile (540 .mu.L)
was stirred at 80.degree. C. for 2.5 hours and at room temperature
overnight. The reaction was diluted with water and extracted with
ethyl acetate three times. The combined organic layers were dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+12 g gold silica gel column eluting with 10-80%
ethyl acetate in dichloromethane to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.33
(d, 1H), 6.70 (d, 1H), 5.44-5.36 (m, 1H), 4.47-4.31 (m, 4H),
3.74-3.37 (m, 10H), 3.30-3.13 (m, 3H), 1.86-1.73 (m, 2H), 1.70-1.48
(m, 2H).
Example 8D
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[4-({[(2S)-1,4-dioxan-2-yl]metho-
xy}methyl)-4-fluoropiperidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluoropheny-
l)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-
-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[-
1,2,3-cd]indene-7-carboxylate
[0644] To a vial containing Example 1Z (40 mg), Example 8C (25 mg)
and triphenylphosphine (39 mg) in toluene (120 .mu.L) and
tetrahydrofuran (120 .mu.L) was added
N,N,N',N'-tetramethylazodicarboxamide (26 mg) and the reaction was
allowed to stir at 50.degree. C. for 2 hours. The reaction was
diluted with ethyl acetate, filtered over diatomaceous earth and
concentrated. The residue was purified by normal phase MPLC on a
Teledyne Isco Combiflash.RTM. Rf+4 g gold silica gel column eluting
with 0-7% methanol in dichloromethane to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.74
(s, 1H), 8.36 (s, 1H), 7.28-7.13 (m, 5H), 6.92-6.77 (m, 2H), 6.73
(d, 1H), 6.02 (dd, 1H), 5.67 (dd, 1H), 5.03-4.83 (m, 2H), 4.80-4.69
(m, 1H), 4.53-4.34 (m, 3H), 3.75-3.35 (m, 12H), 3.29-3.17 (m, 3H),
2.86 (d, 1H), 2.80 (s, 3H), 2.73-2.59 (m, 2H), 2.43-2.21 (m, 4H),
2.15 (s, 3H), 2.09 (s, 3H), 1.90 (s, 3H), 1.87-1.75 (m, 2H),
1.73-1.50 (m, 2H), 1.06 (s, 9H).
Example 8E
(7R,16R)-19,23-dichloro-10-({2-[4-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)--
4-fluoropiperidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-di-
methyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-ethe-
no-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]in-
dene-7-carboxylic Acid
[0645] To a solution of Example 8D (44 mg) in dichloromethane (190
.mu.L) was added trifluoroacetic acid (190 .mu.L), and the reaction
was allowed to stir for 5 hours. The reaction was concentrated
under a stream of nitrogen and was taken up in water and
acetonitrile. The mixture was purified by RP-HPLC on a Gilson PLC
2020 using a Luna.TM. column (250.times.50 mm, 10 mm) (5-85% over
30 minutes with acetonitrile in water containing 10 mM ammonium
acetate) to give the title compound after lyophilization. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.73 (s, 1H),
8.33 (d, 1H), 7.23-7.09 (m, 5H), 6.81 (d, 1H), 6.76-6.69 (m, 2H),
6.25-6.17 (m, 1H), 5.84-5.79 (m, 1H), 5.01-4.81 (m, 3H), 4.49-4.35
(m, 4H), 3.73-3.36 (m, 12H), 3.30-3.17 (m, 5H), 2.98-2.88 (m, 1H),
2.76-2.61 (m, 3H), 2.59-2.33 (m, 6H), 2.25 (s, 3H), 1.97 (s, 6H),
1.86-1.74 (m, 2H), 1.71-1.50 (m, 2H). MS (ESI) m/z 1074.1
(M-H).sup.-.
Example 9
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan-2-yl]methoxy}c-
yclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
Example 9A
phenyl(vinyl)selane
[0646] To a solution of 1,2-diphenyldiselane (7 g) in
tetrahydrofuran (75 mL) at 0.degree. C. was added vinylmagnesium
bromide (49.3 mL, 1 M in tetrahydrofuran) over 25 minutes, and the
reaction was allowed to warm to room temperature and stir
overnight. The reaction was slowly diluted with water with water
bath cooling and extracted with ethyl acetate three times. The
combined organic layers were dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by normal phase
MPLC on a Teledyne Isco Combiflash.RTM. Rf+120 g gold silica gel
column eluting with heptanes to give the title compound. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.57-7.49 (m, 2H), 7.36-7.27
(m, 3H), 6.91-6.79 (m, 1H), 5.83-5.75 (m, 1H), 5.60-5.50 (m,
1H).
Example 9B
(vinylselenonyl)benzene
[0647] To a solution of Example 9A (1.2 g) in tetrahydrofuran (120
mL) was added potassium phosphate dibasic (3.4 g) and magnesium
monoperoxyphthalate hexahydrate (8.1 g), and the reaction was
allowed to stir for 3 hours. The reaction was diluted with ethyl
acetate and washed with 10% aqueous sodium carbonate followed by
brine. The organic layer was dried over anhydrous sodium sulfate,
filtered and concentrated to give the title compound that was used
in the next step without further purification. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. ppm 8.01-7.91 (m, 2H), 7.74-7.60 (m, 3H),
7.08-6.90 (m, 1H), 6.76-6.68 (m, 1H), 6.48-41 (m, 1H).
Example 9C
2-((1r,4r)-4-((1,4-dioxan-2-yl)methoxy)cyclohexyl)-4-(((tert-butyldiphenyl-
silyl)oxy)methyl)pyrimidine
[0648] To a solution of Example 14G (480 mg) in dichloromethane
(6.1 mL) at room temperature was added sodium hydride (66 mg, 60%
oil dispersion), and the reaction was allowed to stir for 10
minutes. A solution of Example 9B (400 mg) in dichloromethane (3
mL) was added, and the reaction was allowed to stir for 5 hours.
The reaction was quenched with saturated aqueous ammonium chloride
and extracted with ethyl acetate three times. The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by normal phase MPLC on a
Teledyne Isco Combiflash.RTM. Rf+24 g gold silica gel column
eluting with 20-75% ethyl acetate in heptanes to give the title
compound as a mixture of isomers. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.75 (d, 1H), 7.68-7.60 (m,
4H), 7.51-7.38 (m, 7H), 4.72 (s, 2H), 3.73-3.66 (m, 2H), 3.64-3.50
(m, 3H), 3.47-3.38 (m, 2H), 3.28-3.17 (m, 2H), 2.74-2.63 (m, 1H),
2.06-1.96 (m, 2H), 1.94-1.85 (m, 2H), 1.59-1.46 (m, 2H), 1.29-1.19
(m, 2H), 1.05 (s, 9H).
Example 9D
(2-((1R,4r)-4-(((R)-1,4-dioxan-2-yl)methoxy)cyclohexyl)pyrimidin-4-yl)meth-
anol
[0649] To a solution of Example 9C (370 mg) in tetrahydrofuran (2.2
mL) and methanol (1.1 mL) was added cesium fluoride (500 mg), and
the reaction was allowed to stir overnight. The reaction was
concentrated, and the residue was taken up in ethyl acetate,
filtered over diatomaceous earth and concentrated. The residue was
purified by normal phase MPLC on a Teledyne Isco Combiflash.RTM.
Rf+12 g gold silica gel column eluting with 0-6.5% methanol in
dichloromethane to give the mixture of enantiomers (160 mg). The
mixture was purified by chiral SFC using a Chiralpak AD-H column
(30.times.250 mm, 5 micron) to give the title compound in high
enantiomeric excess (>95%). Analytical SFC of the title compound
using a Chiralpak AD-H column (5-50% methanol over 10 minutes) gave
a retention time of 4.43 minutes. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.68 (d, 1H), 7.35 (d, 1H),
5.56 (br s, 1H), 4.49 (s, 2H), 3.75-3.66 (m, 2H), 3.65-3.51 (m,
3H), 3.49-3.34 (m, 3H), 3.29-3.20 (m, 2H), 2.78-2.67 (m, 1H),
2.11-2.00 (m, 2H), 1.98-1.88 (m, 2H), 1.66-1.50 (m, 2H), 1.33-1.18
(m, 2H). [.alpha.].sub.D=-7.degree. (c 1.0, CHCl.sub.3).
Example 9E
[0650] The title compound was obtained from the SFC separation
described in Example 9D. Analytical SFC of the title compound using
a Chiralpak AD-H column (5-50% methanol over 10 minutes) gave a
retention time of 4.93 minutes. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.68 (d, 1H), 7.35 (d, 1H),
5.56 (br s, 1H), 4.50 (s, 2H), 3.75-3.66 (m, 2H), 3.65-3.51 (m,
3H), 3.49-3.20 (m, 5H), 2.78-2.67 (m, 1H), 2.11-2.00 (m, 2H),
1.98-1.88 (m, 2H), 1.66-1.50 (m, 2H), 1.33-1.16 (m, 2H).
Example 9F
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan-2-y-
l]methoxy}cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylate
[0651] Example 9D (30 mg) and Example 1Z (26 mg) were azeotroped
with toluene/tetrahydrofuran three times. The residue was taken up
in toluene (80 .mu.L), and tetrahydrofuran (80 .mu.L) and
triphenylphosphine (25 mg) followed by
N,N,N',N'-tetramethylazodicarboxamide (17 mg) were added. The
reaction was heated to 50.degree. C. for 7 hours and stirred at
room temperature overnight. The reaction mixture was diluted with
ethyl acetate, filtered over diatomaceous earth and concentrated.
The residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column, eluting with 1.5-10%
methanol in dichloromethane to give the title compound. MS (ESI) mz
1099.6 (M+H).sup.+.
Example 9G
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan-2-yl]methoxy}c-
yclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
[0652] To a solution of Example 9F (33 mg) in dichloromethane (150
.mu.L) was added trifluoroacetic acid (150 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and was taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 30-80% over 30 minutes
with acetonitrile in water containing 10 mM ammonium acetate) to
give a crude material after lyophilization. The crude material was
purified by normal phase MPLC on a Teledyne Isco Combiflash.RTM.
Rf+4 g gold silica gel column eluting with 10-25% methanol in
dichloromethane to give the title compound. .sup.1H NMR (400 MHz,
Methanol-d.sub.4) .delta. 8.66 (d, 1H), 8.60 (s, 1H), 7.60 (d, 1H),
7.16-7.07 (m, 2H), 7.04-6.94 (m, 2H), 6.76-6.63 (m, 2H), 6.17 (dd,
1H), 6.08 (d, 1H), 5.10 (s, 3H), 4.59-4.48 (m, 3H), 4.36 (d, 1H),
3.81-3.74 (m, 2H), 3.73-3.63 (m, 4H), 3.61-3.43 (m, 3H), 3.42-3.33
(m, 2H), 3.06 (dd, 1H), 2.93-2.67 (m, 9H), 2.57 (s, 3H), 2.20-2.12
(m, 5H), 2.06-1.97 (m, 5H), 1.79-1.66 (m, 2H), 1.42-1.27 (m, 2H),
exchangeable CO.sub.2H not observed. MS (ESI) m/z 1041.0
(M-H).sup.-.
Example 10
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}piperidin-
-1-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-met-
hylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-
-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 10A
tert-butyl
(R)-4-((1,4-dioxan-2-yl)methoxy)piperidine-1-carboxylate
[0653] (S)-(1,4-Dioxan-2-yl)methanol (160 mg) was dissolved in
dichloromethane (6 mL). The mixture was cooled to 0.degree. C.
Triethylamine (0.217 mL) was added. Methanesulfonyl chloride (0.116
mL) was added dropwise. The mixture was allowed to warm to room
temperature. After two hours, saturated aqueous sodium bicarbonate
(3 mL) was added. The layers were separated, and the organic layer
was washed with brine (5 mL). The aqueous layers were combined and
back-extracted with dichloromethane (10 mL). The organic layers
were combined, dried over anhydrous sodium sulfate and filtered.
The solvent was removed under vacuum. The material was taken up in
tetrahydrofuran (1 mL) and added to a solution of tert-butyl
4-hydroxypiperidine-1-carboxylate (300 mg) and sodium hydride (60%,
71.5 mg) that had been pre-stirred for 15 minutes in
tetrahydrofuran (7 mL). The solution was stirred at room
temperature overnight and quenched with a few drops of saturated
aqueous ammonium chloride. The solvent was removed under vacuum.
The residue was taken up in ethyl acetate (10 mL), washed with
water (2 mL), washed with brine (2 mL), dried with anhydrous sodium
sulfate, filtered and concentrated. The material was used without
further purification. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 4.70 (d, 1H), 4.19 (q, 1H),
3.814-3.74 (m, 2H), 3.68-3.59 (m, 4H), 3.52-3.45 (m, 1H), 3.20 (s,
2H), 2.95 (m, 2H), 1.71-1.65 (m, 2H), 1.28-1.20 (m, 2H), 1.40 (s,
9H), 1.41 (m, 1H).
Example 10B
(R)-4-((1,4-dioxan-2-yl)methoxy)piperidine
[0654] Example 10A (448 mg) was dissolved in dichloromethane (1
mL). Trifluoroacetic acid (2 mL) was added, and the solution was
stirred at room temperature for 30 minutes. The solvent was removed
under vacuum, and the material was carried on in the next step as
the trifluoroacetic acid salt without purification.
Example 10C
(R)-(2-(4-((1,4-dioxan-2-yl)methoxy)piperidin-1-yl)pyrimidin-4-yl)methanol
[0655] (2-Chloropyrimidin-4-yl)methanol (170 mg), Example 10B (469
mg) and triethylamine (595 mg) were dissolved in acetonitrile (6.5
mL). The solution was heated to 80.degree. C. for four hours. The
solution was cooled, concentrated under vacuum and purified by
flash column chromatography on silica gel using a gradient of
30-100% ethyl acetate in heptanes. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.70 (d, 1H), 6.67 (d, 1H),
5.36 (t, 1H), 4.70 (d, 1H), 4.34 (d, 2H), 4.26 (dt, 2H), 3.70 (m,
2H), 3.65-3.50 (m, 2H), 3.48-3.35 (m, 1H), 3.21 (m, 2H), 1.75 (m,
4H), 1.29 (m, 4H). MS (ESI) m/z 310.3 (M+H).sup.+.
Example 10D
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methox-
y}piperidin-1-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-
-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,-
9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-
-carboxylate
[0656] The title compound was prepared by substituting Example 10C
for Example 7B in Example 7C. MS (ESI) m/z 1100.3 (M+H).sup.+.
Example 10E
(7R,16R)-19,23-dichloro-10-{[2-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}piperidin-
-1-yl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-met-
hylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-
-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0657] The title compound was prepared by substituting Example 10D
for Example 7C in Example 7D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.69 (bs, 1H), 8.31 (d, 1H),
7.22-7.15 (m, 2H), 7.15-7.08 (m, 2H), 6.79-6.64 (m, 4H), 6.13 (m,
1H), 5.88 (bs, 1H), 4.92 (m, 4H), 4.43 (m, 2H), 4.16 (m, 2H), 3.71
(m 2H), 3.65-3.58 (m, 2H), 3.57-3.52 (m, 2H), 3.47-3.42 (m, 2H),
2.93 (m, 1H), 2.68 (m, 4H), 2.47 (m, 4H), 2.40-2.28 (m, 4H), 2.17
(s, 3H), 2.00 (s, 3H), 1.92-1.90 (m, 4H), 1.88-1.78 (m, 2H),
1.43-1.32 (m, 2H). MS (ESI) m/z 1044.2 (M+H).sup.+.
Example 11
(7R,16R)-19,23-dichloro-10-({2-[1-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)c-
yclobutyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
Example 11A
1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanecarbonitrile
[0658] 1-(Hydroxymethyl)cyclobutanecarbonitrile (2 g) was dissolved
in dichloromethane (36 mL) and imidazole (2.45 g) and
tert-butyldimethylchlorosilane (3.53 g) were added. The resulting
mixture was stirred at room temperature for 4 hours. The mixture
was concentrated onto silica gel and was purified by flash
chromatography on a CombiFlash.RTM. Teledyne Isco system using a
Teledyne Isco RediSep.RTM. Rf gold 80 g silica gel column (eluting
with 0-15% ethyl acetate/heptanes) to afford the title compound. MS
(APCI) m/z 226.5 (M+H).sup.+.
Example 11B
1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutanecarboximidamide
[0659] A 2 M solution of trimethylaluminum in toluene (15.37 mL)
was slowly added to a magnetically stirred suspension of ammonium
chloride (1.645 g) in toluene (38.0 mL) at 0.degree. C. After the
addition, the ice water bath was removed and the mixture was
stirred at room temperature for 2 hours until gas evolution had
ceased. Example 11A (3.85 g) was added as a toluene (20 mL)
solution and the mixture was stirred at 80.degree. C. under
nitrogen for 12 hours, cooled with an ice water bath, quenched
carefully with 100 mL of methanol, and stirred at room temperature
for 2 hours. The material was removed through filtration and washed
with methanol. The combined filtrate was concentrated to afford the
crude title compound. MS (APCI) m/z 243.4 (M+H).sup.+.
Example 11C
2-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclobutyl)-4-(dimethoxymethyl)-
pyrimidine
[0660] Example 11B (4.12 g) and
4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (5.89 g) were taken
up in ethanol (24 mL) and 21% ethanol solution of sodium ethoxide
(33.1 g) was added which warmed the reaction mildly. The mixture
was heated at 80.degree. C. for 15 hours, and cooled back to room
temperature. The mixture was concentrated, saturated aqueous sodium
bicarbonate was added (150 mL) and the mixture was stirred for 2
minutes. The mixture was poured into a 250 mL separatory funnel and
was extracted with three portions of dichloromethane. The organic
layers were combined and the resulting solution was dried over
anhydrous magnesium sulfate, filtered and concentrated onto silica
gel. Purification by flash chromatography on a CombiFlash.RTM.
Teledyne Isco system using a Teledyne Isco RediSep.RTM. Rf gold 40
g silica gel column (eluting with 5-80% ethyl acetate/heptanes)
afforded the title compound. MS (APCI) m/z 353.4 (M+H).sup.+.
Example 11D
(1-(4-(dimethoxymethyl)pyrimidin-2-yl)cyclobutyl)methanol
[0661] To a stirring mixture of Example 11C (11.3 g) in 100 mL of
tetrahydrofuran was added 96 mL of 1 molar tetra n-butylammonium
fluoride and the mixture was stirred at room temperature for 1
hours. The mixture was concentrated onto silica gel and
purification by flash chromatography on a CombiFlash.RTM. Teledyne
Isco system using a Teledyne Isco RediSep.RTM. Rf gold 220 g silica
gel column (eluting with 30-100% ethyl acetate/heptanes) afforded
the title compound. MS (APCI) m/z 239.4 (M+H).sup.+.
Example 11E
(R)-(1,4-dioxan-2-yl)methyl methanesulfonate
[0662] A mixture of (S)-(1,4-dioxan-2-yl)methanol (500 mg) and
triethylamine (1.7 mL) in 10 mL of dichloromethane was stirred at
0.degree. C. and methanesulfonyl chloride (0.5 mL) was added
dropwise. Upon completion of the addition, the cooling bath was
removed and the mixture was stirred at room temperature for an
hour. The mixture was concentrated onto silica gel and purification
by flash chromatography on a CombiFlash.RTM. Teledyne Isco system
using a Teledyne Isco RediSep.RTM. Rf gold 40 g silica gel column
(eluting with 30-100% ethyl acetate/heptanes) afforded the title
compound. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 4.24-4.13 (m, 2H), 3.81-3.71 (m, 3H), 3.67-3.56 (m, 2H),
3.51-3.42 (m, 1H), 3.33-3.27 (m, 1H), 3.19 (s, 3H).
Example 11F
(S)-2-(1-(((1,4-dioxan-2-yl)methoxy)methyl)cyclobutyl)-4-(dimethoxymethyl)-
pyrimidine
[0663] To a stirring solution of Example 11D (400 mg) and Example
1E (659 mg) in 16 mL of acetonitrile was slowly added sodium
hydride (81 mg, 60% in mineral oil) and the mixture was stirred at
45.degree. C. overnight. After cooling to room temperature, a few
drops of saturated aqueous ammonium chloride were added and the
mixture was concentrated onto silica gel. Purification by flash
chromatography on a CombiFlash.RTM. Teledyne Isco system using a
Teledyne Isco RediSep.RTM. Rf gold 40 g silica gel column (eluting
with 10-100% ethyl acetate/heptanes) gave the title compound. MS
(APCI) m/z 339.4 (M+H).sup.+.
Example 11G
(S)-2-(1-(((1,4-dioxan-2-yl)methoxy)methyl)cyclobutyl)pyrimidine-4-carbald-
ehyde
[0664] To a stirring mixture of Example 11F (480 mg) in
tetrahydrofuran (9 mL) was added 6 molar aqueous HCl (8.5 mL) and
the mixture was stirred at 55.degree. C. for 5 hours. After cooling
to room temperature, the mixture was poured into a separatory
funnel containing saturated aqueous sodium bicarbonate. The mixture
was extracted with five portions of dichloromethane, and the
organic layers were combined and dried over anhydrous magnesium
sulfate, filtered and concentrated onto silica gel. Purification by
flash chromatography on a CombiFlash.RTM. Teledyne Isco system
using a Teledyne Isco RediSep.RTM. Rf gold 24 g silica gel column
(eluting with 20-100% ethyl acetate/heptanes) afforded the title
compound. MS (APCI) m/z 293.3 (M+H).sup.+.
Example 11H
(S)-(2-(1-(((1,4-dioxan-2-yl)methoxy)methyl)cyclobutyl)pyrimidin-4-yl)meth-
anol
[0665] To Example 11G (315 mg) in 7 mL of tetrahydrofuran was added
sodium borohydride (82 mg) in one portion followed by 2 mL of
methanol. The mixture was stirred at room temperature for 30
minutes and quenched by careful addition of 5 mL of saturated
aqueous ammonium chloride solution and stirred for an additional 15
minutes. The resulting mixture was poured into a separatory funnel
containing 15 mL of water and was extracted with 3 portions of
dichloromethane. The combined organic layer was dried over
anhydrous magnesium sulfate, filtered and concentrated onto silica
gel. Purification by flash chromatography on a CombiFlash.RTM.
Teledyne Isco system using a Teledyne Isco RediSep.RTM. Rf gold 24
g silica gel column (eluting with solvent A=2:1 ethyl
acetate:ethanol; solvent B=heptane, 10-80% A to B) afforded the
title compound. MS (APCI) m/z 295.3 (M+H).sup.+.
Example 11I
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[1-({[(2S)-1,4-dioxan-2-yl]metho-
xy}methyl)cyclobutyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylate
[0666] A 4 mL vial, equipped with stir bar, was charged with
Example 11H (54.5 mg), Example 1Z (75 mg) and triphenylphosphine
(51.0 mg). The vial was capped with a septa and evacuated and
backfilled with nitrogen twice. Toluene (1 mL) was added and the
mixture was cooled with an ice bath. To the stirring mixture,
(E)-di-tert-butyl diazene-1,2-dicarboxylate (42.7 mg) was added in
one portion. The vial was capped with a septa and the stirring
mixture was evacuated and backfilled with nitrogen twice. The
stirring continued at 0.degree. C. for 10 minutes, the cooling bath
was removed and the mixture was allowed to stir at room temperature
overnight. The mixture was concentrated onto silica gel and
purification by flash chromatography on a CombiFlash.RTM. Teledyne
Isco system using a Teledyne Isco RediSep.RTM. Rf gold 12 g silica
gel column (eluting with 0-20% methanol/dichloromethane) afforded
the title compound. MS (APCI) m/z 1087.4 (M+H).sup.+.
Example 11J
(7R,16R)-19,23-dichloro-10-({2-[1-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)c-
yclobutyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
[0667] To a solution of Example 11I (77 mg) in dichloromethane
(0.75 mL) was added trifluoroacetic acid (0.75 mL) and the reaction
mixture was stirred at room temperature for 5 hours and
concentrated. The crude residue was redissolved into 2 mL of
acetonitrile and purified directly by reverse phase prep LC using a
Gilson 2020 system (Luna.TM., C-18, 250.times.50 mm column, Mobile
phase A: 0.1% trifluoroacetic acid in water; B: acetonitrile; 5-75%
B to A gradient at 75 mL/minute, 30 minute gradient) to afford the
title compound as a trifluoroacetic acid salt. The material
obtained was treated with saturated aqueous sodium bicarbonate and
dichloromethane and poured into a separatory funnel. The mixture
was partitioned between the two phases. The organic layer was
removed and the aqueous layer was washed with two more portions of
dichloromethane. The organic layers were combined, dried over
anhydrous magnesium sulfate, filtered and concentrated to obtain
the title compound. MS (APCI) m/z 1029.3 (M+H).sup.+. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.75 (d, 1H), 8.73
(s, 1H), 7.42 (d, 1H), 7.24-7.08 (m, 4H), 6.86 (d, 1H), 6.74 (dd,
1H), 6.24 (dd, 1H), 5.82 (d, 1H), 5.11 (q, 2H), 4.87 (m, 1H), 4.44
(d, 2H), 3.86 (s, 2H), 3.67-3.45 (m, 5H), 3.41-3.32 (m, 2H), 3.26
(dd, 1H), 3.16-3.05 (m, 1H), 3.01-2.90 (m, 1H), 2.77-2.60 (m, 2H),
2.57-2.36 (m, 11H), 2.24 (s, 3H), 2.18-2.06 (m, 2H), 2.04-1.89 (m,
7H), 1.87-1.69 (m, 1H).
Example 12
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)a-
zetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
Example 12A
tert-butyl
(S)-3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidine-1-carboxylate
[0668] tert-Butyl 3-(hydroxymethyl)azetidine-1-carboxylate (400 mg)
was dissolved in N,N-dimethylformamide (10 mL) and cooled to
0.degree. C. Sodium hydroxide (123 mg, 50%) was added and the
reaction mixture was stirred at 0.degree. C. for 1 hour.
(S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (873 mg)
dissolved in N,N-dimethylformamide (10 mL) was added dropwise. The
mixture was allowed to warm to ambient temperature and stirred for
1 hour at room temperature. The mixture was diluted with water and
dichloromethane. The phases were separated and the organic phase
was washed with water. The organic layer was dried over sodium
sulfate, filtrated and concentrated. Purification of the residue
was performed on a silica gel column (12 g, 0-30% methanol in
dichloromethane). The pure fractions were combined and the solvents
were removed under reduced pressure to provide the title compound.
MS (ESI) m/z 232.1 (M-tert-Bu).sup.+.
Example 12B
(S)-3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidine
2,2,2-trifluoroacetate
[0669] Example 12A (178 mg) was dissolved in dichloromethane (10
mL) and trifluoroacetic acid (0.48 mL) was added. The mixture was
stirred for 3 hours at room temperature. An aliquot was analyzed by
LC/MS indicating complete conversion. The reaction mixture was
concentrated at room temperature and co-distilled with three times
dichloromethane to provide the crude title compound, which was
directly used in the next step without further purification.
.sup.1H NMR (500 MHz, chloroform-d) .delta. ppm 4.54 (d, 1H),
4.39-4.31 (m, 2H), 4.19-4.13 (m, 1H), 4.09-4.04 (m, 1H), 3.95-3.76
(m, 5H), 3.71-3.63 (m, 2H), 3.61 (d, 1H), 3.54-3.46 (m, 2H). MS
(ESI) m/z 188.2 (M+H).sup.+.
Example 12C
(S)-(2-(3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidin-1-yl)pyrimidin-4-yl)m-
ethanol
[0670] (2-Chloropyrimidin-4-yl)methanol (50 mg), Example 12B (93
mg), and triethylamine (0.19 mL) were dissolved in dioxane (4 mL).
The reaction mixture was heated in the microwave to 80.degree. C.
and stirred for 2 hours. The mixture was cooled and diluted with
dichloromethane. The organic layer was washed with water, dried
over sodium sulfate, and concentrated. Purification was performed
on a silica gel column (12 g, 0-20% methanol in dichloromethane).
The pure fractions were combined and the solvents were removed
under reduced pressure to provide the title compound. .sup.1H NMR
(500 MHz, chloroform-d) .delta. ppm 8.23 (d, 1H), 6.44 (d, 1H),
4.57 (d, 2H), 4.23 (dd, 2H), 3.90 (dd, 2H), 3.81-3.68 (m, 8H),
3.63-3.59 (m, 1H), 3.51 (dd, 1H), 3.45 (dd, 1H), 3.41 (dd, 1H),
3.01-2.94 (m, 1H). MS (ESI) m/z 296.2 (M+H).sup.+.
Example 12D
(S)-(2-(3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidin-1-yl)pyrimidin-4-yl)m-
ethyl methanesulfonate
[0671] Example 12C (0.03 g) and triethylamine (0.04 mL) were
dissolved in dichloromethane (0.90 mL) and cooled to 0.degree. C.
by an ice-bath. Methanesulfonyl chloride (8.27 .mu.L) was added and
the reaction mixture was allowed to warm to ambient temperature and
was stirred for 30 minutes at room temperature. Brine was added to
the reaction mixture and the phases were separated. The aqueous
phase was washed with dichloromethane, dried over sodium sulfate,
filtered, and concentrated to yield the crude title compound, which
was directly used in the next step. MS (ESI) m/z 374.1
(M+H).sup.+.
Example 12E
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2S)-1,4-dioxan-2-yl]metho-
xy}methyl)azetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-d-
imethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-eth-
eno-9,13-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]i-
ndene-7-carboxylate
[0672] Example 12D (33 mg), Example 1Z (40 mg), cesium carbonate
(36 mg), and N,N-dimethylformamide (200 .mu.L) were combined under
an argon-atmosphere. The reaction mixture was stirred overnight at
room temperature. To the reaction mixture was added dropwise
aqueous sodium bicarbonate solution (5%) and dichloromethane. The
phases were separated and the aqueous layer was extracted twice
with dichloromethane. The combined organic phase was dried over
sodium sulfate, filtered, and concentrated. Purification was
performed on a silica gel column (4 g, 0-20% methanol in
dichloromethane). The pure fractions were combined and the solvents
were removed under reduced pressure to provide the title compound.
MS (APCI) m/z 1087.4 (M+H).sup.+.
Example 12F
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)a-
zetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
[0673] Example 12E (51 mg) was dissolved in dichloromethane (470
.mu.L) and trifluoroacetic acid (470 .mu.L) was added. The reaction
mixture was stirred for 5 hours at room temperature. The reaction
mixture was concentrated, dissolved in methanol, diluted with
water, and freeze-dried. The crude material was purified by HPLC
(Waters X-Bridge C8 19.times.150 mm 5 m column, gradient 5-100%
acetonitrile+0.2% ammonium hydroxide in water+0.2% ammonium
hydroxide) to provide the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.72 (s, 1H), 8.29 (d, 1H),
7.21-7.12 (m, 4H), 6.80-6.71 (m, 3H), 6.16 (b, 1H), 5.83 (b, 1H),
4.97-4.86 (m, 3H), 4.46-4.40 (m, 2H), 4.07 (t, 2H), 3.75-3.17 (m,
16H), 2.95-2.85 (m, 3H), 2.72-2.36 (m, 8H), 2.18 (s, 3H), 1.99 (s,
3H), 1.96 (s, 3H). MS (APCI) m/z 1030.3 (M+H).sup.+.
Example 13
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2R)-1,4-dioxan-2-yl]methoxy}methyl)a-
zetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
Example 13A
tert-butyl
(R)-3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidine-1-carboxylate
[0674] The title compound was prepared as described in Example 12A
by substituting (S)-(1,4-dioxan-2-yl)methyl
4-methylbenzenesulfonate for (R)-(1,4-dioxan-2-yl)methyl
4-methylbenzenesulfonate. MS (ESI) m/z 232.1 (M-tert-Bu).sup.+.
Example 13B
(R)-3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidine
2,2,2-trifluoroacetate
[0675] The title compound was prepared as described in Example 12B
by substituting Example 13A for Example 12A. MS (ESI) m/z 188.1
(M+H).sup.+.
Example 13C
((R)-(2-(3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidin-1-yl)pyrimidin-4-yl)-
methanol
[0676] The title compound was prepared as described in Example 12C
by substituting Example 13B for Example 12B. .sup.1H NMR (600 MHz,
chloroform-d) .delta. ppm 8.24 (d, 1H), 6.44 (d, 1H), 4.57 (d, 2H),
4.23 (dd, 2H), 3.90 (dd, 2H), 3.81-3.67 (m, 8H), 3.61 (ddd, 1H),
3.53-3.49 (m, 1H), 3.45 (dd, 1H), 3.41 (dd, 1H), 3.01-2.95 (m, 1H).
MS (ESI) m/z 296.4 (M+H).sup.+.
Example 13D
(R)-(2-(3-(((1,4-dioxan-2-yl)methoxy)methyl)azetidin-1-yl)pyrimidin-4-yl)m-
ethyl methanesulfonate
[0677] The title compound was prepared as described in Example 12D
by substituting Example 13C for Example 12C. MS (ESI) m/z 374.4
(M+H).sup.+.
Example 13E
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2R)-1,4-dioxan-2-yl]metho-
xy}methyl)azetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-d-
imethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-eth-
eno-9,13-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]i-
ndene-7-carboxylate
[0678] The title compound was prepared as described in Example 12E
by substituting Example 13D for Example 12D. MS (APCI) m/z 1086.4
(M+H).sup.+.
Example 13F
(7R,16R)-19,23-dichloro-10-({2-[3-({[(2R)-1,4-dioxan-2-yl]methoxy}methyl)a-
zetidin-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16--
[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(m-
etheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-car-
boxylic Acid
[0679] Example 13E (35 mg) was dissolved in dichloromethane (325
.mu.L) and trifluoroacetic acid (325 .mu.L) was added. The reaction
mixture was stirred for 5 hours at room temperature. The reaction
mixture was concentrated at room temperature. The residue was
dissolved in methanol, diluted with water, and freeze-dried. The
crude material was purified by HPLC (Waters X-Bridge C8
19.times.150 mm 5 .mu.m column, gradient 5-100% acetonitrile+0.2%
ammonium hydroxide in water+0.2% ammonium hydroxide) to provide the
title compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.72 (s, 1H), 8.29 (d, 1H), 7.21-7.12 (m, 4H),
6.80-6.71 (m, 3H), 6.17 (b, 1H), 5.82 (b, 1H), 4.97-4.86 (m, 3H),
4.46-4.43 (m, 2H), 4.07 (t, 2H), 3.75-3.16 (m, 16H), 2.94-2.84 (m,
2H), 2.72-2.66 (m, 1H), 2.54-2.32 (m, 8H), 2.18 (s, 3H), 1.97 (s,
3H), 1.95 (s, 3H). MS (APCI) m/z 1030.3 (M+H).sup.+.
Example 14
(7R,16R)-19,23-dichloro-10-[(2-{(1r,4r)-4-[(1,3-dioxolan-4-yl)methoxy]cycl-
ohexyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-me-
thylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno-
)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxyli-
c Acid
Example 14A
4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-chloropyrimidine
[0680] To a solution of (2-chloropyrimidin-4-yl)methanol (3.8 g)
and tert-butylchlorodiphenylsilane (7.23 g) in
N,N-dimethylformamide (30 mL) was added imidazole (3.58 g). The
mixture was stirred under nitrogen at room temperature overnight.
The mixture was diluted with water (50 mL) and ethyl acetate (400
mL). The organic layer was separated, washed with water and brine
and dried over sodium sulfate. Filtration and evaporation of the
solvent gave crude product which was loaded on a RediSep.RTM. Gold
220 g column and eluted with 20% ethyl acetate in heptane to give
the title compound. MS (ESI) m/z 383.2 (M+H).sup.+.
Example 14B
4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(1,4-dioxaspiro[4.5]dec-7-en-8--
yl)pyrimidine
[0681] To a solution of
4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborol-
ane (7.30 g) and Example 14A (10.5 g) in tetrahydrofuran (120 mL)
was added Pd(Ph.sub.3P).sub.4
(tetrakis(triphenylphosphine)palladium(0), 1.58 g) and aqueous
saturated NaHCO.sub.3 (60 mL). The mixture was stirred under
nitrogen at 70.degree. C. overnight. The mixture was concentrated
under vacuum and the residue was diluted with water (120 mL) and
ethyl acetate (600 mL). The organic layer was separated, washed
with water and brine, dried over sodium sulfate, and filtered.
Evaporation of the solvent gave the crude product which was loaded
on a RediSep.RTM. Gold 220 g column and eluted with 20% ethyl
acetate in heptane to give 11.8 g product. MS (ESI) m/z 487.2
(M+H).sup.+.
Example 14C
4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-(1,4-dioxaspiro[4.5]decan-8-yl)-
pyrimidine
[0682] To a solution of Example 14B (10 g) in tetrahydrofuran (120
mL) was added Pd/C (10%, 1.5 g). The mixture was stirred under
hydrogen (25 psi) at room temperature for 4 hours. The mixture was
filtered and concentrated under vacuum to give the title compound.
MS (ESI) m/z 489.2 (M+H).sup.+.
Example 14D
4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-2-yl)cyclohexanone
[0683] To a solution of Example 14C (10 g) in acetone (70 mL) and
water (30 mL) was added pyridinium toluenesulfonate (1.5 g). The
mixture was stirred at reflux for 16 hours. The mixture was
concentrated under vacuum and the residue was diluted with water
(120 mL) and ethyl acetate (600 mL). The organic layer was
separated, washed with water and brine and dried over sodium
sulfate. Filtration and evaporation of the solvent gave the crude
product which was loaded on a RediSep.RTM. Gold 220 g column and
eluted with 20% ethyl acetate in heptane to give the title
compound. MS (ESI) m/z 445.3 (M+H).sup.+.
Example 14E
(1r,4r)-4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-2-yl)cyclohex-
anol
[0684] To a solution of Example 14D (2.2 g) in tetrahydrofuran (20
mL) was added sodium borohydride (0.56 g). The mixture was stirred
at room temperature for 3 hours. The mixture was diluted with water
(20 mL) and ethyl acetate (300 mL). The organic layer was separated
and washed with water and brine and dried over sodium sulfate.
Filtration and evaporation of the solvent gave crude product which
was loaded on a RediSep.RTM. Gold 120 g column and eluted with 40%
ethyl acetate in heptane to give the title compound. MS (ESI) m/z
447.3 (M+H).sup.+.
Example 14F
2-((1r,4r)-4-(allyloxy)cyclohexyl)-4-(((tert-butyldiphenylsilyl)oxy)methyl-
)pyrimidine
[0685] To a suspension of NaH (60% oil dispersion, 660 mg) in
tetrahydrofuran (20 mL), a solution of Example 14E (600 mg) in
tetrahydrofuran (5 mL) was added dropwise at room temperature and
the resulting suspension was stirred at room temperature for 1 hour
under nitrogen. To the mixture, allylbromide (406 mg) was added.
The mixture was stirred for 4 hours at room temperature. The
mixture was quenched with aqueous ammonium chloride, extracted with
ethyl acetate (300 mL), washed with water and brine, and dried over
sodium sulfate. Filtration and evaporation of the solvent gave the
crude product which was loaded on a RediSep.RTM. Gold 40 g column
and eluted with 20% ethyl acetate in heptane to give the title
compound. MS (ESI) m/z 487.0 (M+H).sup.+.
Example 14G
3-(((1r,4r)-4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-2-yl)cycl-
ohexyl)oxy)propane-1,2-diol
[0686] To a solution of Example 14F (340 mg) in tert-butanol (5 mL)
and water (5 mL) at 0.degree. C. was added AD-Mix-alpha (1.4 g).
The resulting suspension was stirred at 0.degree. C. for 4 hours,
and at room temperature overnight. The mixture was quenched with
sodium sulfite and extracted with ethyl acetate (three times, 100
mL). The combined organic phases were washed with brine and dried
over sodium sulfate. Filtration and evaporation of the solvent gave
the title compound. MS (ESI) m/z 521.2 (M+H).sup.+.
Example 14H
2-((1r,4r)-4-((1,3-dioxolan-4-yl)methoxy)cyclohexyl)-4-(((tert-butyldiphen-
ylsilyl)oxy)methyl)pyrimidine
[0687] To a solution of Example 14G (460 mg) in dichloromethane (10
mL) was added dimethoxymethane (672 mg) and para-toluenesulfonic
acid hydrate (168 mg). The resulting mixture was stirred at room
temperature for 4 days. The mixture was diluted with ethyl acetate
(300 mL), washed with water and brine, and dried over sodium
sulfate. Filtration and evaporation of the solvent gave the crude
product which was loaded on a RediSep.RTM. Gold 40 g column and
eluted with 20% ethyl acetate in heptane to give the title
compound. MS (ESI) m/z 533.2 (M+H).sup.+.
Example 14I
(2-((1r,4r)-4-((1,3-dioxolan-4-yl)methoxy)cyclohexyl)pyrimidin-4-yl)methan-
ol
[0688] To a solution of Example 14H (50 mg) in tetrahydrofuran (2
mL) was added cesium fluoride (120 mg) and methanol (1 mL). The
mixture was stirred at room temperature overnight. The solvent was
evaporated under vacuum and the residue was triturated with heptane
(30 mL) to get rid of the non-polar material. The residue was
triturated with ethyl acetate (30 mL). Evaporation of the solvent
gave the title compound. MS (ESI) m/z 295.3 (M+H).sup.+.
Example 14J
tert-butyl
(7R,16R)-19,23-dichloro-10-[(2-{(1r,4r)-4-[(1,3-dioxolan-4-yl)m-
ethoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethy-
l-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13-
,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene--
7-carboxylate
[0689] To a 4 mL vial containing Example 1Z (50 mg), Example 14I
(28 mg) and triphenylphosphine (52.5 mg) was added toluene (500
.mu.L) and tetrahydrofuran (500 .mu.L) followed by
(E)-N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethyldiazene-1,2-dicarboxamide
(34.5 mg). The mixture was purged with argon for 3 minutes and was
stirred at 50.degree. C. for 4 hours. The mixture was diluted with
dichloromethane (10 mL), loaded on a 40 g column, and eluted with
30% ethyl acetate in heptane (1 L) followed by 5% (7N ammonia in
methanol) in dichloromethane (1 L) to give the title compound. MS
(ESI) m/z 1085.5 (M+H).sup.+.
Example 14K
(7R,16R)-19,23-dichloro-10-[(2-{(1r,4r)-4-[(1,3-dioxolan-4-yl)methoxy]cycl-
ohexyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-me-
thylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno-
)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxyli-
c Acid
[0690] To a solution of Example 14J (89 mg) in dichloromethane (3
mL) was added trifluoroacetic acid (3 mL). The mixture was stirred
at room temperature for 6 hours. The mixture was concentrated under
vacuum and the residue was dissolved in N,N-dimethylformamide (3
mL) and loaded on HPLC (Gilson 2020 system, Luna.TM. C-18,
250.times.50 mm column, mobile phase A: 0.1% trifluoroacetic acid
in water; B: acetonitrile; 20-75% B to A gradient at 70 mL/minute
in 35 minute) to afford the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.69 (s, 1H), 8.67 (d, 1H),
7.39 (d, 1H), 7.13 (dtt, 6H), 6.80 (d, 1H), 6.70 (dd, 1H), 6.18
(dd, 1H), 5.78 (d, 1H), 5.05 (q, 3H), 4.85 (s, 3H), 4.75 (s, 1H),
4.40 (d, 3H), 4.07 (p, 1H), 3.92-3.84 (m, 1H), 2.91 (dd, 1H),
2.79-2.58 (m, 4H), 2.18 (s, 4H), 2.08-2.01 (m, 3H), 1.57 (qd, 3H),
1.25 (qd, 3H). MS (ESI) m/z 1029.3 (M+H).sup.+.
Example 15
(7R,16R)-19,23-dichloro-10-[(2-{(1s,4s)-4-[(1,4-dioxan-2-yl)methoxy]cycloh-
exyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-meth-
ylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)--
6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 15A
2-((1r,4r)-4-((1,4-dioxan-2-yl)methoxy)cyclohexyl)-4-(((tert-butyldimethyl-
silyl)oxy)methyl)pyrimidine
[0691] To a stirred solution of Example 14G (740 mg) in
dichloromethane (10 mL) was added NaH (102 mg) at 0.degree. C. The
mixture was stirred for 10 minutes. A solution of Example 9B (400
mg) in dichloromethane (5 mL) was added to the mixture and the
mixture was stirred at room temperature for 3 hours. The mixture
was quenched with aqueous ammonium chloride, extracted with ethyl
acetate (twice, 200 mL), washed with water and brine, and dried
over sodium sulfate. Filtration and evaporation of the solvent gave
crude product which was purified by column chromatography, eluting
with 20% ethyl acetate in heptane, to give the title compound. MS
(ESI) m/z 547.3 (M+H).sup.+.
Example 15B
(2-((1r,4r)-4-((1,4-dioxan-2-yl)methoxy)cyclohexyl)pyrimidin-4-yl)methanol
[0692] To a solution of Example 15A (430 mg) in tetrahydrofuran (5
mL) was added methanol (5 mL) and cesium fluoride (0.6 g). The
mixture was stirred at room temperature overnight. The solvents
were evaporated under vacuum and the residue was first triturated
with 50 mL of heptane and with ethyl acetate (3.times.30 mL). The
combined ethyl acetate extracts were concentrated under vacuum to
give crude product which was loaded on a RediSep.RTM. Gold 220 g
column and eluted with 5% methanol in dichloromethane (500 mL) to
give the title compound. MS (ESI) m/z 309.2 (M+H).sup.+.
Example 15C
tert-butyl
(7R,16R)-19,23-dichloro-10-[(2-{(1s,4s)-4-[(1,4-dioxan-2-yl)met-
hoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl--
16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-
-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7--
carboxylate
[0693] To a 4 mL vial containing Example 1Z (50 mg), Example 15B
(28 mg) and triphenylphosphine (52.5 mg) was added toluene (500
.mu.L) and tetrahydrofuran (500 .mu.L) followed by
(E)-N.sup.1,N.sup.1,N.sup.2,N.sup.2-tetramethyldiazene-1,2-dicarboxamide
(34.5 mg). The mixture was purged with argon for 3 minutes and was
stirred at 50.degree. C. for 4 hours. The mixture was diluted with
dichloromethane (10 mL) and loaded on a 40 g column and eluted with
30% ethyl acetate in heptane (1 L) followed by 5% (7N ammonia in
methanol) in dichloromethane (1 L) to give the title compound. MS
(ESI) m/z 1099.5 (M+H).sup.+.
Example 15D
(7R,16R)-19,23-dichloro-10-[(2-{(1s,4s)-4-[(1,4-dioxan-2-yl)methoxy]cycloh-
exyl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-meth-
ylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)--
6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0694] To a solution of Example 15C (82 mg) in dichloromethane (3
mL) was added trifluoroacetic acid (3 mL). The mixture was stirred
at room temperature for 6 hours. The mixture was concentrated under
vacuum and the residue was dissolved in N,N-dimethylformamide (3
mL) and loaded on a HPLC (Gilson 2020 system, Luna.TM. C-18,
250.times.50 mm column, mobile phase A: 0.1% trifluoroacetic acid
in water; B: acetonitrile; 20-75% B to A gradient at 70 mL/minute
in 35 minutes) to give the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.69-8.59 (m, 2H), 7.35 (d,
1H), 7.20-7.01 (m, 4H), 6.76 (d, 1H), 6.66 (dd, 1H), 6.12 (dd, 1H),
5.75 (d, 1H), 5.02 (q, 2H), 4.88-4.76 (m, 1H), 4.37 (d, 2H),
3.69-3.62 (m, 2H), 3.52 (dddd, 4H), 2.93-2.80 (m, 1H), 2.77-2.57
(m, 2H), 2.36 (d, 4H), 2.13 (s, 3H), 1.98 (dd, 2H), 1.52 (qd, 2H),
1.29-1.08 (m, 2H). MS (ESI) m/z 1043.5 (M+H).sup.+.
Example 16
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
razin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperaz-
in-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-t-
rioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 16A
(R)-2-(4-((1,4-dioxan-2-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane
[0695] To (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
(418 mg) and (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate
(724 mg) dissolved in dimethylformamide (6.3 mL) was added cesium
carbonate (1.24 g) and the reaction mixture was stirred for 90
minutes at ambient temperature and then for 5 hours at 80.degree.
C. To the reaction mixture was added aqueous ammonium hydrochloride
solution (5 mL) and the aqueous phase was extracted twice with
ethyl acetate. The organic phase was washed twice with water, once
with brine, dried over MgSO.sub.4, filtered and concentrated in
vacuo. The residue was purified by normal phase MPLC on a
Teledyne-Isco-Combiflash.RTM. system (eluting with 0-30% ethyl
acetate in n-heptane) to give the title compound. MS (APCI) m/z
321.2 (M+H).sup.+.
Example 16B
(R)-(6-(4-((1,4-dioxan-2-yl)methoxy)phenyl)pyrazin-2-yl)methanol
[0696] A mixture of (6-chloropyrazin-2-yl)methanol (52.6 mg),
Example 16A (106 mg), tris(dibenzylideneacetone)dipalladium(0) (3
mg), (1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8
phosphaadamantane (2.9 mg) and tribasic potassium phosphate (141
mg) were purged with argon for 30 minutes. A solution of
tetrahydrofuran (1.25 mL) and water (0.3 mL) was degassed and
added. The reaction mixture was stirred in a Biotage.RTM. microwave
unit for 8 hours at 65.degree. C. To the reaction mixture was added
ethyl acetate and the mixture was filtrated via a pad of
diatomaceous earth. To the filtrate was added ethyl acetate and
water. The aqueous phase was extracted twice with ethyl acetate.
The combined organic extracts were washed with brine and then dried
over MgSO.sub.4, filtered, and subsequently concentrated in vacuo.
The residue was purified by normal phase MPLC on a
Teledyne-Isco-Combiflash.RTM. system (eluting with 40-100% ethyl
acetate in heptane) to afford the title compound. MS (APCI) m/z
303.2 (M+H).sup.+.
Example 16C
tert-butyl
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methox-
y}phenyl)pyrazin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-me-
thylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno-
)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxyla-
te
[0697] A 4 mL vial, equipped with stir bar, was charged with
Example 1Z (40 mg), Example 16B (17.9 mg), triphenylphosphine (25.9
mg) and tetramethlylazodicarboxamide (17 mg) and the mixture was
purged for 15 minutes with argon. A solution of tetrahydrofuran
(0.5 mL) and toluene (0.5 mL) was added and the reaction mixture
was stirred for 48 hours at room temperature. The material in the
reaction mixture were filtered off and to the organic phase was
added ethyl acetate. The organic phase was washed with water and
brine solution. The organic phase was dried with sodium sulfate,
filtered, and subsequently concentrated in vacuo. The residue was
purified by normal phase MPLC on a Teledyne-Isco-Combiflash.RTM.
system (eluting with 10-35% ethanol in ethyl acetate) to afford the
title compound. MS (APCI) m/z 1093.4 (M+H).sup.+.
Example 16D
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
razin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperaz-
in-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-t-
rioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0698] To a solution of Example 16C (35 mg) in dichloromethane (250
.mu.L) was added trifluoroacetic acid (99 .mu.L). The reaction
mixture was stirred overnight at ambient temperature. The reaction
mixture was then concentrated in vacuo. The residue was dissolved
in dichloromethane and saturated aqueous NaHCO.sub.3-solution was
added. The aqueous phase was extracted twice with dichloromethane.
The combined organic phases were dried via DryDisk.RTM. and
concentrated in vacuo. The residue was purified by HPLC (Waters
X-Bridge C8 19.times.150 mm 5 .mu.m column, gradient 5-100%
acetonitrile+0.2% ammonium hydroxide in water+0.2% ammonium
hydroxide) to provide the title compound. .sup.1H NMR (600 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 9.15 (s, 1H), 8.73 (s, 1H),
8.64 (s, 1H), 8.12 (m, 2H), 7.20 (m, 2H), 7.13 (m, 2H), 7.09 (m,
2H), 6.95 (d, 1H), 6.76 (m, 1H), 6.20 (m, 1H), 5.80 (d, 1H), 5.27
(d, 1H), 5.25 (d, 1H), 4.86 (m, 1H), 4.45 (m, 2H), 4.04 (m, 2H),
3.89 (m, 1H), 3.84 (m, 1H) 3.77 (m, 1H), 3.70-3.60 (m, 3H), 3.51
(m, 1H), 3.42 (m, 1H), 2.95 (m, 1H), 2.66 (m, 2H), 2.55-2.25 (m,
8H), 2.16 (s, 3H), 1.97 (s, 3H), 1.95 (s, 3H). MS (ESI) m/z 1037.3
(M+H).sup.+.
Example 17
(7R,16R)-19,23-dichloro-1-cyclohexyl-10-{[2-(4-{[(2)-1,4-dioxan-2-yl]metho-
xy}phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1--
yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-
-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 17A
4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)thieno[2,3-d]pyrimid-
ine
[0699] To a suspension of Example 1E (4 g) in acetonitrile (50 mL)
was added N-chlorosuccinimide (3.86 g) and tetrafluoroboric acid
diethyl ether complex (4.68 g). The reaction mixture was stirred at
15.degree. C. under nitrogen for 16 hours. The reaction mixture was
diluted with water (30 mL) and extracted three times with ethyl
acetate (200 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by column chromatography on silica gel (petroleum
ether:ethyl acetate from 200:1 to 20:1) to provide the title
compound. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 9.01 (s, 1H), 8.02 (s, 1H), 3.88 (s, 3H), 2.01 (s, 6H).
Example 17B
6-bromo-4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)thieno[2,3-d-
]pyrimidine
[0700] To a solution of Example 17A (3.0 g) in tetrahydrofuran (50
mL) cooled to -78.degree. C., was added lithium diisopropylamide
(2M in tetrahydrofuran/heptane/ethylbenzene, 6.02 mL) and the
mixture was stirred at -78.degree. C. for 90 minutes.
1,2-Dibromotetrachloroethane (3.14 g) was added in three portions
over 10 minutes and stirring was continued at -78.degree. C. for 1
hour. The mixture was allowed to warm to -30.degree. C., water (60
mL) was added, and the mixture was extracted twice with ethyl
acetate (40 mL). The combined organic extracts washed with brine,
dried over magnesium sulfate, filtered and concentrated.
Purification by chromatography on silica gel using an ISCO
CombiFlash.RTM. Companion MPLC (10 g Chromabond.RTM. column,
eluting with 0-20% heptane/ethyl acetate) provided the title
compound. .sup.1H NMR (600 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 10.22 (bs, 1H), 9.00 (s, 1H), 1.96 (s, 6H). MS (ESI) m/z 450.95
(M+H).sup.+.
Example 17C
4-(6-bromo-4-chlorothieno[2,3-d]pyrimidin-5-yl)-2,6-dichloro-3,5-dimethylp-
henol
[0701] To a solution of Example 17B (4.35 g) in 1,2-dichloroethane
(60 mL) at 15.degree. C. was added AlCl.sub.3 (3.84 g) in three
portions over 5 minutes, and the mixture was stirred for 10 minutes
at ambient temperature. Boron trichloride (1 M in
dichloromethane-24.03 mL) was added dropwise over 5 minutes, and
the mixture was stirred for 2 hours. The mixture was allowed to
warm to 5.degree. C., and water (50 mL) was added. The mixture was
extracted twice with dichloromethane (40 mL), and the combined
organic extracts were washed twice with HCl (1 M aqueous
solution-30 mL), dried over magnesium sulfate, filtered, and
concentrated to provide the title compound. MS (ESI) m/z 436.8
(M+H).sup.+.
Example 17D
(R)-5-(4-((1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propan-2-yl-
)oxy)-3,5-dichloro-2,6-dimethylphenyl)-6-bromo-4-chlorothieno[2,3-d]pyrimi-
dine
[0702] The title compound was prepared as described in Example 1L
by substituting Example 17C for Example 1I. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.85 (s, 1H), 7.47-7.41 (m, 2H),
7.36-7.30 (m, 5H), 7.30-7.24 (m, 3H), 7.23-7.15 (m, 1H), 5.82 (ddt,
1H), 5.19 (dq, 1H), 5.11 (dq, 1H), 4.74 (p, 1H), 3.97 (dt, 2H),
3.86-3.81 (m, 2H), 3.79 (s, 6H), 3.59-3.49 (m, 2H), 2.01 (s, 3H),
2.01 (s, 3H). MS (ESI) m/z 877.0 [M+H]*.
Example 17E
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propan-
-2-yl)oxy)-3,5-dichloro-2,6-dimethylphenyl)-6-bromothieno[2,3-d]pyrimidin--
4-yl)oxy)-3-(2-(benzyloxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)propanoa-
te
[0703] The title compound was prepared as described in Example 1R
by substituting Example 17D for Example 1L. .sup.1H NMR (501 MHz,
chloroform-d) .delta. ppm 8.51 (s, 1H), 7.46-7.39 (m, 2H),
7.39-7.32 (m, 2H), 7.35-7.28 (m, 4H), 7.28-7.22 (m, 2H), 7.22-7.15
(m, 1H), 6.83-6.75 (m, 4H), 6.69 (d, 1H), 6.60 (dd, 1H), 6.40 (d,
1H), 5.77 (ddt, 1H), 5.39 (t, 1H), 5.13 (dq, 1H), 5.07 (dq, 1H),
4.98 (d, 1H), 4.94 (d, 1H), 4.60 (p, 1H), 3.90 (ddt, 2H), 3.78 (s,
6H), 3.83-3.72 (m, 2H), 3.59-3.50 (m, 2H), 2.67 (d, 2H), 2.13 (s,
3H), 1.93 (s, 3H), 1.31 (s, 1H), 1.35-1.23 (m, 1H), 1.28 (s, 2H),
1.26 (s, 9H), 0.93 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H). MS (ESI)
m/z 1275 [M+H]*.
Example 17F
(R)-tert-butyl
2-((5-(4-(((S)-1-(allyloxy)-3-hydroxypropan-2-yl)oxy)-3,5-dichloro-2,6-di-
methylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(benzyloxy)-5-(-
(tert-butyldimethylsilyl)oxy)phenyl)propanoate
[0704] The title compound was prepared as described in Example 1S
substituting Example 17E for Example 1R. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.47 (d, 1H), 7.39-7.31 (m, 2H),
7.31-7.23 (m, 2H), 7.27-7.17 (m, 1H), 6.68 (d, 1H), 6.57 (dd, 1H),
6.35 (d, 1H), 5.78 (ddt, 1H), 5.39 (t, 1H), 5.16 (dt, 1H), 5.08
(dd, 1H), 4.96 (d, 1H), 4.92 (d, 1H), 4.53-4.44 (m, 1H), 3.91
(dddd, 3H), 3.81 (ddd, 1H), 3.79-3.70 (m, 2H), 2.66 (dd, 1H), 2.58
(dd, 1H), 2.31 (dd, 1H), 2.09 (s, 3H), 1.91 (s, 3H), 1.22 (s, 9H),
0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). MS (DCI) m/z 973.2
[M+H].sup.+.
Example 17G
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(benzyloxy)--
5-((tert-butyldimethylsilyl)oxy)phenyl)propanoate
[0705] The title compound was prepared as described in Example 1T
substituting Example 17F for Example 1S. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.46 (s, 1H), 7.77-7.68 (m, 2H),
7.36-7.28 (m, 2H), 7.28-7.17 (m, 5H), 6.66 (d, 1H), 6.56 (dd, 1H),
6.34 (d, 1H), 5.75-5.61 (m, 1H), 5.35 (t, 1H), 5.13-5.00 (m, 2H),
4.95 (d, 1H), 4.91 (d, 1H), 4.51 (p, 1H), 4.41 (dd, 1H), 4.33 (dd,
1H), 3.87-3.73 (m, 2H), 3.66 (dd, 1H), 3.61 (dd, 1H), 2.64 (dd,
1H), 2.57 (dd, 1H), 2.38 (s, 3H), 2.06 (s, 3H), 1.87 (s, 3H), 1.22
(s, 9H), 0.88 (s, 9H), 0.06 (s, 3H). MS (ESI) m/z 1127.3
[M+H]*.
Example 17H
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-yl)oxy)-3-(2-(benzyloxy)--
5-hydroxyphenyl)propanoate
[0706] The title compound was prepared as described in Example 1U
substituting Example 17G for Example 1T. .sup.1H NMR (501 MHz,
chloroform-d) .delta. ppm 8.51 (s, 1H), 7.82-7.75 (m, 2H),
7.44-7.38 (m, 2H), 7.37-7.29 (m, 4H), 7.32-7.25 (m, 1H), 6.73 (d,
1H), 6.64 (dd, 1H), 5.96 (d, 1H), 5.76 (ddt, 1H), 5.52 (dd, 1H),
5.16 (dq, 1H), 5.12 (dt, 1H), 5.01 (s, 1H), 4.99 (s, 2H), 4.69-4.61
(m, 1H), 4.48 (dd, 1H), 4.41 (dd, 1H), 3.97-3.82 (m, 2H), 3.78 (dd,
1H), 3.74 (dd, 1H), 2.99 (dd, 1H), 2.43 (s, 3H), 2.39 (dd, 1H),
2.18 (s, 3H), 1.97 (s, 3H), 1.31 (s, 9H). MS (ESI) m/z 1112.8
[M+H]*.
Example 17I
tert-butyl
(7R,16R)-10-(benzyloxy)-1-bromo-19,23-dichloro-20,22-dimethyl-1-
6-{[(prop-2-en-1-yl)oxy]methyl}-7,8,15,16-tetrahydro-18,21-etheno-9,13-(me-
theno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carb-
oxylate
[0707] The title compound was prepared as described in Example 1V
substituting Example 17H for Example 1U. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.59 (s, 1H), 7.47-7.40 (m, 2H),
7.42-7.34 (m, 2H), 7.37-7.28 (m, 1H), 6.80-6.70 (m, 2H), 6.03-5.88
(m, 2H), 5.82 (d, 1H), 5.35 (dq, 1H), 5.24 (dq, 1H), 5.09-5.01 (m,
1H), 5.04-4.94 (m, 2H), 4.63 (dd, 1H), 4.35 (dd, 1H), 4.23-4.07 (m,
2H), 3.91 (dd, 1H), 3.82 (dd, 1H), 3.48 (dd, 1H), 2.91 (dd, 1H),
2.19 (s, 3H), 1.98 (s, 3H), 1.20 (s, 9H). MS (ESI) m/z 841.1
[M+H].sup.+.
Example 17J
tert-butyl
(7R,16R)-10-(benzyloxy)-1-bromo-19,23-dichloro-16-(hydroxymethy-
l)-20,22-dimethyl-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0708] The title compound was prepared as described in Example 1W
substituting Example 171 for Example 1V. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.57 (s, 1H), 7.46-7.40 (m, 2H), 7.37
(ddd, 2H), 7.35-7.26 (m, 1H), 6.75 (d, 1H), 6.71 (dd, 1H), 5.86
(dd, 1H), 5.82 (d, 1H), 5.12 (dddd, 1H), 5.01 (d, 1H), 4.97 (d,
1H), 4.61 (dd, 1H), 4.23 (dd, 1H), 4.06 (ddd, 1H), 3.93 (ddd, 1H),
3.35 (dd, 1H), 2.98 (dd, 1H), 2.34 (dd, 1H), 2.21 (s, 3H), 1.95 (s,
3H), 1.22 (s, 9H). MS (ESI) m/z 801.0 [M+H]*.
Example 17K
tert-butyl
(7R,16S)-10-(benzyloxy)-1-bromo-19,23-dichloro-20,22-dimethyl-1-
6-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}-7,8,15,16-tetrahydro-18,21-eth-
eno-9,13-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]i-
ndene-7-carboxylate
[0709] The title compound was prepared as described in Example 1X
substituting Example 17J for Example 1W. .sup.1H NMR (501 MHz,
Chloroform-d) .delta. 8.57 (s, 1H), 7.89-7.83 (m, 2H), 7.45-7.40
(m, 2H), 7.40-7.33 (m, 4H), 7.35-7.28 (m, 1H), 6.76 (d, 1H), 6.69
(dd, 1H), 5.86 (dd, 1H), 5.77 (d, 1H), 5.09-4.98 (m, 2H), 4.98 (d,
1H), 4.52 (dd, 1H), 4.43 (dd, 1H), 4.37 (dd, 1H), 4.22 (dd, 1H),
3.38 (dd, 1H), 2.93 (dd, 1H), 2.45 (s, 3H), 2.17 (s, 3H), 1.92 (s,
3H), 1.20 (s, 9H). MS (ESI) m/z 955.0 [M+H]*.
Example 17L
tert-butyl
(7R,16S)-10-(benzyloxy)-1-bromo-19,23-dichloro-20,22-dimethyl-1-
6-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}-7,8,15,16-tetrahydro-18,21-eth-
eno-9,13-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]i-
ndene-7-carboxylate
[0710] The title compound was prepared as described in Example 1Y
substituting Example 17K for Example 1X. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.68 (s, 1H), 7.41-7.35 (m,
2H), 7.35-7.28 (m, 2H), 7.31-7.22 (m, 1H), 6.87 (d, 1H), 6.79 (dd,
1H), 5.97 (dd, 1H), 5.59 (d, 1H), 5.01 (d, 1H), 4.93 (d, 1H), 4.70
(tt, 1H), 4.51-4.38 (m, 2H), 3.58-3.49 (m, 1H), 2.78-2.65 (m, 1H),
2.66 (d, 2H), 2.41 (s, 4H), 2.28 (s, 4H), 2.11 (s, 3H), 1.98 (s,
3H), 1.93 (s, 3H), 1.03 (s, 9H). MS (ESI) m/z 883.4 [M+H]*.
Example 17M
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclohex-1-en-1-yl)-10-hydroxy-20,22-
-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-e-
theno-9,13-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd-
]indene-7-carboxylate
[0711] Example 17L (400 mg),
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (35.4 mg), 1-cyclohexen-yl-boronic acid
pinacol ester (160 mg), and cesium carbonate were combined under an
argon atmosphere in dioxane/water (degassed, 4 mL/9 mL). The
reaction mixture was heated to 90.degree. C. and stirred for 45
minutes. The reaction mixture was partitioned between water and
ethyl acetate. The aqueous phase was extracted with ethyl acetate
twice. The combined organic layer was washed with brine, dried over
anhydrous magnesium sulfate, filtrated and concentrated. The
residue was purified on a silica gel column (12 g, 0-10% methanol
in dichloromethane). The desired fractions were combined and the
solvents were removed under reduced pressure to provide the title
compound. MS (ESI) m/z 885.3 (M+H).sup.+.
Example 17N
tert-butyl
(7R,16R)-19,23-dichloro-1-cyclohexyl-10-hydroxy-20,22-dimethyl--
16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-
-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7--
carboxylate
[0712] The title compound was prepared as described in Example 1Z
substituting Example 17M for Example 1Y. .sup.1H NMR (600 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 9.06 (s, 1H), 8.65 (s, 1H),
6.70 (dd, 1H), 6.64 (d, 1H), 5.94 (dd, 1H), 5.49 (d, 1H), 4.68 (q,
1H), 4.50-4.46 (m, 1H), 4.40 (d, 1H), 3.50 (dd, 1H), 2.71-2.65 (m,
2H), 2.57 (d, 1H), 2.51-2.25 (m, 9H), 2.17 (bs, 3H), 2.02 (s, 3H),
1.99 (s, 3H), 1.83 (d, 1H), 1.74-1.58 (m, 4H), 1.49-1.42 (m, 1H),
1.39-1.32 (m, 1H), 1.24-1.08 (m, 3H), 1.07 (s, 9H). MS (ESI) m/z
797.3 (M+H).sup.+.
Example 170
tert-butyl
(7R,16R)-19,23-dichloro-1-cyclohexyl-10-{[2-(4-{[(2)-1,4-dioxan-
-2-yl]methoxy}phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylp-
iperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,1-
4,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0713] Example 17N (29 mg), Example 7B (35 mg), triphenylphosphine
(46 mg), and N,N,N',N'-tetramethylazodicarboxamide (30 mg) were
combined and flushed with argon for 15 minutes. Tetrahydrofuran
(1.0 mL) and toluene (1.0 mL) were mixed, flushed with argon for 15
minutes, and mixed with the solid reactants. The reaction mixture
was stirred over the weekend at room temperature. The reaction
mixture was concentrated. Purification was performed on a silica
gel column (4 g, 0-30% methanol in dichloromethane). The pure
fractions were combined and the solvents were removed under reduced
pressure to provide the title compound. MS (APCI) m/z 1081.4
(M+H).sup.+.
Example 17P
(7R,16R)-19,23-dichloro-1-cyclohexyl-10-{[2-(4-{[(2S)-1,4-dioxan-2-yl]meth-
oxy}phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-
-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-triox-
a-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0714] Example 17O (43 mg) was dissolved in dichloromethane (1.0
mL) and trifluoroacetic acid (0.5 mL) was added. The reaction
mixture was stirred for 6 hours at room temperature. The reaction
mixture was concentrated. The residue was dissolved in methanol,
diluted with water, and freeze-dried. Purification by HPLC (Waters
X-Bridge C8 19.times.150 mm 5 .mu.m column, gradient 5-100%
acetonitrile+0.2% ammonium hydroxide in water+0.2% ammonium
hydroxide) provided the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.81 (d, 1H), 8.63 (s, 1H),
8.35-8.32 (m, 2H), 7.44 (d, 1H), 7.08-7.06 (m, 2H), 6.86 (d, 1H),
6.75-6.73 (m, 1H), 6.21 (b, 1H), 5.84 (b, 1H), 5.23 (d, 1H), 5.16
(d, 1H), 4.89-4.88 (m, 1H), 4.52-4.46 (m, 2H), 4.06-4.02 (m, 2H),
3.91-3.87 (m, 1H), 3.86-3.83 (m, 1H), 3.79-3.77 (m, 1H), 3.69-3.58
(m, 3H), 3.51 (td, 1H), 3.44-3.41 (m, 1H), 2.89-2.86 (m, 1H),
2.73-2.67 (m, 2H), 2.56-2.47 (m, 8H), 2.20-2.16 (m, 1H), 2.15 (s,
3H), 2.04 (s, 3H), 1.89 (s, 3H), 1.77-1.75 (m, 1H), 1.72-1.65 (m,
3H), 1.58-1.56 (m, 1H), 1.44-1.31 (m, 2H), 1.21-1.05 (m, 3H). MS
(APCI) m/z 1025.1 (M+H).sup.+.
Example 18
(7R,16R)-19,23-dichloro-1-{[(2R)-1,4-dioxan-2-yl]methyl}-10-{[2-(2-methoxy-
phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
Example 18A
6-bromo-4-chloro-5-(3,5-dichloro-2,6-dimethyl-4-((triisopropylsilyl)oxy)ph-
enyl)thieno[2,3-d]pyrimidine
[0715] A mixture of Example 17C (4.18 g) and diisopropylethylamine
(4.16 mL) in dichloromethane (50 mL) was stirred for 5 minutes at
ambient temperature. After cooling to 15.degree. C.,
triisopropylchlorosilane (2.83 mL) was added, and the stirring was
continued at ambient temperature for 24 hours. The mixture was
concentrated in vacuo, water (40 mL) and NaHCO.sub.3 (saturated
aqueous solution, 10 mL) were added, and the mixture was extracted
twice with ethyl acetate (20 mL). The combined organic extracts
washed with brine, dried over magnesium sulfate, filtered and
concentrated. Precipitation from ethanol (20 mL) provided the title
compound. MS (ESI) m/z 593.1 (M+H).sup.+.
Example 18B
(R)-tert-butyl
2-acetoxy-3-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)propanoate
[0716] Example 1P (4.5 g) in ethanol (30 mL) was added to 5% Pd/C
(wet JM #9) (0.22 g) in a 100 mL pressure bottle. The mixture was
stirred under 50 psi of hydrogen (g) at 35.degree. C. for 10 hours.
The reaction mixture was cooled to ambient temperature and
filtered. The filtrate was concentrated to obtain the title
compound. .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 6.70 (d,
1H), 6.66-6.60 (m, 2H), 5.59 (s, 1H), 5.18 (dd, 1H), 3.12 (dd, 1H),
3.02 (dd, 1H), 2.11 (s, 3H), 1.43 (s, 9H), 0.97 (s, 9H), 0.17 (d,
6H). MS (ESI) m/z 427.8 [M+NH.sub.4].sup.+.
Example 18C
2-methoxybenzimidamide hydrochloride
[0717] A dried 12 L five-necked flask equipped with a mechanical
stirrer, a gas inlet with tubing leading to a nitrogen regulator, a
gas inlet adapter with tubing leading to a bubbler, and an internal
temperature probe (J-KEM controlled), was charged with ammonium
chloride (86 g). The material was mixed under nitrogen with
anhydrous toluene (2 L). The mixture was cooled to -12.3.degree. C.
in an ice/methanol bath. To the mixture was added, via cannula, 2.0
M trimethylaluminum in toluene (800 mL). Upon addition of the
trimethylaluminum, the mixture started to smoke immediately and gas
was evolved. The temperature of the reaction mixture rose to a high
of -0.4.degree. C. during the addition, and the addition took a
total of about 60 minutes. After all the trimethylaluminum was
added, the mixture was allowed to stir at 20.degree. C. for 3
hours. To the mixture was added 2-methoxybenzonitrile (107 g) as a
liquid (had been melted in bath at about 45.degree. C.). Once the
2-methoxybenzonitrile was added, the reaction mixture was heated at
90.degree. C. overnight with the use of a heating mantle controlled
by a J-KEM. The reaction flask was fitted with a vigreux condenser.
Thin-layer chromatography in 50% ethyl acetate/heptane indicated a
major baseline product. The reaction mixture was cooled to
-8.7.degree. C. in an ice/methanol bath, and to the cold mixture
was added 4 L of methanol, dropwise via an addition funnel. The
addition evolved gas and was exothermic. The temperature of the
reaction mixture reached a high of 7.9.degree. C., and the addition
took a total of about one hour. After all the methanol was added,
the mixture was allowed to stir for three hours at 20.degree. C.
The reaction mixture was filtered through filter paper on a
benchtop filter. The material collected were washed with additional
methanol (2 L). The filtrate was concentrated. The crude material
was mixed with 500 mL of ethyl acetate. The mixture was sonicated
for 30 minutes and was stirred for another 30 minutes. The solids
material was filtered off and washed with more ethyl acetate. The
material collected were air dried for an hour and then dried under
high vacuum for two hours to provide the title compound. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 9.23 (bs, 2H),
7.69 (bs, 1H), 7.63 (ddd, 1H), 7.55 (dd, 1H), 7.25 (dd, 1H), 7.12
(td, 1H), 3.87 (s, 3H). MS (DCI) m/z 151.0 (M+H).sup.+.
Example 18D
4-(dimethoxymethyl)-2-(2-methoxyphenyl)pyrimidine
[0718] An oven-dried 5 L three neck flask equipped with a
mechanical stirrer, nitrogen inlet into a reflux condenser and
outlet to a bubbler, and an internal temperature probe (J-KEM
controlled), was charged with Example 18C (126.9 g) and
(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (177 g).
Anhydrous methanol (1360 mL) was added. To the mixture at room
temperature under nitrogen was added solid sodium methoxide (257 g)
in portions over 20 minutes. The temperature of the reaction went
up from 18.6.degree. C. to 35.7.degree. C. during the addition.
Once the exotherm stopped, the reaction mixture was heated to
65.degree. C. overnight. The reaction mixture was cooled, and
concentrated. The residue was mixed with ethyl acetate (800 mL),
and water (1 L) was added carefully. The two phase mixture was
sonicated for about 30 minutes to dissolve all the material. The
layers were separated, and organic layer was washed with saturated
aqueous NH.sub.4Cl mixture. The combined aqueous extracts were
extracted one time with ethyl acetate. The combined organic
extracts were washed with brine, dried with Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was dissolved in a small
amount of dichloromethane (30 mL) and loaded onto a 2.0 L plug of
silica in a 3 L Buchner funnel that had been equilibrated with 40%
ethyl acetate/heptane. The desired product was eluted with 40% to
50% ethyl acetate/heptane. The fractions containing the desired
product were combined, and were concentrated to provide the title
compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 8.93 (d, 1H), 7.54 (dd, 1H), 7.50-7.43 (m, 2H), 7.16 (dd, 1H),
7.06 (td, 1H), 5.31 (s, 1H), 3.76 (s, 3H), 3.38 (s, 6H). MS (DCI)
m/z 261.0 (M+H).sup.+.
Example 18E
(2-(2-methoxyphenyl)pyrimidin-4-yl)methanol
[0719] A mixture of Example 18D (14.7 g) in 110 mL HCl in dioxane
(4M mixture) and 110 mL water was heated at 50.degree. C. for 14
hours. The mixture was cooled to 0.degree. C., and ground NaOH
(17.60 g) was added in portions. The pH was adjusted to 8 using 10%
K.sub.2CO.sub.3 aqueous mixture. Sodium borohydride (4.27 g) was
added in portions. The mixture was stirred at 0.degree. C. for 45
minutes. The mixture was carefully quenched with 150 mL saturated
aqueous NH.sub.4Cl and was stirred at 0.degree. C. for 30 minutes.
The mixture was extracted with ethyl acetate (5.times.150 mL),
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was triturated in 30 mL ethanol to give a
first crop of the title compound. The filtrate was concentrated and
the residue was purified on a silica gel column (120 g, 55-100%
ethyl acetate in heptanes, dry load) to give a second crop of the
title compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.84 (d, 1H), 7.49 (m, 2H), 7.44 (ddd, 1H), 7.13 (dd,
1H), 7.04 (td, 1H), 5.65 (t, 1H), 4.60 (dd, 2H), 3.75 (s, 3H). MS
(DCI) m/z 217.0 (M+H).sup.+.
Example 18F
(R)-tert-butyl
2-acetoxy-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2-methoxyphenyl)pyri-
midin-4-yl)methoxy)phenyl)propanoate
[0720] To an oven dried 500 mL round bottom flask was added Example
18B (14.7 g), triphenylphosphine (27.4 g), Example 18E (20 g) and
tetrahydrofuran (105 mL). The reaction flask was cooled in an ice
bath. Solid (E)-N,N,N',N'-tetramethyldiazene-1,2-dicarboxamide (18
g) was added and the reaction mixture was allowed to warm up to
ambient temperature and was stirred overnight. The mixture was
filtered and the filter cake was washed with tetrahydrofuran. The
filtrate was concentrated. The residue was taken up in 200 mL of
15% ethyl acetate in heptanes, shaken, and filtered through 200 g
silica gel. The filtrate was concentrated and purified by silica
gel chromatography on a Grace Reveleris X2 MPLC system using a
Teledyne Isco RediSep.RTM. Rf gold 330 g silica column with 20-50%
ethyl acetate/heptanes. Fractions containing desired product were
combined and concentrated to obtain the title compound. .sup.1H NMR
(501 MHz, chloroform-d) .delta. ppm 8.89 (d, 1H), 7.70 (dd, 1H),
7.63 (d, 1H), 7.47-7.41 (m, 1H), 7.09 (tt, 1H), 7.05 (d, 1H),
6.79-6.73 (m, 2H), 6.70 (dd, 1H), 5.25 (dd, 1H), 5.20 (d, 2H), 3.88
(s, 3H), 3.40 (dd, 1H), 3.00 (dd, 1H), 2.06 (s, 3H), 1.47 (s, 9H),
0.99 (s, 9H), 0.18 (s, 6H). MS (ESI) m/z 609.2 [M+H].sup.+.
Example 18G
(R)-tert-butyl
3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2-methoxyphenyl)pyrimidin-4-yl-
)methoxy)phenyl)-2-hydroxypropanoate
[0721] To a mixture of Example 18F (24.4 g) in anhydrous ethanol
(210 mL) was added sodium ethoxide solution (21% in ethanol, 0.78
mL), and the mixture was stirred at room temperature for 2 hours.
Acetic acid (0.24 mL) was added and the solution was concentrated
and purified by silica gel chromatography on a Grace Reveleris X2
MPLC system using a Teledyne Isco RediSep.RTM. Rf gold 330 g silica
column with 30-60% ethyl acetate/heptanes. Fractions containing
desired product were combined and concentrated to obtain the title
compound. .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 8.88 (d,
1H), 7.70 (dd, 1H), 7.58 (dt, 1H), 7.44 (ddd, 1H), 7.09 (td, 1H),
7.05 (dd, 1H), 6.78 (d, 1H), 6.75 (d, 1H), 6.68 (dd, 1H), 5.20 (s,
2H), 4.44 (ddd, 1H), 3.88 (s, 3H), 3.24 (dd, 1H), 2.95 (dd, 1H),
2.92 (d, 1H), 1.47 (s, 9H), 0.98 (s, 9H), 0.18 (s, 6H). MS (ESI)
m/z 567.2 [M+H].sup.+.
Example 18H
tert-butyl
(R)-2-((6-bromo-5-(3,5-dichloro-2,6-dimethyl-4-((triisopropylsi-
lyl)oxy)phenyl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(5-((tert-butyldimethyls-
ilyl)oxy)-2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)propanoate
[0722] A mixture of Example 18A (5.3 g), Example 18G (26.4 g) and
cesium carbonate (6.62 g) in tert-butanol (75 mL) was stirred at
70.degree. C. for 7 hours. After cooling to 10.degree. C., water
(200 mL) was added, and the mixture was extracted twice with ethyl
acetate (70 mL). The combined organic extracts were washed with
brine, dried over magnesium sulfate, filtered and concentrated.
Purification by chromatography on silica gel using an ISCO
CombiFlash.RTM. Companion MPLC (220 g Chromabond.RTM. column,
eluting with 0-60% heptane/ethyl acetate) provided the title
compound. .sup.1H NMR (600 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 8.86 (d, 1H), 8.64 (s, 1H), 7.49 (dd, 1H), 7.48-7.42 (m, 2H),
7.14 (dd, 1H), 7.02 (td, 1H), 6.95 (d, 1H), 6.70 (dd, 1H), 6.53 (d,
1H), 5.45 (dd, 1H), 5.16 (d, 1H), 5.05 (d, 1H), 3.75 (s, 3H), 2.78
(dd, 1H), 2.61-2.56 (m, 1H), 2.08 (s, 3H), 1.97 (s, 3H), 1.39 (h,
3H), 1.18 (s, 9H), 1.05 (dd, 18H), 0.98 (d, 1H), 0.90 (s, 9H), 0.90
(d, 1H), 0.10 (d, 6H).
Example 18I
(R)-2-((6-bromo-5-(3,5-dichloro-4-hydroxy-2,6-dimethylphenyl)thieno[2,3-d]-
pyrimidin-4-yl)oxy)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2-methoxyph-
enyl)pyrimidin-4-yl)methoxy)phenyl)propanoate
[0723] To a solution of Example 18H (9.3 g) in
N,N-dimethylformamide (70 mL) cooled to 15.degree. C., potassium
carbonate (0.077 g) dissolved in 3.7 mL water was added and the
reaction mixture was stirred for 4 hours at ambient temperature.
Water (100 mL) and NaHCO.sub.3 (saturated aqueous solution, 30 mL)
were added, and the resulting mixture was extracted twice with
ethyl acetate (80 mL). The combined organic extracts were washed
with brine, dried over magnesium sulfate, filtered and
concentrated. Purification by chromatography on silica gel using an
ISCO CombiFlash.RTM. Companion MPLC (220 g Chromabond.RTM. column,
eluting with 5-70% heptane/ethyl acetate) provided the title
compound. MS (ESI) m/z 967.2 (M+H).sup.+.
Example 18J
(S)-2,3-dihydroxypropyl 4-methylbenzenesulfonate
[0724] To a stirring mixture of
(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate
(9 g) in 36 mL of methanol was slowly added 42 mL of 1 M aqueous
HCl mixture, and the reaction mixture was stirred at ambient
temperature overnight. The mixture was concentrated under reduced
pressure to remove most of the methanol. The mixture was carefully
poured into 225 mL of saturated aqueous sodium bicarbonate mixture.
The mixture was extracted with three portions of ethyl acetate. The
combined organic layers were washed with saturated aqueous brine,
dried over anhydrous magnesium sulfate, filtered and concentrated
onto silica gel. Purification by silica gel flash chromatography on
a CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 330 g silica gel column (eluting with 10-80%
of 2:1 ethyl acetate:ethanol in heptane) provided the title
compound, which was quickly carried through to the next step before
it solidified. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 2.42 (s, 3H), 3.18-3.27 (m, 1H), 3.29-3.34 (m, 1H),
3.61 (ttd, 1H), 3.84 (dd, 1H), 3.97-4.05 (m, 1H), 4.68 (t, 1H),
5.10 (d, 1H), 7.48 (d, 2H), 7.73-7.85 (m, 2H). LC/MS (APCI) m/z
247.3 (M+H).sup.+.
Example 18K
(S)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)-2-hydroxypropyl
4-methylbenzenesulfonate
[0725] To a stirring mixture of Example 18J (6.3 g) in 128 mL of
dichloromethane at 0.degree. C., was added 4,4'-dimethoxytrityl
chloride (9.10 g) in one portion. To the mixture was added
N,N-diisopropylethylamine (4.69 mL) dropwise over 15 minutes. The
reaction mixture was stirred at 0.degree. C. for an hour and was
quenched with saturated aqueous ammonium chloride (100 mL). The
layers were separated, and the aqueous layer was extracted with two
portions of dichloromethane. The combined organic extracts was
dried over anhydrous magnesium sulfate, filtered and concentrated
onto silica gel. Purification by flash chromatography on a
CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 330 g silica gel column (eluting 0-50% ethyl
acetate/heptane) provided the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 2.39 (s, 3H), 2.84 (dd, 1H),
2.94 (dd, 1H), 3.74 (s, 6H), 3.76-3.81 (m, 1H), 3.96 (dd, 1H),
4.02-4.09 (m, 1H), 5.28 (d, 1H), 6.82-6.92 (m, 4H), 7.12-7.18 (m,
4H), 7.19-7.25 (m, 1H), 7.28 (d, 4H), 7.45 (d, 2H), 7.71-7.79 (m,
2H).
Example 18L
tert-butyl
(R)-2-((5-(4-(((R)-1-(bis(4-methoxyphenyl)(phenyl)methoxy)-3-(t-
osyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-dimethylphenyl)-6-bromothieno[2,-
3-d]pyrimidin-4-yl)oxy)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(2-metho-
xyphenyl)pyrimidin-4-yl)methoxy)phenyl)propanoate
[0726] Example 18I (7.3 g), Example 18K (4.55 g),
triphenylphosphine (2.96 g) and di-tert-butyl azodicarboxylate (2.6
g) were added together in a reaction flask and flushed for 10
minutes with nitrogen. Freshly degassed toluene (60 mL) was added
and the reaction mixture was stirred for 90 minutes at ambient
temperature. The mixture was concentrated on Telos Bulk Sorbent and
was purified twice by chromatography on silica gel using an ISCO
CombiFlash.RTM. Companion MPLC (330 g RediSep.RTM. Gold and 120
Chromabond.RTM. column, eluting with 0-70% heptane/ethyl acetate)
providing the title compound. MS (ESI) m/z 1497.4 (M+H).sup.+.
Example 18M
tert-butyl
(R)-2-((5-(4-((R)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)-2-((t-
osyloxy)methyl)propyl)-3,5-dichloro-2,6-dimethylphenyl)-6-bromothieno[2,3--
d]pyrimidin-4-yl)oxy)-3-(5-hydroxy-2-((2-(2-methoxyphenyl)pyrimidin-4-yl)m-
ethoxy)phenyl)propanoate
[0727] Example 18L (2.24 g) in tetrahydrofuran (20 mL) cooled to
5.degree. C., was treated with tetrabutylammonium fluoride (1 M in
tetrahydrofuran, 3 mL) for 20 minutes. Water (60 mL) was added and
the mixture was extracted twice with ethyl acetate (40 mL). The
combined organic extracts were washed with brine, dried over
magnesium sulfate, filtered and concentrated. Purification by
chromatography on silica gel using an ISCO CombiFlash.RTM.
Companion MPLC (80 g Chromabond.RTM. column, eluting with 0-100%
heptane/ethyl acetate) provided the title compound. MS (ESI) m/z
1383.2 (M+H).sup.+.
Example 18N
tert-butyl
(7R,16S)-16-{[bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-1-bro-
mo-19,23-dichloro-10-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-20,22-di-
methyl-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-2-t-
hia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0728] A mixture of Example 18M (2.0 g) and cesium carbonate (2.35
g) in dimethylformamide (150 mL) was stirred at ambient temperature
for 2 hours. After cooling to 5.degree. C., the reaction mixture
was poured into water (300 mL) and ethyl acetate (100 mL). The
layers were separated and the aqueous layer was extracted with
ethyl acetate (50 mL). The combined organic extracts were washed
with brine, dried over magnesium sulfate, filtered and
concentrated. Purification by chromatography on silica gel using an
ISCO CombiFlash.RTM. Companion MPLC (40 g Chromabond.RTM. column,
eluting with 0-70% heptane/ethyl acetate) provided the title
compound. .sup.1H NMR (600 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 8.90 (d, 1H), 8.76 (s, 1H), 7.56 (d, 1H), 7.53 (dd, 1H), 7.46
(m, 3H), 7.37-7.29 (m, 6H), 7.27-7.21 (m, 1H), 7.15 (dd, 1H), 7.05
(td, 1H), 6.98 (d, 1H), 6.95-6.87 (m, 5H), 6.05 (dd, 1H), 5.69 (d,
1H), 5.21 (d, 1H), 5.14 (d, 1H), 4.89 (m, 1H), 4.59 (dd, 1H), 4.40
(d, 1H), 3.75 (s, 9H), 3.63 (dd, 1H), 3.45-3.30 (m, 3H), 2.90 (m,
1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.10 (s, 9H). MS (ESI) m/z 1211.4
(M+H).sup.+.
Example 18O
tert-butyl
(7R,16R)-1-bromo-19,23-dichloro-16-(hydroxymethyl)-10-{[2-(2-me-
thoxyphenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-7,8,15,16-tetrahydro-18-
,21-etheno-9,13-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2-
,3-cd]indene-7-carboxylate
[0729] To a solution of Example 18N (856 mg) in methanol (3 mL) and
dichloromethane (3 mL) was added formic acid (2.2 mL) and the
mixture was stirred at ambient temperature for 1 hour. The reaction
mixture was cooled to 5.degree. C., water (40 mL) was added, and
the mixture was extracted twice with dichloromethane (30 mL). The
combined organic extracts were washed with NaHCO.sub.3 (saturated
aqueous solution, 30 mL) and water, dried over magnesium sulfate,
filtered and concentrated. Purification by chromatography on silica
gel using an ISCO CombiFlash.RTM. Companion MPLC (25 g
Chromabond.RTM. column, eluting with 0-100% heptane/ethyl acetate)
provided the title compound. MS (ESI) m/z 909.2 (M+H).sup.+.
Example 18P
tert-butyl
(7R,16S)-1-bromo-19,23-dichloro-10-{[2-(2-methoxyphenyl)pyrimid-
in-4-yl]methoxy}-20,22-dimethyl-16-{[(4-methylbenzene-1-sulfonyl)oxy]methy-
l}-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-2-thia--
3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0730] The title compound was prepared as described in Example 1X
substituting Example 180 for Example 1W. MS (ESI) m/z 1063.2
(M+H).sup.+.
Example 18Q
tert-butyl
(7R,16R)-1-bromo-19,23-dichloro-10-{[2-(2-methoxyphenyl)pyrimid-
in-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15-
,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-2-thia-3,5-diaza-
cyclononadeca[1,2,3-cd]indene-7-carboxylate
[0731] The title compound was prepared as described in Example 1Y
substituting Example 18P for Example 1Y. MS (ESI) m/z 1063.2
(M+H).sup.+.
Example 18R
tert-butyl
(7R,16R)-19,23-dichloro-1-{[(2R)-1,4-dioxan-2-yl]methyl}-10-{[2-
-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0732] A pre-catalyst stock solution was prepared using a dry
microwave vial charged with NiCl.sub.2 dimethoxyethane adduct
(1.107 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (1.35 mg) and
dimethoxyethane (0.5 mL) and the solution was sonicated for 5
minutes. To a dry 5 mL microwave vial, which was dried for 24 hours
at 70.degree. C. under vacuum and stored in a glove box, was added
Example 18Q (50 mg), (S)-2-bromomethyl)-1,4-dioxane (40 mg),
Ir[dF(CF.sub.3)ppy].sub.2(dtbbpy) (5.65 mg), and Na.sub.2CO.sub.3
(8 mg) in a glove box. Dry dimethoxyethane (0.5 mL degassed with
nitrogen) and tris(trimethylsilyl)silane (20 .mu.L) was added,
pre-catalyst stock solution (0.5 mL) was syringed into the vial,
and the reaction mixture was exposed to blue light (34 W Blue LED
KESSIL Light, EvoluChem.TM. PhotoRedOx Box) under stirring at
25.degree. C. for 20 hours. Water (5 mL) was added to the mixture
and the mixture was extracted twice with dichloromethane. The
combined organic extracts were dried over magnesium sulfate,
filtered and concentrated in vacuo. Purification by chromatography
using an ISCO CombiFlash.RTM. Companion MPLC (4 g Chromabond.RTM.
silica gel column, eluting with 0-10% dichloromethane/methanol)
provided a mixture of the title compound and the corresponding
des-bromo analogue. MS (ESI) m/z 1013.4 (M+H).sup.+.
Example 18S
(7R,16R)-19,23-dichloro-1-{[(2R)-1,4-dioxan-2-yl]methyl}-10-{[2-(2-methoxy-
phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
[0733] To a solution of Example 18R (120 mg) in dichloromethane (1
mL) was added trifluoroacetic acid (0.1 mL). The mixture was
stirred for 20 hours and concentrated in vacuo. Purification by
HPLC (Gemini NX C18 21.2.times.150 mm 5 .mu.m column, gradient
5-100% acetonitrile+0.2% ammonium hydroxide in water+0.1% ammonium
hydroxide) provided the title compound. .sup.1H NMR (600 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 13.0 (s, 1H), 8.86 (d, 1H),
8.63 (s, 1H), 7.54 (dd, 1H), 7.46 (ddd, 1H), 7.15 (dd, 1H), 7.04
(td, 1H), 6.87 (d, 1H), 6.74 (s, 1H), 6.19 (sb, 1H), 5.81 (s, 1H),
5.20 (d, 1H), 5.12 (d, 1H), 4.91 (s, 1H), 4.49 (m, 2H), 3.76 (s,
3H), 3.69 (m, 1H), 3.61-3.49 (m, 4H), 3.40-3.30 (m, 8H), 3.08 (dd,
1H), 2.87 (dd, 1H), 2.72 (m, 2H), 2.55-2.35 (m, 4H), 2.16 (s, 3H),
2.03 (s, 3H), 1.88 (s, 3H). MS (ESI) m/z 957.4 (M+H).sup.+.
Example 19
(7R,16R)-19,23-dichloro-1-{[(2S)-1,4-dioxan-2-yl]methyl}-10-{[2-(2-methoxy-
phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
Example 19A
tert-butyl
(7R,16R)-19,23-dichloro-1-{[(2S)-1,4-dioxan-2-yl]methyl}-10-{[2-
-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0734] The title compound was prepared as described in Example 18R
by replacing (S)-2-bromomethyl)-1,4-dioxane with
(R)-2-bromomethyl)-1,4-dioxane. MS (ESI) m/z 1013.4
(M+H).sup.+.
Example 19B
(7R,16R)-19,23-dichloro-1-{[(2S)-1,4-dioxan-2-yl]methyl}-10-{[2-(2-methoxy-
phenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
[0735] The title compound was prepared as described in Example 18S
by replacing Example 18R with Example 19A. .sup.1H NMR (600 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.86 (d, 1H), 8.66 (s, 1H),
7.56-7.51 (m, 2H), 7.46 (ddd, 1H), 7.15 (dd, 1H), 7.04 (td, 1H),
6.89 (d, 1H), 6.77 (dd, 1H), 6.23 (s, 1H), 5.82 (s, 1H), 5.20 (d,
1H), 5.12 (d, 1H), 4.89 (m, 1H), 4.50 (m, 2H), 3.76 (s, 3H), 3.72
(m, 1H), 3.64-3.49 (m, 5H), 3.42-3.25 (m, 7H), 3.09 (dd, 1H), 2.91
(dd, 1H), 2.72 (m, 2H), 2.55-2.35 (m, 4H), 2.17 (s, 3H), 2.02 (s,
3H), 1.90 (s, 3H). MS (ESI) m/z 957.4 (M+H).sup.+.
Example 20
(7R,16R)-19,23-dichloro-10-({2-[(2R)-2-{[(1,4-dioxan-2-yl)methoxy]methyl}m-
orpholin-4-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-
-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(-
metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-ca-
rboxylic Acid
Example 20A
(R)-(4-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)morpholin-2-
-yl)methanol
[0736] A solution of (R)-morpholin-2-ylmethanol, trifluoroacetic
acid (210 mg),
4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (200
mg) and N,N-diisopropylethylamine (800 .mu.L) in acetonitrile (1.9
mL) was heated to 80.degree. C. overnight. The reaction was cooled,
diluted with water and extracted with ethyl acetate three times.
The combined organic layers were dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
normal phase MPLC on a Teledyne Isco Combiflash.RTM. Rf+12 g gold
silica gel column eluting with 0-70% ethyl acetate in
dichloromethane to give the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.38 (d, 1H), 6.70 (d, 1H),
4.85-4.74 (m, 1H), 4.60-4.50 (m, 3H), 4.43-4.34 (m, 1H), 3.95-3.86
(m, 1H), 3.55-3.35 (m, 4H), 2.99-2.85 (m, 1H), 2.72-2.58 (m, 1H),
0.91 (s, 9H), 0.09 (s, 6H).
Example 20B
(R)-2-((allyloxy)methyl)-4-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimi-
din-2-yl)morpholine
[0737] To a solution of Example 20A (200 mg) and 3-bromoprop-1-ene
(100 .mu.L) in tetrahydrofuran (3 mL) was added sodium hydride (48
mg, 60% oil dispersion), and the reaction was warmed to 40.degree.
C. after bubbling subsided. After 4 hours, the reaction was cooled,
diluted with saturated aqueous ammonium chloride and extracted with
ethyl acetate three times. The combined organic layers were dried
over anhydrous sodium sulfate, filtered and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+12 g gold silica gel column eluting with 0-25%
ethyl acetate in dichloromethane to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.38
(d, 1H), 6.70 (d, 1H), 5.97-5.81 (m, 1H), 5.31-5.21 (m, 1H),
5.20-5.10 (m, 1H), 4.55 (s, 2H), 4.53-4.45 (m, 1H), 4.42-4.32 (m,
1H), 4.01-3.94 (m, 2H), 3.93-3.86 (m, 1H), 3.62-3.38 (m, 4H),
2.99-2.86 (m, 1H), 2.77-2.66 (m, 1H), 0.91 (s, 9H), 0.09 (s,
6H).
Example 20C
3-(((R)-4-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyrimidin-2-yl)morpholi-
n-2-yl)methoxy)propane-1,2-diol
[0738] To a solution of Example 20B (190 mg) in tert-butanol (2.5
mL) and water (2.5 mL) at 0.degree. C. was added AD-Mix alpha (1.1
g), and the reaction was stirred for 4 hours at 0.degree. C. The
reaction was warmed to room temperature and stirred overnight. The
reaction was quenched with solid sodium sulfite, diluted with water
and extracted with ethyl acetate three times. The combined organic
layers were washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated to give the title compound as a mixture
of diastereomers that was used in the next step without further
purification.
Example 20D
(2R)-2-(((1,4-dioxan-2-yl)methoxy)methyl)-4-(4-(((tert-butyldimethylsilyl)-
oxy)methyl)pyrimidin-2-yl)morpholine
[0739] To a solution of Example 20C (210 mg) in dichloromethane
(3.3 mL) at room temperature was added sodium hydride (36 mg, 60%
oil dispersion), and the reaction was allowed to stir for 10
minutes. A solution of Example 9B (220 mg) in dichloromethane (1.7
mL) was added, and the reaction was allowed to stir for 5 hours.
The reaction was quenched with saturated aqueous ammonium chloride
and extracted with ethyl acetate three times. The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by normal phase MPLC on a
Teledyne Isco Combiflash.RTM. Rf+12 g gold silica gel column
eluting with 0-50% ethyl acetate in dichloromethane to give the
title compound as a mixture of diastereomers. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.38 (d, 1H), 6.70 (d, 1H),
4.55 (s, 2H), 4.51-4.42 (m, 1H), 4.41-4.30 (m, 1H), 3.96-3.81 (m,
2H), 3.76-3.35 (m, 11H), 3.30-3.19 (m, 1H), 3.00-2.85 (m, 1H),
2.78-2.62 (m, 1H), 0.91 (s, 9H), 0.09 (s, 6H).
Example 20E
(2-((2R)-2-(((1,4-dioxan-2-yl)methoxy)methyl)morpholino)pyrimidin-4-yl)met-
hanol
[0740] To a solution of Example 20D (110 mg) in tetrahydrofuran
(860 .mu.L) and methanol (430 .mu.L) was added cesium fluoride (200
mg), and the reaction was allowed to stir for 5.5 hours. The
reaction mixture was concentrated, and the residue was taken up in
ethyl acetate with sonication, filtered over diatomaceous earth,
and concentrated. The residue was purified by normal phase MPLC on
a Teledyne Isco Combiflash.RTM. Rf+4 g gold silica gel column
eluting with 10-100% ethyl acetate in dichloromethane to give the
title compound as a mixture of diastereomers. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.35 (d, 1H), 6.75 (d, 1H),
5.45-5.36 (m, 1H), 4.51-4.43 (m, 1H), 4.41-4.32 (m, 3H), 3.95-3.86
(m, 1H), 3.74-3.36 (m, 12H), 3.30-3.21 (m, 1H), 2.97-2.86 (m, 1H),
2.74-2.64 (m, 1H).
Example 20F
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(2R)-2-{[(1,4-dioxan-2-yl)metho-
xy]methyl}morpholin-4-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22--
dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-et-
heno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]-
indene-7-carboxylate
[0741] A vial containing Example 20E (42 mg), Example 1Z (35 mg),
triphenylphosphine (34 mg) and
N,N,N',N'-tetramethylazodicarboxamide (22 mg) in toluene (110
.mu.L) and tetrahydrofuran (110 .mu.L) was allowed to stir at
50.degree. C. for 4 hours. The reaction was cooled, diluted with
ethyl acetate, filtered over diatomaceous earth and concentrated.
The residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 0.5-9%
methanol in dichloromethane to give the title compound as a mixture
of diastereomers. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.74, (s, 1H), 8.39 (d, 1H), 7.29-7.12 (m, 5H),
6.90-6.74 (m, 3H), 6.06-5.99 (m, 1H), 5.69-5.63 (m, 1H), 5.04-4.85
(m, 2H), 4.79-4.68 (m, 1H), 4.56-4.34 (m, 4H), 3.97-3.87 (m, 1H),
3.75-3.36 (m, 14H), 3.30-3.21 (m, 1H), 3.02-2.57 (m, 8H), 2.44-2.20
(m, 4H), 2.14 (s, 3H), 2.10 (s, 3H), 1.06 (s, 9H).
Example 20G
(7R,16R)-19,23-dichloro-10-({2-[(2R)-2-{[(1,4-dioxan-2-yl)methoxy]methyl}m-
orpholin-4-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-
-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(-
metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-ca-
rboxylic Acid
[0742] To a solution of Example 20F (41 mg) in dichloromethane (190
.mu.L) was added trifluoroacetic acid (190 .mu.L), and the reaction
was allowed to stir for 4 hours. The reaction was concentrated
under a stream of nitrogen and taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 5-85% over 30 minutes with
acetonitrile in water containing 10 mM ammonium acetate) to give
the title compound after lyophilization as a mixture of
diastereomers. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.73 (s, 1H), 8.35 (d, 1H), 7.23-7.09 (m, 5H),
6.83-6.68 (m, 3H), 6.25-6.16 (m, 1H), 5.85-5.77 (m, 1H), 5.03-4.81
(m, 3H), 4.54-4.33 (m, 3H), 3.95-3.86 (m, 1H), 3.74-3.22 (m, 11H),
3.00-2.87 (m, 2H), 2.77-2.59 (m, 2H), 2.48-2.35 (m, 2H), 2.22 (s,
3H), 2.02-1.93 (m, 6H). MS (ESI) m/z 1060.4 (M+H).sup.+.
Example 21
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
acid Example 21A
(R)-2-(3-((1,4-dioxan-2-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-diox-
aborolane
[0743] The title compound was prepared by substituting
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol for
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol in Example
2A. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm
7.30 (m, 1H), 7.26 (d, 1H), 7.15 (d, 1H), 7.07 (dd, 1H), 3.96 (d,
2H), 3.86-3.80 (m, 2H), 3.77-3.75 (m, 1H), 3.69-3.58 (m, 2H), 3.50
(td, 1H), 3.42 (t, 1H), 1.29 (s, 12H). MS (ESI) m/z 338.1
(M+NH.sub.4).sup.+.
Example 21B
(R)-(2-(3-((1,4-dioxan-2-yl)methoxy)phenyl)pyrimidin-4-yl)methanol
[0744] The title compound was prepared by substituting Example 21A
for Example 2A in Example 2B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.88 (d, 1H), 7.99 (d, 1H),
7.92 (t, 1H), 7.50 (d, 1H), 7.43 (t, 1H), 7.11 (dd, 1H), 5.68 (t,
1H), 4.64 (d, 2H), 4.04 (d, 2H), 3.91-3.77 (m, 3H), 3.69-3.62 (m,
2H), 3.53 (dd, 1H), 3.45 (t, 1H). MS (ESI) m/z 303.1
(M+H).sup.+.
Example 21C
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2R)-1,4-dioxan-2-yl]methox-
y}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
late
[0745] The title compound was prepared by substituting Example 21B
for Example 7B in Example 7C. MS (ESI) m/z 1095.4 (M+H).sup.+.
Example 21D
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0746] The title compound was prepared by substituting Example 21C
for Example 7C in Example 7D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.89 (d, 1H), 8.74 (s, 1H),
8.00 (d, 1H), 7.94 (d, 1H), 7.54 (d, 1H), 7.44 (t, 1H), 7.23-7.10
(m, 5H), 6.90 (d, 1H), 6.76 (dd, 1H), 6.24 (m, 1H), 5.81 (d, 1H),
5.24 (q, 2H), 4.86 (m, 1H), 4.45 (m, 2H), 4.04 (d, 2H), 3.92-3.84
(m, 2H), 3.79-3.75 (m, 1H), 3.69-3.61 (m, 3H), 3.54-3.45 (m, 2H),
2.98 (d, 2H), 2.73-2.61 (m, 3H), 2.48-2.28 (m, 6H), 2.18 (s, 3H),
1.99 (s, 3H), 1.95 (s, 3H). MS (ESI) m/z 1037.5 (M+H).sup.+.
Example 22
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 22A
(S)-2-(3-((1,4-dioxan-2-yl)methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane
[0747] The title compound was prepared by substituting
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol for
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and
(R)-(1,4-dioxan-2-yl)methanol for (S)-(1,4-dioxan-2-yl)methanol in
Example 2A. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 7.30 (m, 1H), 7.26 (d, 1H), 7.15 (d, 1H), 7.06 (dd,
1H), 3.96 (d, 2H), 3.86-3.79 (m, 2H), 3.77-3.75 (m, 1H), 3.67-3.59
(m, 2H), 3.50 (td, 1H), 3.42 (t, 1H), 1.29 (s, 12H). MS (ESI) m/z
337.9 (M+NH.sub.4).
Example 22B
(S)-(2-(3-((1,4-dioxan-2-yl)methoxy)phenyl)pyrimidin-4-yl)methanol
[0748] The title compound was prepared by substituting Example 22A
for Example 2A in Example 2B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.88 (d, 1H), 7.99 (d, 1H),
7.92 (dd, 1H), 7.50 (d, 1H), 7.43 (t, 1H), 7.11 (dd, 1H), 5.67 (t,
1H), 4.64 (d, 2H), 4.04 (d, 2H), 3.91-3.82 (m, 2H), 3.81-3.76 (m,
1H), 3.70-3.61 (m, 2H), 3.53 (dd, 1H), 3.45 (t, 1H). MS (ESI) m/z
303.1 (M+H).sup.+.
Example 22C
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2S)-1,4-dioxan-2-yl]methox-
y}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
late
[0749] The title compound was prepared by substituting Example 22B
for Example 7B in Example 7C. MS (ESI) m/z 1093.3 (M+H).sup.+.
Example 22D
(7R,16R)-19,23-dichloro-10-{[2-(3-{[(2S)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0750] The title compound was prepared by substituting Example 22C
for Example 7C in Example 7D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.89 (d, 1H), 8.73 (s, 1H),
8.00 (d, 1H), 7.94 (s, 1H), 7.54 (d, 1H), 7.43 (t, 1H), 7.22-7.12
(m, 5H), 6.89 (d, 1H), 6.75 (dd, 1H), 6.24 (m, 1H), 5.83 (s, 1H),
5.23 (q, 2H), 4.87 (m, 1H), 4.45 (bs, 2H), 4.04 (d, 2H), 3.93-3.84
(m, 2H), 3.79-3.75 (m, 1H), 3.70-3.60 (m, 3H), 3.54-3.45 (m, 2H),
2.98 (d, 2H), 2.73-2.61 (m, 3H), 2.48-2.31 (m, 6H), 2.17 (s, 3H),
1.98 (s, 3H), 1.96 (s, 3H). MS (ESI) m/z 1037.5 (M+H).sup.+.
Example 23
(7R,16R)-19,23-dichloro-10-{[4-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 23A
(R)-(4-(4-((1,4-dioxan-2-yl)methoxy)phenyl)pyrimidin-2-yl)methanol
[0751] A mixture of (4-chloropyrimidin-2-yl)methanol (36.6 mg),
Example 16A (70 mg), tris(dibenzylideneacetone)dipalladium(0) (2
mg), (1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8
phosphaadamantane (1.9 mg) and tribasic potassium phosphate (93 mg)
were purged with argon for 30 minutes. A solution of
tetrahydrofuran (0.87 mL) and water (0.22 mL) was degassed and
added. The reaction mixture was stirred in a Biotage.RTM. Initiator
microwave unit for 8 hours at 65.degree. C. To the reaction mixture
was added ethyl acetate and the mixture was filtrated via a pad of
diatomaceous earth. To the filtrate was added ethyl acetate and
water. The aqueous phase was extracted twice with ethyl acetate.
The combined organic extracts were washed with brine and then dried
over magnesium sulfate, filtered, and subsequently concentrated in
vacuo. The residue was purified by normal phase MPLC on a
Teledyne-Isco-Combiflash.RTM. system (eluting with 40-100% ethyl
acetate in heptane) to afford the title compound. MS (APCI) m/z
303.2 (M+H).sup.+.
Example 23B
tert-butyl
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methox-
y}phenyl)pyrimidin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
late
[0752] A 4 mL vial, equipped with stir bar, was charged with
Example 1Z (35 mg), Example 23A (15.7 mg), triphenylphosphine (22.7
mg) and tetramethlylazodicarboxamide (14.9 mg) and purged for 30
minutes with argon. A solution of tetrahydrofuran (0.5 mL) and
toluene (0.5 mL) were added and the reaction mixture was stirred
for 19 hours at ambient temperature. To the reaction mixture were
added triphenylphosphine (11.3 mg) and tetramethlylazodicarboxamide
(7.5 mg) and stirring was continued for 28 hours at ambient
temperature. To the reaction mixture were added triphenylphosphine
(11.3 mg) and tetramethlylazodicarboxamide (7.5 mg) and stirring
was continued for 17 hours at ambient temperature. The material in
the reaction mixture were filtered off and to the organic phase was
added dichloromethane. The material was washed with
dichloromethane. The combined organic phases were washed with water
and brine solution. The organic phase was dried via DryDisk.RTM.
and subsequently concentrated in vacuo. The residue was purified by
normal phase MPLC on a Teledyne-Isco-Combiflash.RTM. system
(eluting with 0-20% methanol in dichloromethane) to afford the
title compound. MS (APCI) m/z 1093.3 (M+H).sup.+.
Example 23C
(7R,16R)-19,23-dichloro-10-{[4-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0753] To a solution of Example 23B (38 mg) in dichloromethane (270
.mu.L) was added trifluoroacetic acid (268 .mu.L). The reaction
mixture was stirred for 24 hours at ambient temperature. The
reaction mixture was then concentrated in vacuo. The residue was
dissolved in dichloromethane and saturated aqueous
NaHCO.sub.3-solution was added. The aqueous phase was extracted
twice with dichloromethane. The combined organic phases were dried
via DryDisk.RTM. and concentrated in vacuo. The residue was
purified by HPLC (Waters X-Bridge C8 19.times.150 mm 5 .mu.m
column, gradient 5-100% acetonitrile+0.2% ammonium hydroxide in
water+0.2% ammonium hydroxide) to provide the title compound.
.sup.1H NMR (600 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.75
(d, 1H), 8.72 (s, 1H), 8.17 (m, 2H), 7.92 (d, 1H), 7.19 (m, 2H),
7.13 (m, 2H), 7.05 (m, 2H), 6.83 (d, 1H), 6.68 (m, 1H), 6.20 (m,
1H), 5.81 (s, 1H), 5.24 (s, 2H), 4.86 (m, 1H), 4.41 (m, 2H), 4.03
(m, 2H), 3.89 (m, 1H), 3.84 (m, 1H) 3.77 (m, 1H), 3.70-3.60 (m,
3H), 3.51 (m, 1H), 3.43 (m, 1H), 2.98 (m, 1H), 2.63 (m, 2H),
2.55-2.25 (m, 8H), 2.14 (s, 3H), 1.96 (s, 3H), 1.91 (s, 3H). MS
(ESI) m/z 1037.1 (M+H).sup.+.
Example 24
(7R,16R)-19,23-dichloro-10-[(2-{[(2)-1,4-dioxan-2-yl]methoxy}pyrimidin-4-y-
l)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)m-
ethyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-2-t-
hia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
Example 24A
(S)-2-((1,4-dioxan-2-yl)methoxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)p-
yrimidine
[0754] (R)-(1,4-Dioxan-2-yl)methanol (91 mg),
4-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyrimidine (200
mg), and triethylamine (0.4 mL) were dissolved in acetonitrile (2.5
mL) and heated to 80.degree. C. for 3 hours. Sodium hydride (111
mg, 50%) was added at room temperature and the mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated. The residue was dissolved in dichloromethane and
washed with water. The organic layer was dried over sodium sulfate,
filtered, and concentrated. Purification was performed on a silica
gel column (4 g, 0-20% methanol in dichloromethane). The pure
fractions were combined and the solvents were removed under reduced
pressure to provide the title compound. MS (ESI) m/z 341.2
(M+H).sup.+.
Example 24B
(S)-(2-((1,4-dioxan-2-yl)methoxy)pyrimidin-4-yl)methanol
[0755] Example 24A (66.5 mg) was dissolved in tetrahydrofuran (1
mL) and cooled to 0.degree. C. by an ice bath. Tetrabutylammonium
fluoride (1M in tetrahydrofuran, 0.39 mL) was added and the mixture
was stirred for 2 hours at 0.degree. C. The reaction mixture was
partitioned between ethyl acetate and brine. The organic layer was
washed with brine, dried over sodium sulfate, filtered, and
concentrated. Purification was performed on a silica gel column (4
g, 0-50% methanol in dichloromethane). The pure fractions were
combined and the solvents were removed under reduced pressure to
provide the title compound. MS (ESI) m/z 227.1 (M+H).sup.+.
Example 24C
tert-butyl
(7R,16R)-19,23-dichloro-10-[(2-{[(2S)-1,4-dioxan-2-yl]methoxy}p-
yrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0756] Example 24B (42 mg), Example 1Z (25 mg), triphenylphosphine
(32 mg), and N,N,N',N'-tetramethylazodicarboxamide (21 mg) were
combined and flushed with argon for 15 minutes. Tetrahydrofuran
(0.2 mL) and toluene (0.2 mL) were mixed, flushed with argon for 15
minutes, and added to the solid reactants. The reaction mixture was
stirred over the weekend at room temperature. The reaction mixture
was concentrated. Purification was performed on a silica gel column
(4 g, 0-30% methanol in dichloromethane). The pure fractions were
combined and the solvents were removed under reduced pressure to
provide the title compound. MS (APCI) m/z 1017.3 (M+H).sup.+.
Example 24D
(7R,16R)-19,23-dichloro-10-[(2-{[(2S)-1,4-dioxan-2-yl]methoxy}pyrimidin-4--
yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
[0757] Example 24C (70 mg) was dissolved in dichloromethane (1.0
mL) and trifluoroacetic acid (0.24 mL) was added. The reaction
mixture was stirred overnight at room temperature. The reaction
mixture was concentrated at 25.degree. C. The residue was dissolved
in methanol, diluted with water and freeze-dried. The crude
material was purified by HPLC (Waters X-Bridge C8 19.times.150 mm 5
.mu.m column, gradient 5% to 100% acetonitrile+0.2% ammonium
hydroxide in water+0.2% ammonium hydroxide) to provide the title
compound. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 8.73 (s, 1H), 8.58 (d, 1H), 7.25 (d, 1H), 7.22-7.18 (m, 2H),
7.16-7.12 (m, 2H), 6.83 (d, 1H), 6.75-6.73 (m, 1H), 6.19 (b, 1H),
5.81 (b, 1H), 5.10 (d, 1H), 5.02 (d, 1H), 4.90-4.86 (m, 1H),
4.47-4.41 (m, 2H), 4.31-4.25 (m, 2H), 3.90-3.85 (m, 1H), 3.78 (ddd,
2H), 3.67-3.57 (m, 3H), 3.49 (td, 1H), 3.42-3.38 (m, 1H), 2.96-2.92
(m, 1H), 2.72-2.65 (m, 2H), 2.55-2.49 (m, 8H), 2.19 (s, 3H), 1.98
(s, 3H), 1.96 (s, 3H). MS (APCI) m/z 961.3 (M+H).sup.+.
Example 25
(7R,16R)-19,23-dichloro-10-[(2-{[(2R)-1,4-dioxan-2-yl]methoxy}pyrimidin-4--
yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
Example 25A
[0758] The title compound was prepared as described in Example 24A
by substituting (S)-(1,4-dioxan-2-yl)methanol for
(R)-(1,4-dioxan-2-yl)methanol. MS (ESI) m/z 341.2 (M+H).sup.+.
Example 25B
(R)-(2-((1,4-dioxan-2-yl)methoxy)pyrimidin-4-yl)methanol
[0759] The title compound was prepared as described in Example 24B
by substituting Example 25A for Example 24A. MS (ESI) m/z 227.1
(M+H).sup.+.
Example 25C
tert-butyl
(7R,16R)-19,23-dichloro-10-[(2-{[(2R)-1,4-dioxan-2-yl]methoxy}p-
yrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0760] The title compound was prepared as described in Example 24C
by substituting Example 25B for Example 24B. MS (APCI) m/z 1017.3
(M+H).sup.+.
Example 25D
(7R,16R)-19,23-dichloro-10-[(2-{[(2R)-1,4-dioxan-2-yl]methoxy}pyrimidin-4--
yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)-
methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)-6,14,17-trioxa-2--
thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
[0761] Example 25C (67 mg) was dissolved in dichloromethane (1.0
mL) and trifluoroacetic acid (0.23 mL) was added. The reaction
mixture was stirred overnight at room temperature. The reaction
mixture was concentrated at 25.degree. C. The residue was dissolved
in methanol, diluted with water and freeze-dried. The crude
material was purified by HPLC (Waters X-Bridge C8 19.times.150 mm 5
.mu.m column, gradient 5-100% acetonitrile+0.2% ammonium hydroxide
in water+0.2% ammonium hydroxide) to provide the title compound.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.73
(s, 1H), 8.58 (d, 1H), 7.25 (d, 1H), 7.22-7.18 (m, 2H), 7.16-7.12
(m, 2H), 6.83 (d, 1H), 6.75-6.73 (m, 1H), 6.19 (b, 1H), 5.81 (b,
1H), 5.10 (d, 1H), 5.02 (d, 1H), 4.90-4.86 (m, 1H), 4.47-4.41 (m,
2H), 4.32-4.25 (m, 2H), 3.90-3.86 (m, 1H), 3.78 (ddd, 2H),
3.67-3.56 (m, 3H), 3.49 (td, 1H), 3.42-3.38 (m, 1H), 2.96-2.92 (m,
1H), 2.72-2.63 (m, 2H), 2.55-2.42 (m, 8H), 2.18 (s, 3H), 1.98 (s,
3H), 1.96 (s, 3H). MS (APCI) m/z 961.2 (M+H).sup.+.
Example 26
(7R,16R)-19,23-dichloro-10-[(2-{4-[(1,4-dioxan-2-yl)methanesulfonyl]pipera-
zin-1-yl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
lic Acid
Example 26A tert-butyl
4-(((1,4-dioxan-2-yl)methyl)sulfonyl)piperazine-1-carboxylate
[0762] tert-Butyl piperazine-1-carboxylate (102 mg) was dissolved
in dichloromethane (3 mL). Triethylamine (151 mg) was added,
followed by (1,4-dioxan-2-yl)methanesulfonyl chloride (100 mg). The
solution was mixed at room temperature overnight. The solvent was
removed under vacuum, and the residue was taken up in ethyl acetate
(10 mL). The solution was washed with 0.1 M aqueous HCl (3 mL). The
solution was washed with brine, dried over anhydrous sodium
sulfate, and filtered. The solvent was removed under vacuum, and
the material was carried on without further purification. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 3.94 (m, 1H),
3.80 (d, 2H), 3.74-3.63 (m, 2H), 3.57-3.48 (m, 1H), 3.45 (m, 4H),
3.35-3.30 (m, 1H), 3.27-3.23 (m, 2H), 3.18 (m, 4H), 1.47 (s, 9H).
MS (ESI) m/z 251.2 (M-tert-butyl carboxylate).sup.+.
Example 26B
1-(((1,4-dioxan-2-yl)methyl)sulfonyl)piperazine
[0763] The title compound was prepared by substituting Example 26A
for Example 10A in Example 10B. The material was isolated as the
trifluoroacetic acid salt and was carried on in the next step
without further purification.
Example 26C
(2-(4-(((1,4-dioxan-2-yl)methyl)sulfonyl)piperazin-1-yl)pyrimidin-4-yl)met-
hanol
[0764] The title compound was prepared by substituting Example 26B
for Example 10B in Example 10C. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.37 (d, 1H), 6.77 (d, 1H),
5.43 (t, 1H), 4.37 (d, 2H), 3.93-3.85 (m, 1H), 3.80 (m, 4H), 3.72
(m, 2H), 3.64-3.55 (m, 2H), 3.48-3.43 (m, 1H), 3.29-3.19 (m, 7H).
MS (ESI) m/z 359.2 (M+H).sup.+.
Example 26D
tert-butyl
(7R,16R)-19,23-dichloro-10-[(2-{4-[(1,4-dioxan-2-yl)methanesulf-
onyl]piperazin-1-yl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimet-
hyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno--
13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inden-
e-7-carboxylate
[0765] The title compound was prepared by substituting Example 26C
for Example 7B in Example 7C. MS (ESI) m/z 1149.5 (M+H).sup.+.
Example 26E
(7R,16R)-19,23-dichloro-10-[(2-{4-[(1,4-dioxan-2-yl)methanesulfonyl]pipera-
zin-1-yl}pyrimidin-4-yl)methoxy]-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
lic Acid
[0766] The title compound was prepared by substituting Example 26D
for Example 7C in Example 7D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.72 (s, 1H), 8.38 (d, 1H),
7.22-7.11 (m, 4H), 6.83-6.77 (m, 2H), 6.74 (dd, 1H), 6.18 (m, 1H),
5.82 (s, 1H), 4.95 (q, 2H), 4.89 (m, 1H), 4.44 (m, 2H), 3.92-3.87
(m, 1H), 3.83 (m, 4H), 3.76-3.68 (m, 3H), 3.65-3.53 (m, 6H),
3.49-3.44 (m, 4H), 2.96 (d, 2H), 2.75-2.65 (m, 3H), 2.47 (m, 2H),
2.42-2.32 (m, 4H), 2.18 (s, 3H), 1.97 (bs, 6H). MS (ESI) m/z 1093.4
(M+H).sup.+.
Example 27
(7R,16R)-19,23-dichloro-1-(5,6-dihydro-1,4-dioxin-2-yl)-10-{[2-(2-methoxyp-
henyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)m-
ethyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-t-
hia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
Example 27A
tert-butyl
(7R,16R)-19,23-dichloro-1-(5,6-dihydro-1,4-dioxin-2-yl)-10-{[2--
(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0767] A microwave vial, equipped with stir bar, was charged with
Example 18Q (50 mg),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-dioxine
(20 mg), 1'-bis(di-tert-butylphosphino)ferrocene-palladium
dichloride dichloromethane complex (3 mg) and CsCO.sub.3 (45 mg)
and degassed for 10 minutes with nitrogen. Freshly degassed dioxane
(0.8 mL) and water (0.2 mL) were added. The vial was capped and the
reaction mixture was heated in a Biotage.RTM. Initiator microwave
to 90.degree. C. for 90 minutes. Water (2 mL) and dichloromethane
(4 mL) were added, the organic layer separated via Chromabond.RTM.
PTS cartridge, the aqueous layer re-extracted with dichloromethane
(2 mL), and the combined organic layers concentrated in vacuo.
Purification by chromatography on silica gel using an ISCO
CombiFlash.RTM. Companion MPLC (5 g Chromabond.RTM. column, eluting
with 0-10% dichloromethane/methanol) provided the title compound.
MS (ESI) m/z 997.4 (M+H).sup.+.
Example 27B
(7R,16R)-19,23-dichloro-1-(5,6-dihydro-1,4-dioxin-2-yl)-10-{[2-(2-methoxyp-
henyl)pyrimidin-4-yl]methoxy}-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)m-
ethyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-t-
hia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
[0768] The title compound was prepared as described in Example 18S
by replacing Example 18R with Example 27A. .sup.1H NMR (600 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.86 (d, 1H), 8.66 (s, 1H),
7.54 (dd, 1H), 7.52 (d, 1H), 7.46 (ddd, 1H), 7.15 (dd, 1H), 7.05
(td, 1H), 6.90 (d, 1H), 6.78 (dd, 1H), 6.24 (s, 1H), 5.78 (s, 1H),
5.47 (s, 1H), 5.21 (d, 1H), 5.13 (d, 1H), 4.87 (m, 1H), 4.50 (m,
2H), 4.13 (m, 1H), 4.07 (m, 1H), 4.01 (m, 2H), 3.76 (s, 3H), 3.64
(dd, 1H), 2.91 (dd, 1H), 2.71 (m, 2H), 2.55-2.45 (m, 6H), 2.39 (s,
2H), 2.17 (s, 3H), 2.05 (s, 3H), 1.97 (s, 3H). MS (ESI) m/z 941.4
(M+H).sup.+.
Example 28
(7R,16R)-19,23-dichloro-10-({2-[(1R,4s)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
Example 28A
(S)-8-(((1,4-dioxan-2-yl)methoxy)methyl)-8-fluoro-1,4-dioxaspiro[4.5]decan-
e
[0769] To a solution of Example 39D (1.7 g) in dimethylformamide
(20 mL) was added sodium hydride (1.1 g, 60% oil dispersion) at
0.degree. C. under nitrogen. After 10 minutes, a solution of
(S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (3.8 g) in
dimethylformamide (20 mL) was added to the reaction. The reaction
was stirred at 50.degree. C. for 12 hours. Two additional reactions
were set up as above. All three reactions were combined. The
reaction was poured into ice water and exacted with ethyl acetate
twice. The combined organic layers were dried over anhydrous sodium
sulfate, filtered and concentrated to give a residue which was
purified by column chromatography on silica gel (eluting with
petroleum ether:ethyl acetate=100:1 to 20:3) to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 4.03-3.87
(m, 4H), 3.85-3.66 (m, 5H), 3.65-3.37 (m, 6H), 2.02-1.80 (m, 4H),
1.79-1.55 (m, 4H).
Example 28B
(S)-4-(((1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohexanone
[0770] To a solution of Example 28A (1.8 g) in tetrahydrofuran (54
mL) was added aqueous HCl (54 mL, 6 M) at 0.degree. C. The reaction
was stirred at 25.degree. C. for 16 hours under a nitrogen
atmosphere. Two additional reactions were set up as above. All
three reactions were combined. The pH of the combined mixture was
adjusted to 8 by addition of solid NaOH at 0.degree. C., and the
mixture was extracted with ethyl acetate eight times. The combined
organics were dried over anhydrous sodium sulfate, filtered and
concentrated to give the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 3.89-3.20 (m, 11H), 2.76-2.57 (m, 2H),
2.40-2.17 (m, 4H), 1.99-1.77 (m, 2H).
Example 28C
4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-yl
trifluoromethanesulfonate
[0771] To a stirred solution of diisopropylamine (1.8 g) in dry
tetrahydrofuran (150 mL) was added n-butyllithium (7.3 mL, 1 M) at
0.degree. C. under nitrogen flow. After 5 minutes, a solution of
Example 28B (3 g) in dry tetrahydrofuran (150 mL) was added to the
reaction mixture. The mixture was stirred for 15 minutes at
0.degree. C. A solution of
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(5.6 g) in tetrahydrofuran (150 mL) was added to the mixture at
-78.degree. C. under nitrogen atmosphere, and the reaction was
warmed to 20.degree. C. and stirred for 16 hours under nitrogen
atmosphere. The reaction was poured into ice water and extracted
with ethyl acetate twice. The organic phases were combined and
washed with brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by column
chromatography on silica gel (eluting with petroleum ether:ethyl
acetate=3:1 to 1:1) to give the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 5.68 (br s, 1H), 3.86-3.37 (m, 11H),
2.70-2.27 (m, 4H), 2.17-2.06 (m, 1H), 1.99-1.78 (m, 1H).
Example 28D
2-(4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-yl)-4,-
4,5,5-tetramethyl-1,3,2-dioxaborolane
[0772] To a solution of Example 28C (3.4 g) in 1,4-dioxane (102 mL)
was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.9
g), potassium acetate (1.6 g) and
[1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.7 g)
at 20.degree. C. under nitrogen. The mixture was stirred at
80.degree. C. for 12 hours. The reaction was cooled to 20.degree.
C. One additional vial was set up as described above, and both of
the two mixtures were combined. The mixture was filtered and
concentrated to give a residue. The residue was purified by column
chromatography on silica gel (eluted with petroleum ether:ethyl
acetate=100:1 to 20:1) to give the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 6.44 (br d, 1H), 3.85-3.36 (m, 11H),
2.42-2.11 (m, 5H), 1.95-1.84 (m, 1H), 1.82-1.64 (m, 1H), 1.33-1.20
(m, 15H).
Example 28E
(2-(4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-yl)py-
rimidin-4-yl)methanol
[0773] To a solution of Example 28D (1.9 g) and
(2-chloropyrimidin-4-yl) methanol (0.6 g) in dioxane (30 mL) was
added tetrakis(triphenylphosphine)palladium(0) (0.2 g) and
saturated aqueous sodium bicarbonate (10 mL) at 15.degree. C. under
nitrogen atmosphere. The mixture was stirred under nitrogen at
100.degree. C. for 16 hours. The reaction mixture was cooled,
extracted with ethyl acetate three times, and the combined organic
phases were washed with brine twice, dried over anhydrous magnesium
sulfate, filtered and concentrated. The residue was purified by
prep-HPLC on a Gilson 281 semi-preparative HPLC using a Nano-micro
Kromazil C18 column (100.times.30 mm, 5 micron) eluting with
acetonitrile (14-100% over 10 minutes) in water containing 0.075%
trifluoroacetic acid to give the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.63 (d, 1H), 7.22 (br s, 1H), 7.07
(d, 1H), 4.74 (s, 2H), 3.91-3.38 (m, 12H), 2.79 (br d, 2H),
2.70-2.45 (m, 2H), 2.14 (qd, 1H), 1.98-1.81 (m, 1H).
Example 28F
(2-((1R,4s)-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohexyl)py-
rimidin-4-yl)methanol
[0774] To a solution of Example 28E (0.35 g) and triethylamine (0.2
mL) in dry tetrahydrofuran (10 mL) was added 10% Pd/C (0.1 g), and
the suspension was stirred for 16 hours under hydrogen (15 psi) at
25.degree. C. One additional reaction was set up as above. Both of
the two reactions were combined. The mixture was filtered and
concentrated to get the crude product. The crude material was
purified by chiral SFC on a Thar SFC80 preparative SFC using a
Chiralpak AS-H column (250.times.30 mm, 5 micron) with isopropanol
containing 0.1% ammonium hydroxide to give the title compound.
Analytical SFC of Example 28F on a Thar analytical SFC using a
Chiralpak AS-3 (0.46.times.10 cm, 3 micron) column with isopropanol
containing 0.05% isopropylamine from 5-40% in 5 minutes and a flow
rate of 4.0 mL/minute gave a retention time of 1.31 minutes.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.63 (d, 1H), 7.10
(d, 1H), 4.74 (s, 2H), 3.88-3.38 (m, 11H), 2.98-2.83 (m, 1H),
2.15-1.91 (m, 7H), 1.69-1.44 (m, 2H).
Example 28G
(2-((1R,4s)-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohexyl)py-
rimidin-4-yl)methanol
[0775] The title compound was obtained from the SFC separation in
Example 28F. Analytical SFC of Example 28G on a Thar analytical SFC
using a Chiralpak AS-3 (0.46.times.10 cm, 3 micron) column with
isopropanol containing 0.05% isopropylamine from 5-40% in 5 minutes
and a flow rate of 4.0 mL/minute gave a retention time of 1.05
minutes. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.69-8.57
(m, 1H), 7.11 (d, 1H), 4.74 (s, 2H), 3.87-3.36 (m, 11H), 3.16-3.00
(m, 1H), 2.17-1.51 (m, 8H).
Example 28H
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1R,4s)-4-({[(2S)-1,4-dioxan-2--
yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorop-
henyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylate
[0776] A vial containing Example 28F (50 mg), Example 1Z (40 mg),
triphenylphosphine (39 mg) and
N,N,N',N'-tetramethylazodicarboxamide (26 mg) in toluene (120
.mu.L) and tetrahydrofuran (120 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was cooled, diluted with
ethyl acetate, filtered over diatomaceous earth and concentrated.
The residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 0-9.5%
methanol in dichloromethane to give the title compound.
Example 28I
(7R,16R)-19,23-dichloro-10-({2-[(1R,4s)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
[0777] To a solution of Example 28H (56 mg) in dichloromethane (250
.mu.L) was added trifluoroacetic acid (250 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and taken up in water and acetonitrile. The
mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 5-80% over 30 minutes with
acetonitrile in water containing 10 mM ammonium acetate) to give
the title compound after lyophilization. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.75-8.67 (m, 2H), 7.44 (d,
1H), 7.24-7.08 (m, 5H), 6.84 (d, 1H), 6.76-6.66 (m, 1H), 6.25-6.14
(m, 1H), 5.87-5.78 (m, 1H), 5.20-5.00 (m, 2H), 4.94-4.80 (m, 1H),
4.50-4.37 (m, 2H), 3.76-3.22 (m, 10H), 3.00-2.77 (m, 4H), 2.75-2.58
(m, 3H), 2.45 (br s, 4H), 2.23 (s, 3H), 2.03-1.74 (m, 12H),
1.69-1.40 (m, 4H). MS (ESI) m/z 1073.0 (M-H).sup.-.
Example 29
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-[(2-{(1r,4r)-4-[(1,4-dioxan-2-yl)m-
ethoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 29A
tert-butyl
(7R,16R)-10-(benzyloxy)-19,23-dichloro-1-cyclobutyl-20,22-dimet-
hyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno--
13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inden-
e-7-carboxylate
[0778] To a 5 mL microwave vial, which was dried for 24 hours at
70.degree. C. under vacuum and stored in a glove box, was added
Example 17L (200 mg), potassium cyclobutyltrifluoroborate (80 mg),
Cs.sub.2CO.sub.3 (150 mg), [Ni(dtbbpy)]C12 (9 mg), and
Ir[dF(CF.sub.3)ppy].sub.2(dtbbpy) (25 mg) in a glove box. Freshly
degassed dioxane (1 mL) was added and the reaction mixture was
exposed to blue light (34 W Blue LED KESSIL Light, EvoluChem.TM.
PhotoRedOx Box) with stirring at 25.degree. C. for 20 hours. The
reaction mixture was concentrated, water (20 mL) was added and the
mixture was extracted twice with ethyl acetate (10 mL). The
combined organic extracts were washed with brine, dried over
MgSO.sub.4, filtered and concentrated in vacuo. Purification by
chromatography on silica gel using an ISCO CombiFlash.RTM.
Companion MPLC (4 g Chromabond.RTM. silica gel column, eluting with
0-10% dichloromethane/methanol) and subsequent purification by SFC
(Viridis PFP 250.times.19 mm 5 .mu.m column; gradient 5-50% liquid
CO.sub.2 in methanol+0.2% ammonium hydroxide) provided the title
compound. MS (ESI) m/z 859.3 (M+H).sup.+.
Example 29B
tert-butyl
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-hydroxy-20,22-dimethyl--
16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-
-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7--
carboxylate
[0779] A Tinyclave steel reactor (Buechi) was charged with Example
29A (165 mg) in tetrahydrofuran (10 mL) and Pd/C (50% wet with
water, 50 mg) was added. The reactor was purged with hydrogen gas
three times, and stirred under hydrogen first with a pressure of 50
psi for 24 hours and then under a pressure of 100 psi for 96 hours.
The reaction was vented, the mixture filtered over a filter funnel
packed with diatomaceous earth, and the filtrate then concentrated
in vacuo. Purification by chromatography on silica gel using an
ISCO CombiFlash.RTM. Companion MPLC (4 g Chromabond.RTM. silica gel
column, eluting with 0-10% dichloromethane/methanol) provided the
title compound. MS (ESI) m/z 769.3 (M+H).sup.+.
Example 29C
(2-((1R,4r)-4-(((R)-1,4-dioxan-2-yl)methoxy)cyclohexyl)pyrimidin-4-yl)meth-
yl methanesulfonate
[0780] To a solution of Example 9D (45 mg) in dichloromethane (1
mL) at a temperature of 5.degree. C. was added triethylamine (0.06
mL) and methanesulfonyl chloride (0.017 mL). The reaction was
allowed to warm to ambient temperature and was stirred for 1 hour.
Dichloromethane (3 mL) and water (4 mL) were added, the organic
layer separated via Chromabond.RTM. PTS cartridge, the aqueous
layer re-extracted with dichloromethane (2 mL), and the combined
organic layers concentrated in vacuo to give the title compound. MS
(ESI) m/z 387.2 (M+H).sup.+.
Example 29D
tert-butyl
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-[(2-{(1r,4r)-4-[(1,4-di-
oxan-2-yl)methoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylate
[0781] To a solution of Example 29B (57 mg) and Example 29C (40 mg)
in N,N-dimethylformamide, (1 mL) CsCO.sub.3 (61.5 mg) was added.
The mixture was stirred for 2 hours at ambient temperature. Ethyl
acetate (10 mL) and water (20 mL) were added, and the aqueous layer
re-extracted with ethyl acetate (10 mL). The combined organic
layers were washed with brine, dried over magnesium sulfate,
filtered and concentrated in vacuo. Purification of the crude
product by chromatography on silica gel using an ISCO
CombiFlash.RTM. Companion MPLC (4 g Chromabond.RTM. silica gel
column, eluting with 0-10% dichloromethane/methanol) provided the
title compound. MS (ESI) m/z 1059.4 (M+H).sup.+.
Example 29E
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-[(2-{(1r,4r)-4-[(1,4-dioxan-2-yl)m-
ethoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dimethyl-16-[(4-methylpipe-
razin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,1-
7-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0782] The title compound was prepared as described in Example 18S
by replacing Example 18R with Example 29D. .sup.1H NMR (600 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.70 (d, 1H), 8.65 (s, 1H),
7.40 (d, 1H), 6.84 (d, 1H), 6.75 (dd, 1H), 6.23 (m, 1H), 5.78 (d,
1H), 5.12 (d, 1H), 5.04 (d, 1H), 4.86 (m, 1H), 4.48 (m, 2H), 3.71
(m, 2H), 3.65-3.52 (m, 4H), 3.44 (m, 2H), 3.38-3.26 (m, 5H), 3.17
(t, 1H), 2.86 (dd, 1H), 2.76 (m, 1H), 2.72 (m, 2H), 2.55-2.45 (m,
8H), 2.20 (s, 3H), 2.13-1.99 (m, 4H), 1.98 (s, 3H), 1.95-1.93 (m,
2H), 1.88 (s, 3H), 1.92-1.81 (m, 1H), 1.74 (m, 1H), 1.59 (m, 2H),
1.26 (m, 2H). MS (ESI) m/z 1003.4 (M+H).sup.+.
Example 30
(7R,16R)-19,23-dichloro-10-{[2-(1,4-dioxepan-6-yl)pyrimidin-4-yl]methoxy}--
1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,-
15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-dia-
zacyclononadeca[1,2,3-cd]indene-7-carboxylic acid Example 30A
3,5-dihydro-2H-1,4-dioxepin-6-yl
1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate
[0783] To a solution of 1,4-dioxepan-6-one (300 mg) and
nonafluorobutanesulfonyl fluoride (900 mg) in dry dimethylformamide
(5 mL) was added 2-methyl-N-(tri(pyrrolidin-1-yl)
phosphoranylidene)-propan-2-amine (930 mg) dropwise at 0.degree. C.
The reaction mixture was stirred at 20.degree. C. for 1 hours. Two
additional vials were set up as described above. All three
reactions were combined, and the mixture was quenched with
saturated aqueous ammonium chloride solution and extracted with
petroleum ether three times. The combined organic layers were
washed with water and brine, dried over sodium sulfate, filtered
and concentrated under reduced pressure to give the title compound
which was used directly in the next step without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 6.93
(s, 1H), 4.42 (s, 2H), 4.21-4.15 (m, 2H), 3.90-3.84 (m, 2H),
3.27-3.15 (m, 1H).
Example 30B
2-(2,3-dihydro-5H-1,4-dioxepin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborola-
ne
[0784] To a solution of Example 30A (400 mg) in dimethoxyethane (5
mL) was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (280
mg), potassium acetate (300 mg), (1,1'-bis(diphenylphosphino)
ferrocenedichloro palladium(II) dichloromethane complex) (37 mg)
and (1,1'-bis(diphenylphosphino)ferrocene) (28 mg) under N.sub.2
atmosphere. The mixture was stirred at 80.degree. C. for 12 hours
under nitrogen atmosphere. Two other vials were set up as described
above. All three reactions were combined, and the reaction mixture
was concentrated under reduced pressure to give the title compound
which was used directly in the next step without further
purification.
Example 30C
(2-(3,5-dihydro-2H-1,4-dioxepin-6-yl)pyrimidin-4-yl)methanol
[0785] To a solution of Example 30B (680 mg) and
(2-chloropyrimidin-4-yl)methanol (400 mg) in 1,4-dioxane (4 mL) was
added tetrakis[triphenylphosphine]palladium(0) (140 mg) and
saturated aqueous sodium bicarbonate solution (1 mL). The mixture
was stirred under nitrogen at 110.degree. C. for 12 hours. The
reaction liquid was cooled to 25.degree. C., and filtered. The
filtrate was exacted with ethyl acetate three times. The organic
phases were combined and washed with brine twice. The organic phase
was dried over magnesium sulfate, filtered, and concentrated to
give the crude product which was purified by column chromatography
on silica gel (eluted with dichloromethane:methanol=1:5 to 1:3) to
afford the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.52 (d, 1H), 8.00 (s, 1H), 6.99 (d, 1H), 4.90 (s, 2H),
4.69 (br d, 2H), 4.34-4.30 (m, 2H), 4.03-3.97 (m, 2H), 3.49 (br s,
1H).
Example 30D
(2-(1,4-dioxepan-6-yl)pyrimidin-4-yl)methanol
[0786] To a mixture of 10% Pd/C (153 mg) in tetrahydrofuran (20 mL)
was added Example 30C (300 mg). The reaction mixture was stirred at
25.degree. C. under 15 psi of H.sub.2 for 12 hours. The reaction
was filtered, and the filtrate was concentrated under reduced
pressure to give the crude product. The crude product was purified
by column chromatography on silica gel (petroleum ether:ethyl
acetate 60:40-40:60) to give the title compound. .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. ppm 8.69 (d, 1H), 7.45 (d, 1H), 4.65 (s,
2H), 4.23-4.13 (m, 4H), 3.87-3.79 (m, 4H), 3.70-3.60 (m, 1H).
Example 30E
tert-butyl
(7R,16R)-19,23-dichloro-10-{[2-(1,4-dioxepan-6-yl)pyrimidin-4-y-
l]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)m-
ethyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-t-
hia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0787] A vial containing Example 30D (31 mg), Example 1Z (40 mg),
triphenylphosphine (39 mg) and
N,N,N',N'-tetramethylazodicarboxamide (26 mg) in toluene (120
.mu.L) and tetrahydrofuran (120 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was diluted with ethyl
acetate, filtered over diatomaceous earth and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 1.5-10%
methanol in dichloromethane to give the title compound.
Example 30F
(7R,16R)-19,23-dichloro-10-{[2-(1,4-dioxepan-6-yl)pyrimidin-4-yl]methoxy}--
1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,-
15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-dia-
zacyclononadeca[1,2,3-cd]indene-7-carboxylic Acid
[0788] To a solution of Example 30E (45 mg) in dichloromethane (230
.mu.L) was added trifluoroacetic acid (230 .mu.L), and the reaction
was allowed to stir for overnight. The reaction was concentrated
under a stream of nitrogen and taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 5-85% over 30 minutes with
acetonitrile in water containing 10 mM ammonium acetate) to give
the title compound after lyophilization. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.78-8.68 (m, 2H), 7.47 (d,
1H), 7.26-7.08 (m, 5H), 6.85 (d, 1H), 6.79-6.68 (m, 1H), 6.27-6.17
(m, 1H), 5.87-5.76 (m, 1H), 5.20-5.00 (m, 2H), 4.93-4.80 (m, 1H),
4.52-4.36 (m, 2H), 4.17-4.02 (m, 4H), 3.81-3.53 (m, 8H), 3.01-2.87
(m, 1H), 2.75-2.59 (m, 2H), 2.49-2.37 (br s, 4H), 2.24 (s, 3H),
1.97 (s, 6H). MS (ESI) m/z 944.25 (M-H).sup.-.
Example 31
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 31A
(R)-(6-(4-((1,4-dioxan-2-yl)methoxy)phenyl)pyrimidin-4-yl)methanol
[0789] A mixture of (6-chloropyrimidin-4-yl)methanol (102 mg),
Example 16A (200 mg), tris(dibenzylideneacetone)dipalladium(0) (5.7
mg), (1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8
phosphaadamantane (5.5 mg) and tribasic potassium phosphate (265
mg) were purged with argon for 30 minutes. A solution of
tetrahydrofuran (2.5 mL) and water (0.62 mL) was degassed and
added. The reaction mixture was stirred in a Biotage.RTM. Initiator
microwave unit for 3 hours at 65.degree. C. To the reaction mixture
was added ethyl acetate and the mixture was filtrated through a pad
of diatomaceous earth. To the filtrate was added ethyl acetate and
water. The aqueous phase was extracted twice with ethyl acetate.
The combined organic extracts were washed with brine and then dried
over magnesium sulfate, filtered and subsequently concentrated in
vacuo. The residue was purified by normal phase MPLC on a
Teledyne-Isco-Combiflash.RTM. system (eluting with 40-100% ethyl
acetate in heptane) to afford the title compound. MS (APCI) m/z
303.2 (M+H).sup.+.
Example 31B
tert-butyl
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methox-
y}phenyl)pyrimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4--
methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(methe-
no)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxy-
late
[0790] A 4 mL vial, equipped with stir bar, was charged with
Example 1Z (35 mg), Example 31A (15.7 mg), triphenylphosphine (22.7
mg) and tetramethlylazodicarboxamide (14.9 mg) and purged for 30
minutes with argon. A solution of tetrahydrofuran (0.5 mL) and
toluene (0.5 mL) were added and the reaction mixture was stirred
for 19 hours at ambient temperature. To the reaction mixture were
added triphenylphosphine (22.7 mg) and tetramethlylazodicarboxamide
(14.9 mg) and stirring was continued for 21 hours at ambient
temperature. The material in the reaction mixture was filtered off
and to the organic phase was added dichloromethane. The material
was washed with dichloromethane. The combined organic phases were
washed with water and brine solution. The organic phase was dried
via DryDisk.RTM. and subsequently concentrated in vacuo. The
residue was purified by normal phase MPLC on a
Teledyne-Isco-Combiflash.RTM. system (eluting with 0-20% methanol
in dichloromethane) to afford the title compound. MS (APCI) m/z
1093.3 (M+H).sup.+.
Example 31C
(7R,16R)-19,23-dichloro-10-{[6-(4-{[(2R)-1,4-dioxan-2-yl]methoxy}phenyl)py-
rimidin-4-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-methylpiper-
azin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-
-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0791] To a solution of Example 31B (44 mg) in dichloromethane (270
.mu.L) was added trifluoroacetic acid (310 .mu.L). The reaction
mixture was stirred for 24 hours at ambient temperature. The
reaction mixture was then concentrated in vacuo. The residue was
dissolved in dichloromethane and saturated aqueous sodium
bicarbonate solution was added. The aqueous phase was extracted
twice with dichloromethane. The combined organic phases were dried
via DryDisk.RTM. and concentrated in vacuo. The residue was
purified by HPLC (Waters X-Bridge C8 19.times.150 mm 5 .mu.m
column, gradient 5% to 100% acetonitrile+0.2% ammonium hydroxide in
water+0.2% ammonium hydroxide) to provide the title compound.
.sup.1H NMR (600 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 9.14
(d, 1H), 8.73 (s, 1H), 8.18 (m, 2H), 8.00 (s, 1H), 7.20 (m, 2H),
7.14 (m, 2H), 7.09 (m, 2H), 6.88 (d, 1H), 6.75 (m, 1H), 6.18 (m,
1H), 5.80 (s, 1H), 5.20 (d, 1H), 5.15 (d, 1H), 4.87 (m, 1H), 4.41
(m, 2H), 4.05 (m, 2H), 3.89 (m, 1H), 3.84 (m, 1H) 3.77 (m, 1H),
3.70-3.60 (m, 3H), 3.51 (m, 1H), 3.42 (m, 1H), 3.05 (m, 1H), 2.65
(m, 2H), 2.55-2.25 (m, 8H), 2.18 (s, 3H), 1.97 (s, 3H), 1.95 (s,
3H). MS (ESI) m/z 1037.4 (M+H).sup.+.
Example 32
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-[(2-{(1r,4r)-4-[(1,4-di-
oxan-2-yl)methoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
Example 32A
(R)-tert-butyl
2-acetoxy-3-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)propanoate
[0792] To a solution of Example 1P (12 g) in tetrahydrofuran (300
mL) was added Pd/C (0.210 g) under a nitrogen atmosphere. The
suspension was degassed and purged with hydrogen three times. The
reaction mixture was stirred under 50 psi of hydrogen at 50.degree.
C. for 10 hours. The mixture was cooled, filtered and concentrated
to give a residue which was purified by column chromatography on
silica gel (eluted with petroleum ether:ethyl acetate=100:1 to
100:5) to give the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 6.71-6.69 (m, 1H), 6.64-6.61 (m, 2H), 5.55
(s, 1H), 5.19-5.15 (dd, 1H), 3.14-3.02 (m, 2H), 2.12 (s, 3H), 1.43
(s, 9H), 0.97 (s, 9H), 0.17 (s, 6H).
Example 32B
(R)-tert-butyl
2-acetoxy-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(trimethylsilyl)ethox-
y)methoxy)phenyl)propanoate
[0793] To a solution of Example 32A (8.8 g) in tetrahydrofuran (280
mL) was added sodium hydride (0.120 g, 60% dispersion) at 0.degree.
C. After 15 minutes, (2-(chloromethoxy)ethyl)-trimethylsilane
(0.810 g) was added into the mixture dropwise. The reaction was
stirred at 25.degree. C. for 12 hours under a nitrogen atmosphere.
One additional vial was set up as described above and both of the
two mixtures were combined. The reaction was quenched with water
and extracted with ethyl acetate three times. The combined organic
layers were washed with brine twice, dried over anhydrous sodium
sulfate, filtered and concentrated to give a residue which was
purified by column chromatography on silica gel (petroleum
ether:ethyl acetate=100:1 to 100:5) to give the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 6.97-6.95 (m, 1H),
6.67-6.64 (m, 2H), 5.20-5.12 (m, 3H), 3.79-3.75 (m, 2H), 3.20-3.15
(dd, 1H), 2.97-2.91 (dd, 1H), 2.05 (s, 3H), 1.43 (s, 9H), 0.99-0.94
(m, 11H), 0.17-0.16 (m, 6H), 0.03-0.00 (m, 9H).
Example 32C
(R)-tert-butyl
3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(trimethylsilyl)ethoxy)methoxy)-
phenyl)-2-hydroxypropanoate
[0794] To a solution of Example 32B (9 g) in ethyl alcohol (280 mL)
was added sodium ethanolate (6.3 mg) at 0.degree. C. under nitrogen
flow. After 15 minutes, the reaction mixture was stirred at
25.degree. C. for 1 hour. The reaction was quenched with water and
extracted with ethyl acetate three times. The combined organic
layers were washed with brine twice, dried over anhydrous sodium
sulfate, filtered and concentrated to give a residue which was
purified by column chromatography on silica gel (petroleum
ether:ethyl acetate=100:1 to 100:5) to give the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 6.96 (d, 1H),
6.70-6.63 (m, 2H), 5.18 (s, 2H), 4.36-4.31 (m, 1H), 3.79-3.75 (m,
2H), 3.04-2.90 (m, 3H), 1.43 (s, 9H), 0.99-0.95 (m, 11H), 0.17 (s,
6H), 0.04-0.01 (m, 9H).
Example 32D
4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)thieno[2,3-d]pyrimid-
ine
[0795] To a suspension of Example 1E (25 g) in acetonitrile (300
mL) was added N-chlorosuccinimide (24 g) and HBF.sub.4Et.sub.2O (29
g). The reaction mixture was stirred at 15.degree. C. under
nitrogen atmosphere for 16 hours. Another reaction was set up as
above, and the two reaction mixtures were combined. The reaction
mixture was diluted with water and extracted with ethyl acetate
three times. The combined organic layers were dried over anhydrous
sodium sulfate, filtered and concentrated. The residue was purified
by column chromatography on silica gel (petroleum:ethyl acetate
from 200:1 to 20:1) to give the title compound. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 9.01 (s, 1H), 8.02 (s,
1H), 3.88 (s, 3H), 2.01 (s, 6H).
Example 32E
4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)-6-iodothieno[2,3-d]-
pyrimidine
[0796] To a suspension of Example 32D (20 g) in tetrahydrofuran
(200 mL) was added lithium diisopropylamide (38.1 mL, 2M) at
-78.degree. C. under nitrogen, and the reaction was stirred for 0.5
hours. Iodine (19.4 g) in tetrahydrofuran (100 mL) was added, and
the reaction mixture was stirred at the same temperature for 0.5
hours. The reaction mixture was warmed to 15.degree. C. under
nitrogen atmosphere for 1 hour. Two other vials were set up as
described above. The three reactions were combined, and the
resulting mixture was treated with saturated aqueous sodium
thiosulfate and extracted with ethyl acetate three times. The
combined organic layers were dried over anhydrous sodium sulfate,
filtered and concentrated. The crude material was purified by
column chromatography on silica gel (petroleum ether:ethyl acetate
from 100:1 to 40:1) to give the title compound. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.96 (s, 1H), 3.90 (s,
3H), 1.95 (s, 6H).
Example 32F
2,6-dichloro-4-(4-chloro-6-iodothieno[2,3-d]pyrimidin-5-yl)-3,5-dimethylph-
enol
[0797] To a solution of Example 32E (7.5 g) in dichloroethane (100
mL) was added aluminum chloride (6.0 g) at 0.degree. C. and heated
at 68.degree. C. for 6 hours. Two additional vials were set up as
described above. The three reactions were combined, and the
resulting mixture was quenched with saturated aqueous sodium
bicarbonate and saturated aqueous ammonium chloride at 0.degree. C.
The mixture was extracted with ethyl acetate/tetrahydrofuran=1:1
three times, and the combined organic phases were washed with
brine, dried over anhydrous magnesium sulfate, filtered and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel (n-hexane/ethyl
acetate/tetrahydrofuran=20:1:1 to 10:1:1) to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.85 (s,
1H), 6.23 (s, 1H), 2.00 (s, 6H).
Example 32G
2,6-dichloro-4-(4-chloro-6-(cyclopent-1-en-1-yl)thieno[2,3-d]pyrimidin-5-y-
l)-3,5-dimethylphenol
[0798] To a suspension of Example 32F (2.3 g) and
2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1.3 g) in water (5 mL) and dioxane (50 mL) was added cesium
carbonate (3 g) and tetrakis(triphenylphosphine)palladium(0) (0.535
g). The reaction mixture was heated to 80.degree. C. under nitrogen
atmosphere for 2 hours. The resulting mixture was diluted with
water and extracted with ethyl acetate three times. The combined
organic layers were washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. The residue was
purified by column chromatography on silica gel (n-hexane/ethyl
acetate=100:1 to 15:1) to give the title compound. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 10.13 (br s, 1H),
8.71-9.01 (m, 1H), 6.10 (d, 1H), 2.39 (td, 2H), 2.08-2.17 (m, 2H),
1.94 (s, 6H), 1.80 (quin, 2H).
Example 32H
(R)-5-(4-((1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propan-2-yl-
)oxy)-3,5-dichloro-2,6-dimethylphenyl)-4-chloro-6-(cyclopent-1-en-1-yl)thi-
eno[2,3-d]pyrimidine
[0799] To a suspension of Example 32G (6.6 g) and Example 1K (9.4
g) in tetrahydrofuran (80 mL) was added triphenylphosphine (8.1 g)
and (E)-di-tert-butyl diazene-1,2-dicarboxylate (7.1 g) at
0.degree. C. The reaction mixture was warmed to 25.degree. C. and
stirred for 12 hours. The reaction was concentrated to give a
residue which was purified by column chromatography on silica gel
(eluted with petroleum ether:ethyl acetate=94:6) to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.79 (s,
1H), 7.47 (d, 2H), 7.35 (d, 4H), 7.31-7.25 (m, 3H), 7.19 (dd, 2H),
6.87-6.77 (m, 5H), 5.95 (br s, 1H), 5.88-5.74 (m, 1H), 5.26-5.07
(m, 2H), 4.81-4.70 (m, 1H), 3.96 (d, 2H), 3.90-3.83 (m, 2H),
3.81-3.77 (m, 7H), 3.53 (d, 2H), 2.42-2.32 (m, 2H), 2.19 (br t,
2H), 2.01 (d, 6H), 1.89-1.77 (m, 3H).
Example 32I
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propan-
-2-yl)oxy)-3,5-dichloro-2,6-dimethylphenyl)-6-(cyclopent-1-en-1-yl)thieno[-
2,3-d]pyrimidin-4-yl)oxy)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(trime-
thylsilyl)ethoxy)methoxy)phenyl)propanoate
[0800] To a suspension of Example 32H (4.8 g) and Example 32C (3.3
g) in tert-butanol (60 mL) was added cesium carbonate (6.6 g) at
25.degree. C. under nitrogen flow. The reaction mixture was stirred
at 65.degree. C. for 16 hours. The reaction was quenched with water
and extracted with ethyl acetate three times. The combined organic
layers were washed with brine twice, dried over anhydrous sodium
sulfate, filtered and concentrated to give a residue which was
purified by column chromatography on silica gel (eluted with
petroleum ether:ethyl acetate=95:5) to give the title compound
which was used to the next step without further purification.
Example 32J
(R)-tert-butyl
2-((5-(4-(((S)-1-(allyloxy)-3-hydroxypropan-2-yl)oxy)-3,5-dichloro-2,6-di-
methylphenyl)-6-(cyclopent-1-en-1-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(5-
-((tert-butyldimethylsilyl)oxy)-2-((2-(trimethylsilyl)ethoxy)methoxy)pheny-
l)propanoate
[0801] To a solution of Example 321 (3.5 g) in methanol (25 mL) and
dichloromethane (25 mL) was added formic acid (4.1 mL) at 0.degree.
C. The reaction was stirred at 25.degree. C. for 16 hours. Three
additional vials were set up as described above, and all the four
reaction mixtures were combined. The combined mixture was poured
into saturated aqueous sodium bicarbonate solution at 0.degree. C.
and extracted with ethyl acetate three times. The combined organic
phases were washed with brine twice, dried over anhydrous sodium
sulfate, filtered and concentrated to get the crude product. The
crude product was purified by column chromatography on silica gel
(eluted with petroleum ether:ethyl acetate=97:3 to 90:10) to give
the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
8.48 (s, 1H), 7.35-7.24 (m, 2H), 7.21-7.14 (m, 1H), 6.91 (d, 1H),
6.87-6.79 (m, 1H), 6.61 (dd, 1H), 6.38 (d, 1H), 5.94-5.77 (m, 2H),
5.34 (t, 1H), 5.23 (dd, 1H), 5.19-5.09 (m, 3H), 4.59-4.50 (m, 1H),
4.04-3.93 (m, 3H), 3.92-3.79 (m, 5H), 3.78-3.70 (m, 5H), 2.58 (d,
2H), 2.51 (dd, 1H), 2.45-2.36 (m, 2H), 2.27-2.15 (m, 5H), 2.00 (s,
3H), 1.92-1.80 (m, 5H), 1.27 (s, 11H), 1.02-0.82 (m, 14H), 0.10 (d,
6H), 0.01 (s, 9H).
Example 32K
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-(cyclopent-1-en-1-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-
-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(trimethylsilyl)ethoxy)methoxy)ph-
enyl)propanoate
[0802] To a solution of Example 32J (4.6 g) and triethylamine (2.6
mL) in dichloromethane (100 mL) was added para-toluenesulfonyl
chloride (2.6 g) at 0.degree. C., and the reaction was stirred at
25.degree. C. for 40 hours. One additional vial was setup as
described above. Both of the two mixtures were combined and poured
into water and extracted with dichloromethane three times. The
combined organic phases were washed with brine twice, dried over
anhydrous magnesium sulfate, filtered and concentrated under
reduced pressure to afford the crude product which was purified by
column chromatography on silica gel (eluted with petroleum
ether:ethyl acetate=97:3 to 90:10) to give the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.47 (s, 1H), 7.81
(d, 2H), 7.34 (d, 2H), 6.92 (d, 1H), 6.61 (dd, 1H), 6.39 (d, 1H),
5.91 (br s, 1H), 5.82-5.67 (m, 1H), 5.35-5.27 (m, 1H), 5.21-5.06
(m, 4H), 4.67-4.57 (m, 1H), 4.51-4.37 (m, 2H), 4.14 (q, 1H),
3.94-3.79 (m, 3H), 3.78-3.66 (m, 4H), 2.62-2.49 (m, 2H), 2.46-2.37
(m, 5H), 2.23 (br t, 2H), 2.16 (s, 3H), 1.99 (s, 3H), 1.92-1.81 (m,
2H), 1.33-1.15 (m, 12H), 0.93 (s, 11H), 0.10 (d, 6H), 0.00 (s,
9H).
Example 32L
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-(cyclopent-1-en-1-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-
-(5-hydroxy-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)propanoate
[0803] To a solution of Example 32K (4.6 g) in dichloromethane (46
mL) was added tetra-N-butylammonium fluoride (5.2 mL, 1M) at
0.degree. C. After the addition, the reaction was stirred at
25.degree. C. for 16 hours under nitrogen atmosphere. One
additional vial was set up as described above. Both of the two
mixtures were combined, poured into water and extracted with ethyl
acetate three times. The combined organic layers were washed with
brine twice, dried over anhydrous sodium sulfate, filtered and
concentrated to give a residue which was purified by column
chromatography on silica gel (petroleum ether:ethyl acetate=100:1
to 100:5) to give the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.47 (s, 1H), 7.80 (d, 2H), 7.34 (d, 2H),
6.92 (d, 1H), 6.65 (dd, 1H), 6.02 (d, 1H), 5.89 (br s, 1H),
5.83-5.68 (m, 1H), 5.39 (dd, 1H), 5.22-5.09 (m, 5H), 4.70 (t, 1H),
4.51-4.41 (m, 2H), 3.98-3.67 (m, 7H), 2.83 (dd, 1H), 2.49-2.34 (m,
6H), 2.28-2.15 (m, 5H), 2.00-1.81 (m, 5H), 1.33 (s, 10H), 0.99-0.91
(m, 2H), 0.04-0.03 (m, 9H).
Example 32M
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-20,22-dimethyl--
16-{[(prop-2-en-1-yl)oxy]methyl}-10-{[2-(trimethylsilyl)ethoxy]methoxy}-7,-
8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-d-
iazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0804] To a solution of Example 32L (3.6 g) in dimethylformamide
(40 mL) was added cesium carbonate (5.6 g) at 0.degree. C., and the
reaction was stirred at 25.degree. C. for 16 hours under nitrogen
atmosphere. One additional vial was set up as described above. Both
of the mixtures were combined, quenched with water and extracted
with ethyl acetate three times. The combined organic layers were
washed with brine twice, dried over anhydrous sodium sulfate,
filtered and concentrated to give a residue which was purified by
column chromatography on silica gel (petroleum ether:ethyl
acetate=100:1 to 100:5) to give the title compound. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 8.55 (s, 1H), 6.95 (d, 1H), 6.74
(dd, 1H), 6.03-5.90 (m, 1H), 5.87 (dd, 1H), 5.79-5.67 (m, 2H), 5.34
(qd, 1H), 5.28-5.20 (m, 1H), 5.15 (s, 2H), 5.03-4.92 (m, 1H), 4.68
(dd, 1H), 4.37-4.29 (m, 1H), 4.21-4.06 (m, 2H), 3.91-3.70 (m, 4H),
3.49 (dd, 1H), 2.87-2.77 (m, 1H), 2.35 (dt, 2H), 2.13 (s, 3H),
2.09-1.99 (m, 5H), 1.79 (m, 2H), 1.13 (s, 10H), 0.01-0.00 (m,
9H).
Example 32N
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-16-(hydroxymeth-
yl)-20,22-dimethyl-10-{[2-(trimethylsilyl)ethoxy]methoxy}-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylate
[0805] To a degassed solution of Example 32M (2.3 g) in
tetrahydrofuran (50 mL) and methanol (50 mL) under nitrogen
atmosphere was added 1,3-dimethylpyrimidine-2,4,6,(1H,3H,5H)-trione
(2.5 g) and tetrakis(triphenylphosphine) palladium(0) (2.3 g), and
the reaction was stirred at 30.degree. C. for 18 hours. One
additional vial was set up as described above. Both of the mixtures
were combined, poured into water and extracted with ethyl acetate
three times. The combined organic phases were washed with brine
twice, dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure to afford the crude product
which was purified by column chromatography on silica gel (eluted
with petroleum ether:ethyl acetate=100:6 to 100:10) to give the
title compound which was used in the next step directly.
Example 320
tert-butyl
(7R,16S)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-20,22-dimethyl--
16-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}-10-{[2-(trimethylsilyl)ethoxy-
]methoxy}-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa--
2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0806] To a solution of Example 32N (1.3 g) and triethylamine (1.1
mL) in dichloromethane (50 mL) was added toluenesulfonyl chloride
(1.2 g) under nitrogen atmosphere at 0.degree. C., and the reaction
was stirred at 25.degree. C. for 12 hours. Three additional vials
were set up as described above. The mixtures were combined,
quenched with water and extracted with ethyl acetate three times.
The combined organic layers were washed with brine twice, dried
over anhydrous sodium sulfate, filtered and concentrated to give a
residue which was purified by column chromatography on silica gel
(petroleum ether:ethyl acetate=100:1 to 100:5) to give the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.55 (s,
1H), 7.86 (d, 2H), 7.37 (d, 2H), 6.96 (d, 1H), 6.69 (dd, 1H), 5.81
(dd, 1H), 5.76-5.68 (m, 2H), 5.15 (s, 2H), 5.03-4.87 (m, 1H), 4.58
(dd, 1H), 4.46-4.36 (m, 2H), 4.20 (d, 1H), 3.76 (t, 3H), 3.41 (dd,
1H), 2.84 (br d, 1H), 2.47 (s, 3H), 2.36 (br s, 2H), 2.13 (s, 3H),
1.98 (s, 5H), 1.90-1.73 (m, 3H), 1.29 (br d, 2H), 1.14 (s, 9H),
1.00-0.92 (m, 3H), 0.00 (s, 9H).
Example 32P
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-20,22-dimethyl--
16-[(4-methylpiperazin-1-yl)methyl]-10-{[2-(trimethylsilyl)ethoxy]methoxy}-
-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,-
5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylate
[0807] To a solution of Example 320 (1.6 g) in
N,N-dimethylformamide (16 mL) was added 1-methylpiperazine (16 mL)
under nitrogen atmosphere at 0.degree. C., and the reaction was
stirred at 55.degree. C. for 12 hours. Two other vials were set up
as described above. The three reaction mixtures were combined and
concentrated to a residue. The residue was dissolved in ethyl
acetate and washed with brine twice. The organic phase was dried
over anhydrous magnesium sulfate, filtered and concentrated to give
the crude product. The crude product was purified by column
chromatography on silica gel (eluted with petroleum ether:ethyl
acetate=1:1) to provide the title compound.
Example 32Q
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-hydroxy-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylate
[0808] To a solution of Example 32P (2.1 g) in dichloromethane (75
mL) was added HCl (1.1 mL, 1 M in methanol) under nitrogen
atmosphere at 0.degree. C., and the reaction was stirred at
25.degree. C. for 2 hours. Two additional vials were set up as
described above. The three reaction mixtures were combined,
quenched with saturated aqueous sodium bicarbonate solution at
0.degree. C. and extracted with ethyl acetate three times. The
combined organic layers were washed with brine twice, dried over
anhydrous sodium sulfate, filtered and concentrated to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.57
(s, 1H), 6.76-6.61 (m, 2H), 5.94 (dd, 1H), 5.73 (br s, 1H), 5.64
(d, 1H), 4.89 (q, 1H), 4.67-4.52 (m, 1H), 4.31 (br d, 1H),
3.66-3.49 (m, 1H), 2.91 (dd, 1H), 2.83-2.67 (m, 3H), 2.66-2.43 (m,
6H), 2.43-2.27 (m, 5H), 2.17-1.99 (m, 8H), 1.81 (m, 2H), 1.11 (s,
9H).
Example 32R
(2-((1r,4r)-4-((1,4-dioxan-2-yl)methoxy)cyclohexyl)pyrimidin-4-yl)methanol
[0809] To a stirred solution of Example 9C (750 mg) in
tetrahydrofuran (10 mL) at room temperature was added cesium
fluoride (2 g) and methanol (3 mL), and reaction was stirred for 3
days. The reaction was diluted with ethyl acetate, washed with
water and brine, dried over anhydrous sodium sulfate, filtered and
concentrated. The crude product was purified by normal phase silica
gel chromatography eluting with 30% ethyl acetate in
dichloromethane, then 5% 7N ammonia in methanol in dichloromethane
to give the title compound as a mixture of isomers. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. ppm 8.60 (d, 1H), 7.09 (d, 1H),
4.77-4.66 (m, 2H), 3.86-3.67 (m, 5H), 3.66-3.57 (m, 2H), 3.53 (dd,
1H), 3.49-3.39 (m, 2H), 3.37-3.26 (m, 1H), 2.93-2.82 (m, 1H),
2.23-2.13 (m, 2H), 2.12-2.05 (m, 2H), 1.76-1.61 (m, 2H), 1.48-1.35
(m, 2H).
Example 32S
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-[(2-{(1r,4r)-
-4-[(1,4-dioxan-2-yl)methoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylate
[0810] A vial containing Example 32R (47 mg), Example 32Q (40 mg),
triphenylphosphine (40 mg) and
N,N,N',N'-tetramethylazodicarboxamide (26 mg) in toluene (130
.mu.L) and tetrahydrofuran (130 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was diluted with ethyl
acetate, filtered over diatomaceous earth and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 0-10%
methanol in dichloromethane to give the title compound as a mixture
of diastereomers.
Example 32T
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-[(2-{(1r,4r)-4-[(1,4-di-
oxan-2-yl)methoxy]cyclohexyl}pyrimidin-4-yl)methoxy]-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
[0811] To a solution of Example 32S (48 mg) in dichloromethane (230
.mu.L) was added trifluoroacetic acid (230 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and was taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 5-85% over 30 minutes with
acetonitrile in water containing 10 mM ammonium acetate) to give
the title compound after lyophilization. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.69 (d, 1H), 8.64 (s, 1H),
7.40 (d, 1H), 6.82 (d, 1H), 6.77-6.69 (m, 1H), 6.24-6.15 (m, 1H),
5.85-5.80 (m, 1H), 5.79-5.72 (m, 1H), 5.16-4.98 (m, 2H), 4.94-4.80
(m, 1H), 4.56-4.39 (m, 2H), 3.75-3.66 (m, 2H), 3.65-3.19 (m, 12H),
2.92-2.61 (m, 6H), 2.45 (br s, 4H), 2.36-2.26 (m, 2H), 2.22 (s,
3H), 2.10-1.83 (m, 10H), 1.80-1.67 (m, 2H), 1.65-1.50 (m, 2H),
1.36-1.15 (m, 2H). MS (ESI) m/z 1013.0 (M-H).sup.-.
Example 33
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1R,4s)-4-({[(2S)--
1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
Example 33A
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1R,4s)-
-4-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4--
yl}methoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-t-
etrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclo-
nonadeca[1,2,3-cd]indene-7-carboxylate
[0812] A vial containing Example 28F (52 mg), Example 32Q (40 mg),
triphenylphosphine (40 mg) and
N,N,N',N'-tetramethylazodicarboxamide (26 mg) in toluene (130
.mu.L) and tetrahydrofuran (130 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was diluted with ethyl
acetate, filtered over diatomaceous earth and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 1-10%
methanol in dichloromethane to give the title compound.
Example 33B
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1R,4s)-4-({[(2S)--
1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
[0813] To a solution of Example 33A (46 mg) in dichloromethane (210
.mu.L) was added trifluoroacetic acid (210 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and was taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 5-85% over 30 min with
acetonitrile in water containing 10 mM ammonium acetate) to give
the title compound after lyophilization. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.70 (d, 1H), 8.64 (s, 1H),
7.42 (d, 1H), 6.82 (d, 1H), 6.75-6.69 (m, 1H), 6.23-6.15 (m, 1H),
5.86-5.81 (m, 1H), 5.79-5.73 (m, 1H), 5.18-5.01 (m, 2H), 4.92-4.85
(m, 1H), 4.55-4.43 (m, 2H), 3.75-3.35 (m, 10H), 3.31-3.21 (m, 1H),
2.91-2.60 (m, 6H), 2.44 (br s, 6H), 2.36-2.25 (m, 2H), 2.21 (s,
3H), 2.03 (s, 3H), 1.98-1.66 (m, 9H), 1.66-1.42 (m, 4H). MS (ESI)
m/z 1044.9 (M-H).sup.-.
Example 34
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4-({[(2R)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
Example 34A
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4--
({[(2R)-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimid-
in-4-yl}methoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15-
,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diaza-
cyclononadeca[1,2,3-cd]indene-7-carboxylate
[0814] A vial containing Example 40A (52 mg), Example 32Q (40 mg),
triphenylphosphine (40 mg) and
N,N,N',N'-tetramethylazodicarboxamide (26 mg) in toluene (130
.mu.L) and tetrahydrofuran (130 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was diluted with ethyl
acetate, filtered over diatomaceous earth and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 1-8.5%
methanol in dichloromethane to give the title compound.
Example 34B
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4-({[(2R)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
[0815] To a solution of Example 34A (47 mg) in dichloromethane (210
.mu.L) was added trifluoroacetic acid (210 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and was taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 10-95% over 30 minutes
with acetonitrile in water containing 10 mM ammonium acetate) to
give the title compound after lyophilization. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.72 (d, 1H), 8.63 (s, 1H),
7.40 (d, 1H), 7.16-7.08 (m, 1H), 6.84-6.78 (m, 1H), 6.74-6.68 (m,
1H), 6.23-6.15 (m, 1H), 5.86-5.81 (m, 1H), 5.79-5.73 (m, 1H),
5.19-5.02 (m, 2H), 4.90-4.84 (m, 1H), 4.54-4.43 (m, 2H), 3.76-3.35
(m, 12H), 3.32-3.25 (m, 1H), 2.91-2.81 (m, 1H), 2.76-2.61 (m, 4H),
2.48-2.26 (m, 8H), 2.20 (s, 3H), 2.07-1.66 (m, 14H). MS (ESI) m/z
1045.1 (M-H).sup.-.
Example 35
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4-({[(2S)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
Example 35A
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4--
({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimid-
in-4-yl}methoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15-
,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diaza-
cyclononadeca[1,2,3-cd]indene-7-carboxylate
[0816] A vial containing Example 45A (52 mg), Example 32Q (40 mg),
triphenylphosphine (40 mg) and
N,N,N',N'-tetramethylazodicarboxamide (26 mg) in toluene (130
.mu.L) and tetrahydrofuran (130 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was diluted with ethyl
acetate, filtered over diatomaceous earth and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 0.5-9%
methanol in dichloromethane to give the title compound.
Example 35B
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4S)-4-({[(2S)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
[0817] To a solution of Example 35A (50 mg) in dichloromethane (2
30 .mu.L) was added trifluoroacetic acid (230 .mu.L), and the
reaction was allowed to stir overnight. The reaction was
concentrated under a stream of nitrogen and was taken up in water
and acetonitrile. The mixture was purified by RP-HPLC on a Gilson
PLC 2020 using a Luna.TM. column (250.times.50 mm, 10 mm, 10-95%
over 30 minutes with acetonitrile in water containing 10 mM
ammonium acetate) to give the title compound after lyophilization.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.73
(d, 1H), 8.65 (s, 1H), 7.39 (d, 1H), 7.16-7.08 (m, 1H), 6.83 (d,
1H), 6.77-6.70 (m, 1H), 6.25-6.19 (m, 1H), 5.84-5.79 (m, 1H),
5.78-5.75 (m, 1H), 5.20-5.04 (m, 2H), 4.90-4.81 (m, 1H), 4.54-4.43
(m, 2H), 3.75-3.39 (m, 12H), 3.32-3.25 (m, 1H), 2.92-2.84 (m, 1H),
2.76-2.61 (m, 4H), 2.48-2.26 (m, 8H), 2.22 (s, 3H), 2.06-1.68 (in,
14H). MS (ESI) m/z 1043.0 (M-H).sup.-.
Example 36
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2S)-1,4-dioxan-2-yl]methyl}amino)pyr-
idin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
Example 36A
(S)--N-((1,4-dioxan-2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)pyridin-2-amine
[0818]
2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(325 mg) was dissolved in dimethylsulfoxide (5 mL).
(S)-(1,4-Dioxan-2-yl)methanamine hydrochloride (246 mg) was added,
followed by N-ethyl-N-isopropylpropan-2-amine (753 mg). The
solution was heated to 120.degree. C. for six hours and was cooled.
The solution was added to water (15 mL) and brine (3 mL). The
solution was extracted with dichloromethane (20 mL) three times.
The extracts were combined, dried on anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel using a 0% to 10% gradient of
methanol in dichloromethane. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.22 (d, 1H), 7.52 (dd, 1H),
6.95 (t, 1H), 6.47 (d, 1H), 3.73 (dd, 2H), 3.66-3.61 (m, 2H), 3.55
(td, 1H), 3.46 (td, 1H), 3.31 (m, 2H), 3.23 (dd, 1H), 1.31 (s, 3H),
1.25 (s, 6H), 1.07 (s, 3H). MS (ESI) m/z 321.3 (M+H).sup.+, 319.1
(M-H).sup.-.
Example 36B
(S)-(2-(6-(((1,4-dioxan-2-yl)methyl)amino)pyridin-3-yl)pyrimidin-4-yl)meth-
anol
[0819] The title compound was prepared by substituting Example 36A
for Example 2A in Example 2B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.99 (d, 1H), 8.75 (d, 1H),
8.26 (dd, 1H), 7.34 (d, 1H), 7.13 (t, 1H), 6.61 (d, 1H), 5.60 (t,
1H), 4.57 (d, 2H), 3.76 (td, 2H), 3.72-3.63 (m, 2H), 3.58 (td, 1H),
3.48 (td, 1H), 3.38 (m, 2H), 3.27 (m, 1H). MS (ESI) m/z 303.1
(M+H).sup.+.
Example 36C
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2S)-1,4-dioxan-2-yl]methy-
l}amino)pyridin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylate
[0820] The title compound was prepared by substituting Example 36B
for Example 7B in Example 7C. MS (ESI) m/z 1095.4 (M+H).sup.+.
Example 36D
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2S)-1,4-dioxan-2-yl]methyl}amino)pyr-
idin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
[0821] The title compound was prepared by substituting Example 36C
for Example 7C in Example 7D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 9.00 (s, 1H), 8.75 (s, 2H),
8.26 (dd, 1H), 7.36 (d, 1H), 7.24-7.11 (m, 5H), 6.87 (d, 1H), 6.75
(m, 1H), 6.62 (m, 1H), 6.24 (m, 1H), 5.80 (s, 1H), 5.17 (q, 2H),
4.85 (m, 1H), 4.45 (m, 2H), 3.78-3.72 (m, 2H), 3.68-3.59 (m, 4H),
3.58-3.53 (m, 2H), 3.51-3.45 (m, 2H), 2.98 (d, 2H), 2.72-2.62 (m,
3H), 2.50-2.32 (m, 6H), 2.18 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H).
MS (ESI) m/z 1037.5 (M+H).sup.+.
Example 37
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1S,4r)-4-({[(2S)--
1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
Example 37A
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1S,4r)-
-4-({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4--
yl}methoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-t-
etrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclo-
nonadeca[1,2,3-cd]indene-7-carboxylate
[0822] A vial containing Example 28G (33 mg), Example 32Q (30 mg),
triphenylphosphine (25 mg) and
N,N,N',N'-tetramethylazodicarboxamide (17 mg) in toluene (100
.mu.L) and tetrahydrofuran (100 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was diluted with ethyl
acetate, filtered over diatomaceous earth and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+12 g gold silica gel column eluting with 0-9%
methanol in dichloromethane to give the title compound.
Example 37B
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(1S,4r)-4-({[(2S)--
1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
[0823] To a solution of Example 37A (21 mg) in dichloromethane (100
.mu.L) was added trifluoroacetic acid (100 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and was taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 30-80% over 30 minutes
with acetonitrile in water containing 10 mM ammonium acetate) to
give the title compound after lyophilization. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.71 (d, 1H), 8.63 (s, 1H),
7.43 (d, 1H), 6.83 (d, 1H), 6.77-6.64 (m, 1H), 6.23-6.13 (m, 1H),
5.89-5.80 (m, 1H), 5.79-5.72 (m, 1H), 5.19-5.00 (m, 2H), 4.96-4.82
(m, 1H), 4.58-4.37 (m, 2H), 3.74-3.21 (m, 12H), 3.04-2.92 (m, 1H),
2.91-2.81 (m, 1H), 2.78-2.61 (m, 2H), 2.41 (br s, 6H), 2.35-2.26
(m, 2H), 2.21 (s, 3H), 2.03 (s, 3H), 2.00-1.58 (m, 12H). MS (ESI)
m/z 1045.1 (M-H).sup.-.
Example 38
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4-({[(2S)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
Example 38A
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4--
({[(2S)-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimid-
in-4-yl}methoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15-
,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diaza-
cyclononadeca[1,2,3-cd]indene-7-carboxylate
[0824] A vial containing Example 42A (52 mg), Example 32Q (40 mg),
triphenylphosphine (40 mg) and
N,N,N',N'-tetramethylazodicarboxamide (26 mg) in toluene (130
.mu.L) and tetrahydrofuran (130 .mu.L) was allowed to stir at
50.degree. C. overnight. The reaction was diluted with ethyl
acetate, filtered over diatomaceous earth and concentrated. The
residue was purified by normal phase MPLC on a Teledyne Isco
Combiflash.RTM. Rf+4 g gold silica gel column eluting with 0.5-8.5%
methanol in dichloromethane to give the title compound.
Example 38B
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4-({[(2S)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
[0825] To a solution of Example 38A (49 mg) in dichloromethane (220
.mu.L) was added trifluoroacetic acid (220 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and was taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 30-80% over 30 minutes
with acetonitrile in water containing 10 mM ammonium acetate) to
give the title compound after lyophilization. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.72 (d, 1H), 8.64 (s, 1H),
7.40 (d, 1H), 7.16-7.08 (m, 1H), 6.81 (d, 1H), 6.76-6.68 (m, 1H),
6.23-6.13 (m, 1H), 5.86-5.81 (m, 1H), 5.79-5.73 (m, 1H), 5.20-5.02
(m, 2H), 4.91-4.82 (m, 1H), 4.56-4.40 (m, 2H), 3.78-3.38 (m, 12H),
3.33-3.24 (m, 1H), 2.92-2.81 (m, 1H), 2.78-2.62 (m, 4H), 2.60-2.25
(m, 8H), 2.19 (s, 3H), 2.09-1.65 (in, 14H). MS (ESI) m/z 1042.9
(M-H).sup.-.
Example 39
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
Example 39A
8-methylene-1,4-dioxaspiro[4.5]decane
[0826] To a solution of methyltriphenylphosphonium bromide (68.6 g)
in tetrahydrofuran (200 mL) was added n-butyllithium (77 mL, 2.5 M
in tetrahydrofuran) at -78.degree. C. The reaction mixture was
stirred for 10 minutes at -78.degree. C., 30 minutes at 0.degree.
C., and cooled to -78.degree. C. A solution of
1,4-dioxaspiro[4.5]decan-8-one (50 g) in tetrahydrofuran (200 mL)
was added. The reaction mixture was stirred for 16 hours at
25.degree. C. and filtered. The filtrate was concentrated. The
residue was purified by column chromatography on silica gel (eluted
with petroleum ether:ethyl acetate=5:1) to provide the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 4.67 (s,
2H), 3.97 (s, 4H), 2.31-2.27 (m, 4H), 1.72-1.64 (m, 3H).
Example 39B
8-(bromomethyl)-8-fluoro-1,4-dioxaspiro[4.5]decane
[0827] To a mixture of Example 39A (10 g) and
1-bromopyrrolidine-2,5-dione (13.85 g) in dichloromethane (150 mL)
was added triethylamine trihydrofluoride (15.68 g) at 0.degree. C.
The reaction mixture was stirred at 20.degree. C. for 2 hours,
poured into saturated aqueous sodium bicarbonate solution (500 mL)
and extracted with dichloromethane (500 mL). The combined organic
extracts were washed with 0.1M aqueous HCl (2.times.200 mL) and 5%
aqueous sodium hydrogen carbonate solution (2.times.200 mL), dried
over MgSO.sub.4, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (eluted with
petroleum ether:ethyl acetate=3:1) to provide the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 3.99-3.92 (m, 4H),
3.48 (d, 2H), 2.10-2.05 (m, 2H), 1.91-1.64 (m, 6H).
Example 39C
(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methyl acetate
[0828] To a mixture of Example 39B (10 g) and potassium iodide
(0.656 g) in dimethylformamide (100 mL) was added potassium acetate
(38.8 g) at 25.degree. C. The mixture was heated at 135.degree. C.
for 16 hours, cooled, poured into water and extracted with ethyl
acetate. The combined organic layer was washed with brine
(2.times.100 mL). The organic phase was dried over sodium sulfate,
filtered, and concentrated. The residue was purified by column
chromatography on silica gel (eluted with petroleum ether:ethyl
acetate=3:1 to 1:1) to provide the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 4.11 (d, 2H), 3.99-3.93 (m, 4H), 2.10
(s, 3H), 1.97-1.63 (m, 8H).
Example 39D
(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methanol
[0829] To a solution of Example 39C (25 g) in tetrahydrofuran (200
mL) and water (100 mL) was added lithium hydroxide monohydrate
(6.78 g) at 0.degree. C. The reaction mixture was stirred for 16
hours at 25.degree. C., poured into H.sub.2O (500 mL) and extracted
with ethyl acetate (3.times.500 mL). The combined organic phase was
washed with brine (2.times.100 mL). The organic layers were
combined, dried over magnesium sulfate, filtered, and concentrated.
The residue was purified by column chromatography on silica gel
(eluted with petroleum ether:ethyl acetate=3:1) to provide the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
3.99-3.93 (m, 4H), 3.64-3.57 (m, 2H), 2.03-2.01 (m, 2H), 1.89-1.86
(m, 3H), 1.68-1.63 (m, 4H).
Example 39E
(R)-8-(((1,4-dioxan-2-yl)methoxy)methyl)-8-fluoro-1,4-dioxaspiro[4.5]decan-
e
[0830] The title compound was prepared as described in Example 28A
by replacing (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate
with (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 4.01-3.89 (m, 4H), 3.84-3.67
(m, 5H), 3.65-3.38 (m, 6H), 2.03-1.83 (m, 4H), 1.80-1.57 (m,
4H).
Example 39F
(R)-4-(((1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohexanone
[0831] The title compound was prepared as described in Example 28B
by replacing Example 28A with Example 39E. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 3.89-3.29 (m, 11H), 2.67 (dt, 2H),
2.41-2.20 (m, 4H), 2.04-1.75 (m, 2H).
Example 39G
4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-yl
trifluoromethanesulfonate
[0832] The title compound was prepared as described in Example 28C
by replacing Example 28B with Example 39F. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 5.67 (br s, 1H), 3.87-3.32 (m, 11H),
2.68-2.26 (m, 4H), 2.16-2.06 (m, 1H), 1.99-1.78 (m, 1H).
Example 39H
2-(4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-yl)-4,-
4,5,5-tetramethyl-1,3,2-dioxaborolane
[0833] The title compound was prepared as described in Example 28D
by replacing Example 28C with Example 39G. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 6.43 (br d, 1H), 3.84-3.38 (m, 11H),
2.42-2.12 (m, 4H), 1.97-1.83 (m, 1H), 1.82-1.57 (m, 1H), 1.26 (s,
17H).
Example 391
(2-(4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-yl)py-
rimidin-4-yl)methanol
[0834] The title compound was prepared as described in Example 28E
by replacing Example 28D with Example 39H. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.63 (d, 1H), 7.21 (br s, 1H), 7.07 (d,
1H), 4.73 (s, 2H), 3.87-3.39 (m, 11H), 2.78 (br d, 2H), 2.70-2.45
(m, 2H), 2.20-2.08 (m, 1H), 1.99-1.80 (m, 1H).
Example 39J
(2-((1R,4S)-4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohexyl)py-
rimidin-4-yl)methanol
[0835] The title compound was prepared as described in Example 28F
by replacing Example 28E with Example 39. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.63 (d, 1H), 7.10 (d, 1H), 4.74 (d, 2H),
3.88-3.39 (m, 11H), 2.98-2.85 (m, 1H), 2.20-1.92 (m, 6H), 1.69-1.42
(m, 3H). MS (ESI) m/z 341.1 (M+H).sup.+.
Example 39K
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2R)-1,4-dioxan-2--
yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorop-
henyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylate
[0836] The title compound was prepared as described in Example 5F
by replacing Example 5E with Example 39J.
Example 39L
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
[0837] The title compound was prepared as described in Example 5G
by replacing Example 5F with Example 39K. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.77-8.70 (m, 2H), 7.43 (d, 1H),
7.25-7.10 (m, 4H), 6.87 (d, 1H), 6.76 (dd, 1H), 6.24 (dd, 1H), 5.78
(d, 1H), 5.11 (q, 2H), 4.90-4.83 (m, 1H), 4.45 (d, 2H), 3.78-3.52
(m, 12H), 3.03-2.79 (m, 4H), 2.73-2.65 (m, 3H), 2.24 (s, 3H), 2.00
(s, 3H), 1.97-1.78 (m, 9H), 1.16-1.14 (m, 2H). MS (ESI) m/z 1075.5
(M+H).sup.+.
Example 40
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}met-
hyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
Example 40A
(2-((S)-4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-y-
l)pyrimidin-4-yl)methanol
[0838] Racemic Example 391 was separated by SFC on a Thar SFC80
preparative SFC (Column: Chiralpak AD-H, 250.times.30 mm i.d. 5
.mu.m; Mobile phase: A for CO.sub.2 and B for methanol (0.1%
NH.sub.3--H.sub.2O); Gradient: B %=45%; Flow rate: 85 g/minute;
Wavelength: 220 nm; Column temperature: 40.degree. C.; System back
pressure: 100 bar; Cycle time: 22 minutes; Injection amount: 25 mg
per injection) to provide the title compound. .sup.1H NMR S ppm
8.63 (d, 1H), 7.22 (br s, 1H), 7.07 (d, 1H), 4.73 (d, 2H),
3.92-3.38 (m, 12H), 2.92-2.41 (m, 4H), 2.21-2.02 (m, 1H), 1.98-1.77
(m, 1H).
Example 40B
(2-((R)-4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-y-
l)pyrimidin-4-yl)methanol
[0839] The title compound was obtained from the SFC separation in
Example 40A. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.63 (d,
1H), 7.21 (br s, 1H), 7.08 (d, 1H), 4.73 (s, 2H), 3.92-3.37 (m,
12H), 2.90-2.43 (m, 4H), 2.18-2.04 (m, 1H), 1.98-1.77 (m, 1H).
Example 40C
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2R)-1,4-dioxan-2-yl]-
methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fl-
uorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-t-
etrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclo-
nonadeca[1,2,3-cd]indene-7-carboxylate
[0840] The title compound was prepared as described in Example 5F
by replacing Example 5E with Example 40A. MS (ESI) m/z 1129.5
(M+H).sup.+.
Example 40D
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}met-
hyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
[0841] The title compound was prepared as described in Example 5G
by replacing Example 5F with Example 40C. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.74 (t, 2H), 7.40 (d, 1H),
7.25-7.10 (m, 5H), 6.85 (d, 1H), 6.75 (dd, 1H), 6.23 (dd, 1H), 5.79
(d, 1H), 5.13 (q, 2H), 4.89-4.82 (m, 1H), 4.44 (d, 2H), 3.78-3.44
(m, 15H), 2.96 (d, 2H), 2.72-2.62 (m, 3H), 2.44-2.27 (m, 6H), 2.21
(s, 3H), 2.08-1.92 (m, 14H), 1.88-1.66 (m, 2H). MS (ESI) m/z 1073.5
(M+H).sup.+.
Example 41
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2R)-1,4-dioxan-2-yl]methyl}amino)pyr-
idin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
Example 41A
(R)--N-((1,4-dioxan-2-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
-2-yl)pyridin-2-amine
[0842] The title compound was prepared by substituting
(R)-(1,4-dioxan-2-yl)methanamine hydrochloride for
(S)-(1,4-dioxan-2-yl)methanamine hydrochloride in Example 36A.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.22
(d, 1H), 7.52 (dd, 1H), 6.95 (t, 1H), 6.47 (d, 1H), 3.73 (dd, 2H),
3.66-3.60 (m, 2H), 3.55 (td, 1H), 3.45 (td, 1H), 3.31 (m, 2H), 3.23
(dd, 1H), 1.31 (s, 3H), 1.25 (s, 6H), 1.07 (s, 3H). MS (ESI) m/z
321.3 (M+H).sup.+.
Example 41B
(R)-(2-(6-(((1,4-dioxan-2-yl)methyl)amino)pyridin-3-yl)pyrimidin-4-yl)meth-
anol
[0843] The title compound was prepared by substituting Example 41A
for Example 2A in Example 2B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.95 (d, 1H), 8.71 (d, 1H),
8.22 (dd, 1H), 7.30 (d, 1H), 7.09 (t, 1H), 6.57 (d, 1H), 5.56 (t,
1H), 4.53 (d, 2H), 3.73 (td, 2H), 3.68-3.58 (m, 2H), 3.54 (td, 1H),
3.44 (td, 1H), 3.34 (m, 2H), 3.23 (m, 1H). MS (ESI) m/z 303.3
(M+H).sup.+.
Example 41C
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2R)-1,4-dioxan-2-yl]methy-
l}amino)pyridin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylate
[0844] The title compound was prepared by substituting Example 41B
for Example 7B in Example 7C. MS (ESI) m/z 1095.4 (M+H).sup.+.
Example 41D
(7R,16R)-19,23-dichloro-10-({2-[6-({[(2R)-1,4-dioxan-2-yl]methyl}amino)pyr-
idin-3-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
[0845] The title compound was prepared by substituting Example 41C
for Example 7C in Example 7D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.93 (s, 1H), 8.67 (s, 2H),
8.19 (dd, 1H), 7.29 (d, 1H), 7.15-7.04 (m, 5H), 6.80 (d, 1H), 6.68
(dd, 1H), 6.54 (d, 1H), 6.17 (dd, 1H), 5.74 (d, 1H), 5.10 (q, 2H),
4.78 (m, 1H), 4.37 (m, 2H), 3.72-3.65 (m, 2H), 3.63-3.54 (m, 2H),
3.50 (td, 2H), 3.40 (td, 2H), 3.31 (m, 2H), 3.20 (dd, 1H), 2.90 (d,
2H), 2.60 (m, 2H), 2.37 (m, 6H), 2.14 (s, 3H), 1.92 (s, 3H), 1.88
(s, 3H). MS (ESI) m/z 1037.5 (M+H).sup.+.
Example 42
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}met-
hyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
Example 42A
(2-((R)-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-y-
l)pyrimidin-4-yl)methanol
[0846] Racemic Example 28E was separated by SFC on a Thar SFC80
preparative SFC (Column: Chiralpak AD-H, 250.times.30 mm i.d. 5
.mu.m; Mobile phase: A for CO.sub.2 and B for methanol (0.1%
ammonium hydroxide); Gradient: B %=45%; Flow rate: 85 g/min;
Wavelength: 220 nm; Column temperature: 40.degree. C.; System back
pressure: 100 bar; Cycle time: 22 minutes; Injection amount: 25 mg
per injection) to provide the title compound. .sup.1H NMR 6 ppm
8.63 (d, 1H), 7.22 (br s, 1H), 7.07 (d, 1H), 4.73 (d, 2H),
3.92-3.38 (m, 12H), 2.92-2.41 (m, 4H), 2.21-2.02 (m, 1H), 1.98-1.77
(m, 1H).
Example 42B
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2$)-1,4-dioxan-2-yl]-
methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fl-
uorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-t-
etrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclo-
nonadeca[1,2,3-cd]indene-7-carboxylate
[0847] The title compound was prepared as described in Example 5F
by replacing Example 5E with Example 42A.
Example 42C
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2)-1,4-dioxan-2-yl]methoxy}meth-
yl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)--
20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18-
,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2-
,3-cd]indene-7-carboxylic Acid
[0848] The title compound was prepared as described in Example 5G
by replacing Example 5F with Example 42B. .sup.1H NMR (501 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.74 (t, 2H), 7.40 (d, 1H),
7.24-7.11 (m, 5H), 6.85 (d, 1H), 6.75 (dd, 1H), 6.23 (dd, 1H), 5.78
(d, 1H), 5.20-5.06 (m, 2H), 4.89-4.82 (m, 1H), 4.45 (d, 2H),
3.76-3.68 (m, 3H), 3.66-3.53 (m, 9H), 3.01-2.90 (m, 1H), 2.68 (dd,
3H), 2.45 (s, 1H), 2.39 (s, 2H), 2.20 (s, 3H), 2.00 (s, 4H), 1.95
(s, 3H), 1.86-1.68 (m, 1H). MS (ESI) m/z 1073.5 (M+H).sup.+.
Example 43
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}met-
hyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
Example 43A
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2R)-1,4-dioxan-2-yl]-
methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fl-
uorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-t-
etrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclo-
nonadeca[1,2,3-cd]indene-7-carboxylate
[0849] A vial containing Example 40B (63 mg), Example 1Z (50 mg),
triphenylphosphine (49 mg) and
N,N,N',N'-tetramethylazodicarboxamide (32 mg) in toluene (150
.mu.L) and tetrahydrofuran (150 .mu.L) was allowed to stir at
50.degree. C. for 2.5 hours and at room temperature overnight. The
reaction was diluted with ethyl acetate, filtered over diatomaceous
earth and concentrated. The residue was purified by normal phase
MPLC on a Teledyne Isco Combiflash.RTM. Rf+4 g gold silica gel
column eluting with 0.5-9.5% methanol in dichloromethane to give
the title compound.
Example 43B
(7R,16R)-19,23-dichloro-10-({2-[(4R)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}met-
hyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
[0850] To a solution of Example 43A (49 mg) in dichloromethane (300
.mu.L) was added trifluoroacetic acid (300 .mu.L), and the reaction
was allowed to stir for 5 hours. The reaction was concentrated
under a stream of nitrogen and was taken up in water and
acetonitrile. The mixture was purified by RP-HPLC on a Gilson PLC
2020 using a Luna.TM. column (250.times.50 mm, 10 mm, 30-80% over
30 minutes with acetonitrile in water containing 10 mM ammonium
acetate) to give a residue after lyophilization that was further
purified by normal phase MPLC on a Teledyne Isco Combiflash.RTM.
Rf+4 g gold silica gel column eluting with 10-25% methanol in
dichloromethane to give the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.77-8.70 (m, 2H), 7.40 (d,
1H), 7.24-7.09 (m, 5H), 6.84 (d, 1H), 6.78-6.70 (m, 1H), 6.27-6.19
(m, 1H), 5.84-5.78 (m, 1H), 5.21-5.03 (m, 2H), 4.91-4.80 (m, 1H),
4.50-4.38 (m, 2H), 3.77-3.39 (m, 12H), 3.32-3.24 (m, 1H), 3.00-2.90
(m, 1H), 2.78-2.60 (m, 4H), 2.58-2.37 (m, 6H), 2.23 (s, 3H),
2.07-1.91 (m, 8H), 1.85-1.66 (m, 2H). MS (ESI) m/z 1073.1
(M-H).sup.-.
Example 44
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-{[(2S)-1,4-dioxan-2-yl]methoxy}c-
yclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
Example 44A
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-{[(2S)-1,4-dioxan-2-y-
l]methoxy}cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dime-
thyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-
-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]inde-
ne-7-carboxylate
[0851] Example 9E (74 mg) and Example 1Z (65 mg) were azeotroped
with toluene and tetrahydrofuran three times. The residue was taken
up in toluene (200 .mu.L) and tetrahydrofuran (200 .mu.L), and
triphenylphosphine (63 mg) and
N,N,N',N'-tetramethylazodicarboxamide (41 mg) were added. The
reaction was heated to 50.degree. C. for 6 hours. The reaction was
diluted with ethyl acetate, filtered over diatomaceous earth and
concentrated. The residue was purified by normal phase MPLC on a
Teledyne Isco Combiflash.RTM. Rf+4 g gold silica gel column eluting
with 1-10% methanol in dichloromethane to give the title
compound.
Example 44B
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-{[(2S)-1,4-dioxan-2-yl]methoxy}c-
yclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylic Acid
[0852] To a solution of Example 44A (85 mg) in dichloromethane (390
.mu.L) was added trifluoroacetic acid (390 .mu.L), and the reaction
was allowed to stir overnight. The reaction was concentrated under
a stream of nitrogen and was taken up in water and acetonitrile.
The mixture was purified by RP-HPLC on a Gilson PLC 2020 using a
Luna.TM. column (250.times.50 mm, 10 mm, 30-80% over 30 minutes
with acetonitrile in water containing 10 mM ammonium acetate) to
give the title compound after lyophilization. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.72-8.67 (m, 2H), 7.44 (d,
1H), 7.23-7.09 (m, 5H), 6.81 (d, 1H), 6.71 (dd, 1H), 6.18-6.11 (m,
1H), 5.87-5.80 (m, 1H), 5.17-5.00 (m, 2H), 4.94-4.83 (m, 1H),
4.49-4.36 (m, 2H), 3.75-3.66 (m, 2H), 3.65-3.52 (m, 6H), 3.48-3.22
(m, 6H), 2.97-2.88 (m, 1H), 2.82-2.60 (m, 3H), 2.56-2.28 (br m,
4H), 2.18 (s, 3H), 2.09-2.00 (m, 2H), 1.99-1.91 (m, 8H), 1.66-1.52
(m, 2H), 1.33-1.18 (m, 2H).
Example 45
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}met-
hyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
Example 45A
(2-((S)-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohex-1-en-1-y-
l)pyrimidin-4-yl)methanol
[0853] Racemic Example 28E was separated by SFC on a Thar SFC80
preparative SFC (Column: Chiralpak AD-H, 250.times.30 mm i.d. 5
.mu.m; Mobile phase: A for CO.sub.2 and B for methanol (0.1%
NH.sub.3--H.sub.2O); Gradient: B %=45%; Flow rate: 85 g/minute;
Wavelength: 220 nm; Column temperature: 40.degree. C.; System back
pressure: 100 bar; Cycle time: 22 minute; Injection amount: 25 mg
per injection) to provide the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.63 (d, 1H), 7.22 (br s, 1H), 7.07 (d,
1H), 4.73 (br s, 2H), 3.95-3.33 (m, 12H), 2.88-2.39 (m, 4H),
2.20-2.04 (m, 1H), 1.99-1.79 (m, 1H).
Example 45B
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2S)-1,4-dioxan-2-yl]-
methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fl-
uorophenyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-t-
etrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclo-
nonadeca[1,2,3-cd]indene-7-carboxylate
[0854] The title compound was prepared as described in Example 5F
by replacing Example 5E with Example 45A. MS (ESI) m/z 1129.6
(M+H).sup.+.
Example 45C
(7R,16R)-19,23-dichloro-10-({2-[(4S)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}met-
hyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-
-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-1-
8,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,-
2,3-cd]indene-7-carboxylic Acid
[0855] The title compound was prepared as described in Example 5G
by replacing Example 5F with Example 45B. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.77-8.71 (m, 2H), 7.40 (d,
1H), 7.25-7.10 (m, 5H), 6.85 (d, 1H), 6.75 (dd, 1H), 6.24 (dd, 1H),
5.78 (d, 1H), 5.21-5.05 (m, 2H), 4.85 (q, 1H), 4.45 (d, 2H),
3.78-3.50 (m, 11H), 2.96 (d, 2H), 2.72-2.64 (m, 3H), 2.48-2.29 (m,
9H), 2.23 (s, 3H), 2.00 (s, 4H), 1.95 (s, 3H), 1.88-1.65 (m, 1H).
MS (ESI) m/z 1073.4 (M+H).sup.+.
Example 46
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
Example 46A
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2S)-1,4-dioxan-2--
yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorop-
henyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylate
[0856] The title compound was prepared as described in Example 5F
by replacing Example 5E with Example 28G. MS (ESI) m/z 1131.54
(M+H).sup.+.
Example 46B
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
[0857] The title compound was prepared as described in Example 5G
by replacing Example 5F with Example 46A. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.76-8.69 (m, 2H), 7.45 (d,
1H), 7.24-7.09 (m, 4H), 6.84 (d, 1H), 6.73 (dd, 1H), 6.17 (d, 1H),
5.83 (d, 1H), 5.10 (q, 2H), 4.89 (s, 1H), 4.44 (d, 2H), 3.73-3.51
(m, 13H), 3.51-3.41 (m, 3H), 3.05-2.87 (m, 3H), 2.68 (t, 3H), 2.36
(s, 2H), 2.18 (s, 3H), 1.94 (dd, 9H), 1.85-1.78 (m, 2H), 1.72-1.62
(m, 2H). MS (ESI) m/z 1073.1 (M-H).sup.-.
Example 47
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
Example 47A
(2-((1R,4r)-4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)-4-fluorocyclohexyl)py-
rimidin-4-yl)methanol
[0858] The title compound was prepared as described in Example 28F
by replacing Example 28E with Example 39I.
Example 47B
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2R)-1,4-dioxan-2--
yl]methoxy}methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorop-
henyl)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrah-
ydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononad-
eca[1,2,3-cd]indene-7-carboxylate
[0859] The title compound was prepared as described in Example 5F
by replacing Example 5E with Example 47A. MS (ESI) m/z 1133.5
(M+H).sup.+.
Example 47C
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}-
methyl)-4-fluorocyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,2-
2-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21--
etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-c-
d]indene-7-carboxylic Acid
[0860] The title compound was prepared as described in Example 5G
by replacing Example 5F with Example 47B. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.73 (d, 2H), 7.44 (d, 1H),
7.24-7.09 (m, 4H), 6.85 (d, 1H), 6.74 (dd, 1H), 6.20 (dd, 1H), 5.81
(d, 1H), 5.10 (q, 2H), 4.88 (d, 1H), 4.44 (d, 2H), 3.73-3.38 (m,
5H), 3.01-2.90 (m, 3H), 2.75-2.61 (m, 3H), 2.46 (s, 2H), 2.38 (s,
2H), 2.19 (s, 3H), 1.97 (d, 9H), 1.82 (d, 2H), 1.66 (q, 2H). MS
(ESI) m/z 1075.6 (M+H).sup.+.
Example 48
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4-({[(2R)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
Example 48A
tert-butyl
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4--
({[(2R)-1,4-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimid-
in-4-yl}methoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15-
,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diaza-
cyclononadeca[1,2,3-cd]indene-7-carboxylate
[0861] Example 40B (43 mg) and Example 32P (50 mg) were azeotroped
with toluene and tetrahydrofuran three times. The residue was taken
up in toluene (160 .mu.L) and tetrahydrofuran (160 .mu.L), and
triphenylphosphine (50 mg) and
N,N,N',N'-tetramethylazodicarboxamide (33 mg) were added. The
reaction mixture was heated to 50.degree. C. overnight. The
reaction mixture was diluted with ethyl acetate, filtered over
diatomaceous earth, and concentrated. The residue was purified by
normal phase MPLC on a Teledyne Isco Combiflash.RTM. Rf+4 g gold
silica gel column eluting with 0-7% methanol in dichloromethane to
give the title compound.
Example 48B
(7R,16R)-19,23-dichloro-1-(cyclopent-1-en-1-yl)-10-({2-[(4R)-4-({[(2R)-1,4-
-dioxan-2-yl]methoxy}methyl)-4-fluorocyclohex-1-en-1-yl]pyrimidin-4-yl}met-
hoxy)-20,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahy-
dro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononade-
ca[1,2,3-cd]indene-7-carboxylic Acid
[0862] To a solution of Example 48A (59 mg) in dichloromethane (270
.mu.L) was added trifluoroacetic acid (270 .mu.L), and the reaction
mixture was allowed to stir overnight. The reaction mixture was
concentrated under a stream of nitrogen and taken up in water and
acetonitrile. The mixture was purified by RP-HPLC on a Gilson PLC
2020 using a Luna.RTM. column (250.times.50 mm, 10 mm, 30-80% over
30 minutes with acetonitrile in water containing 10 mM ammonium
acetate) to give the title compound after lyophilyzation. .sup.1H
NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 8.72 (d, 1H),
8.64 (s, 1H), 7.40 (d, 1H), 7.17-7.08 (m, 1H), 6.82 (d, 1H),
6.77-6.68 (m, 1H), 6.24-6.15 (m, 1H), 5.87-5.80 (m, 1H), 5.79-5.73
(m, 1H), 5.20-5.02 (m, 2H), 4.93-4.81 (m, 1H), 4.57-4.41 (m, 2H),
3.77-3.38 (m, 16H), 3.33-3.23 (m, 1H), 2.93-2.82 (m, 1H), 2.78-2.60
(m, 3H), 2.58-2.26 (m, 8H), 2.21 (s, 3H), 2.07-1.86 (m, 8H),
1.81-1.65 (m, 2H). MS (ESI) m/z 1043.2 (M-H).sup.-.
Example 49
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}-
methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethy-
l-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13-
,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene--
7-carboxylic Acid
Example 49A
4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-chloropyrimidine
[0863] To a flask containing (2-chloropyrimidin-4-yl)methanol (5.00
g) in N,N-dimethylformamide (40 mL) was added
tert-butylchlorodiphenylsilane (9.51 g) followed by imidazole (4.71
g). The resulting mixture was stirred at ambient temperature
overnight. The mixture was diluted with water (100 mL) and
extracted with ethyl acetate (3.times.150 mL). The organic layer
was separated, washed with water and brine, dried over sodium
sulfate, filtered and concentrated. The residue was purified by
flash chromatography on AnaLogix IntelliFlash.sup.280 system (100 g
silica gel cartridge, eluting with 0-30% ethyl acetate/hexanes) to
give the title compound. MS (ESI) m/z 383.2 (M+H).sup.+.
Example 49B
ethyl
4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-2-yl)cyclohex-3-
-enecarboxylate
[0864] A 250 mL flask, equipped with stir bar, was charged with
Example 49A (4.00 g), ethyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate
(3.80 g),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.764
gl) and potassium phosphate (5.54 g). The flask was capped then
evacuated and backfilled with nitrogen twice. 1,4-Dioxane (55 mL)
was added followed by water (13.75 mL) and the stirring mixture was
evacuated and backfilled with nitrogen twice again. The mixture was
stirred at 80.degree. C. for 16 hours. The mixture was cooled to
ambient temperature, poured into a separatory funnel containing
water and brine, and extracted three times with ethyl acetate. The
organics were combined and concentrated. The residue was purified
by flash chromatography on AnaLogix IntelliFlash.sup.280 system
(100 g silica gel cartridge, eluting with 0-30% ethyl
acetate/hexanes) to give the title compound. MS (ESI) m/z 501.2
(M+H).sup.+.
Example 49C
(4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-2-yl)cyclohex-3-en-1-
-yl)methanol
[0865] To a solution of Example 49B (2.081 g) in tetrahydrofuran (5
mL) at 0.degree. C. was added lithium
diisobutyl-tert-butoxyaluminum hydride (0.25 M in
tetrahydrofuran/hexanes, 66.5 mL). The mixture was stirred at
0.degree. C. for 25 minutes. The reaction mixture was quenched at
0.degree. C. by slow addition of saturated aqueous Rochelle's salt
solution (20 mL). The mixture was stirred at ambient temperature
for 15 minutes. The mixture was extracted three times with ethyl
acetate and the organics were concentrated. The residue was
purified by flash chromatography on an AnaLogix
IntelliFlash.sup.280 system using a Teledyne Isco RediSep.RTM. Rf
gold 100 g silica gel column (eluting with 0-100% ethyl
acetate/hexanes) to afford the title compound. MS (ESI) m/z 459.4
(M+H).sup.+.
Example 49D
((1r,4r)-4-(4-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidin-2-yl)cyclohe-
xyl)methanol
[0866] Example 49C (2.095 g) and tetrahydrofuran (14.5 mL) were
added to Ra--Ni 2800 water slurry (2.0 g) in a 25 mL Hast C
reactor, and the mixture was stirred at 50 psi hydrogen for one
hour. The reaction mixture was filtered and concentrated. The
residue was purified by flash chromatography on an AnaLogix
IntelliFlash.sup.280 system using a Teledyne Isco RediSep.RTM. Rf
gold 100 g silica gel column (eluting with 20-100% ethyl
acetate/hexanes) to afford the title compound. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.75 (d, 1H), 7.64 (dt,
4H), 7.43 (dddd, 7H), 4.72 (s, 2H), 4.37 (s, 1H), 3.28-3.15 (m,
2H), 2.65 (tt, 1H), 1.96-1.77 (m, 4H), 1.58-1.31 (m, 3H), 1.05 (s,
9H), 1.04-0.93 (m, 2H). MS (ESI) m/z 461.3 (M+H).sup.+.
Example 49E
(S)-(1,4-dioxan-2-yl)methyl trifluoromethanesulfonate
[0867] A stirring mixture of (R)-(1,4-dioxan-2-yl)methanol (1.5 g)
and pyridine (1.078 mL) in dichloromethane (52.4 mL) was evacuated
and back filled with nitrogen twice. The reaction mixture was
cooled to -10.degree. C. using a methanol/ice cooling bath. The
trifluoromethanesulfonic anhydride (3.76 g) was next added dropwise
as a dichloromethane (7.49 mL) solution. Stirring was continued at
-10.degree. C. for 2 minutes. The cooling bath was removed and the
mixture was stirred for 15 minutes. The mixture was diluted with
dichloromethane, washed with 1 M HCl aqueous solution and brine,
dried over anhydrous magnesium sulfate, filtered and concentrated
to give the title compound. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 4.51-4.40 (m, 2H), 3.97-3.88 (m, 1H), 3.88-3.70 (m,
4H), 3.63 (ddd, 1H), 3.46 (dd, 1H).
Example 49F
2-((1R,4r)-4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)cyclohexyl)-4-(((tert-b-
utyldiphenylsilyl)oxy)methyl)pyrimidine
[0868] To a stirring mixture of Example 49D (200 mg) in anhydrous
tetrahydrofuran (2.90 mL) was added sodium hydride (26.0 mg). The
mixture was stirred for 5 minutes before being cooled to 0.degree.
C. with an ice bath. A mixture of Example 49E (272 mg) in
tetrahydrofuran (0.97 mL) was added dropwise. Stirring was
continued at 0.degree. C. for 5 minutes, the cooling bath was
removed and the mixture was stirred at ambient temperature under
nitrogen for 5 hours. Saturated aqueous ammonium chloride solution
(15 drops) was added to quench the sodium hydride. The mixture was
concentrated onto silica gel and purified by flash chromatography
on a CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 12 g silica gel column (eluting with 20-100%
ethyl acetate/hexanes) to afford the title compound. .sup.1H NMR
(501 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.76 (d, 1H),
7.69-7.61 (m, 4H), 7.52-7.39 (m, 7H), 4.73 (d, 2H), 3.69 (dd, 2H),
3.66-3.58 (m, 2H), 3.55 (td, 1H), 3.43 (td, 1H), 3.36 (dd, 1H),
3.29 (dd, 1H), 3.25 (dd, 1H), 3.22 (d, 2H), 2.73-2.61 (m, 1H),
1.97-1.87 (m, 2H), 1.84-1.74 (m, 2H), 1.59-1.44 (m, 3H), 1.06 (s,
9H), 1.05-0.96 (m, 2H). MS (APCI) m/z 561.4 (M+H).sup.+.
Example 49G
(2-((1R,4r)-4-((((R)-1,4-dioxan-2-yl)methoxy)methyl)cyclohexyl)pyrimidin-4-
-yl)methanol
[0869] To a stirring mixture of Example 49F (198 mg) in
tetrahydrofuran (1.12 mL) was added tetra-N-butylammonium fluoride
(1.0 M in tetrahydrofuran, 1.06 mL) and the mixture was stirred for
10 minutes. The mixture was concentrated onto silica gel and
purified by flash chromatography on a CombiFlash.RTM. Teledyne Isco
system using a Teledyne Isco RediSep.RTM. Rf gold 24 g silica gel
column (solvent A=2:1 ethyl acetate:ethanol, solvent B=heptane,
eluting with 10-100% A to B) to afford the title compound. .sup.1H
NMR (501 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 8.69 (d, 1H),
7.36 (dt, 1H), 5.56 (t, 1H), 4.51 (dd, 2H), 3.76-3.67 (m, 2H),
3.67-3.60 (m, 2H), 3.56 (td, 1H), 3.44 (td, 1H), 3.37 (dd, 1H),
3.32-3.26 (m, 2H), 3.26-3.22 (m, 2H), 2.70 (tt, 1H), 1.98-1.88 (m,
2H), 1.87-1.78 (m, 2H), 1.62-1.47 (m, 3H), 1.05 (qd, 2H). MS (APCI)
m/z 323.2 (M+H).sup.+.
Example 49H
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2R)-1,4-dioxan-2--
yl]methoxy}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20-
,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,2-
1-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-
-cd]indene-7-carboxylate
[0870] A 4 mL vial, equipped with stir bar, was charged with
Example 1Z (120 mg), Example 49G (96 mg), and triphenylphosphine
(82 mg). The vial was capped with septa, and evacuated and
backfilled with nitrogen twice. Toluene (1.48 mL) was added, and
the mixture was cooled with an ice bath. (E)-Di-tert-butyl
diazene-1,2-dicarboxylate (68.2 mg) was added in one solid portion,
and the vial was capped with septa, evacuated and backfilled with
nitrogen twice again. The mixture was stirred at 0.degree. C. for
10 minutes, the cooling bath was removed and the mixture was
allowed to stir for 7 hours. The reaction nixWurc was concentrated
and purified by flash chromatography on an AnaLogix
IntelliFlash.sup.280 system using a Teledyne Isco RediSep.RTM. Rf
gold 25 g silica gel column (eluting with 1-20%
methanol/dichloromethane over 35 minutes) to afford the title
compound. MS (ESI) m/z 1113.3 (M+H).sup.+.
Example 491
(7R,16R)-19,23-dichloro-10-({2-[(1S,4r)-4-({[(2R)-1,4-dioxan-2-yl]methoxy}-
methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethy-
l-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13-
,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene--
7-carboxylic Acid
[0871] To a solution of Example 49H (107 mg) in dichloromethane
(0.6 mL) was added trifluoroacetic acid (0.9 mL). The mixture was
stirred for 2 hours. The mixture was concentrated in vacuo. The
residue was purified by reverse phase prep LC using a
Phenomenex.RTM. Luna.TM. C-18 250.times.50 mm column, 70 mL/minute
flow, 10 to 95% acetonitrile in 10 mM ammonium acetate in water
over 35 minutes. The title compound was obtained after
lyophilization. .sup.1H NMR (501 MHz, dimethylsulfoxide-d.sub.6)
.delta. ppm 8.73 (s, 1H), 8.70 (d, 1H), 7.41 (d, 1H), 7.23-7.16 (m,
2H), 7.16-7.11 (m, 2H), 6.84 (d, 1H), 6.73 (dd, 1H), 6.21 (dd, 1H),
5.81 (d, 1H), 5.17-4.98 (m, 2H), 4.92-4.84 (m, 1H), 4.46-4.40 (m,
2H), 7.72-3.68 (m, 2H), 3.67-3.17 (m, 12H), 2.98-2.91 (m, 1H),
2.79-2.60 (m, 3H), 2.48-2.32 (m, 6H), 2.21 (s, 3H), 1.97 (s, 3H),
1.96 (s, 3H), 1.94-1.92 (m, 2H), 1.86-1.77 (m, 2H), 1.62-1.49 (m,
3H), 1.12-0.98 (m, 2H), exchangeable CO.sub.2H not observed. MS
(ESI) m/z 1157.6 (M+H).sup.+.
Example 50
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2)-1,4-dioxan-2-yl]methoxy}m-
ethyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethyl-
-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,-
9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-
-carboxylic Acid
Example 50A
1,4-dioxaspiro[4.5]decan-8-ylmethyl 4-methylbenzenesulfonate
[0872] To a stirring solution of
1,4-dioxaspiro[4.5]decan-8-ylmethanol (5.0 g),
4-dimethylaminopyridine (0.177 g) and triethylamine (8.09 mL) in
100 mL of dichloromethane at 0.degree. C. was added
para-toluenesulfonyl chloride (6.64 g) in one portion. Stirring was
continued at 0.degree. C. for 5 minutes, the cooling bath was
removed, and the mixture stirred for 4 hours before it was
concentrated onto silica gel. Purification by flash chromatography
on a CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 220 g silica gel column (eluting with 10-60%
ethyl acetate/heptanes) afforded the title compound. MS (APCI) m/z
327.3 (M+H).sup.+.
Example 50B
(S)-8-(((1,4-dioxan-2-yl)methoxy)methyl)-1,4-dioxaspiro[4.5]decane
[0873] To a stirring mixture of (S)-(1,4-dioxan-2-yl)methanol (2.71
g) in 15 mL of N,N-dimethylformamide was added sodium hydride (0.55
g) in one portion. The flask was capped with septa and stirred for
15 minutes. Example 50A (2.5 g) was added as a solution in 2 mL of
N,N-dimethylformamide. The mixture was stirred at 45.degree. C. for
4 hours. After cooling to room temperature, the mixture was
quenched by addition of 30 mL of saturated aqueous ammonium
chloride. The mixture was poured into a separatory funnel, diluted
with water, and extracted with three portions of ethyl acetate. The
organic layers were combined, washed twice with brine, dried over
anhydrous magnesium sulfate, filtered and concentrated onto silica
gel. Purification by flash chromatography on a CombiFlash.RTM.
Teledyne Isco system using a Teledyne Isco RediSep.RTM. Rf gold 220
g silica gel column (eluting with 20-100% ethyl acetate/heptanes)
afforded the title compound. MS (APCI) m/z 273.6 (M+H).sup.+.
Example 50C
(S)-4-(((1,4-dioxan-2-yl)methoxy)methyl)cyclohexanone
[0874] To a solution of Example 50B (1.8 g) in 20 mL of
tetrahydrofuran was added 30 mL of a 6 molar aqueous solution of
HCl. The reaction mixture was stirred at room temperature for 16
hours. The mixture was poured into a 125 mL separatory funnel and
diluted with 50 mL of water. The aqueous layer was extracted with
three portions of dichloromethane. The organic layers were
combined, dried over anhydrous magnesium sulfate, filtered and
concentrated onto silica gel. Purification by flash chromatography
on a CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 40 g silica gel column (eluting 0-60% ethyl
acetate/heptanesane) afforded the title compound. MS (APCI) m/z
229.3 (M+H).sup.+.
Example 50D
(S)-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)cyclohex-1-en-1-yl
trifluoromethanesulfonate
[0875] To a stirring solution of Example 50C (1.31 g) in 35 mL of
tetrahydrofuran, at -78.degree. C., was slowly added 4.3 mL of a 2
molar solution of lithium diisopropylamide in tetrahydrofuran. The
mixture was stirred at -78.degree. C. for 30 minutes, and a
solution of N,N-bis(trifluoromethylsulfonyl)aniline (2.67 g) in 18
mL of tetrahydrofuran was slowly added over 20 minutes. The dry ice
from the cooling bath was removed to allow for the reaction to
slowly warm to room temperature. Stirring was continued at room
temperature for 16 hours. The reaction mixture was cooled back to
0.degree. C., and quenched with the addition of 20 mL of saturated
aqueous sodium bicarbonate. The mixture was poured into a 250 mL
separatory funnel, diluted with water, and extracted with three
portions of dichloromethane. The organic layers were combined,
dried over anhydrous magnesium sulfate, filtered and concentrated
onto silica gel. Purification by flash chromatography on a
CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 80 g silica gel column (eluting with 10-60%
ethyl acetate/heptanes, then 100% ethyl acetate) afforded the title
compound. MS (APCI) m/z 360.6 (M+H).sup.+.
Example 50E
2-(4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)cyclohex-1-en-1-yl)-4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolane
[0876] A 100 mL round bottom flask, equipped with stir bar, was
charged with Example 50D (1.260 g), bis(pinacolato)diboron (1.154
g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(0.256 g) and potassium acetate (0.686 g). The flask was capped and
evacuated and backfilled with nitrogen twice. Dioxane (30 mL) was
added and the stirring mixture was evacuated and backfilled with
nitrogen twice and stirred at 80.degree. C. for 4 hours. After
cooling to room temperature, the mixture was filtered through a
diatomaceous earth pad and the filter cake was washed with ethyl
acetate. The mixture was then concentrated onto silica gel.
Purification by flash chromatography on a CombiFlash.RTM. Teledyne
Isco system using a Teledyne Isco RediSep.RTM. Rf gold 80 g silica
gel column (eluting 0-60% ethyl acetate/heptanes) afforded the
title compound. MS (APCI) m/z 338.1 (M+H).sup.+.
Example 50F
2-(4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)cyclohex-1-en-1-yl)-4-(((tert-b-
utyldiphenylsilyl)oxy)methyl)pyrimidine
[0877] A 100 mL flask, equipped with stir bar, was charged with
Example 14A (525 mg), Example 50E (556 mg),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100
mg) and potassium phosphate (727 mg). The flask was capped with a
septa and evacuated and backfilled with nitrogen twice. Dioxane
(7.3 mL) was added followed by water (1.8 mL) and the stirring
mixture was evacuated and backfilled with nitrogen twice again
before it was heated at 80.degree. C. for 4 hours. After cooling to
room temperature, the mixture was poured into a separatory funnel
containing water and brine and the mixture was extracted three
times with ethyl acetate. The organic layers were combined, dried
over anhydrous magnesium sulfate, filtered and concentrated onto
silica gel. Purification by flash chromatography on a
CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 40 g silica gel column (eluting with 10-70%
ethyl acetate/heptanes) afforded the title compound. MS (APCI) m/z
559.4 (M+H).sup.+.
Example 50G
cis-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)cyclohexyl)-4-(((tert-butyldip-
henylsilyl)oxy)methyl)pyrimidine
[0878] Example 50F (675 mg) was dissolved in 2.5 mL of
tetrahydrofuran and loaded onto a RS10 high pressure reactor.
Palladium on carbon (5%, 100 mg, wet) was added and the reactor was
purged with argon. The mixture was stirred at 1200 RPM under 45 psi
of hydrogen at 40.degree. C. for 24 hours. After cooling back to
room temperature, the solution obtained was concentrated onto
silica gel and purification by flash chromatography on a
CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 80 g silica gel column (eluting 10-100% ethyl
acetate/heptanes) afforded the title compound which was the cis
isomer and the faster eluting isomer. Example 50H was eluted which
was the trans isomer and the slower eluting isomer. MS (APCI) m/z
561.4 (M+H).sup.+.
Example 50H
trans-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)cyclohexyl)-4-(((tert-butyld-
iphenylsilyl)oxy)methyl)pyrimidine
[0879] The title compound was also obtained as described in Example
50G. MS (APCI) m/z 561.4 (M+H).sup.+.
Example 50I
cis-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)cyclohexyl)pyrimidin-4-yl)meth-
anol
[0880] To a stirring mixture of Example 50G (68 mg) in
tetrahydrofuran (0.4 mL) was added 0.4 mL of a 1 molar solution of
tetra-N-butylammonium fluoride in tetrahydrofuran and the mixture
was stirred at room temperature for 10 minutes before it was
concentrated onto silica gel. Purification by flash chromatography
on a CombiFlash.RTM. Teledyne Isco system using a Teledyne Isco
RediSep.RTM. Rf gold 12 g silica gel column (eluting with solvent
A=2:1 ethyl acetate:ethanol, solvent B=heptane, 10-80% A to B)
afforded the title compound. MS (APCI) m/z 323.4 (M+H).sup.+.
Example 50J
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2S)-1,4-dioxan-2--
yl]methoxy}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20-
,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,2-
1-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-
-cd]indene-7-carboxylate
[0881] Example 50J was synthesized according to the procedure
described for Example 111, substituting Example 501 for Example
11H. MS (APCI) m/z 1114.1 (M+H).sup.+.
Example 50K
(7R,16R)-19,23-dichloro-10-({2-[(1S,4s)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethy-
l-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13-
,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene--
7-carboxylic Acid
[0882] Example 50K was synthesized according to the procedure
described for Example 11J, substituting Example 50J for Example
111. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm
8.76-8.64 (m, 2H), 7.37 (d, 1H), 7.22-7.05 (m, 4H), 6.81 (d, 1H),
6.70 (dd, 1H), 6.19 (dd, 1H), 5.77 (d, 1H), 5.06 (q, 2H), 4.83 (p,
1H), 4.40 (d, 2H), 3.68-3.47 (m, 6H), 3.30-3.15 (m, 5H), 3.00-2.86
(m, 2H), 2.74-2.57 (m, 2H), 2.53-2.34 (m, 9H), 2.19 (s, 3H),
2.03-1.88 (m, 8H), 1.82-1.71 (m, 1H), 1.71-1.56 (m, 2H), 1.58-1.44
(m, 2H), 1.44-1.32 (m, 2H). MS (APCI) m/z 1058.0 (M+H).sup.+.
Example 51
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethy-
l-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13-
,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene--
7-carboxylic Acid
Example 51A
trans-4-((((S)-1,4-dioxan-2-yl)methoxy)methyl)cyclohexyl)pyrimidin-4-yl)me-
thanol
[0883] Example 51A was synthesized according to the procedure
described for Example 501, substituting Example 50H for Example
50G. MS (APCI) m/z 323.4 (M+H).sup.+.
Example 51B
tert-butyl
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2S)-1,4-dioxan-2--
yl]methoxy}methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20-
,22-dimethyl-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,2-
1-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-
-cd]indene-7-carboxylate
[0884] Example 51B was synthesized according to the procedure
described for Example 11I, substituting Example 51A for Example
11H. MS (APCI) m/z 1114.3 (M+H).sup.+.
Example 51C
(7R,16R)-19,23-dichloro-10-({2-[(1R,4r)-4-({[(2S)-1,4-dioxan-2-yl]methoxy}-
methyl)cyclohexyl]pyrimidin-4-yl}methoxy)-1-(4-fluorophenyl)-20,22-dimethy-
l-16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13-
,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene--
7-carboxylic Acid
[0885] Example 51C was synthesized according to the procedure
described for Example 11J, substituting Example 51B for Example
111. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm
8.73 (s, 1H), 8.70 (d, 1H), 7.41 (d, 1H), 7.24-7.16 (m, 2H),
7.16-7.10 (m, 2H), 6.84 (d, 1H), 6.74 (dd, 1H), 6.22 (dd, 1H), 5.80
(d, 1H), 5.19-5.02 (m, 2H), 4.86 (p, 1H), 4.44 (d, 2H), 3.70 (dt,
2H), 3.66-3.61 (m, 2H), 3.61-3.52 (m, 1H), 3.47-3.41 (m, 2H),
3.39-3.34 (m, 2H), 3.28-3.22 (m, 2H), 2.99-2.91 (m, 1H), 2.80-2.60
(m, 3H), 2.56-2.35 (m, 9H), 2.23 (s, 3H), 2.03-1.91 (m, 7H),
1.88-1.77 (m, 2H), 1.65-1.48 (m, 4H), 1.15-0.97 (m, 2H). MS (APCI)
m/z 1060.0 (M+H).sup.+.
Example 52
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan-2-
-yl]methoxy}cyclohexyl]pyrimidin-4-yl}methoxy)-20,22-dimethyl-16-[(4-methy-
lpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6-
,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 52A
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(bis(4-methoxyphenyl)(phenyl)methoxy)propan-
-2-yl)oxy)-3,5-dichloro-2,6-dimethylphenyl)-6-bromothieno[2,3-d]pyrimidin--
4-yl)oxy)-3-(5-((tert-butyldimethylsilyl)oxy)-2-((2-(trimethylsilyl)ethoxy-
)methoxy)phenyl)propanoate
[0886] The title compound was prepared as described in Example 1R
by substituting Example 17D for Example 1L and substituting Example
32C for Example 1Q.
Example 52B
(R)-tert-butyl
2-((5-(4-(((S)-1-(allyloxy)-3-hydroxypropan-2-yl)oxy)-3,5-dichloro-2,6-di-
methylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-yl)oxy)-3-(5-((tert-butyldim-
ethylsilyl)oxy)-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)propanoate
[0887] The title compound was prepared as described in Example 1S
substituting Example 52A for Example 1R. MS (ESI) m/z 1012.8
(M-H).sup.-.
Example 52C
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-yl)oxy)-3-(5-((tert-butyl-
dimethylsilyl)oxy)-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)propanoate
[0888] The title compound was prepared as described in Example 1T
substituting Example 52B for Example 1S. MS (ESI) m/z 1185.0
(M+NH.sub.4).
Example 52D
(R)-tert-butyl
2-((5-(4-(((R)-1-(allyloxy)-3-(tosyloxy)propan-2-yl)oxy)-3,5-dichloro-2,6-
-dimethylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-yl)oxy)-3-(5-hydroxy-2-((-
2-(trimethylsilyl)ethoxy)methoxy)phenyl)propanoate
[0889] The title compound was prepared as described in Example 1U
substituting Example 52C for Example 1T. MS (ESI) m/z 1051.4
(M-H).sup.-.
Example 52E
tert-butyl
(7R,16R)-1-bromo-19,23-dichloro-20,22-dimethyl-16-{[(prop-2-en--
1-yl)oxy]methyl}-10-{[2-(trimethylsilyl)ethoxy]methoxy}-7,8,15,16-tetrahyd-
ro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadec-
a[1,2,3-cd]indene-7-carboxylate
[0890] The title compound was prepared as described in Example 1V
substituting Example 52D for Example 1U. MS (ESI) m/z 880.8
(M-H).sup.-.
Example 52F
tert-butyl
(7R,16R)-1-bromo-19,23-dichloro-16-(hydroxymethyl)-20,22-dimeth-
yl-10-{[2-(trimethylsilyl)ethoxy]methoxy}-7,8,15,16-tetrahydro-18,21-ethen-
o-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]ind-
ene-7-carboxylate
[0891] The title compound was prepared as described in Example 1W,
substituting Example 52E for Example 1V. MS (ESI) m/z 843.1
(M+H).sup.+.
Example 52G
tert-butyl
(7R,16S)-1-bromo-19,23-dichloro-20,22-dimethyl-16-{[(4-methylbe-
nzene-1-sulfonyl)oxy]methyl}-10-{[2-(trimethylsilyl)ethoxy]methoxy}-7,8,15-
,16-tetrahydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diaza-
cyclononadeca[1,2,3-cd]indene-7-carboxylate
[0892] The title compound was prepared as described in Example 1X,
substituting Example 52F for Example 1W. MS (ESI) m/z 997.0
(M+H).sup.+.
Example 52H
tert-butyl
(7R,16R)-1-bromo-19,23-dichloro-20,22-dimethyl-16-[(4-methylpip-
erazin-1-yl)methyl]-10-{[2-(trimethylsilyl)ethoxy]methoxy}-7,8,15,16-tetra-
hydro-18,21-etheno-13,9-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclonona-
deca[1,2,3-cd]indene-7-carboxylate
[0893] The title compound was prepared as described in Example 1Y,
substituting Example 52G for Example 1X. MS (ESI) m/z 925.4
(M+H).sup.+.
Example 512I
tert-butyl
(7R,16R)-1-bromo-19,23-dichloro-10-hydroxy-20,22-dimethyl-16-[(-
4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(met-
heno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbo-
xylate
[0894] The title compound was prepared as described in Example 32Q,
substituting Example 52H for Example 32P. MS (ESI) m/z 796.0
(M+H).sup.+.
Example 52J
tert-butyl
(7R,16R)-19,23-dichloro-1-bromo-10-({2-[(1R,4r)-4-{[(2R)-1,4-di-
oxan-2-yl]methoxy}cyclohexyl]pyrimidin-4-yl}methoxy)-20,22-dimethyl-16-[(4-
-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(meth-
eno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carbox-
ylate
[0895] A microwave vial in a glove box was charged with Example 521
(200 mg) and Example 9D (116 mg). Degassed tetrahydrofuran (1 mL)
and toluene (1 mL) were added. In a separate vial
N,N,N',N'-tetramethylazodicarboxamide (152 mg) and
triphenylphosphine (231 mg) were dissolved in degassed
tetrahydrofuran (1 mL) and toluene (1 mL). The resulting solution
was stirred for 5 minutes. The solutions were combined, and the
mixture stirred for 4 hours at ambient temperature and for 20 hours
at 50.degree. C. The crude mixture was concentrated and the residue
was purified by chromatography on silica gel using an ISCO
CombiFlash.RTM. Companion MPLC (12 g RediSep.RTM. Gold column,
eluting with 0-20% dichloromethane/methanol) to provide the title
compound. MS (APCI) m/z 1083.3 (M+H).sup.+.
Example 52K
tert-butyl
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-({2-[(1R,4r)-4-{[(2R)-1-
,4-dioxan-2-yl]methoxy}cyclohexyl]pyrimidin-4-yl}methoxy)-20,22-dimethyl-1-
6-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9--
(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-c-
arboxylate
[0896] In a microwave vial Example 52J (45 mg) and
dichloro[1,3-bis(2,6-di-3-pentylphenyl)-imidazole-2-ylidene](3-chloropyri-
dyl)palladium (II) (3 mg) were degassed for 10 minutes with
nitrogen. Toluene (1 mL, degassed with nitrogen) was added. The
mixture was cooled to 5.degree. C., dicyclobutylzinc (0.5 mL, 0.25
molar in tetrahydrofuran) was added and the mixture was stirred for
20 hours at ambient temperature. Water (5 mL) was added, the
mixture extracted twice with ethyl acetate (20 mL), and the
combined organic layers washed with brine, dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification by
chromatography on silica gel using an ISCO CombiFlash.RTM.
Companion MPLC (4 g Chromabond.RTM. silica gel column, eluting with
0-10% dichloromethane/methanol) provided the title compound. MS
(APCI) m/z 1059.4 (M+H).sup.+.
Example 52L
(7R,16R)-19,23-dichloro-1-cyclobutyl-10-({2-[(1R,4r)-4-{[(2R)-1,4-dioxan-2-
-yl]methoxy}cyclohexyl]pyrimidin-4-yl}methoxy)-20,22-dimethyl-16-[(4-methy-
lpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-13,9-(metheno)-6-
,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0897] The title compound was prepared as described in Example 18S
by replacing Example 18R with Example 52K. Purification by HPLC
(Waters XBridge C8 150.times.19 mm, 5 m column, gradient 5-100%
acetonitrile+0.2% ammonium hydroxide in water+0.2% ammonium
hydroxide) provided the title compound. .sup.1H NMR (600 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 8.70 (d, 1H), 8.60 (s, 1H),
7.43 (d, 1H), 6.79 (d, 1H), 6.69 (m, 1H), 6.15 (bs, 1H), 5.92 (bs,
1H), 5.11 (d, 1H), 5.03 (d, 1H), 4.93 (s, 1H), 4.48 (m, 2H), 3.71
(m, 2H), 3.63-3.54 (m, 2H), 3.44-3.24 (m, 6H), 2.83 (d, 1H), 2.76
(m, 1H), 2.74-2.67 (m, 2H), 2.55-2.30 (m, 9H), 2.18 (s, 3H),
2.11-1.93 (m, 8H), 1.86 (m, 1H), 1.81 (s, 3H), 1.73 (m, 1H),
1.63-1.54 (m, 2H), 1.31-1.21 (m, 5H). MS (APCI) m/z 1003.4
(M+H).sup.+.
Example 53
(7R,16R)-19,23-dichloro-10-{[3-{[(2)-1,4-dioxan-2-yl]methoxy}-6-(2-methoxy-
phenyl)pyridin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-meth-
ylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)--
6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
Example 53A
3-hydroxy-6-(2-methoxyphenyl)picolinic acid
[0898] 2-(2-Methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(524 mg), methyl 6-chloro-3-hydroxypicolinate (400 mg) and
1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (139 mg) were combined and flushed with
argon for 5 minutes. 1,4-Dioxane (11 mL, degassed with argon) and
aqueous sodium carbonate solution (2 M, 3.20 mL, degassed with
argon) was added. The reaction mixture was heated at 120.degree. C.
in a Biotage.RTM. Initiator microwave reactor for 4 hours. The
reaction mixture was diluted with dichloromethane and washed with
water. The aqueous layer was washed with dichloromethane (twice)
and acidified with aqueous hydrochloric acid (1 M) to pH 2. The
aqueous layer was extracted with dichloromethane (three times). The
organic layer was dried by a PTS-cartridge and concentrated to
yield the title compound. MS (ESI) m/z 246.4 (M+H).sup.+.
Example 53B
methyl 3-hydroxy-6-(2-methoxyphenyl)picolinate
[0899] Example 53B (600 mg) was added to methanol (5.0 mL).
Sulfuric acid (3.0 mL) was carefully added dropwise. The reaction
mixture was stirred at 100.degree. C. in a CEM microwave reactor
for 16 hours. The reaction mixture was carefully poured into
ice-water. The aqueous phase was extracted with dichloromethane
(seven times). The organic layer was dried by a PTS-cartridge.
Purification was performed on a silica gel column (12 g, 0-30%
methanol in dichloromethane). The pure fractions were combined and
the solvents were removed under reduced pressure to provide the
title compound. MS (ESI) m/z 260.2 (M+H).sup.+.
Example 53C
methyl
(S)-3-((1,4-dioxan-2-yl)methoxy)-6-(2-methoxyphenyl)picolinate
[0900] Example 53B (150 mg) and cesium carbonate (566 mg) were
suspended in N, N-dimethyl formamide (5.0 mL).
(S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate (284 mg) was
added. The reaction mixture was stirred at 25.degree. C. for 2
days. Additional (S)-(1,4-dioxan-2-yl)methyl
4-methylbenzenesulfonate (284 mg) and cesium carbonate (566 mg)
were added and the reaction mixture was stirred overnight at room
temperature. The reaction mixture was diluted with water and the
phases were separated. The aqueous layer was extracted with
dichloromethane (three times) and ethyl acetate (three times). The
combined organic phases were dried over magnesium sulfate,
filtered, and concentrated. Purification was performed on a silica
gel column (4 g, 0-23% methanol in dichloromethane), followed by a
second purification (4 g, 0-50% ethyl acetate in n-heptane). The
desired fractions were combined and the solvents were removed under
reduced pressure to provide the title compound. MS (APCI) m/z 360.2
(M+H).sup.+.
Example 53D
(S)-(3-((1,4-dioxan-2-yl)methoxy)-6-(2-methoxyphenyl)pyridin-2-yl)methanol
[0901] Example 53C (67 mg) was dissolved in tetrahydrofuran (2.0
mL) and cooled by an ice-bath to 0.degree. C. Lithium aluminum
hydride (1M in tetrahydrofuran, 0.38 mL) was added dropwise. The
reaction mixture was stirred for 10 minutes while warming up to
room temperature. The reaction mixture was diluted with
dichloromethane and water. The phases were separated. The organic
phase was dried over sodium sulfate, filtrated and concentrated.
Purification of the residue was performed on a silica gel column (4
g, 0-30% methanol in dichloromethane). The pure fractions were
combined and the solvents were removed under reduced pressure to
provide the title compound. MS (APCI) m/z 332.1 (M+H).sup.+.
Example 53E
tert-butyl
(7R,16R)-19,23-dichloro-10-{[3-{[(2)-1,4-dioxan-2-yl]methoxy}-6-
-(2-methoxyphenyl)pyridin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl--
16-[(4-methylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-
-(metheno)-6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7--
carboxylate
[0902] Example 53D (20 mg), Example 1Z (25 mg), triphenylphosphine
(28 mg) and N,N,N',N'-tetramethylazodicarboxamide (19 mg) were
combined and flushed with argon for 15 minutes. Toluene (0.7 mL,
flushed with argon) was added and the reaction mixture was stirred
overnight at room temperature. The reaction mixture was
concentrated. Purification was performed on a silica gel column (4
g, 0-30% methanol in dichloromethane). The pure fractions were
combined and the solvents were removed under reduced pressure to
provide the title compound. MS (APCI) m/z 1122.2 (M+H).sup.+.
Example 53F
(7R,16R)-19,23-dichloro-10-{[3-{[(2)-1,4-dioxan-2-yl]methoxy}-6-(2-methoxy-
phenyl)pyridin-2-yl]methoxy}-1-(4-fluorophenyl)-20,22-dimethyl-16-[(4-meth-
ylpiperazin-1-yl)methyl]-7,8,15,16-tetrahydro-18,21-etheno-9,13-(metheno)--
6,14,17-trioxa-2-thia-3,5-diazacyclononadeca[1,2,3-cd]indene-7-carboxylic
Acid
[0903] Example 53E (57 mg) was dissolved in dichloromethane,
trifluoroacetic acid (0.39 mL) was added, and the reaction mixture
was stirred overnight at room temperature. All volatiles were
evaporated and the crude material was purified by HPLC (Waters
XSelect CSH C18 30.times.150 mm 5 .mu.m column, gradient 5-100%
acetonitrile+0.1% TFA in water+0.1% TFA) to provide the title
compound. .sup.1H NMR (600 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 8.71 (s, 1H), 7.82 (d, 1H), 7.71 (dd, 1H), 7.53 (d, 1H), 7.34
(ddd, 1H), 7.21-7.18 (m, 2H), 7.14-7.11 (m, 3H), 7.04-6.99 (m, 2H),
6.74 (dd, 1H), 6.17 (dd, 1H), 5.78 (b, 1H), 5.14 (d, 1H), 5.08 (d,
1H), 4.95-4.91 (m, 1H), 4.48-4.40 (m, 2H), 4.10 (qd, 2H), 3.88-3.84
(m, 1H), 3.82 (s, 3H), 3.81-3.80 (m, 1H), 3.75-3.72 (m, 1H),
3.63-3.57 (m, 2H), 3.48-3.40 (m, 3H), 2.88 (dd, 1H), 2.71-2.63 (m,
2H), 2.52-2.29 (m, 8H), 2.18 (s, 3H), 1.94 (s, 3H), 1.92 (s, 3H).
MS (APCI) m/z 1066.1 (M+H).sup.+.
Biological Examples
Exemplary MCL-1 Inhibitors Bind MCL-1
[0904] The ability of the exemplary MCL-1 inhibitors of Examples 1
through 151 to bind MCL-1 was demonstrated using the Time
Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay.
Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.
PV4216).
[0905] Probe Synthesis
[0906] Reagents
[0907] All reagents were used as obtained from the vendor unless
otherwise specified. Peptide synthesis reagents including
diisopropylethylamine (DIEA), dichloromethane (DCM),
N-methylpyrrolidone (NMP),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBt) and
piperidine were obtained from Applied Biosystems, Inc. (ABI),
Foster City, Calif. or American Bioanalytical, Natick, Mass.
[0908] Preloaded 9-Fluorenylmethyloxycarbonyl (Fmoc) amino acid
cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)-OH,
Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH,
Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH,
Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH,
Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH,
Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec, San Jose,
Calif.
[0909] The peptide synthesis resin (Fmoc-Rink amide MBHA resin) and
Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,
Calif.
[0910] Single-isomer 6-carboxyfluorescein succinimidyl ester
(6-FAM-NHS) was obtained from Anaspec.
[0911] Trifluoroacetic acid (TFA) was obtained from Oakwood
Products, West Columbia, S.C.
[0912] Thioanisole, phenol, triisopropylsilane (TIS),
3,6-dioxa-1,8-octanedithiol (DODT) and isopropanol were obtained
from Aldrich Chemical Co., Milwaukee, Wis.
[0913] Matrix-assisted laser desorption ionization mass-spectra
(MALDI-MS) were recorded on an Applied Biosystems Voyager DE-PRO
MS).
[0914] Electrospray mass-spectra (ESI-MS) were recorded on Finnigan
SSQ7000 (Finnigan Corp., San Jose, Calif.) in both positive and
negative ion mode.
[0915] General Procedure for Solid-Phase Peptide Synthesis
(SPPS)
[0916] Peptides were synthesized with, at most, 250 .mu.mol
preloaded Wang resin/vessel on an ABI 433A peptide synthesizer
using 250 .mu.mol scale Fastmoc.TM. coupling cycles. Preloaded
cartridges containing 1 mmol standard Fmoc-amino acids, except for
the position of attachment of the fluorophore, where 1 mmol
Fmoc-Lys(Mtt)-OH was placed in the cartridge, were used with
conductivity feedback monitoring. N-terminal acetylation was
accomplished by using 1 mmol acetic acid in a cartridge under
standard coupling conditions.
[0917] Removal of 4-Methyltrityl (Mtt) from Lysine
[0918] The resin from the synthesizer was washed thrice with
dichloromethane and kept wet. 150 mL of 95:4:1
dichloromethane:triisopropylsilane:trifluoroacetic acid was flowed
through the resin bed over 30 minutes. The mixture turned deep
yellow then faded to pale yellow. 100 mL of N,N-dimethylformamide
(DMF) was flowed through the bed over 15 minutes. The resin was
then washed thrice with DMF and filtered. Ninhydrin tests showed a
strong signal for primary amine.
[0919] Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)
[0920] The resin was treated with 2 equivalents 6-FAM-NHS in 1%
DIEA/DMF and stirred or shaken at ambient temperature overnight.
When complete, the resin was drained, washed thrice with DMF,
thrice with (1.times.dichloromethane and 1.times.methanol) and
dried to provide an orange resin that was negative by ninhydrin
test.
[0921] General Procedure for Cleavage and Deprotection of
Resin-Bound Peptide
[0922] Peptides were cleaved from the resin by shaking for 3 hours
at ambient temperature in a cleavage cocktail consisting of 80%
TFA, 5% water, 5% thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1
mL/0.1 g resin). The resin was removed by filtration and rinsing
twice with TFA. The TFA was evaporated from the filtrates, and
product was precipitated with ether (10 mL/0.1 g resin), recovered
by centrifugation, washed twice with ether (10 mL/0.1 g resin) and
dried to give the crude peptide.
[0923] General Procedure for Purification of Peptides
[0924] The crude peptides were purified on a Gilson preparative
HPLC system running Unipoint.RTM. analysis software (Gilson, Inc.,
Middleton, Wis.) on a radial compression column containing two
25.times.100 mm segments packed with Delta-Pak.TM. C18 15 M
particles with 100 Apore size and eluted with one of the gradient
methods listed below. One to two milliliters of crude peptide
solution (10 mg/mL in 90% DMSO/water) was purified per injection.
The peaks containing the product(s) from each run were pooled and
lyophilized. All preparative runs were run at 20 mL/min with
eluents as buffer A: 0.1% TFA-water and buffer B: acetonitrile.
[0925] General Procedure for Analytical HPLC
[0926] Analytical HPLC was performed on a Hewlett-Packard 1200
series system with a diode-array detector and a Hewlett-Packard
1046A fluorescence detector running HPLC 3D ChemStation software
version A.03.04 (Hewlett-Packard. Palo Alto, Calif.) on a
4.6.times.250 mm YMC column packed with ODS-AQ 5 m particles with a
120 Apore size and eluted with one of the gradient methods listed
below after preequilibrating at the starting conditions for 7
minutes. Eluents were buffer A: 0.1% TFA-water and buffer B:
acetonitrile. The flow rate for all gradients was 1 mL/minute.
[0927] Synthesis of Probe F-Bak
[0928] Peptide probe F-bak, which binds MCL-1, was synthesized as
described below. Probe F-Bak is acetylated at the N-terminus,
amidated at the C-terminus and has the amino acid sequence
GQVGRQLAIIGDKINR (SEQ ID NO:1). It is fluoresceinated at the lysine
residue (K) with 6-FAM. Probe F-Bak can be abbreviated as follows:
acetyl-GQVGRQLAIIGDK(6-FAM)INR--NH.sub.2.
[0929] To make probe F-Bak, Fmoc-Rink amide MBHA resin was extended
using the general peptide synthesis procedure to provide the
protected resin-bound peptide (1.020 g). The Mtt group was removed,
labeled with 6-FAM-NHS and cleaved and deprotected as described
hereinabove to provide the crude product. This product was purified
by RP-HPLC. Fractions across the main peak were tested by
analytical RP-HPLC, and the pure fractions were isolated and
lyophilized, with the major peak providing the title compound
(0.0802 g); MALDI-MS m/z=2137.1 [(M+H).sup.+].
[0930] Alternative Synthesis of Peptide Probe F-Bak
[0931] In an alternative method, the protected peptide was
assembled on 0.25 mmol Fmoc-Rink amide MBHA resin (Novabiochem) on
an Applied Biosystems 433A automated peptide synthesizer running
Fastmoc.TM. coupling cycles using pre-loaded 1 mmol amino acid
cartridges, except for the fluorescein(6-FAM)-labeled lysine, where
1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge. The
N-terminal acetyl group was incorporated by putting 1 mmol acetic
acid in a cartridge and coupling as described hereinabove.
Selective removal of the 4-methyltrityl group was accomplished with
a solution of 95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin
over 15 minutes, followed by quenching with a flow of
dimethylformamide. Single-isomer 6-carboxyfluorescein-NHS was
reacted with the lysine side-chain in 1% DIEA in DMF and confirmed
complete by ninhydrin testing. The peptide was cleaved from the
resin and side-chains deprotected by treating with 80:5:5:5:2.5:2.5
TFA/water/phenol/thioanisole/triisopropylsilane:
3,6-dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide
was recovered by precipitation with diethyl ether. The crude
peptide was purified by reverse-phase high-performance liquid
chromatography, and its purity and identity were confirmed by
analytical reverse-phase high-performance liquid chromatography and
matrix-assisted laser-desorption mass-spectrometry (m/z=2137.1
((M+H).sup.+).
[0932] Time Resolved-Fluorescence Resonance Energy Transfer
(TR-FRET) Assay
[0933] The ability of exemplary MCL-1 inhibitors Example 1 to
Example 3 to compete with probe F-Bak for binding MCL-1 was
demonstrated using a Time Resolved Fluorescence Resonance Energy
Transfer (TR-FRET) binding assay.
[0934] Method
[0935] For the assay, an acoustic dispenser was used to prepare
dilution series from 10 mM test compounds in 100% DMSO and directly
transfer 160 nL into low volume 384-well assay plates. 8 .mu.L of a
protein/probe/antibody mix was then added to each well resulting in
final concentrations listed below: Test compound: 11 three-fold
dilutions beginning at 25 .mu.M
TABLE-US-00003 Protein: GST-MCL-1 1 nM Antibody Tb-anti-GST 1 nM
Probe: F-Bak 100 nM
[0936] The samples were then mixed on a shaker for 1 minute and
incubated for an additional 2 hours at room temperature. For each
assay plate, a probe/antibody and protein/antibody/probe mixture
were included as a negative and a positive control, respectively.
Fluorescence was measured on the Envision (Perkin Elmer) using a
340/35 nm excitation filter and 520/525 (F-Bak) and 495/510 nm
(Tb-labeled anti-his antibody) emission filters. Dissociation
constants (K.sub.i) were determined using Wang's equation (Wang,
1995, FEBS Lett. 360:111-114). The TR-FRET assay can be performed
in the presence of varying concentrations of human serum (HS) or
fetal bovine serum (FBS). Compounds were tested both without HS and
in the presence of 10% HS.
[0937] Results
[0938] The results of binding assays (K.sub.i in nanomolar) are
provided in Table 2, below, and demonstrate the ability of
compounds of the disclosure to bind MCL-1 protein.
TABLE-US-00004 TABLE 2 TR-FRET MCL-1 Binding Data MCL-1 Binding
MCL-1 Binding Example K.sub.i (nM) K.sub.i (nM, 10% HS) 1 0.042
0.582 2 0.052 1.04 3 0.033 0.365 4 0.055 0.32 5 0.048 0.71 6 0.926
6.09 7 0.036 0.92 8 0.194 2.27 9 0.005 0.10 10 0.346 3.07 11 0.184
0.62 12 0.076 0.61 13 0.079 1.07 14 0.006 0.09 15 0.013 0.15 16
0.048 0.83 17 0.090 4.11 18 0.111 0.24 19 0.156 0.64 20 0.058 0.47
21 0.011 1.01 22 0.016 0.89 23 4.980 41.00 24 0.038 0.38 25 0.003
0.19 26 0.104 1.74 27 0.008 0.02 28 0.017 0.18 29 0.011 0.55 30
0.015 0.16 31 0.373 5.27 32 0.022 0.27 33 0.023 0.30 34 0.030 0.54
35 0.027 0.52 36 0.001 0.05 37 0.051 0.63 38 0.036 0.63 39 0.004
0.06 40 0.014 0.63 41 0.009 0.14 42 0.018 0.24 43 0.020 0.18 44
0.020 0.16 45 0.012 0.16 46 0.022 0.24 47 0.0133 0.521 48 0.026
0.648 49 <0.01 0.128 50 0.022 0.249 51 <0.01 0.131 52
<0.01 0.72 53 13.7 114 NT = not tested, NV = not valid
Exemplary MCL-1 Inhibitors Demonstrate In Vitro Efficacy in Tumor
Cell Viability Assays
[0939] The in vitro efficacy of exemplary MCL-1 inhibitors can be
determined in cell-based killing assays using a variety of cell
lines and mouse tumor models. For example, their activity on cell
viability can be assessed on a panel of cultured tumorigenic and
non-tumorigenic cell lines, as well as primary mouse or human cell
populations. MCL-1 inhibitory activity of exemplary MCL-1
inhibitors was confirmed in a cell viability assay with AMO-1 and
NCI-H929 human multiple myeloma tumor cell lines.
[0940] Method
[0941] In one exemplary set of conditions, NCI-H929 or AMO-1 (ATCC,
Manassas, Va.) were plated 4,000 cells per well in 384-well tissue
culture plates (Corning, Corning, N.Y.) in a total volume of 25
.mu.L RPMI tissue culture medium supplemented with 10% fetal bovine
serum (Sigma-Aldrich, St. Louis, Mo.) and treated with a 3-fold
serial dilution of the compounds of interest with a Labcyte Echo
from a final concentration of 10 .mu.M to 0.0005 .mu.M. Each
concentration was tested in duplicate at least 3 independent times.
A luminescent signal proportional to the number of viable cells
following 24 hours of compound treatment was determined using the
CellTiter-Glo.RTM. Luminescent Cell Viability Assay according to
the manufacturer's recommendations (Promega Corp., Madison, Wis.).
The plates were read in a Perkin Elmer Envision using a
Luminescence protocol. To generate dose response curves the data is
normalized to percent viability by setting the averages of the
staurosporine (10 uM) and DMSO only control wells to 0% and 100%
viability respectively. The IC50 values for the compounds are
generated by fitting the normalized data with Accelrys Assay
Explorer 3.3 to a sigmoidal curve model using linear regression,
Y=(100*xn)/(Kn+xn), where Y is the measured response, x is the
compound concentration, n is the Hill Slope and K is the IC50 and
the lower and higher asymptotes are constrained to 0 and 100
respectively.
[0942] Results
[0943] The results of AMO-1 and H929 cell viability assays
(IC.sub.50 in nanomolar) carried out in the presence of 10% FBS for
exemplary MCL-1 inhibitors are provided in Table 3, below. The
results demonstrate the ability of compounds of the disclosure to
potently inhibit the growth of human tumor cells in vitro.
TABLE-US-00005 TABLE 3 MCL-1 Inhibitor In Vitro Cell Efficacy Data
AMO-1 H929 Viability IC.sub.50 Viability IC.sub.50 EXAMPLE (.mu.M,
10% FBS) (.mu.M, 10% FBS) 1 0.00031 0.00502 2 0.00019 0.0033 3
0.00026 0.0037 4 0.00273 0.00572 5 0.000178 0.00037 6 0.000135
0.000359 7 0.000171 0.000406 8 0.00086 0.00176 9 0.000165 0.000245
10 0.000502 0.00217 11 0.000188 0.000545 12 0.00104 0.00208 13
0.00126 0.00311 14 0.000114 0.000236 15 0.000156 0.000294 16
0.000245 0.000592 17 0.0010 0.00565 18 0.00612 0.00995 19 0.00974
0.0152 20 0.000286 0.000513 21 0.0000488 0.000168 22 0.000142
0.000333 23 0.00315 0.00849 24 0.000687 0.00197 25 0.000629 0.00188
26 0.00020 0.000241 27 0.000435 0.0015 28 0.000211 0.000337 29
0.0000812 0.000346 30 0.000285 0.000974 31 0.00419 0.011 32 0.00017
0.000296 33 0.000222 0.000586 34 0.000235 0.0010 35 0.000261
0.00111 36 0.0000488 0.000183 37 0.000187 0.00053 38 0.000267
0.000748 39 0.000235 0.000239 40 0.000352 0.000271 41 0.000589
0.000595 42 0.000404 0.000356 43 0.000346 0.000365 44 0.000268
0.000286 45 0.000249 0.000258 46 0.000579 0.000418 47 0.000463
0.000344 48 0.000641 0.000593 49 0.000172 0.000314 50 0.000249
0.000255 51 0.000267 0.000299 52 0.000448 0.00118 53 0.311 >1.0
NT = not tested, NV = not valid
[0944] The ability of certain exemplary compounds of the present
disclosure to inhibit the growth of tumor cells in mice was
demonstrated in xenograft models derived from a human multiple
myeloma cell line, AMO-1.
Evaluation of Efficacy in Xenograft Models Methods
[0945] AMO-1 cells were obtained from the Deutsche Sammlung von
Microorganismen und Zellkulturen (DSMZ, Braunschweig, Germany). The
cells were cultured as monolayers in RPMI-1640 culture media
(Invitrogen, Carlsbad, Calif.) that was supplemented with 10% Fetal
Bovine Serum (FBS, Hyclone, Logan, Utah). To generate xenografts,
5.times.10.sup.6 viable cells were inoculated subcutaneously into
the right flank of immune deficient female SCID/bg mice (Charles
River Laboratories, Wilmington, Mass.) respectively. The injection
volume was 0.2 mL and composed of a 1:1 mixture of S MEM and
Matrigel (BD, Franklin Lakes, N.J.). Tumors were size matched at
approximately 200 mm.sup.3. MCL-1 inhibitors were formulated in 5%
DMSO, 20% cremaphor EL and 75% D5W for injection and injected
intraperitoneally. Injection volume did not exceed 200 .mu.L.
Alternatively, MCL-1 inhibitors were formulated in 5% DMSO, 10%
cremaphor and 85% D5W for injection and injected intravenously.
Injection volume did not exceed 200 L. Therapy began within 24
hours after size matching of the tumors. Mice weighed approximately
21 g at the onset of therapy. Tumor volume was estimated two to
three times weekly. Measurements of the length (L) and width (W) of
the tumor were taken via electronic caliper and the volume was
calculated according to the following equation:
V=L.times.W.sup.2/2. Mice were euthanized when tumor volume reached
3,000 mm3 or skin ulcerations occurred. Eight mice were housed per
cage. Food and water were available ad libitum. Mice were
acclimated to the animal facilities for a period of at least one
week prior to commencement of experiments. Animals were tested in
the light phase of a 12-hour light: 12-hour dark schedule (lights
on at 06:00 hours).
[0946] To refer to efficacy of therapeutic agents, parameters of
amplitude (TGI.sub.max), durability (TGD) of therapeutic response
are used. TGI.sub.max is the maximum tumor growth inhibition during
the experiment. Tumor growth inhibition is calculated by
100*(1-T.sub.v/C.sub.v) where T.sub.v and C.sub.v are the mean
tumor volumes of the treated and control groups, respectively. TGD
or tumor growth delay is the extended time of a treated tumor
needed to reach a volume of 1 cm.sup.3 relative to the control
group. TGD is calculated by 100*(T.sub.t/C.sub.t-1) where T.sub.t
and C.sub.t are the median time periods to reach 1 cm.sup.3 of the
treated and control groups, respectively.
Results
[0947] As shown in Tables 4-6, compounds of the present disclosure
are efficacious in an AMO-1 xenograft model of multiple myeloma,
rendering significant tumor growth inhibition and tumor growth
delay after intraperitoneal (IP) or intravenous (IV) dosing of
drug.
TABLE-US-00006 TABLE 4 In vivo Efficacy of MCL-1 Inhibitors in
AMO-1 Xenograft Model Dose Route/ Treatment (mg/kg/day) Regimen
TGI.sub.max (%) TGD (%) Vehicle 0 IP.sup.(a)/QDx1 0 0 Example 1 25
IP/QDx1 95* 133* Example 3 25 IP/QDx1 75* 58* .sup.(a)IP
Formulation = 5% DMSO, 20% cremophor EL, 75% D5W *= p < 0.05 as
compared to control treatment 7 mice per treatment group
TABLE-US-00007 TABLE 5 In vivo Efficacy of MCL-1 Inhibitors in
AMO-1 Xenograft Model Dose Route/ Treatment (mg/kg/day) Regimen
TGI.sub.max (%) TGD (%) Vehicle 0 IP.sup.(a)/QDx1 0 0 Example 7 25
IP/QDx1 99* 477* Example 8 25 IP/QDx1 79* 46* .sup.(a)IP
Formulation = 5% DMSO, 20% cremophor EL, 75% D5W *= p < 0.05 as
compared to control treatment 7 mice per treatment group
TABLE-US-00008 TABLE 6 In vivo Efficacy of MCL-1 Inhibitors in
AMO-1 Xenograft Model Dose Route/ Treatment (mg/kg/day) Regimen
TGI.sub.max (%) TGD (%) Vehicle 0 IV.sup.(a)/QDx1 0 0 Example 28
6.25 IV/QDx1 89* 233* Example 30 6.25 IV/QDx1 79* 133* Example 44
6.25 IV/QDx1 88* 156* Example 51 6.25 IV/QDx1 74* 111* .sup.(a)IP
Formulation = 5% DMSO, 10% cremophor EL, 85% D5W *= p < 0.05 as
compared to control treatment 7 mice per treatment group
[0948] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the present disclosure,
which is defined solely by the appended claims and their
equivalents. Various changes and modifications to the disclosed
embodiments will be apparent to those skilled in the art. All
publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
Sequence CWU 1
1
1116PRTArtificial
SequenceSYNTHESIZEDMOD_RES(1)..(1)ACETYLATIONMISC_FEATURE(13)..(13)FLUORE-
SCEINATED WITH 6-FAMMOD_RES(16)..(16)AMIDATION 1Gly Gln Val Gly Arg
Gln Leu Ala Ile Ile Gly Asp Lys Ile Asn Arg1 5 10 15
* * * * *