U.S. patent application number 17/222862 was filed with the patent office on 2022-01-06 for compounds and methods of use.
The applicant listed for this patent is Ferro Therapeutics, Inc.. Invention is credited to Ruihong Chen, Athisayamani Jeyaraj Duraiswamy, Chun Jiang, Biswajit Kalita, Anjali Pandey.
Application Number | 20220002280 17/222862 |
Document ID | / |
Family ID | 1000005826041 |
Filed Date | 2022-01-06 |
United States Patent
Application |
20220002280 |
Kind Code |
A1 |
Jiang; Chun ; et
al. |
January 6, 2022 |
COMPOUNDS AND METHODS OF USE
Abstract
This present disclosure relates to compounds with ferroptosis
inducing activity, a method of treating a subject with cancer with
the compounds, and combination treatments with a second therapeutic
agent.
Inventors: |
Jiang; Chun; (Hillsborough,
CA) ; Pandey; Anjali; (Fremont, CA) ; Chen;
Ruihong; (Burlingame, CA) ; Kalita; Biswajit;
(Bangalore, IN) ; Duraiswamy; Athisayamani Jeyaraj;
(Bangalore, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ferro Therapeutics, Inc. |
Palo Alto |
CA |
US |
|
|
Family ID: |
1000005826041 |
Appl. No.: |
17/222862 |
Filed: |
April 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16803862 |
Feb 27, 2020 |
11040964 |
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17222862 |
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PCT/US2019/019854 |
Feb 27, 2019 |
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16803862 |
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16287805 |
Feb 27, 2019 |
11098040 |
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PCT/US2019/019854 |
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62893092 |
Aug 28, 2019 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/04 20130101;
A61K 45/06 20130101; A61P 35/00 20180101; C07D 471/04 20130101;
C07D 215/20 20130101; C07D 401/12 20130101; C07D 413/10 20130101;
C07D 495/04 20130101 |
International
Class: |
C07D 413/10 20060101
C07D413/10; C07D 215/20 20060101 C07D215/20; C07D 495/04 20060101
C07D495/04; C07D 471/04 20060101 C07D471/04; C07D 401/12 20060101
C07D401/12; A61P 35/00 20060101 A61P035/00; C07D 401/04 20060101
C07D401/04 |
Claims
1-28. (canceled)
29. A method of inhibiting GPX4 in a cell, comprising contacting a
cell with an effective amount of a compound of Formula I, or a
tautomer, stereoisomer, mixture of stereoisomers, isotopically
enriched analog, or pharmaceutically acceptable salt thereof:
##STR00221## wherein: ring A is C.sub.4-C.sub.10cycloalkyl,
heterocyclyl, aryl, or heteroaryl; X is --O--, --S--, --NR.sup.9--,
--CR.sup.5.dbd.CR.sup.5--, or --CR.sup.5.dbd.N--; p is 0, 1, or 2;
q is 0, 1, 2, or 3; R.sup.1 is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.10cycloalkyl, --CN,
--OR.sup.7, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6,
--S(O).sub.2R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --S(O)R.sup.8, --N(R.sup.7).sub.2,
--NO.sub.2, --C.sub.1-C.sub.6alkyl-OR.sup.7, or
--Si(R.sup.15).sub.3; R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2alkylhalo and --C.sub.2-C.sub.3alkenylhalo are
unsubstituted or substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are unsubstituted or substituted with one
--CH.sub.3; each R.sup.3 is independently halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.4 is independently halo, --CN, --OH, --OR.sup.8, --NH.sub.2,
--NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.5 is independently hydrogen, halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.6 is independently hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each R.sup.6 is
independently unsubstituted or substituted with one to three
R.sup.11; each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7, together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl, wherein each R.sup.7 or ring formed thereby
is independently unsubstituted or substituted with one to three
R.sup.11; each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each R.sup.8 is
independently unsubstituted or substituted with one to three
R.sup.11; R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl; each
R.sup.10 is independently halo, --CN, --OR.sup.12, --NO.sub.2,
--N(R.sup.12).sub.2, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--S(O)N(R.sup.12).sub.2, --S(O).sub.2N(R.sup.12).sub.2,
--Si(R.sup.12).sub.3, --C(O)R.sup.12, --C(O)OR.sup.12,
--C(O)N(R.sup.12).sub.2, --NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12,
--OC(O)OR.sup.12, --OC(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)OR.sup.12, --OC(O)CHR.sup.12N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or heteroaryl,
wherein each C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or heteroaryl of
R.sup.10 is independently unsubstituted or substituted with one to
three R.sup.11; each R.sup.11 is independently halo, --CN,
--OR.sup.12, --NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl; each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl; each R.sup.13
is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; and each R.sup.15 is independently
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl.
30. The method of claim 29, wherein the cell is a cancer cell.
31. A method of treating cancer in a subject, comprising
administering to a subject having cancer a therapeutically
effective amount of a compound of Formula I, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof: ##STR00222##
wherein: ring A is C.sub.4-C.sub.10cycloalkyl, heterocyclyl, aryl,
or heteroaryl; X is --O--, --S--, --NR.sup.9--,
--CR.sup.5.dbd.CR.sup.5--, or --CR.sup.5.dbd.N--; p is 0, 1, or 2;
q is 0, 1, 2 or 3; R.sup.1 is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.10cycloalkyl, --CN,
--OR.sup.7, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6,
--S(O).sub.2R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --S(O)R.sup.8, --N(R.sup.7).sub.2,
--NO.sub.2, --C.sub.1-C.sub.6alkyl-OR.sup.7, or
--Si(R.sup.15).sub.3; R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2alkylhalo and --C.sub.2-C.sub.3alkenylhalo are
unsubstituted or substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are unsubstituted or substituted with one
--CH.sub.3; each R.sup.3 is independently halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.4 is independently halo, --CN, --OH, --OR.sup.8, --NH.sub.2,
--NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.5 is independently hydrogen, halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.6 is independently hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each R.sup.6 is
independently unsubstituted or substituted with one to three
R.sup.11; each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7, together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl, wherein each R.sup.7 or ring formed thereby
is independently unsubstituted or substituted with one to three
R.sup.11; each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each R.sup.8 is
independently unsubstituted or substituted with one to three
R.sup.11; R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl; each
R.sup.10 is independently halo, --CN, --OR.sup.12, --NO.sub.2,
--N(R.sup.12).sub.2, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--S(O)N(R.sup.12).sub.2, --S(O).sub.2N(R.sup.12).sub.2,
--Si(R.sup.12).sub.3, --C(O)R.sup.12, --C(O)OR.sup.12,
--C(O)N(R.sup.12).sub.2, --NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12,
--OC(O)OR.sup.12, --OC(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)OR.sup.12, --OC(O)CHR.sup.12N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or heteroaryl,
wherein each C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or heteroaryl of
R.sup.10 is independently unsubstituted or substituted with one to
three R.sup.11; each R.sup.11 is independently halo, --CN,
--OR.sup.12, --NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl; each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl; each R.sup.13
is independently C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.10cycloalkyl; and each R.sup.15 is independently
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl.
32. The method of claim 31, wherein the cancer is adrenocortical
cancer, anal cancer, biliary cancer, bladder cancer, bone cancer,
brain cancer, breast cancer, cervical cancer, colon cancer,
endometrial cancer, esophageal cancer, head and neck cancer,
hematologic cancer, intestinal cancer, liver cancer, lung cancer,
oral cancer, ovarian cancer, pancreatic cancer, renal cancer,
prostate cancer, salivary gland cancer, skin cancer, stomach
cancer, testicular cancer, throat cancer, thyroid cancer, uterine
cancer, vaginal cancer, sarcoma, or a soft tissue carcinoma.
33. The method of claim 32, wherein the cancer is osteosarcoma,
glioma, astrocytoma, neuroblastoma, cancer of the small intestine,
bronchial cancer, small cell lung cancer, non-small cell lung
cancer, basal cell carcinoma, or melanoma.
34. The method of claim 32, wherein the cancer is a hematologic
cancer.
35. The method of claim 33, wherein the hematologic cancer is acute
lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),
Hodgkin's lymphoma, Non-Hodgkin's lymphoma, Burkitt's lymphoma,
chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia
(CML), Hairy Cell chronic myelogenous leukemia (CML), or multiple
myeloma.
36. The method of claim 31, further comprising administering a
therapeutically effective amount of a second therapeutic agent.
37. The method of claim 36, wherein the second therapeutic agent is
a platinating agent, an alkylating agent, an anti-cancer
antibiotic, an antimetabolite, a topoisomerase I inhibitor, a
topoisomerase II inhibitor, or an antimicrotubule agent.
38. A process for preparing a compound of Formula I, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or salt thereof: ##STR00223## comprising contacting a
compound of Formula 1-5 with a compound of Formula 1-6:
##STR00224## under reaction conditions sufficient to provide the
compound of Formula I, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or salt thereof;
wherein: ring A is C.sub.4-C.sub.10cycloalkyl, heterocyclyl, aryl,
or heteroaryl; X is --O--, --S--, --NR.sup.9--,
--CR.sup.5.dbd.CR.sup.5--, or --CR.sup.5.dbd.N--; p is 0, 1, or 2;
q is 0, 1, 2 or 3; R.sup.1 is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.10cycloalkyl, --CN,
--OR.sup.7, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6,
--S(O).sub.2R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --S(O)R.sup.8, --N(R.sup.7).sub.2,
--NO.sub.2, --C.sub.1-C.sub.6alkyl-OR.sup.7, or
--Si(R.sup.15).sub.3; R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2alkylhalo and --C.sub.2-C.sub.3alkenylhalo are
unsubstituted or substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are unsubstituted or substituted with one
--CH.sub.3; each R.sup.3 is independently halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.4 is independently halo, --CN, --OH, --OR.sup.8, --NH.sub.2,
--NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.5 is independently hydrogen, halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is independently
unsubstituted or substituted with one to three R.sup.10; each
R.sup.6 is independently hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each R.sup.6 is
independently unsubstituted or substituted with one to three
R.sup.11; each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7, together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl, wherein each R.sup.7 or ring formed thereby
is independently unsubstituted or substituted with one to three
R.sup.11; each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl, wherein each R.sup.8 is
independently unsubstituted or substituted with one to three
R.sup.11; R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl; each
R.sup.10 is independently halo, --CN, --OR.sup.12, --NO.sub.2,
--N(R.sup.12).sub.2, --S(O)R.sup.13, --S(O).sub.2R.sup.13,
--S(O)N(R.sup.12).sub.2, --S(O).sub.2N(R.sup.12).sub.2,
--Si(R.sup.12).sub.3, --C(O)R.sup.12, --C(O)OR.sup.12,
--C(O)N(R.sup.12).sub.2, --NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12,
--OC(O)OR.sup.12, --OC(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)OR.sup.12, --OC(O)CHR.sup.12N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or heteroaryl,
wherein each C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or heteroaryl of
R.sup.10 is independently unsubstituted or substituted with one to
three R.sup.11; each R.sup.11 is independently halo, --CN,
--OR.sup.12, --NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl; each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl; each R.sup.13
is independently C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.10cycloalkyl; and each R.sup.15 is independently
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl.
39. The method of claim 31, wherein at least one of the following
is true: 1) R.sup.1 is other than --C(O)OCH.sub.3; 2) R.sup.2 is
--C.sub.2alkynyl optionally substituted with one --CH.sub.3; or 3)
when R.sup.1 is --C(O)OCH.sub.3 and R.sup.2 is --CH.sub.2Cl, then
the moiety ##STR00225## is other than 1,3-benzodioxol-5-yl,
4-nitrophenyl, 4-bromophenyl, cyclohexyl, furyl, or
4-methoxyphenyl.
40. The method of claim 31, wherein the compound is represented by
a compound of Formula II, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or pharmaceutically
acceptable salt thereof: ##STR00226##
41. The method of claim 31, wherein the compound is represented by
a compound of Formula III, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or pharmaceutically
acceptable salt thereof: ##STR00227## wherein R.sup.14 is halo.
42. The method of claim 31, wherein ring A is
C.sub.4-C.sub.10cycloalkyl.
43. The method of claim 31, wherein ring A is heterocyclyl.
44. The method of claim 31, wherein ring A is aryl.
45. The method of claim 31, wherein ring A is heteroaryl.
46. The method of claim 31, wherein the compound is represented by
a compound of Formula VIII, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or pharmaceutically
acceptable salt thereof: ##STR00228##
47. The method of claim 31, wherein R.sup.1 is
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.10cycloalkyl, --CN, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, --N(R.sup.7).sub.2, --OR.sup.7, or
--C.sub.1-C.sub.6alkyl-OR.sup.7.
48. The method of claim 31, wherein R.sup.1 is --C(O)OR.sup.6 or
--C(O)N(R.sup.7).sub.2.
49. The method of claim 31, wherein R.sup.1 is
C.sub.1-C.sub.6alkyl.
51. The method of claim 31, wherein p is 0 or 1.
52. The method of claim 31, wherein the compound is represented by
a compound of Formula IX, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or pharmaceutically
acceptable salt thereof: ##STR00229## wherein R.sup.16 is hydrogen
or C.sub.2-C.sub.5alkyl.
53. The method of claim 31, wherein q is 2 or 3.
54. The method of claim 31, wherein each R.sup.4 is independently
halo, --CN, --OH, --OR.sup.8, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.10cycloalkyl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkynyl, or
C.sub.3-C.sub.10cycloalkyl of R.sup.4 is independently
unsubstituted or substituted with one to three R.sup.10.
55. The method of claim 31, wherein q is 1.
56. A method of claim 31, wherein the compound is: ##STR00230##
##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235##
##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240## or
a tautomer, stereoisomer, mixture of stereoisomers, isotopically
enriched analog, or pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/803,862, filed on Feb. 27, 2020, which is a
continuation-in-part of PCT application number PCT/US2019/019854,
filed Feb. 27, 2019, a continuation-in-part of U.S. patent
application Ser. No. 16/287,805, filed Feb. 27, 2019, and claims
the benefit under 35 U.S.C. .sctn. 119(e) to U.S. Provisional
Patent Application No. 62/893,092, filed Aug. 28, 2019, the
contents of which are incorporated herein in their entirety.
BACKGROUND
[0002] Glutathione peroxidase 4 (GPX4) can directly reduce
phospholipid hydroperoxide. Depletion of GPX4 induces lipid
peroxidation-dependent cell death. Cancer cells in a drug-induced,
therapy-resistant state have an enhanced dependence on the lipid
peroxidase activity of GPX4 to prevent undergoing ferroptotic cell
death. Studies have shown that lipophilic antioxidants, such as
Ferrostatin, can rescue cells from GPX4 inhibition-induced
ferroptosis. For instance, mesenchymal state GPX4-knockout cells
can survive in the presence of Ferrostatin, however, when the
supply of Ferrostatin is terminated, these cells undergo
ferroptosis (see, e.g., Viswanathan et al., Nature 547:453-7,
2017). It has also been experimentally determined that that GPX4i
can be rescued by blocking other components of the ferroptosis
pathways, such as lipid ROS scavengers (Ferrostatin, Liproxstatin),
lipoxygenase inhibitors, iron chelators and caspase inhibitors,
which an apoptotic inhibitor does not rescue. These findings are
suggestive of non-apoptotic, iron-dependent, oxidative cell death
(i.e., ferroptosis). Accordingly, a GPX4 inhibitor can be useful to
induce ferroptotic cancer cell death and thus treat cancer.
SUMMARY
[0003] The present disclosure relates to compounds having
ferroptosis inducing activity, and methods of using the compounds
for the treatment of cancer. In certain embodiments, provided
herein is a compound of Formula I:
##STR00001##
[0004] or a tautomer, stereoisomer, mixture of stereoisomers,
isotopically enriched analog, or pharmaceutically acceptable salt
thereof, wherein:
[0005] ring A is C.sub.4-C.sub.10cycloalkyl, heterocyclyl, aryl, or
heteroaryl;
[0006] X is --O--, --S--, --NR.sup.9--, --CR.sup.5.dbd.CR.sup.5--,
or --CR.sup.5.dbd.N--;
[0007] p is 0, 1 or 2;
[0008] q is 0, 1, 2 or 3;
[0009] R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.10cycloalkyl, --CN, --OR.sup.7, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2,
--S(O)R.sup.8, --N(R.sup.7).sub.2, --NO.sub.2,
--C.sub.1-C.sub.6alkyl-OR.sup.7, or --Si(R.sup.15).sub.3;
[0010] R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2alkylhalo and --C.sub.2-C.sub.3alkenylhalo are
optionally substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are optionally substituted with one
--CH.sub.3;
[0011] each R.sup.3 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
optionally substituted with one to three R.sup.10;
[0012] each R.sup.4 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is optionally
independently optionally substituted with one to three
R.sup.10;
[0013] each R.sup.5 is independently hydrogen, halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is optionally
independently optionally substituted with one to three
R.sup.10;
[0014] each R.sup.6 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.6 is
independently further substituted with one to three R.sup.11;
[0015] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl,
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7 together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl; wherein each R.sup.7 or ring formed thereby
is independently further substituted with one to three
R.sup.11;
[0016] each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.8 is
independently further substituted with one to three R.sup.11;
[0017] R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl;
[0018] each R.sup.10 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl, wherein each C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl of R.sup.10 is optionally independently
substituted with one to three R.sup.11;
[0019] each R.sup.11 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl;
[0020] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl;
[0021] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; and
[0022] each R.sup.15 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, and
--C.sub.2-C.sub.6alkenylheteroaryl; provided that at least one of
the following is true:
[0023] 1) R.sup.1 is other than --C(O)OCH.sub.3;
[0024] 2) R.sup.2 is --C.sub.2alkynyl optionally substituted with
one --CH.sub.3; or
[0025] 3) when R.sup.1 is --C(O)OCH.sub.3 and R.sup.2 is
--CH.sub.2Cl, then the moiety
##STR00002##
is other than 1,3-benzodioxol-5-yl, 4-nitrophenyl, 4-bromophenyl,
cyclohexyl, furyl, or 4-methoxyphenyl.
[0026] In certain embodiments, the compounds, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof, or
pharmaceutical compositions comprising the same, exhibit GPX4
inhibiting activity, and in certain embodiments, exhibit altered or
enhanced stability (e.g., metabolic stability) and/or enhanced
activity or other characteristics as compared to other GPX4
inhibitors. In certain embodiments, the compounds described herein,
or a tautomer, stereoisomer, mixture of stereoisomers, isotopically
enriched analog, or pharmaceutically acceptable salt thereof, or
pharmaceutical compositions comprising the same, are selective for
GPX4 over other GPXs. In certain embodiments, the compounds are
used in a method of inhibiting GPX4 in a cell, comprising
contacting a cell with an effective amount of the compound
described herein, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or pharmaceutically
acceptable salt thereof, or pharmaceutical compositions comprising
the same, to inhibit GPX4 in the cell. In certain embodiments, the
cell is a cancer cell.
[0027] In certain embodiments, provided is a method of inducing
ferroptosis in a cell comprising contacting the cell with an
effective amount of a compound of Formula I:
##STR00003##
[0028] or a tautomer, stereoisomer, mixture of stereoisomers,
isotopically enriched analog, or pharmaceutically acceptable salt
thereof, wherein:
[0029] ring A is C.sub.4-C.sub.10cycloalkyl, heterocyclyl, aryl, or
heteroaryl;
[0030] X is --O--, --S--, --NR.sup.9--, --CR.sup.5.dbd.CR.sup.5--,
or --CR.sup.5.dbd.N--;
[0031] p is 0, 1 or 2;
[0032] q is 0, 1, 2 or 3;
[0033] R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.10cycloalkyl, --CN, --OR.sup.7, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2,
--S(O)R.sup.8, --N(R.sup.7).sub.2, --NO.sub.2,
--C.sub.1-C.sub.6alkyl-OR.sup.7, or --Si(R.sup.15).sub.3;
[0034] R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2alkylhalo and --C.sub.2-C.sub.3alkenylhalo are
optionally substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are optionally substituted with one
--CH.sub.3;
[0035] each R.sup.3 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
optionally substituted with one to three R.sup.10;
[0036] each R.sup.4 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is optionally
independently optionally substituted with one to three
R.sup.10;
[0037] each R.sup.5 is independently hydrogen, halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is optionally
independently optionally substituted with one to three
R.sup.10;
[0038] each R.sup.6 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.6 is
independently further substituted with one to three R.sup.11;
[0039] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl,
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7 together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl; wherein each R.sup.7 or ring formed thereby
is independently further substituted with one to three
R.sup.11;
[0040] each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.8 is
independently further substituted with one to three R.sup.11;
[0041] R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl;
[0042] each R.sup.10 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl, wherein each C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl of R.sup.10 is optionally independently
substituted with one to three R.sup.11;
[0043] each R.sup.11 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl;
[0044] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl;
[0045] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; and
[0046] each R.sup.15 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, and
--C.sub.2-C.sub.6alkenylheteroaryl, or pharmaceutical composition
comprising the same.
[0047] In certain embodiments, provided is a method for treating a
cancer in a patient in need thereof, comprising administering an
effective amount of a compound, or a tautomer, stereoisomer,
mixture of stereoisomers, isotopically enriched analog, or
pharmaceutically acceptable salt thereof, or pharmaceutical
composition provided herein. In certain embodiments, provided is a
method for treating a malignant solid tumor in a patient in need
thereof, comprising administering an effective amount of a
compound, or a tautomer, stereoisomer, mixture of stereoisomers,
isotopically enriched analog, or pharmaceutically acceptable salt
thereof, or pharmaceutical composition provided herein to the
patient. In certain embodiments, the malignant solid tumor is a
sarcoma, carcinoma, or lymphoma. In certain embodiments, the method
comprises a compound of Formula I:
##STR00004##
[0048] or a tautomer, stereoisomer, mixture of stereoisomers,
isotopically enriched analog, or pharmaceutically acceptable salt
thereof, wherein:
[0049] ring A is C.sub.4-C.sub.10cycloalkyl, heterocyclyl, aryl, or
heteroaryl;
[0050] X is --O--, --S--, --NR.sup.9--, --CR.sup.5.dbd.CR.sup.5--,
or --CR.sup.5.dbd.N--;
[0051] p is 0, 1 or 2;
[0052] q is 0, 1, 2 or 3;
[0053] R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.10cycloalkyl, --CN, --OR.sup.7, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2,
--S(O)R.sup.8, --N(R.sup.7).sub.2, --NO.sub.2,
--C.sub.1-C.sub.6alkyl-OR.sup.7, or --Si(R.sup.15).
[0054] R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2alkylhalo and --C.sub.2-C.sub.3alkenylhalo are
optionally substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are optionally substituted with one
--CH.sub.3;
[0055] each R.sup.3 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
optionally substituted with one to three R.sup.10;
[0056] each R.sup.4 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is optionally
independently optionally substituted with one to three R.sup.10;
[0057] each R.sup.5 is independently hydrogen, halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is optionally
independently optionally substituted with one to three
R.sup.10;
[0058] each R.sup.6 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.6 is
independently further substituted with one to three R.sup.11;
[0059] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl,
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7 together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl; wherein each R.sup.7 or ring formed thereby
is independently further substituted with one to three
R.sup.11;
[0060] each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.10 is
independently further substituted with one to three R.sup.11;
[0061] R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl;
[0062] each R.sup.10 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl, wherein each C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl of R.sup.10 is optionally independently
substituted with one to three R.sup.11;
[0063] each R.sup.11 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl;
[0064] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl;
[0065] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; and
[0066] each R.sup.15 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, and
--C.sub.2-C.sub.6alkenylheteroaryl.
BRIEF DESCRIPTION OF THE DRAWINGS
[0067] FIG. 1 shows compound 40 tested in cell-based Western blot
analysis of GPX4.
[0068] FIG. 2 shows Kinact/Ki data for compounds as described
herein.
DETAILED DESCRIPTION
[0069] As used in this specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly indicates otherwise. Thus, for example,
reference to "a protein" includes more than one protein, and
reference to "a compound" refers to more than one compound.
[0070] Also, the use of "or" means "and/or" unless stated
otherwise. Similarly, "comprise," "comprises," "comprising"
"include," "includes," and "including" are interchangeable and not
intended to be limiting.
[0071] It is to be further understood that where descriptions of
various embodiments use the term "comprising," those skilled in the
art would understand that in some specific instances, an embodiment
can be alternatively described using language "consisting
essentially of" or "consisting of."
[0072] It is to be understood that both the foregoing general
description, including the drawings, and the following detailed
description are exemplary and explanatory only and are not
restrictive of this disclosure. The section headings used herein
are for organizational purposes only and not to be construed as
limiting the subject matter described.
1. Definitions
[0073] In reference to the present disclosure, the technical and
scientific terms used in the descriptions herein will have the
meanings commonly understood by one of ordinary skill in the art,
unless specifically defined otherwise. Accordingly, the following
terms are intended to have the meanings as described below.
[0074] "Ferroptosis" refers to a form of cell death understood in
the art as involving generation of reactive oxygen species mediated
by iron, and characterized by, in part, lipid peroxidation.
[0075] "Ferroptosis inducer" or "ferroptosis activator" refers to
an agent which induces, promotes or activates ferroptosis.
[0076] "GPX4 inhibitor" refers to any agent that inhibits the
activity of the enzyme glutathione peroxidase 4 (GPX4). A GPX4
inhibitor can be either a direct or indirect inhibitor. GPX4 is a
phospholipid hydroperoxidase that in catalyzing the reduction of
hydrogen peroxide and organic peroxides, thereby protects cells
against membrane lipid peroxidation, or oxidative stress. GPX4 has
a selenocysteine in the active site that is oxidized to a selenenic
acid by the peroxide to afford a lipid-alcohol. The glutathione
acts to reduce the selenenic acid (--SeOH) back to the selenol
(--SeH). Should this catalytic cycle be disrupted, cell death
occurs through an intracellular iron-mediated process known as
ferroptosis.
[0077] "Subject" as used herein refers to a mammal, for example a
dog, a cat, a horse, or a rabbit. In certain embodiments, the
subject is a non-human primate, for example a monkey, chimpanzee,
or gorilla. In certain embodiments, the subject is a human,
sometimes referred to herein as a patient.
[0078] "Treating" or "treatment" of a disease, disorder, or
syndrome, as used herein, includes (i) preventing the disease,
disorder, or syndrome from occurring in a subject, i.e. causing the
clinical symptoms of the disease, disorder, or syndrome not to
develop in an animal that may be exposed to or predisposed to the
disease, disorder, or syndrome but does not yet experience or
display symptoms of the disease, disorder, or syndrome; (ii)
inhibiting the disease, disorder, or syndrome, i.e., arresting its
development; and (iii) relieving the disease, disorder, or
syndrome, i.e., causing regression of the disease, disorder, or
syndrome. As is known in the art, adjustments for systemic versus
localized delivery, age, body weight, general health, sex, diet,
time of administration, drug interaction and the severity of the
condition may be necessary, and will be ascertainable with routine
experimentation by one of ordinary skill in the art, particularly
in view of the guidance provided in the present disclosure.
[0079] "Therapeutically effective amount" refers to that amount
which, when administered to an animal (e.g., human) for treating a
disease, is sufficient to effect such treatment for the disease,
disorder, or condition. In certain embodiments, the treatment
provides a therapeutic benefit such as amelioration of symptoms or
slowing of disease progression. For example, a therapeutically
effective amount may be an amount sufficient to decrease a symptom
of a disease or condition of as described herein.
[0080] "Alkyl" refers to a straight or branched chain hydrocarbon
group of 1 to 20 carbon atoms (C.sub.1-C.sub.20 or C.sub.1-20), 1
to 12 carbon atoms (C.sub.1-C.sub.12 or C.sub.1-12), or 1 to 8
carbon atoms (C.sub.1-C.sub.8 or C.sub.1-8). Exemplary "alkyl"
includes, but are not limited to, methyl, ethyl, n-propyl,
i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl, and
the like.
[0081] "Alkenyl" refers to a straight or branched chain hydrocarbon
group of 2 to 20 carbon atoms (C.sub.2-C.sub.20 or C.sub.2-20), 2
to 12 carbon atoms (C.sub.2-C.sub.12 or C.sub.2-12), or 2 to 8
carbon atoms (C.sub.2-C.sub.8 or C.sub.2-8), having at least one
double bond. Exemplary "alkenyl" includes, but are not limited to,
vinyl, ethenyl, allyl, isopropenyl, 1-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl and 5-hexenyl, and the like.
[0082] "Alkynyl" refers to a straight or branched chain hydrocarbon
group of 2 to 12 carbon atoms (C.sub.2-C.sub.12 or C.sub.2-12), 2
to 8 carbon atoms (C.sub.2-C.sub.8 or C.sub.2-8), containing at
least one triple bond. Exemplary "alkynyl" includes ethynyl,
1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,
1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,
2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl, and the like.
[0083] "Alkylene," "alkenylene" and "alkynylene" refers to a
straight or branched chain divalent hydrocarbon radical of the
corresponding alkyl, alkenyl, and alkynyl, respectively. In certain
embodiments, "alkyl," "alkenyl," and "alkynyl" can represent the
corresponding "alkylene," "alkenylene" and "alkynylene," such as,
by way of example and not limitation, cycloalkylalkyl-,
heterocycloalkylalkyl-, arylalkyl-, heteroarylalkyl-,
cycloalkylalkenyl-, heterocycloalkylalkenyl-, arylalkenyl-,
heteroarylalkenyl-, cycloalkylalkynyl-, heterocycloalkylalkynyl-,
arylalkynyl-, heteroarylalkynyl-, and the like, wherein the
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is
connected, as a substituent via the corresponding alkylene,
alkenylene, or alkynylene group.
[0084] "Lower" in reference to substituents refers to a group
having between one and six carbon atoms.
[0085] "Alkylhalo" or "haloalkyl" refers to a straight or branched
chain hydrocarbon group of 1 to 20 carbon atoms (C.sub.1-C.sub.20
or C.sub.1-20), 1 to 12 carbon atoms (C.sub.1-C.sub.12 or
C.sub.1-12), or 1 to 8 carbon atoms (C.sub.1-C.sub.8 or C.sub.1-8)
wherein one or more (e.g., one to three, or one) hydrogen atom is
replaced by a halogen (e.g., Cl, F, etc.). In certain embodiments,
the term "alkylhalo" refers to an alkyl group as defined herein,
wherein one hydrogen atom is replaced by a halogen (e.g., Cl, F,
etc.). In certain embodiments, the term "alkylhalo" refers to an
alkylchloride.
[0086] "Alkenylhalo" or "haloalkenyl" refers to a straight or
branched chain hydrocarbon group of 2 to 20 carbon atoms
(C.sub.2-C.sub.20 or C.sub.2-20), 2 to 12 carbon atoms
(C.sub.2-C.sub.12 or C.sub.2-12), or 2 to 8 carbon atoms
(C.sub.2-C.sub.8 or C.sub.2-8), having at least one double bond,
wherein one or more (e.g., one to three, or one) hydrogen atom is
replaced by a halogen (e.g., Cl, F, etc.). In certain embodiments,
the term "alkenylhalo" refers to an alkenyl group as defined
herein, wherein one hydrogen atom is replaced by a halogen (e.g.,
Cl, F, etc.). In certain embodiments, the term "alkenylhalo" refers
to an alkenylchloride.
[0087] "Heteroalkyl" refers to a straight or branched chain
hydrocarbon group of 1 to 20 carbon atoms (C.sub.1-C.sub.20 or
C.sub.1-20), 1 to 12 carbon atoms (C.sub.1-C.sub.12 or C.sub.1-12),
or 1 to 8 carbon atoms (C.sub.1-C.sub.8 or C.sub.1-8), wherein 1 to
3 carbon atoms are replaced by a heteroatom. Heteroatoms and/or
heteroatomic groups which can replace the carbon atoms include, but
are not limited to, --O--, --S--, --NR.sup.40--, --PH--, --C(O)--,
--S(O)--, --S(O).sub.2--, --S(O)NR.sup.40--,
--S(O).sub.2NR.sup.40--, and the like, including combinations
thereof, wherein each R.sup.40 is independently hydrogen or lower
alkyl.
[0088] "Cycloalkyl" refers to any stable monocyclic or polycyclic
system which consists of carbon atoms, any ring of which being
saturated. "Cycloalkenyl" refers to any stable monocyclic or
polycyclic system which consists of carbon atoms, with at least one
ring thereof being partially unsaturated. Examples of cycloalkyls
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloalkyls and
tricycloalkyls (e.g., adamantyl).
[0089] "Heterocycloalkyl" or "heterocyclyl" refers to a 4 to 14
membered, mono- or polycyclic (e.g., bicyclic), non-aromatic
hydrocarbon ring, wherein 1 to 3 carbon atoms are replaced by a
heteroatom. Heteroatoms and/or heteroatomic groups which can
replace the carbon atoms include, but are not limited to, --O--,
--S--, --S--O--, --NR.sup.40--, --PH--, --C(O)--, --S(O)--,
--S(O).sub.2--, --S(O)NR.sup.40--, --S(O).sub.2NR.sup.40--, and the
like, including combinations thereof, where each R.sup.40 is
independently hydrogen or lower alkyl. Examples include
thiazolidinyl, thiadiazolyl, triazinyl, morpholinyl,
pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl,
2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl,
oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,
dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. In
certain embodiments, the "heterocycloalkyl" or "heterocyclyl" is a
substituted or unsubstituted 4 to 7 membered monocyclic ring,
wherein 1 to 3 carbon atoms are replaced by a heteroatom as
described above.
[0090] In certain embodiments, the "heterocycloalkyl" or
"heterocyclyl" is a 4 to 10, or 4 to 9, or 5 to 9, or 5 to 7, or 5
to 6 membered mono- or polycyclic (e.g., bicyclic) ring, wherein 1
to 3 carbon atoms are replaced by a heteroatom as described above.
In certain embodiments, when the "heterocycloalkyl" or
"heterocyclyl" is a substituted or unsubstituted bicyclic ring, one
ring may be aromatic, provided at least one ring is non-aromatic,
regardless of the point of attachment to the remainder of the
molecule (e.g., indolinyl, isoindolinyl, and the like).
[0091] "Aryl" refers to a 6 to 14-membered, mono- or bi-carbocyclic
ring, wherein the monocyclic ring is aromatic and at least one of
the rings in the bicyclic ring is aromatic. Unless stated
otherwise, the valency of the group may be located on any atom of
any ring within the radical, valency rules permitting. Examples of
"aryl" groups include phenyl, naphthyl, indenyl, biphenyl,
phenanthrenyl, naphthacenyl, and the like.
[0092] "Heteroaryl" means an aromatic heterocyclic ring, including
monocyclic and polycyclic (e.g., bicyclic) ring systems, where at
least one carbon atom of one or both of the rings is replaced with
a heteroatom independently selected from nitrogen, oxygen, and
sulfur, or at least two carbon atoms of one or both of the rings
are replaced with a heteroatom independently selected from
nitrogen, oxygen, and sulfur. In certain embodiments, the
heteroaryl can be a 5 to 6 membered monocyclic, or 7 to 11 membered
bicyclic ring systems. Examples of "heteroaryl" groups include
pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl,
thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl,
purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl,
quinolyl, and the like.
[0093] "Bridged bicyclic" refers to any bicyclic ring system, i.e.
carbocyclic or heterocyclic, saturated or partially unsaturated,
having at least one bridge. As defined by IUPAC, a "bridge" is an
unbranched chain of atoms or an atom or a valence bond connecting
two bridgeheads, where a "bridgehead" is any skeletal atom of the
ring system which is bonded to three or more skeletal atoms
(excluding hydrogen). In certain embodiments, a bridged bicyclic
group has 5-12 ring members and 0-4 heteroatoms independently
selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic
groups include those groups set forth below where each group is
attached to the rest of the molecule at any substitutable carbon or
nitrogen atom. Exemplary bridged bicyclics include, but are not
limited to:
##STR00005##
[0094] "Fused ring" refers a ring system with two or more rings
having at least one bond and two atoms in common. A "fused aryl"
and a "fused heteroaryl" refer to ring systems having at least one
aryl and heteroaryl, respectively, that share at least one bond and
two atoms in common with another ring.
[0095] "Halogen" or "halo" refers to fluorine, chlorine, bromine
and iodine.
[0096] "Acyl" refers to --C(O)R.sup.43, where R.sup.43 is hydrogen,
or an optionally substituted alkyl, heteroalkyl, cycloalkyl,
cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl as defined herein.
Exemplary acyl groups include, but are not limited to, formyl,
acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,
benzylcarbonyl, and the like.
[0097] "Alkyloxy" or "alkoxy" refers to --OR.sup.44, wherein
R.sup.44 is an optionally substituted alkyl.
[0098] "Aryloxy" refers to --OR.sup.45, wherein R.sup.45 is an
optionally substituted aryl.
[0099] "Carboxy" refers to --COO.sup.- or COOM, wherein M is H or a
counterion (e.g., a cation, such as Na.sup.+, Ca.sup.2+, Mg.sup.2+,
etc.).
[0100] "Carbamoyl" refers to --C(O)NR.sup.46R.sup.46, wherein each
R.sup.46 is independently selected from H or an optionally
substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocylcoalkylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl.
[0101] "Ester" refers to a group such as --C(.dbd.O)OR.sup.47,
alternatively illustrated as --C(O)OR.sup.47, wherein R.sup.47 is
selected from an optionally substituted alkyl, cycloalkyl,
cycloalkylalkyl, heterocycloalkyl, heterocyclolalkylalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl.
[0102] "Ether" refers to the group -alkyl-O-alkyl, where the term
alkyl is as defined herein.
[0103] "Sulfanyl" refers to --SR.sup.48, wherein R.sup.48 is
selected from an optionally substituted alkyl, cycloalkyl,
cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl. For example,
--SR.sup.48, wherein R.sup.48 is an alkyl is an alkylsulfanyl.
[0104] "Sulfonyl" refers to --S(O).sub.2--, which may have various
substituents to form different sulfonyl groups including sulfonic
acids, sulfonamides, sulfonate esters, and sulfones. For example,
--S(O).sub.2R.sup.49, wherein R.sup.49 is an alkyl refers to an
alkylsulfonyl. In certain embodiments of --S(O).sub.2R.sup.49,
R.sup.49 is selected from an optionally substituted alkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl.
[0105] "Sulfinyl" refers to --S(O)--, which may have various
substituents to form different sulfinyl groups including sulfinic
acids, sulfinamides, and sulfinyl esters. For example,
--S(O)R.sup.50, wherein R.sup.50 is an alkyl refers to an
alkylsulfinyl. In certain embodiments of --S(O)R.sup.50, R.sup.50
is selected from an optionally substituted alkyl, cycloalkyl,
cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl.
[0106] "Silyl" refers to Si, which may have various substituents,
for example --SiR.sup.51R.sup.51R.sup.51, where each R.sup.51 is
independently selected from alkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl. As defined herein, any
heterocycloalkyl or heteroaryl group present in a silyl group has
from 1 to 3 heteroatoms selected independently from O, N, and
S.
[0107] "Amino" or "amine" refers to the group --NR.sup.52R.sup.52
or --N+R.sup.52R.sup.52R.sup.52, wherein each R.sup.52 is
independently selected from hydrogen and an optionally substituted
alkyl, cycloalkyl, heterocycloalkyl, alkyloxy, aryl, heteroaryl,
heteroarylalkyl, acyl, --C(O)--O-alkyl, sulfanyl, sulfinyl,
sulfonyl, and the like. Exemplary amino groups include, but are not
limited to, dimethylamino, diethylamino, trimethylammonium,
triethylammonium, methylysulfonylamino, furanyl-oxy-sulfamino, and
the like.
[0108] "Amide" refers to a group such as
--C(.dbd.O)NR.sup.53R.sup.53, wherein each R.sup.53 is
independently selected from H and an optionally substituted alkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl.
[0109] "Carbamate" refers to a group such as
--O--C(.dbd.O)NR.sup.53R.sup.53 or --NR.sup.53--C(.dbd.O)OR.sup.53,
wherein each R.sup.53 is independently selected from H and an
optionally substituted alkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl.
[0110] "Sulfonamide" refers to --S(O).sub.2NR.sup.54R.sup.54,
wherein each R.sup.54 is independently selected from H and an
optionally substituted alkyl, heteroalkyl, heteroaryl, heterocycle,
alkenyl, alkynyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl,
alkylene-C(O)--OR.sup.55, or alkylene-O--C(O)--OR.sup.55, where
R.sup.55 is selected from H, alkyl, heteroalkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, arylalkyl,
heterocycloalkyl, heteroarylalkyl, amino, and sulfinyl.
[0111] "Adamantyl" refers to tricyclo[3.3.1.1.sup.3,7]decanyl,
where bonding can be via a 3-coordinated carbon site or a
2-coordinated carbon site (i.e., 1-adamantyl or 2-adamantyl). In
certain embodiments, "adamantyl" refers to a compound of structural
formula:
##STR00006##
[0112] where optional substitutions can be present on one or more
of R.sup.a, R.sup.b, R.sup.c, and R.sup.d. Adamantyl includes
substituted adamantyl, e.g., 1- or 2-adamantyl, substituted by one
or more substituents, including alkyl, halo, --OH, --NH.sub.2, and
alkoxy. Exemplary derivatives include methyladamatane,
haloadamantane, hydroxyadamantane, and aminoadamantane (e.g.,
amantadine).
[0113] "N-protecting group" as used herein refers to those groups
intended to protect a nitrogen atom against undesirable reactions
during synthetic procedures. Exemplary N-protecting groups include,
but is not limited to, acyl groups such acetyl and t-butylacetyl,
pivaloyl, alkoxycarbonyl groups such as methyloxycarbonyl and
t-butyloxycarbonyl (Boc), aryloxycarbonyl groups such as
benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc) and
aroyl groups such as benzoyl. N-protecting groups are described in
Greene's Protective Groups in Organic Synthesis, 5th Edition, P. G.
M. Wuts, ed., Wiley (2014).
[0114] "Optional" or "optionally" refers to a described event or
circumstance may or may not occur, and that the description
includes instances where the event or circumstance occurs and
instances where the event or circumstance does not. For example,
"optionally substituted alkyl" refers to an alkyl group that may or
may not be substituted and that the description encompasses both
substituted alkyl group and unsubstituted alkyl group.
[0115] "Substituted" as used herein means one or more hydrogen
atoms of the group is replaced with a substituent atom or group
commonly used in pharmaceutical chemistry. Each substituent can be
the same or different. Examples of suitable substituents include,
but are not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heterocycloalkyl, heteroaryl, --OR.sup.56 (e.g.,
hydroxyl, alkyloxy (e.g., methoxy, ethoxy, and propoxy), ether,
ester, carbamate, etc.), hydroxyalkyl, --C(O)O-alkyl,
--O-alkyl-O-alkyl, haloalkyl, alkyl-O-alkyl, SR.sup.56 (e.g., --SH,
--S-alkyl, --S-aryl, --S-heteroaryl, arylalkyl-S--, etc.),
S.sup.+R.sup.56.sub.2, S(O)R.sup.56, SO.sub.2R.sup.56,
NR.sup.56R.sup.57 (e.g., primary amine (i.e., NH.sub.2), secondary
amine, tertiary amine, amide, carbamate, urea, etc.), hydrazide,
halo, nitrile, nitro, sulfide, sulfoxide, sulfone, sulfonamide,
--SH, carboxy, aldehyde, keto, carboxylic acid, ester, amide,
imine, and imide (e.g., --C(O)NR.sup.56C(O)R.sup.57), including
seleno and thio derivatives thereof, wherein each R.sup.56 and
R.sup.57 are independently alkyl, alkenyl, alkynyl, heteroalkyl,
cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or
heteroarylalkyl, and wherein each of the substituents can be
optionally further substituted. In embodiments in which a
functional group with an aromatic carbon ring is substituted, such
substitutions will typically number less than about 10
substitutions, or about 1 to 5, with about 1 or 2 substitutions in
certain embodiments.
[0116] "Pharmaceutically acceptable salt" is meant to include salts
of the active compounds which are prepared with relatively nontoxic
acids or bases, depending on the particular substituents found on
the compounds described herein. When compounds as disclosed herein
contain relatively acidic functionalities, base addition salts can
be obtained by contacting the neutral form of such compounds with a
sufficient amount of the desired base, either neat or in a suitable
inert solvent. Examples of pharmaceutically acceptable base
addition salts include sodium, potassium, calcium, ammonium,
organic amino, or magnesium salt, or a similar salt. When compounds
as disclosed herein contain relatively basic functionalities, acid
addition salts can be obtained by contacting the neutral form of
such compounds with a sufficient amount of the desired acid, either
neat or in a suitable inert solvent. Examples of pharmaceutically
acceptable acid addition salts include those derived from inorganic
acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric,
partially neutralized phosphoric acids, sulfuric, partially
neutralized sulfuric, hydroiodic, or phosphorous acids and the
like, as well as the salts derived from relatively nontoxic organic
acids like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like. Certain specific compounds of the present
disclosure may contain both basic and acidic functionalities that
allow the compounds to be converted into either base or acid
addition salts. Lists of suitable salts are found in Remington's
Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton,
Pa., (1985) and Journal of Pharmaceutical Science, 66:2 (1977),
each of which is incorporated herein by reference in its
entirety.
[0117] "Pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" refers to an excipient, carrier or adjuvant
that can be administered to a subject, together with at least one
compound, and which does not destroy the pharmacological activity
thereof and is generally safe, nontoxic and neither biologically
nor otherwise undesirable when administered in doses sufficient to
deliver a therapeutic amount of the agent.
[0118] Any compound or structure given herein, is also intended to
represent unlabeled forms as well as isotopically labeled forms of
the compounds. These forms of compounds may also be referred to as
"isotopically enriched analogs." Isotopically labeled compounds
have structures depicted herein, except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into the disclosed
compounds include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, fluorine, chlorine and iodine, such as .sup.2H,
.sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.13N, .sup.15N,
.sup.15O, .sup.17O, .sup.18O, .sup.31P, .sup.32P, .sup.35S,
.sup.18F, .sup.36Cl, .sup.123I, and .sup.125I, respectively.
Various isotopically labeled compounds of the present disclosure,
for example those into which radioactive isotopes such as .sup.3H,
and .sup.14C are incorporated. Such isotopically labelled compounds
may be useful in metabolic studies, reaction kinetic studies,
detection or imaging techniques, such as positron emission
tomography (PET) or single-photon emission computed tomography
(SPECT) including drug or substrate tissue distribution assays or
in radioactive treatment of patients.
[0119] The term "isotopically enriched analogs" includes
"deuterated analogs" of compounds described herein in which one or
more hydrogens is/are replaced by deuterium, such as a hydrogen on
a carbon atom. Such compounds exhibit increased resistance to
metabolism and are thus useful for increasing the half-life of any
compound when administered to a mammal, e.g., a human. See, for
example, Foster, "Deuterium Isotope Effects in Studies of Drug
Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such
compounds are synthesized by means well known in the art, for
example by employing starting materials in which one or more
hydrogens have been replaced by deuterium.
[0120] Deuterium labelled or substituted therapeutic compounds of
the disclosure may have improved DMPK (drug metabolism and
pharmacokinetics) properties, relating to distribution, metabolism
and excretion (ADME). Substitution with heavier isotopes such as
deuterium may afford certain therapeutic advantages resulting from
greater metabolic stability, for example increased in vivo
half-life, reduced dosage requirements and/or an improvement in
therapeutic index. An .sup.18F, .sup.3H, .sup.11C labeled compound
may be useful for PET or SPECT or other imaging studies.
Isotopically labeled compounds of this disclosure and prodrugs
thereof can generally be prepared by carrying out the procedures
disclosed in the schemes or in the examples and preparations
described below by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent. It is
understood that deuterium in this context is regarded as a
substituent in a compound described herein.
[0121] The concentration of such a heavier isotope, specifically
deuterium, may be defined by an isotopic enrichment factor. In the
compounds of this disclosure any atom not specifically designated
as a particular isotope is meant to represent any stable isotope of
that atom. Unless otherwise stated, when a position is designated
specifically as "H" or "hydrogen," the position is understood to
have hydrogen at its natural abundance isotopic composition.
Accordingly, in the compounds of this disclosure any atom
specifically designated as a deuterium (D) is meant to represent
deuterium.
[0122] Some of the compounds exist as tautomers. Tautomers are in
equilibrium with one another. For example, amide containing
compounds may exist in equilibrium with imidic acid tautomers.
Regardless of which tautomer is shown and regardless of the nature
of the equilibrium among tautomers, the compounds are understood by
one of ordinary skill in the art to comprise both amide and imidic
acid tautomers. Thus, the amide containing compounds are understood
to include their imidic acid tautomers. Likewise, the imidic acid
containing compounds are understood to include their amide
tautomers.
[0123] The compounds as disclosed herein, or their pharmaceutically
acceptable salts include an asymmetric center and may thus give
rise to enantiomers, diastereomers, and other stereoisomeric forms
that may be defined, in terms of absolute stereochemistry, as (R)-
or (S)- or, as (D)- or (L)- for amino acids. The present disclosure
is meant to include all such possible isomers, as well as their
racemic and optically pure forms. Optically active (+) and (-),
(R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral
synthons or chiral reagents, or resolved using conventional
techniques, for example, chromatography and fractional
crystallization. Conventional techniques for the
preparation/isolation of individual enantiomers include chiral
synthesis from a suitable optically pure precursor or resolution of
the racemate (or the racemate of a salt or derivative) using, for
example, chiral high pressure liquid chromatography (HPLC). When
the compounds described herein contain olefinic double bonds or
other centers of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers.
[0124] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present disclosure contemplates various stereoisomers and mixtures
thereof and includes "enantiomers," which refers to two
stereoisomers whose molecules are non-superimposable mirror images
of one another.
[0125] "Diastereomers" are stereoisomers that have at least two
asymmetric atoms, but which are not mirror-images of each
other.
[0126] Relative centers of the compounds as depicted herein are
indicated graphically using the "thick bond" style (bold or
parallel lines) and absolute stereochemistry is depicted using
wedge bonds (bold or parallel lines).
2. Compounds
[0127] In certain embodiments, provided herein is a compound of
Formula I or a tautomer, stereoisomer, mixture of stereoisomers,
isotopically enriched analog, or pharmaceutically acceptable salt
thereof:
##STR00007##
[0128] wherein:
[0129] ring A is C.sub.4-C.sub.10cycloalkyl, heterocyclyl, aryl, or
heteroaryl;
[0130] X is --O--, --S--, --NR.sup.9--, --CR.sup.5.dbd.CR.sup.5--,
or --CR.sup.5.dbd.N--;
[0131] p is 0, 1 or 2;
[0132] q is 0, 1, 2 or 3;
[0133] R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.10cycloalkyl, --CN, --OR.sup.7, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2,
--S(O)R.sup.8, --N(R.sup.7).sub.2, --NO.sub.2,
--C.sub.1-C.sub.6alkyl-OR.sup.7, or --Si(R.sup.15).sub.3;
[0134] R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2haloalkyl and --C.sub.2-C.sub.3alkenylhalo are
optionally substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are optionally substituted with one
--CH.sub.3;
[0135] each R.sup.3 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
optionally substituted with one to three R.sup.10;
[0136] each R.sup.4 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is optionally
independently optionally substituted with one to three
R.sup.10;
[0137] each R.sup.5 is independently hydrogen, halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is optionally
independently optionally substituted with one to three
R.sup.10;
[0138] each R.sup.6 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.6 is
independently further substituted with one to three R.sup.11;
[0139] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl,
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7 together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl; wherein each R.sup.7 or ring formed thereby
is independently further substituted with one to three
R.sup.11;
[0140] each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.8 is
independently further substituted with one to three R.sup.11;
[0141] R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl;
[0142] each R.sup.10 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.2C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl, wherein each C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl of R.sup.10 is optionally independently
substituted with one to three R.sup.11;
[0143] each R.sup.11 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl;
[0144] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl;
[0145] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; and
[0146] each R.sup.15 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, and
--C.sub.2-C.sub.6alkenylheteroaryl.
[0147] In certain embodiments, provided is a compound of Formula I
or a tautomer, stereoisomer, mixture of stereoisomers, isotopically
enriched analog, or pharmaceutically acceptable salt thereof:
##STR00008##
[0148] wherein:
[0149] ring A is C.sub.4-C.sub.10cycloalkyl, heterocyclyl, aryl, or
heteroaryl;
[0150] X is --O--, --S--, --NR.sup.9--, --CR.sup.5.dbd.CR.sup.5--,
or --CR.sup.5.dbd.N--;
[0151] p is 0, 1 or 2;
[0152] q is 0, 1, 2 or 3;
[0153] R.sup.1 is C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.10cycloalkyl, --CN, --OR.sup.7, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2,
--S(O)R.sup.8, --N(R.sup.7).sub.2, --NO.sub.2,
--C.sub.1-C.sub.6alkyl-OR.sup.7, or --Si(R.sup.15).sub.3;
[0154] R.sup.2 is --C.sub.1-C.sub.2haloalkyl,
--C.sub.2-C.sub.3alkenyl, --C.sub.2-C.sub.3haloalkenyl,
C.sub.2alkynyl, or --CH.sub.2OS(O).sub.2-phenyl, wherein the
C.sub.1-C.sub.2alkylhalo and --C.sub.2-C.sub.3alkenylhalo are
optionally substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl and phenyl are optionally substituted with one
--CH.sub.3;
[0155] each R.sup.3 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)R.sup.8, --C(O)R.sup.6,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.3 is independently
optionally substituted with one to three R.sup.10;
[0156] each R.sup.4 is independently halo, --CN, --OH, --OR.sup.8,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.4 is optionally
independently optionally substituted with one to three
R.sup.10;
[0157] each R.sup.5 is independently hydrogen, halo, --CN, --OH,
--OR.sup.8, --NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2,
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.15).sub.3,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --NR.sup.12C(O)R.sup.8,
--OC(O)R.sup.8, --C(O)R.sup.6, --NR.sup.12C(O)OR.sup.8,
--OC(O)N(R.sup.7).sub.2, --OC(O)CHR.sup.8N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl of R.sup.5 is optionally
independently optionally substituted with one to three
R.sup.10;
[0158] each R.sup.6 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.6 is
independently further substituted with one to three R.sup.11;
[0159] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, heteroaryl, --C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl,
--C.sub.2-C.sub.6alkenylheteroaryl, or two R.sup.7 together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl; wherein each R.sup.7 or ring formed thereby
is independently further substituted with one to three
R.sup.11;
[0160] each R.sup.8 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl,
--C.sub.2-C.sub.6alkenylC.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl,
--C.sub.2-C.sub.6alkenylheterocyclyl, --C.sub.1-C.sub.6alkylaryl,
--C.sub.2-C.sub.6alkenylaryl, --C.sub.1-C.sub.6alkylheteroaryl, or
--C.sub.2-C.sub.6alkenylheteroaryl; wherein each R.sup.8 is
independently further substituted with one to three R.sup.11;
[0161] R.sup.9 is hydrogen or C.sub.1-C.sub.6alkyl;
[0162] each R.sup.10 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl, wherein each C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl of R.sup.10 is optionally independently
substituted with one to three R.sup.11;
[0163] each R.sup.11 is independently halo, --CN, --OR.sup.12,
--NO.sub.2, --N(R.sup.12).sub.2, --S(O)R.sup.13,
--S(O).sub.2R.sup.13, --S(O)N(R.sup.12).sub.2,
--S(O).sub.2N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)R.sup.12, --C(O)OR.sup.12, --C(O)N(R.sup.12).sub.2,
--NR.sup.12C(O)R.sup.12, --OC(O)R.sup.12, --OC(O)OR.sup.12,
--OC(O)N(R.sup.12).sub.2, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
aryl, or heteroaryl;
[0164] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl;
[0165] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; and
[0166] each R.sup.15 is independently C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, aryl, heteroaryl,
--C.sub.1-C.sub.6alkylaryl, --C.sub.2-C.sub.6alkenylaryl,
--C.sub.1-C.sub.6alkylheteroaryl, and
--C.sub.2-C.sub.6alkenylheteroaryl; provided that at least one of
the following is true:
[0167] 1) R.sup.1 is other than --C(O)OCH.sub.3;
[0168] 2) R.sup.2 is --C.sub.2alkynyl optionally substituted with
one --CH.sub.3; or
[0169] 3) when R.sup.1 is --C(O)OCH.sub.3 and R.sup.2 is
--CH.sub.2Cl, then the moiety
##STR00009##
is other than 1,3-benzodioxol-5-yl, 4-nitrophenyl, 4-bromophenyl,
cyclohexyl, furyl, or 4-methoxyphenyl.
[0170] In certain embodiments, R.sup.1 is other than --C(O)OR.sup.6
or R.sup.2 is --C.sub.2alkynyl optionally substituted with one
--CH.sub.3. In certain embodiments, R.sup.1 is other than
--C(O)OCH.sub.3 or R.sup.2 is --C.sub.2alkynyl optionally
substituted with one --CH.sub.3. In certain embodiments, R.sup.1 is
other than --C(O)OR.sup.6 and R.sup.2 is --C.sub.2alkynyl
optionally substituted with one --CH.sub.3. In certain embodiments,
R.sup.1 is other than --C(O)OCH.sub.3 and R.sup.2 is
--C.sub.2alkynyl optionally substituted with one --CH.sub.3. In
certain embodiments, R.sup.1 is other than --C(O)OR.sup.6. In
certain embodiments, R.sup.1 is other than --C(O)OCH.sub.3. In
certain embodiments, R.sup.2 is --C.sub.2alkynyl optionally
substituted with one --CH.sub.3. In certain embodiments, R.sup.2 is
--C.sub.2alkynyl.
[0171] Also provided is a compound of Formula IA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00010##
[0172] wherein each of ring A, X, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, p, and q are independently as defined herein.
[0173] Also provided is a compound of Formula IB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00011##
[0174] wherein each of ring A, X, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, p, and q are independently as defined herein.
[0175] Also provided is a compound of Formula II, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00012##
[0176] wherein each of ring A, X, R.sup.1, R.sup.3, R.sup.4, p, and
q are independently as defined herein.
[0177] Also provided is a compound of Formula IIA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00013##
[0178] wherein each of ring A, X, R.sup.1, R.sup.3, R.sup.4, p, and
q are independently as defined herein.
[0179] Also provided is a compound of Formula IIB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00014##
[0180] wherein each of ring A, X, R.sup.1, R.sup.3, R.sup.4, p, and
q are independently as defined herein.
[0181] Also provided is a compound of Formula III, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00015##
[0182] wherein each of ring A, X, R.sup.1, R.sup.3, R.sup.4, p, and
q are independently as defined herein, and R.sup.14 is halo.
[0183] Also provided is a compound of Formula IIIA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00016##
[0184] wherein each of ring A, X, R.sup.1, R.sup.3, R.sup.4, p, and
q are independently as defined herein, and R.sup.14 is halo.
[0185] Also provided is a compound of Formula IIIB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00017##
[0186] wherein each of ring A, X, R.sup.1, R.sup.3, R.sup.4, p, and
q are independently as defined herein, and R.sup.14 is halo.
[0187] In certain embodiments,
[0188] ring A is aryl or heteroaryl;
[0189] X is --O--, --S--, --NH--, --CH.dbd.CH--, or
--CH.dbd.N--;
[0190] p is 0, 1 or 2;
[0191] q is 1;
[0192] R.sup.1 is C.sub.1-C.sub.6alkyl,
--C(O)O--C.sub.1-C.sub.6alkyl, or
--C(O)N(C.sub.1-C.sub.6alkyl).sub.2;
[0193] R.sup.3 is halo, --NHR.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, or heterocyclyl;
[0194] each R.sup.4 is independently --OR.sup.8;
[0195] R.sup.6 is C.sub.1-C.sub.6alkyl;
[0196] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl, wherein each
R.sup.7 is independently further substituted with one to three
R.sup.11;
[0197] each R.sup.8 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; wherein each R.sup.8 is independently
further substituted with one to three R.sup.11; [0198] each
R.sup.11 is independently --O--C.sub.1-C.sub.6alkyl; and
[0199] R.sup.14 is halo.
[0200] In certain embodiments,
[0201] ring A is aryl or heteroaryl;
[0202] X is --O--, --S--, --NH--, --CH.dbd.CH--, or
--CH.dbd.N--;
[0203] p is 0, 1 or 2;
[0204] q is 1;
[0205] R.sup.1 is C.sub.1-C.sub.6alkyl or
--C(O)N(C.sub.1-C.sub.6alkyl).sub.2;
[0206] R.sup.3 is halo, --NHR.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, or heterocyclyl;
[0207] each R.sup.4 is independently --OR.sup.8;
[0208] R.sup.6 is C.sub.1-C.sub.6alkyl;
[0209] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl, wherein each
R.sup.7 is independently further substituted with one to three
R.sup.11;
[0210] each R.sup.8 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; wherein each R.sup.8 is independently
further substituted with one to three R.sup.11;
[0211] each R.sup.11 is independently --O--C.sub.1-C.sub.6alkyl;
and
[0212] R.sup.14 is halo.
[0213] In certain embodiments, X is --O--, --S--, or --NR.sup.9--.
In certain embodiments, X is --O--, --S--, or --NH--. In certain
embodiments, X is --O--. In certain embodiments, X is --S--. In
certain embodiments, X is --NR.sup.9--. In certain embodiments, X
is --NH--.
[0214] In certain embodiments, X is --CR.sup.5.dbd.CR.sup.5-- or
--CR.sup.5.dbd.N--. In certain embodiments, X is --CH.dbd.CH-- or
--CH.dbd.N--. In certain embodiments, X is
--CR.sup.5.dbd.CR.sup.5--. In certain embodiments, X is
--CR.sup.5.dbd.N--.
[0215] In certain embodiments, R.sup.5 is R.sup.4.
[0216] In certain embodiments, when X is --CH.dbd.CH--, p is 1 or
2, each R.sup.4 is methoxy, ring A is phenyl, and q is 1, then
R.sup.3 is other than adamantylamine, fluoro, or
--C(O)NH-cyclopropyl. In certain embodiments, when X is
--CH.dbd.CH--, p is 1 or 2, each R.sup.4 is methoxy, R.sup.1 is
methyl, n-butyl or --C(O)OCH.sub.3, ring A is phenyl, and q is 1,
then R.sup.3 is other than adamantylamine, fluoro, and
--C(O)NH-cyclopropyl. In certain embodiments, when X is
--CH.dbd.CH--, p is 1 or 2, each R.sup.4 is methoxy, R.sup.1 is
methyl, n-butyl or --C(O)OCH.sub.3, R.sup.2 is --CH.sub.2Cl or
C.sub.2alkynyl, ring A is phenyl, and q is 1, then R.sup.3 is other
than adamantylamine, fluoro, or --C(O)NH-cyclopropyl.
[0217] In certain embodiments, when X is --CR.sup.5.dbd.CR.sup.5--,
p is 1 or 2, ring A is phenyl, cyclohexyl, or furyl, and q is 0 or
1, then at least one R.sup.4 is other than methoxy. In certain
embodiments, when R.sup.1 is --C(O)OCH.sub.3 and R.sup.2 is
--CH.sub.2Cl, ring A is phenyl, cyclohexyl, or furyl, q is 0 or 1,
R.sup.3 is --NO.sub.2, Br, or --OCH.sub.3, and p is 1 or 2, then at
least one R.sup.4 is other than methoxy. In certain embodiments,
when R.sup.2 is --CH.sub.2Cl, X is --CR.sup.5.dbd.CR.sup.5--, p is
1 or 2, ring A is phenyl, cyclohexyl, or furyl, and q is 0 or 1,
then at least one R.sup.4 is other than methoxy. In certain
embodiments, when R.sup.1 is --C(O)OCH.sub.3, R.sup.2 is
--CH.sub.2Cl, X is --CR.sup.5.dbd.CR.sup.5--, p is 1 or 2, ring A
is phenyl, cyclohexyl, or furyl, and q is 0 or 1, then at least one
R.sup.4 is other than methoxy.
[0218] In certain embodiments, when R.sup.1 is --C(O)OCH.sub.3 and
R.sup.2 is --CH.sub.2Cl, then X is other than
--CR.sup.5.dbd.CR.sup.5--. In certain embodiments, when X is
--CH.dbd.CH--, p is 1 or 2, ring A is phenyl, and q is 1, then at
least one R.sup.4 is other than methoxy.
[0219] In certain embodiments, the compound is not
N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-propioloyl-1,2,3,4-tetrahyd-
roisoquinolin-1-yl)benzamide,
4-((1S,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoqui-
nolin-1-yl)-N-cyclopropylbenzamide,
1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(-
1H)-yl)-2-chloroethan-1-one,
4-((1S,3S)-3-butyl-2-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquin-
olin-1-yl)-N-cyclopropylbenzamide,
4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinolin-1-
-yl)-N-cyclopropylbenzamide,
1-((1S,3S)-1-(4-(adamantan-1-ylamino)phenyl)-3-butyl-6-methoxy-3,4-dihydr-
oisoquinolin-2(1H)-yl)-2-chloroethan-1-one,
1-((1S,3S)-1-(4-(adamantan-1-ylamino)phenyl)-3-butyl-6-methoxy-3,4-dihydr-
oisoquinolin-2(1H)-yl)prop-2-yn-1-one, methyl
(1S,3R)-1-(4-(adamantan-1-ylamino)phenyl)-2-(2-chloroacetyl)-6-methoxy-1,-
2,3,4-tetrahydroisoquinoline-3-carboxylate, methyl
(1S,3R)-1-(4-(adamantan-1-ylamino)phenyl)-6-methoxy-2-propioloyl-1,2,3,4--
tetrahydroisoquinoline-3-carboxylate,
4-((1S,3S)-3-butyl-2-(2-chloroacetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinolin-1-yl)-N-cyclopropylbenzamide, or
4-((1S,3S)-3-butyl-6,7-dimethoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinol-
in-1-yl)-N-cyclopropylbenzamide.
[0220] In certain embodiments, when R.sup.2 is
--C.sub.1-C.sub.2haloalkyl, then ring A is not
benzo[d][1,3]dioxole.
[0221] In certain embodiments, R.sup.5 is R.sup.4.
[0222] Also provided is a compound of Formula IV, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00018##
[0223] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0224] Also provided is a compound of Formula IV, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00019##
[0225] wherein:
[0226] ring A is aryl or heteroaryl;
[0227] p is 0, 1 or 2;
[0228] q is 1;
[0229] R.sup.1 is C.sub.1-C.sub.6alkyl,
--C(O)O--C.sub.1-C.sub.6alkyl, or
--C(O)N(C.sub.1-C.sub.6alkyl).sub.2; R.sup.3 is halo, --NHR.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, or heterocyclyl;
[0230] each R.sup.4 is independently --OR.sup.1;
[0231] R.sup.6 is C.sub.1-C.sub.6alkyl;
[0232] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl, wherein each
R.sup.7 is independently further substituted with one to three
R.sup.11;
[0233] each R.sup.8 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl, wherein each R.sup.8 is independently
further substituted with one to three R.sup.11; and
[0234] each R.sup.11 is independently
--O--C.sub.1-C.sub.6alkyl.
[0235] Also provided is a compound of Formula IVA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00020##
[0236] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0237] Also provided is a compound of Formula IVB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00021##
[0238] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0239] Also provided is a compound of Formula V, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00022##
[0240] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein, and R.sup.14 is halo.
[0241] Also provided is a compound of Formula V, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00023##
[0242] wherein:
[0243] ring A is aryl or heteroaryl;
[0244] p is 0, 1 or 2;
[0245] q is 1;
[0246] R.sup.1 is C.sub.1-C.sub.6alkyl,
--C(O)O--C.sub.1-C.sub.6alkyl, or
--C(O)N(C.sub.1-C.sub.6alkyl).sub.2;
[0247] R.sup.3 is halo, --NHR.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, or heterocyclyl;
[0248] each R.sup.4 is independently --OR.sup.1;
[0249] R.sup.6 is C.sub.1-C.sub.6alkyl;
[0250] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl, wherein each
R.sup.7 is independently further substituted with one to three
R.sup.11;
[0251] each R.sup.8 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; wherein each R.sup.8 is independently
further substituted with one to three R.sup.11;
[0252] each R.sup.11 is independently --O--C.sub.1-C.sub.6alkyl;
and
[0253] R.sup.14 is halo.
[0254] In certain embodiments, R.sup.1 is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.10cycloalkyl, --CN,
--OR.sup.7, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6,
--S(O).sub.2R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --S(O)R.sup.8, --N(R.sup.7).sub.2,
--NO.sub.2, --C.sub.1-C.sub.6alkyl-OR.sup.7, or
--Si(R.sup.15).sub.3. In certain embodiments, R.sup.1 is
C.sub.1-C.sub.6alkyl.
[0255] Also provided is a compound of Formula VA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00024##
[0256] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein, and R.sup.14 is halo.
[0257] Also provided is a compound of Formula VB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00025##
[0258] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein, and R.sup.14 is halo.
[0259] In certain embodiments, R.sup.1 is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.10cycloalkyl, --CN,
--OR.sup.7, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6,
--S(O).sub.2R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --S(O)R.sup.8, --N(R.sup.7).sub.2,
--NO.sub.2, --C.sub.1-C.sub.6alkyl-OR.sup.7, or
--Si(R.sup.15).sub.3. In certain embodiments, R.sup.1 is
C.sub.1-C.sub.6alkyl.
[0260] Also provided is a compound of Formula VI, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00026##
[0261] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0262] Also provided is a compound of Formula VI, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00027##
[0263] wherein:
[0264] ring A is aryl or heteroaryl;
[0265] p is 0, 1 or 2;
[0266] q is 1;
[0267] R.sup.1 is C.sub.1-C.sub.6alkyl,
--C(O)O--C.sub.1-C.sub.6alkyl, or
--C(O)N(C.sub.1-C.sub.6alkyl).sub.2; R.sup.3 is halo, --NHR.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --C(O)OR.sup.6,
--C(O)N(R.sup.7).sub.2, or heterocyclyl;
[0268] each R.sup.4 is independently --OR.sup.1;
[0269] R.sup.6 is C.sub.1-C.sub.6alkyl;
[0270] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl, wherein each
R.sup.7 is independently further substituted with one to three
R.sup.11;
[0271] each R.sup.8 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; wherein each R.sup.8 is independently
further substituted with one to three R.sup.11; and
[0272] each R.sup.11 is independently
--O--C.sub.1-C.sub.6alkyl.
[0273] Also provided is a compound of Formula VIA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00028##
[0274] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0275] Also provided is a compound of Formula VIB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00029##
[0276] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0277] Also provided is a compound of Formula VII, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00030##
[0278] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein, and R.sup.14 is halo.
[0279] Also provided is a compound of Formula VII, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00031##
[0280] wherein:
[0281] ring A is aryl or heteroaryl;
[0282] p is 0, 1 or 2;
[0283] q is 1;
[0284] R.sup.1 is C.sub.1-C.sub.6alkyl,
--C(O)O--C.sub.1-C.sub.6alkyl, or
--C(O)N(C.sub.1-C.sub.6alkyl).sub.2;
[0285] R.sup.3 is halo, --NHR.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, or heterocyclyl;
[0286] each R.sup.4 is independently --OR.sup.8;
[0287] R.sup.6 is C.sub.1-C.sub.6alkyl;
[0288] each R.sup.7 is independently hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.10cycloalkyl, wherein each
R.sup.7 is independently further substituted with one to three
R.sup.11;
[0289] each R.sup.7 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl; wherein each R.sup.7 is independently
further substituted with one to three R.sup.11; and
[0290] each R.sup.8 is independently --O--C.sub.1-C.sub.6alkyl;
and
[0291] R.sup.14 is halo.
[0292] Also provided is a compound of Formula VIIA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00032##
[0293] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein, and R.sup.14 is halo.
[0294] Also provided is a compound of Formula VIIB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00033##
[0295] wherein each of ring A, R.sup.1, R.sup.3, R.sup.4, p, and q
are independently as defined herein, and R.sup.14 is halo.
[0296] Also provided is a compound of Formula VIII, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00034##
[0297] wherein each of ring A, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
p, and q are independently as defined herein.
[0298] In certain embodiments, ring A, or the moiety
##STR00035##
is:
##STR00036##
[0299] wherein 0 to 3 of U, V, W, X Y, Z is independently N, S, or
O, and the remaining variables are CH or CR.sup.3 and each
independently represents a single or double bond, which comply with
valency requirements based on U, V, W, X, Y and Z.
[0300] In certain embodiments, ring A, or the moiety
##STR00037##
is:
##STR00038##
wherein 1 to 3 of U, W, X, Y, and Z is N, S, or O, and the
remaining variables are CH or CR.sup.3 and represents a single or
double bond, which comply with valency requirements based on U, W,
X, Y and Z.
[0301] In certain embodiments, ring A is aryl or heteroaryl. In
certain embodiments, ring A is a monocyclic aryl or monocyclic
heteroaryl. In certain embodiments, ring A is heterocyclyl. In
certain embodiments, ring A is a 4 to 7 membered heterocyclyl. In
certain embodiments, ring A is aryl. In certain embodiments, ring A
is phenyl. In certain embodiments, ring A is heteroaryl. In certain
embodiments, ring A is pyridyl. In certain embodiments, ring A is
pyrazolyl. In certain embodiments, ring A is phenyl, pyridyl,
piperidynyl, piperazinyl, or morpholinyl.
[0302] In certain embodiments, ring A is aryl or heteroaryl, each
of which is substituted by one to three R.sup.3. In certain
embodiments, ring A is aryl or heteroaryl, each of which is
substituted by one to three R.sup.3, where at least one R.sup.3 is
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein each C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, and
heteroaryl of R.sup.3 is optionally substituted with one to three
R.sup.10.
[0303] In certain embodiments, ring A is aryl or heteroaryl, each
of which is substituted by one to three R.sup.3, where at least one
R.sup.3 is C.sub.3-C.sub.10cycloalkyl, heterocyclyl, aryl, or
heteroaryl; and wherein each C.sub.3-C.sub.10cycloalkyl,
heterocyclyl, aryl, and heteroaryl of R.sup.3 is optionally
substituted with one to three R.sup.10;
[0304] each R.sup.10 is independently --OR.sup.12,
--N(R.sup.12).sub.2, --S(O).sub.2R.sup.13,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, or C.sub.1-C.sub.6alkyl,
wherein the C.sub.1-C.sub.6alkyl, of R.sup.10 is optionally
independently substituted with one to three R.sup.11;
[0305] each R.sup.11 is independently halo, --OR.sup.12,
--N(R.sup.12).sub.2, --Si(R.sup.12).sub.3, --C(O)OR.sup.12,
--NR.sup.12C(O)OR.sup.12, --OC(O)CHR.sup.12N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, or heterocyclyl;
[0306] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl; and
[0307] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl.
[0308] In certain embodiments, ring A is bicyclo[1.1.1]pentan-1-yl,
phenyl, piperidinyl, pyrazolyl, pyridyl, or quinolinyl, each of
which is optionally substituted by one, two or three R.sup.3. In
certain embodiments, ring A is bicyclo[1.1.1]pentan-1-yl, phenyl,
piperidinyl, pyrazolyl, pyridyl, or quinolinyl, each of which is
substituted by one, two or three R.sup.3. In certain embodiments,
ring A is bicyclo[1.1.1]pentan-1-yl, phenyl, piperidinyl,
pyrazolyl, pyridyl, or quinolinyl, each of which is substituted by
two or three R.sup.3.
[0309] In certain embodiments, ring A is aryl or heteroaryl, each
of which is substituted by two or three R.sup.3. In certain
embodiments, ring A is aryl or heteroaryl, each of which is
substituted by two or three R.sup.3; wherein at least one R.sup.3
is halo.
[0310] In certain embodiments, ring A is cyclohexyl. In certain
embodiments, ring A is C.sub.4-C.sub.10cycloalkyl. In certain
embodiments, ring A is a C.sub.4-C.sub.7cycloalkyl. In certain
embodiments, ring A is bicyclo[1.1.1]pentanyl. In certain
embodiments, ring A is selected from cyclobutyl, cyclopentyl,
cyclohexyl, and cycloheptyl.
[0311] In certain embodiments, ring A, or the moiety
##STR00039##
is:
##STR00040##
where q and each R.sup.3 is independently as defined herein.
[0312] In certain embodiments, ring A, or the moiety
##STR00041##
is:
##STR00042##
where R.sup.3 is independently as defined herein.
[0313] In certain embodiments, ring A is a bridged bicyclic ring
selected from:
##STR00043##
wherein each is substituted with one to three R.sup.3. In certain
embodiments, ring A is a bridged bicyclic ring selected from:
##STR00044##
wherein each R.sup.3 is attached to a carbon atom on the bridged
bicyclic ring.
[0314] In certain embodiments, ring A, or the moiety
##STR00045##
is:
##STR00046##
[0315] Also provided is a compound of Formula VIII, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00047##
[0316] wherein each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0317] Also provided is a compound of Formula VIIIA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00048##
[0318] wherein each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0319] Also provided is a compound of Formula VIIIB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00049##
[0320] wherein each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, p, and q
are independently as defined herein.
[0321] In certain embodiments, R.sup.1 is C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.10cycloalkyl, --CN,
--C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2, --N(R.sup.7).sub.2,
--OR.sup.7, or --C.sub.1-C.sub.6alkyl-OR.sup.7.
[0322] In certain embodiments, R.sup.1 is --C(O)OR.sup.6 or
--C(O)N(R.sup.7).sub.2.
[0323] In certain embodiments, R.sup.1 is C.sub.1-C.sub.6alkyl. In
certain embodiments, In certain embodiments, R.sup.1 is
C.sub.2-C.sub.6alkyl. In certain embodiments, R.sup.1 is
C.sub.3-C.sub.6alkyl. In certain embodiments, R.sup.1 is
C.sub.5-C.sub.6alkyl. In certain embodiments, R.sup.1 is
C.sub.2-C.sub.3alkyl. In certain embodiments, R.sup.1 is
C.sub.4-C.sub.6alkyl. In certain embodiments, R.sup.1 is methyl. In
certain embodiments, R.sup.1 is n-butyl.
[0324] In certain embodiments, R.sup.1 is --CH.sub.2--R.sup.16,
wherein R.sup.16 is C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5alkenyl,
C.sub.2-C.sub.5alkynyl, C.sub.1-C.sub.5haloalkyl, or
--C.sub.1-C.sub.5alkyl-OR.sup.7.
[0325] In certain embodiments, R.sup.1 is C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6haloalkyl,
C.sub.3-C.sub.10cycloalkyl, --CN, --OR.sup.7,
--C(O)N(R.sup.7).sub.2, --OC(O)R.sup.6, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sup.2,
--S(O)R.sup.8, --N(R.sup.7).sup.2, --NO.sub.2,
--C.sub.1-C.sub.6alkyl-OR.sup.7, or --Si(R.sup.15).sub.3.
[0326] In certain embodiments, R.sup.1 is other than methyl. In
certain embodiments, R.sup.1 is other than n-butyl. In certain
embodiments, R.sup.1 is other than --C(O)OR.sup.6. In certain
embodiments, R.sup.1 is other than --C(O)OCH.sub.3.
[0327] Also provided is a compound of Formula IX, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00050##
[0328] wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.16, p, and
q are independently as defined herein. In certain embodiments,
R.sup.16 is hydrogen or C.sub.2-C.sub.5alkyl.
[0329] Also provided is a compound of Formula IXA, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00051##
[0330] wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.16, p, and
q are independently as defined herein. In certain embodiments,
R.sup.16 is hydrogen or C.sub.2-C.sub.5alkyl.
[0331] Also provided is a compound of Formula IXB, or a tautomer,
stereoisomer, mixture of stereoisomers, isotopically enriched
analog, or pharmaceutically acceptable salt thereof:
##STR00052##
[0332] wherein each of R.sup.2, R.sup.3, R.sup.4, R.sup.16, p, and
q are independently as defined herein. In certain embodiments,
R.sup.16 is hydrogen or C.sub.2-C.sub.5alkyl.
[0333] In certain embodiments, R.sup.2 is
--C.sub.1-C.sub.2haloalkyl, --C.sub.2-C.sub.3alkenyl,
--C.sub.2-C.sub.3haloalkenyl, C.sub.2alkynyl, wherein the
C.sub.1-C.sub.2haloalkyl and --C.sub.2-C.sub.3alkenylhalo are
optionally substituted with one or two --CH.sub.3, and the
C.sub.2alkynyl is optionally substituted with one --CH.sub.3. In
certain embodiments, R.sup.2 is --C.sub.1-C.sub.2haloalkyl. In
certain embodiments, R.sup.2 is --C.sub.2-C.sub.3alkenyl. In
certain embodiments, R.sup.2 is C.sub.2-C.sub.3haloalkenyl. In
certain embodiments, R.sup.2 is C.sub.2alkynyl.
[0334] In certain embodiments, at least one R.sup.3 is halo,
--NH.sub.2, --NHR.sup.8, --N(R.sup.8).sub.2, --S(O).sub.2R.sup.8,
--S(O)R.sup.8, --S(O).sub.2N(R.sup.7).sub.2,
--S(O)N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8, --OC(O)R.sup.8,
--C(O)R.sup.6, or --OC(O)CHR.sup.8N(R.sup.12).sub.2.
[0335] In certain embodiments, at least one R.sup.3 is halo.
[0336] In certain embodiments, at least one R.sup.3 is --NHR.sup.8.
In certain embodiments, at least one R.sup.3 is --N(R.sup.8).sub.2.
In certain embodiments, q is 2, and one R.sup.3 is halo and the
other R.sup.3 is --N(R.sup.8).sub.2. In certain embodiments, q is
3, and two R.sup.3 are independently halo and one R.sup.3 is
--N(R.sup.8).sub.2.
[0337] In certain embodiments, at least one R.sup.3 is
--C(O)OR.sup.6 or --C(O)R.sup.6.
[0338] In certain embodiments, at least one R.sup.3 is
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2, or
--C(O)N(R.sup.7).sub.2.
[0339] In certain embodiments, at least one R.sup.3 is
--S(O).sub.2R.sup.8, --S(O)R.sup.8, --NR.sup.12C(O)R.sup.8,
--NR.sup.12C(O)OR.sup.8, --OC(O)R.sup.8, or
--OC(O)CHR.sup.8N(R.sup.12).sub.2.
[0340] In certain embodiments, each R.sup.3 is independently halo,
--CN, --OR.sup.8, --NHR.sup.8, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8, --OC(O)R.sup.8,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, heteroaryl, or
--C.sub.1-C.sub.6alkylheterocyclyl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
heteroaryl, or --C.sub.1-C.sub.6alkylheterocyclyl of R.sup.3 is
independently optionally substituted with one to three
R.sup.10.
[0341] In certain embodiments, each R.sup.3 is independently halo,
--CN, --OR.sup.8, --NHR.sup.8, --S(O).sub.2R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --NO.sub.2, --Si(R.sup.12).sub.3,
--SF.sub.5, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --NR.sup.12C(O)OR.sup.8, --OC(O)R.sup.8,
--OC(O)CHR.sup.8N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.10cycloalkyl, heterocyclyl, heteroaryl, or
--C.sub.1-C.sub.6alkylheterocyclyl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl, heterocyclyl,
heteroaryl, or --C.sub.1-C.sub.6alkylheterocyclyl is independently
optionally substituted with one to three substituents independently
selected from --OR.sup.12, --N(R.sup.12).sub.2,
--S(O).sub.2R.sup.13, --OC(O)CHR.sup.12N(R.sup.12).sub.2, and
C.sub.1-C.sub.6alkyl optionally substituted with one to three halo,
--OR.sup.12, --N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)OR.sup.12, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl, or
heterocyclyl; wherein
[0342] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl; and
[0343] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl.
[0344] In certain embodiments, each R.sup.3 is independently
--NH.sub.2, fluoro, methyl, pyridine-4-carboxamido,
pyridin-3-amino, pentyloxycarbonylamino,
N-(3-aminobicyclo[1.1.1]pentan-1-yl)amino, morpholin-4-yl,
methoxycarbonyl, dimethylcarbamoyl, cyclopropylcarbamoyl,
cyclohexyl, cyclobutylcarbamoyl, cyclobutylaminosulfonyl,
adamantylamino, (adamantan-1-ylamino)methyl,
3-methyl-1,2,4-oxadiazol-5-yl, 2-methylpyridine-4-carboxamido,
(bicyclo[1.1.1]pentan-1-ylamino)methyl, (adamantan-1-yl)carbamoyl,
or (2-methoxyethyl)carbamoyl.
[0345] In certain embodiments, q is 0 or 1, and R.sup.3 is
--NH.sub.2, fluoro, methyl, pyridine-4-carboxamido,
pyridin-3-amino, pentyloxycarbonylamino,
N-(3-aminobicyclo[1.1.1]pentan-1-yl)amino, morpholin-4-yl,
methoxycarbonyl, dimethylcarbamoyl, cyclopropylcarbamoyl,
cyclohexyl, cyclobutylcarbamoyl, cyclobutylaminosulfonyl,
adamantylamino, (adamantan-1-ylamino)methyl,
3-methyl-1,2,4-oxadiazol-5-yl, 2-methylpyridine-4-carboxamido,
(bicyclo[1.1.1]pentan-1-ylamino)methyl, (adamantan-1-yl)carbamoyl,
or (2-methoxyethyl)carbamoyl.
[0346] In certain embodiments, each R.sup.4 is independently halo,
--CN, --OH, --OR.sup.8, --NH.sub.2, --NHR.sup.8,
--N(R.sup.8).sub.2, --S(O).sub.2R.sup.8, --S(O)R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2, --NO.sub.2,
--Si(R.sup.15).sub.3, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --OC(O)R.sup.8, --C(O)R.sup.6,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.10cycloalkyl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.10cycloalkyl of R.sup.4 is
independently optionally substituted with one to three
R.sup.10.
[0347] In certain embodiments, each R.sup.4 is independently halo,
--CN, --OR.sup.7, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkynyl, or
C.sub.3-C.sub.10cycloalkyl; wherein each C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.10cycloalkyl of R.sup.4 is
independently optionally substituted with one to three
R.sup.10.
[0348] In certain embodiments, each R.sup.4 is independently halo,
--CN, --OH, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkynyl, or
C.sub.3-C.sub.10cycloalkyl.
[0349] In certain embodiments, each R.sup.4 is independently halo,
--CN, --OH, --OR.sup.8, C.sub.1-C.sub.6alkyl, or
C.sub.2-C.sub.6alkynyl; wherein the C.sub.1-C.sub.6alkyl of R.sup.4
is optionally substituted with one to three R.sup.10.
[0350] In certain embodiments, each R.sup.4 is independently halo,
--CN, --OH, --OR.sup.8, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkynyl; wherein the C.sub.1-C.sub.6alkyl of R.sup.4
is optionally substituted with one to three substituents
independently selected from --OR.sup.12, --N(R.sup.12).sub.2,
--S(O).sub.2R.sup.13, --OC(O)CHR.sup.12N(R.sup.12).sub.2, and
C.sub.1-C.sub.6alkyl optionally substituted with one to three halo,
--OR.sup.12, --N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)OR.sup.12, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl, or
heterocyclyl; wherein
[0351] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl; and
[0352] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl.
[0353] In certain embodiments, each R.sup.5 is independently halo,
--CN, --OH, --OR.sup.8, --NH.sub.2, --NHR.sup.8,
--N(R.sup.8).sub.2, --S(O).sub.2R.sup.8, --S(O)R.sup.8,
--S(O).sub.2N(R.sup.7).sub.2, --S(O)N(R.sup.7).sub.2, --NO.sub.2,
--Si(R.sup.15).sub.3, --C(O)OR.sup.6, --C(O)N(R.sup.7).sub.2,
--NR.sup.12C(O)R.sup.8, --OC(O)R.sup.8, --C(O)R.sup.6,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.10cycloalkyl; wherein each
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.10cycloalkyl of R.sup.5 is
independently optionally substituted with one to three
R.sup.10.
[0354] In certain embodiments, each R.sup.5 is independently halo,
--CN, --OR.sup.7, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkynyl, or
C.sub.3-C.sub.10cycloalkyl; wherein each C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.10cycloalkyl of R.sup.5 is
independently optionally substituted with one to three
R.sup.10.
[0355] In certain embodiments, each R.sup.5 is independently halo,
--CN, --OH, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkynyl, or
C.sub.3-C.sub.10cycloalkyl.
[0356] In certain embodiments, each R.sup.5 is independently halo,
--CN, --OH, --OR.sup.8, C.sub.1-C.sub.6alkyl, or
C.sub.2-C.sub.6alkynyl; wherein the C.sub.1-C.sub.6alkyl of R.sup.5
is optionally substituted with one to three R.sup.10.
[0357] In certain embodiments, each R.sup.5 is independently halo,
--CN, --OH, --OR.sup.8, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkynyl; wherein the C.sub.1-C.sub.6alkyl of R.sup.5
is optionally substituted with one to three substituents
independently selected from --OR.sup.12, --N(R.sup.12).sub.2,
--S(O).sub.2R.sup.13, --OC(O)CHR.sup.12N(R.sup.12).sub.2, and
C.sub.1-C.sub.6alkyl optionally substituted with one to three halo,
--OR.sup.12, --N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)OR.sup.12, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl, or
heterocyclyl; wherein
[0358] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl; and
[0359] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl.
[0360] In certain embodiments, each R.sup.6 is independently
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, or
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl; wherein each
R.sup.6 is independently further substituted with one to three
R.sup.11.
[0361] In certain embodiments, each R.sup.6 is independently
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, or
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl; wherein each
R.sup.6 is independently further substituted with one to three
halo, --OR.sup.12, --N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)OR.sup.12, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl, or
heterocyclyl; wherein
[0362] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl.
[0363] In certain embodiments, each R.sup.7 is independently
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
heterocyclyl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl, or two R.sup.7 together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl; wherein each R.sup.7 or ring formed thereby
is independently further substituted with one to three
R.sup.11.
[0364] In certain embodiments, each R.sup.7 is independently
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.10cycloalkyl,
heterocyclyl, heteroaryl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.6cycloalkyl,
--C.sub.1-C.sub.6alkylheterocyclyl, or two R.sup.7 together with
the nitrogen atom to which they are attached, form a 4 to 7
membered heterocyclyl; wherein each R.sup.7 or ring formed thereby
is independently further substituted with one to three halo,
--OR.sup.12, --N(R.sup.12).sub.2, --Si(R.sup.12).sub.3,
--C(O)OR.sup.12, --NR.sup.12C(O)OR.sup.12,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, C.sub.1-C.sub.6alkyl, or
heterocyclyl; wherein each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl.
[0365] In certain embodiments, each R.sup.8 is independently
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl, or
--C.sub.1-C.sub.6alkylaryl; wherein each R.sup.8 is independently
further substituted with one to three R.sup.11.
[0366] In certain embodiments, each R.sup.8 is independently
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.10cycloalkyl,
--C.sub.1-C.sub.6alkylC.sub.3-C.sub.10cycloalkyl, or
--C.sub.1-C.sub.6alkylaryl; wherein each R.sup.8 is independently
further substituted with one to three halo, --OR.sup.12,
--N(R.sup.12).sub.2, --Si(R.sup.12).sub.3, --C(O)OR.sup.12,
--NR.sup.12C(O)OR.sup.12, --OC(O)CHR.sup.12N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, or heterocyclyl; wherein
[0367] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl.
[0368] In certain embodiments, each R.sup.10 is independently
--OR.sup.12, --N(R.sup.12).sub.2, --S(O).sub.2R.sup.13,
--OC(O)CHR.sup.12N(R.sup.12).sub.2, or C.sub.1-C.sub.6alkyl,
wherein the C.sub.1-C.sub.6alkyl, of R.sup.10 is optionally
independently substituted with one to three R.sup.11;
[0369] each R.sup.11 is independently halo, --OR.sup.12,
--N(R.sup.12).sub.2, --Si(R.sup.12).sub.3, --C(O)OR.sup.12,
--NR.sup.12C(O)OR.sup.12, --OC(O)CHR.sup.12N(R.sup.12).sub.2,
C.sub.1-C.sub.6alkyl, or heterocyclyl;
[0370] each R.sup.12 is independently hydrogen,
C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.10cycloalkyl; and
[0371] each R.sup.13 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.10cycloalkyl.
[0372] In certain embodiments, each R.sup.15 is independently
C.sub.1-C.sub.6alkyl.
[0373] In certain embodiments, p is 0. In certain embodiments, p is
0 or 1. In certain embodiments, p is 1 or 2. In certain
embodiments, p is 1. In certain embodiments, p is 2.
[0374] In certain embodiments, q is 0. In certain embodiments, q is
0 or 1. In certain embodiments, q is 1 or 2. In certain
embodiments, q is 1. In certain embodiments, q is 2. In certain
embodiments, q is 3.
[0375] Also provided is a compound, or a tautomer, stereoisomer,
mixture of stereoisomers, isotopically enriched analog, or
pharmaceutically acceptable salt thereof, selected from Table
1:
TABLE-US-00001 TABLE 1 No. Structure 1 ##STR00053## 2 ##STR00054##
3 ##STR00055## 4 ##STR00056## 5 ##STR00057## 6 ##STR00058## 7
##STR00059## 8 ##STR00060## 9 ##STR00061## 10 ##STR00062## 11
##STR00063## 12 ##STR00064## 13 ##STR00065## 14 ##STR00066## 15
##STR00067## 16 ##STR00068## 17 ##STR00069## 18 ##STR00070## 19
##STR00071## 20 ##STR00072## 21 ##STR00073## 22 ##STR00074## 23
##STR00075## 24 ##STR00076## 25 ##STR00077## 26 ##STR00078## 27
##STR00079## 28 ##STR00080## 29 ##STR00081## 30 ##STR00082## 31
##STR00083## 32 ##STR00084## 33 ##STR00085## 34 ##STR00086## 35
##STR00087## 36 ##STR00088## 37 ##STR00089## 38 ##STR00090## 39
##STR00091## 40 ##STR00092## 41 ##STR00093## 42 ##STR00094## 43
##STR00095## 44 ##STR00096## 45 ##STR00097## 46 ##STR00098## 47
##STR00099## 48 ##STR00100## 49 ##STR00101## 50 ##STR00102## 51
##STR00103## 52 ##STR00104## 53 ##STR00105## 54 ##STR00106## 55
##STR00107## 56 ##STR00108## 57 ##STR00109## 58 ##STR00110## 59
##STR00111## 60 ##STR00112## 61 ##STR00113## 62 ##STR00114## 63
##STR00115## 64 ##STR00116## 65 ##STR00117## 66 ##STR00118## 67
##STR00119## 68 ##STR00120## 69 ##STR00121## 70 ##STR00122## 71
##STR00123## 72 ##STR00124## 73 ##STR00125## 74 ##STR00126## 75
##STR00127## 76A ##STR00128## 76 ##STR00129## 77 ##STR00130## 78
##STR00131## 79 ##STR00132## 80 ##STR00133## 81 ##STR00134## 82
##STR00135## 83 ##STR00136## 84 ##STR00137## 85 ##STR00138## 86
##STR00139## 87 ##STR00140## 88 ##STR00141## 89 ##STR00142## 90
##STR00143## 91 ##STR00144## 92 ##STR00145## 93 ##STR00146## 94
##STR00147## 95 ##STR00148## 96 ##STR00149## 97 ##STR00150## 98
##STR00151## 99A ##STR00152## 99 ##STR00153## 100A ##STR00154## 100
##STR00155## 101 ##STR00156## 102 ##STR00157##
3. Methods of Use
[0376] In certain embodiments, the compounds described herein are
used in a method of treating cancer. In certain embodiments, the
method of treating cancer comprises administering to a subject in
need thereof a therapeutically effective amount any of the
compounds described herein.
[0377] In certain embodiments, the compounds are used in a method
of inhibiting GPX4 in a cell, comprising contacting a cell with an
effective amount of a compound or composition described herein to
inhibit GPX4 in the cell. In certain embodiments, the cell is a
cancer cell. In certain embodiments, the method comprises
administering an effective amount of a compound or composition
described herein to a patient in need thereof.
[0378] In certain embodiments, the compounds are used in a method
of inducing ferroptosis in a cell comprising contacting the cell
with an effective amount of a compound or composition provided
herein. In certain embodiments, the method comprises administering
an effective amount of a compound or composition described herein
to a patient in need thereof.
[0379] In certain embodiments, provided is a method for treating a
cancer in a patient in need thereof, comprising administering an
effective amount of a compound or composition provided herein.
[0380] In certain embodiments, the compounds are used in a method
of treating cancer in a subject in need thereof, comprising
administering to a subject having cancer a therapeutically
effective amount of a ferroptosis inducing compound disclosed
herein. Various cancers for treatment with the compounds include,
but are not limited to, adrenocortical cancer, anal cancer, biliary
cancer, bladder cancer, bone cancer, gliomas, astrocytoma,
neuroblastoma, breast cancer, cervical cancer, colon cancer,
endometrial cancer, esophageal cancer, head and neck cancer,
intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian
cancer, pancreatic cancer, renal cancer, prostate cancer, salivary
gland cancer, skin cancer, stomach cancer, testicular cancer,
throat cancer, thyroid cancer, uterine cancer, vaginal cancer,
sarcoma, and soft tissue carcinomas. In certain embodiments, the
compound is used to treat pancreatic cancer.
[0381] In certain embodiments, the cancer is renal cell carcinoma
(RCC), pancreatic cancer, lung cancer, breast cancer, or prostate
cancer. In certain embodiments, provided is a method for treating
renal cell carcinoma (RCC) in a patient in need thereof, comprising
administering an effective amount of a compound or composition
provided herein. In certain embodiments, provided is a method for
treating pancreatic cancer in a patient in need thereof, comprising
administering an effective amount of a compound or composition
provided herein. In certain embodiments, provided is a method for
treating lung cancer in a patient in need thereof, comprising
administering an effective amount of a compound or composition
provided herein. In certain embodiments, provided is a method for
treating breast cancer in a patient in need thereof, comprising
administering an effective amount of a compound or composition
provided herein. In certain embodiments, provided is a method for
treating prostate cancer in a patient in need thereof, comprising
administering an effective amount of a compound or composition
provided herein.
[0382] In certain embodiments, provided is a method for treating a
malignant solid tumor in a patient in need thereof, comprising
administering an effective amount of a compound or composition
provided herein to the patient. In certain embodiments, the
malignant solid tumor is a carcinoma. In certain embodiments, the
malignant solid tumor is a lymphoma. In certain embodiments, the
malignant solid tumor is a sarcoma.
[0383] In certain embodiments, the cancer for treatment with the
compound can be selected from, among others, adrenocortical cancer,
anal cancer, biliary cancer, bladder cancer, bone cancer (e.g.,
osteosarcoma), brain cancer (e.g., gliomas, astrocytoma,
neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer,
endometrial cancer, esophageal cancer, head and neck cancer,
hematologic cancer (e.g., leukemia and lymphoma), intestinal cancer
(small intestine), liver cancer, lung cancer (e.g., bronchial
cancer, small cell lung cancer, non-small cell lung cancer, etc.),
oral cancer, ovarian cancer, pancreatic cancer, renal cancer,
prostate cancer, salivary gland cancer, skin cancer (e.g., basal
cell carcinoma, melanoma), stomach cancer, testicular cancer,
throat cancer, thyroid cancer, uterine cancer, vaginal cancer,
sarcoma, and soft tissue carcinomas. In certain embodiments, the
cancer is renal cell carcinoma (RCC). In certain embodiments, the
cancer is pancreatic cancer. In certain embodiments, the cancer is
lung cancer. In certain embodiments, the cancer is breast cancer.
In certain embodiments, the cancer is prostate cancer.
[0384] In certain embodiments, the cancer for treatment with the
compound is pancreatic cancer. In certain embodiments, the
pancreatic cancer for treatment with the compounds is pancreatic
adenocarcinoma or metastatic pancreatic cancer. In certain
embodiments, the cancer for treatment with the compounds is stage
I, stage II, stage III, or stage IV pancreatic adenocarcinoma.
[0385] In certain embodiments, the cancer for treatment with the
compounds is lung cancer. In certain embodiments, the lung cancer
for treatment with the compounds is small cell lung cancer or
non-small cell lung cancer. In certain embodiments, the non-small
cell lung cancer for treatment with the compounds is an
adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
In certain embodiments, the lung cancer for treatment with the
compounds is metastatic lung cancer.
[0386] In certain embodiments, the cancer for treatment with the
compounds is a hematologic cancer. In certain embodiments, the
hematologic cancer is selected from acute lymphoblastic leukemia
(ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin's
lymphoma, Non-Hodgkin's lymphoma, Burkitt's lymphoma), chronic
lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),
Hairy Cell chronic myelogenous leukemia (CML), and multiple
myeloma.
[0387] In certain embodiments, the cancer for treatment with the
compounds is a leukemia selected from acute lymphoblastic leukemia
(ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia
(CLL), chronic myelogenous leukemia (CML), Hairy Cell chronic
myelogenous leukemia (CML), and multiple myeloma.
[0388] In certain embodiments, the cancer for treatment with the
compound is a lymphoma selected from Hodgkin's lymphoma,
Non-Hodgkin's lymphoma, and Burkitt's lymphoma.
[0389] In certain embodiments, the cancer for treatment with the
compound is a cancer characterized by mesenchymal features or
mesenchymal phenotype. In some cancers, gain of mesenchymal
features is associated with migratory (e.g., intravasation) and
invasiveness of cancers. Mesenchymal features can include, among
others, enhanced migratory capacity, invasiveness, elevated
resistance to apoptosis, and increased production of extracellular
matrix (ECM) components. In addition to these physiological
characteristics, the mesenchymal features can include expression of
certain biomarkers, including among others, E-cadherin, N-cadherin,
integrins, FSP-1, .alpha.-SMA, vimentin, .beta.-catenin, collagen
I, collagen II, collagen III, collagen IV, fibronectin, laminin 5,
SNAIL-1, SNAIL-2, Twist-1, Twist-2, and Lef-1. In certain
embodiments, the cancer selected for treatment with the compounds
herein include, among others, breast cancer, lung cancer, head and
neck cancer, prostate cancer, and colon cancer. In certain
embodiments, the mesenchymal features can be inherent to the cancer
type or induced by or selected for by treatment of cancers with
chemotherapy and/or radiation therapy.
[0390] In certain embodiments, the cancer for treatment with the
compound is identified as having or determined to have an
activating or oncogenic RAS activity. In certain embodiments, the
RAS is K-RAS, H-RAS or N-RAS. In certain embodiments, the
activating or oncogenic RAS is an activating or oncogenic RAS
mutation.
[0391] In certain embodiments, the cancer selected for treatment
with the compounds are determined to have or identified as having
an activating or oncogenic RAS activity. In certain embodiments,
the activating or oncogenic RAS activity is an activating or
oncogenic RAS mutations. In certain embodiments, the activating or
oncogenic RAS activity is an activating or activating K-RAS
activity, particularly an activating or oncogenic K-RAS mutation.
In certain embodiments, the activating or oncogenic RAS activity is
an activating or activating N-RAS activity, particularly an
activating or oncogenic N-RAS mutation. In certain embodiments, the
activating or oncogenic RAS activity is an activating or activating
H-RAS activity, particularly an activating or oncogenic H-RAS
mutation.
[0392] In certain embodiments, the compounds can be used to treat a
cancer that is refractory to one or more other chemotherapeutic
agents, particularly cytotoxic chemotherapeutic agents; or treat a
cancer resistant to radiation treatment. In certain embodiments,
the compounds are used to treat cancers that have developed
tolerance to chemotherapeutic agents activating other cell death
pathways, such as apoptosis, mitotic catastrophe, necrosis,
senescence and/or autophagy.
[0393] In certain embodiments, the cancer for treatment with the
compounds is identified as being refractory or resistant to
chemotherapy. In certain embodiments, the cancer is refractory or
resistant to one or more of alkylating agents, anti-cancer
antibiotic agents, antimetabolic agents (e.g., folate antagonists,
purine analogs, pyrimidine analogs, etc.), topoisomerase inhibiting
agents, anti-microtubule agents (e.g., taxanes, vinca alkaloids),
hormonal agents (e.g., aromatase inhibitors), plant-derived agents
and their synthetic derivatives, anti-angiogenic agents,
differentiation inducing agents, cell growth arrest inducing
agents, apoptosis inducing agents, cytotoxic agents, agents
affecting cell bioenergetics i.e., affecting cellular ATP levels
and molecules/activities regulating these levels, biologic agents,
e.g., monoclonal antibodies, kinase inhibitors and inhibitors of
growth factors and their receptors.
[0394] In certain embodiments, the cancer for treatment with the
compounds is a cancer identified as being refractory or resistant
to one or more of afatinib, afuresertib, alectinib, alisertib,
alvocidib, amsacrine, amonafide, amuvatinib, axitinib, azacitidine,
azathioprine, bafetinib, barasertib, bendamustine, bleomycin,
bosutinib, bortezomib, busulfan, cabozantinib, camptothecin,
canertinib, capecitabine, cabazitaxel, carboplatin, carmustine,
cenisertib, ceritinib, chlorambucil, cisplatin, cladribine,
clofarabine, crenolanib, crizotinib, cyclophosphamide, cytarabine,
dabrafenib, dacarbazine, dacomitinib, dactinomycin, danusertib,
dasatinib, daunorubicin, decitabine, dinaciclib, docetaxel,
dovitinib, doxorubicin, epirubicin, epitinib, eribulin mesylate,
errlotinib, etirinotecan, etoposide, everolimus, exemestane,
floxuridine, fludarabine, fluorouracil, gefitinib, gemcitabine,
hydroxyurea, ibrutinib, icotinib, idarubicin, ifosfamide, imatinib,
imetelstat, ipatasertib, irinotecan, ixabepilone, lapatinib,
lenalidomide, lestaurtinib, lomustine, lucitanib, masitinib,
mechlorethamine, melphalan, mercaptopurine, methotrexate,
midostaurin, mitomycin, mitoxantrone, mubritinib, nelarabine,
neratinib, nilotinib, nintedanib, omacetaxine mepesuccinate,
orantinib, oxaliplatin, paclitaxel, palbociclib, palifosfamide
tris, pazopanib, pelitinib, pemetrexed, pentostatin, plicamycin,
ponatinib, poziotinib, pralatrexate, procarbazine, quizartinib,
raltitrexed, regorafenib, ruxolitinib, seliciclib, sorafenib,
streptozocin, sulfatinib, sunitinib, tamoxifen, tandutinib,
temozolomide, temsirolimus, teniposide, theliatinib, thioguanine,
thiotepa, topotecan, uramustine, valrubicin, vandetanib,
vemurafenib (Zelborae), vincristine, vinblastine, vinorelbine, and
vindesine.
[0395] In certain embodiments, the cancer for treatment with the
compound is identified as being refractory or resistant to one or
more chemotherapeutics agents selected from cyclophosphamide,
chlorambucil, melphalan, mechlorethamine, ifosfamide, busulfan,
lomustine, streptozocin, temozolomide, dacarbazine, cisplatin,
carboplatin, oxaliplatin, procarbazine, uramustine, methotrexate,
pemetrexed, fludarabine, cytarabine, fluorouracil, floxuridine,
gemcitabine, capecitabine, vinblastine, vincristine, vinorelbine,
etoposide, paclitaxel, docetaxel, doxorubicin, daunorubicin,
epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin,
hydroxyurea, topotecan, irinotecan, amsacrine, teniposide, and
erlotinib.
[0396] In certain embodiments, the cancer for treatment with the
compounds is a cancer resistant to ionizing radiation therapy. The
radioresistance of the cancer can be inherent or as a result of
radiation therapy. In certain embodiments, the cancers for
treatment with the compounds is, among others, a radioresistant
adrenocortical cancer, anal cancer, biliary cancer, bladder cancer,
bone cancer (e.g., osteosarcoma), brain cancer (e.g., gliomas,
astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer,
colon cancer, endometrial cancer, esophageal cancer, head and neck
cancer, hematologic cancer (e.g., leukemia and lymphoma),
intestinal cancer (small intestine), liver cancer, lung cancer
(e.g., bronchial cancer, small cell lung cancer, non-small cell
lung cancer, etc.), oral cancer, ovarian cancer, pancreatic cancer,
renal cancer, prostate cancer, salivary gland cancer, skin cancer
(e.g., basal cell carcinoma, melanoma), stomach cancer, testicular
cancer, throat cancer, thyroid cancer, uterine cancer, or vaginal
cancer. In certain embodiments, the cancer is pancreatic cancer,
breast cancer, glioblastoma, advanced non-small-cell lung cancer,
bladder cancer, sarcoma, or soft tissue carcinoma.
4. Combination Treatments
[0397] In certain embodiments, the compounds described herein are
used in combination with one or more of other (e.g., second
therapeutic agent) therapeutic treatments for cancer. In certain
embodiments, the compounds can be used as monotherapy, or as
further provided below, in a combination therapy with one or more
therapeutic treatments, particularly in combination with one or
more chemotherapeutic agents. In certain embodiments, the compounds
are used in combination with a second therapeutic agent, where the
compounds are used at levels that sensitizes the cancer or cancer
cell to the second therapeutic agent, for example at levels of the
compound that do not cause significant cell death. In certain
embodiments, the compounds can be used in combination with
radiation therapy, either to sensitize the cells to radiation
therapy or as an adjunct to radiation therapy (e.g., at doses
sufficient to activate cell death pathway).
[0398] In certain embodiments, a subject with cancer is treated
with a combination of a compound described herein and radiation
therapy. In certain embodiments, the method comprises administering
to a subject with cancer a therapeutically effective amount of a
compound of the disclosure, and adjunctively treating the subject
with an effective amount of radiation therapy. In certain
embodiments, the compound is administered to the subject in need
thereof prior to, concurrently with, or subsequent to the treatment
with radiation.
[0399] In certain embodiments, the method comprises administering
an effective amount of a compound described herein to a subject
with cancer to sensitize the cancer to radiation treatment, and
administering a therapeutically effective amount of radiation
therapy to treat the cancer. In certain embodiments, an effective
amount of X-ray and gamma ray is administered to the subject. In
certain embodiments, an effective amount of particle radiation is
administered to the subject, where the particle radiation is
selected from electron beam, proton beam, and neutron beam
radiation. In certain embodiments, the radiation therapy is
fractionated.
[0400] In certain embodiments, a subject with cancer is
administered a therapeutically effective amount of a compound
described herein, or a first pharmaceutical composition thereof,
and adjunctively administered a therapeutically effective amount of
a second chemotherapeutic agent, or a second pharmaceutical
composition thereof.
[0401] In certain embodiments, the second chemotherapeutic agent is
selected from an platinating agent, alkylating agent, anti-cancer
antibiotic agent, antimetabolic agent (e.g., folate antagonists,
purine analogs, pyrimidine analogs, etc.), topoisomerase I
inhibiting agent, topoisomerase II inhibiting agent antimicrotubule
agent (e.g., taxanes, vinca alkaloids), hormonal agent (e.g.,
aromatase inhibitors), plant-derived agent and synthetic
derivatives thereof, anti-angiogenic agent, differentiation
inducing agent, cell growth arrest inducing agent, apoptosis
inducing agent, cytotoxic agent, agent affecting cell
bioenergetics, i.e., affecting cellular ATP levels and
molecules/activities regulating these levels, anti-cancer biologic
agent (e.g., monoclonal antibodies), kinase inhibitors and
inhibitors of growth factors and their receptors.
[0402] In certain embodiments, the second chemotherapeutic agent is
an angiogenesis inhibitor, such as but not limited to, an inhibitor
of soluble VEGFR-1, NRP-1, angiopoietin 2, TSP-1, TSP-2,
angiostatin and related molecules, endostatin, vasostatin,
calreticulin, platelet factor-4, TIMP, CDAI, Meth-1, Meth-2,
IFN-.alpha., IFN-.beta., IFN-.gamma., CXCL10, IL-4, IL-12, IL-18,
prothrombin (kringle domain-2), antithrombin III fragment,
prolactin, VEGI, SPARC, osteopontin, maspin, canstatin (a fragment
of COL4A2), or proliferin-related protein. In certain embodiments,
the angiogenesis inhibitor is bevacizumab (Avastin), itraconazole,
carboxyamidotriazole, TNP-470 (an analog of fumagillin), CM101,
IFN-.alpha., IL-12, platelet factor-4, suramin, SU5416,
thrombospondin, a VEGFR antagonist, an angiostatic steroid plus
heparin, cartilage-derived angiogenesis inhibitory factor (CDAI), a
matrix metalloproteinase inhibitor, angiostatin, endostatin,
2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide,
thrombospondin, prolactin, a .alpha.V.beta.3 inhibitor, linomide,
ramucirumab, tasquinimod, ranibizumab, sorafenib (Nexavar),
sunitinib (Sutent), pazopanib (Votrient), or everolimus
(Afinitor).
[0403] In certain embodiments, the second chemotherapeutic agent is
a cyclin-dependent kinase (CDK) inhibitor (e.g., a CDK4/CDK6
inhibitor). Examples include, but are not limited to, palbociclib
(Ibrance), Ribociclib (optionally further in combination with
letrozole), abemaciclib (LY2835219; Verzenio), P1446A-05, and
Trilaciclib (G1T28).
[0404] In certain embodiments, the second chemotherapeutic agent is
a Bruton's tyrosine kinase (BTK) inhibitor, such as but not limited
to, Ibrutinib (PCI-32765), acalabrutinib, ONO-4059 (GS-4059),
spebrutinib (AVL-292, CC-292), BGB-3111, and HM71224.
[0405] In certain embodiments, the second chemotherapeutic agent is
a BRAF inhibitor. Examples include, but are not limited to,
BAY43-9006 (Sorafenib, Nexavar), PLX-4032 (Vemurafenib), GDC-0879,
PLX-4720, dabrafenib and LGX818.
[0406] In certain embodiments, the second chemotherapeutic agent is
a EGFR inhibitor. Examples include, but are not limited to,
gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab,
osimertinib, panitumumab, brigatinib, lapatinib, cimaVax-EGF, and
veristrat.
[0407] In certain embodiments, the second chemotherapeutic agent is
a human epidermal growth factor receptor 2 (HER2) inhibitor.
Examples include, but are not limited to, trastuzumab, pertuzumab
(optionally further in combination with trastuzumab), margetuximab,
and NeuVax.
[0408] In certain embodiments, disclosed herein is a method of
increasing a subject's responsiveness to an immunotherapeutic or
immunogenic chemotherapeutic agent, the method comprising
administering to the subject in need thereof an effective amount of
a compound described herein and an effective amount of an
immunotherapeutic agent and/or an immunogenic chemotherapeutic
agent. In certain embodiments, the method further includes
administering to the subject a lipoxygenase inhibitor. In certain
embodiments, the subject has a tumor whose cellular
microenvironment is stromal cell rich. In certain embodiments, the
administration of compound described herein results in killing one
or more stromal cells in the tumor cells' microenvironment. In
certain embodiments, the administration of an effective amount of
an immunotherapeutic agent and/or an immunogenic chemotherapeutic
agent results in killing one or more tumor cells. Also provided
herein is a combination comprising a compound described herein and
an immunotherapeutic agent, lipoxygenase inhibitor, or immunogenic
chemotherapeutic agent. In certain embodiments, the
immunotherapeutic agent is selected from a CTLA4, PDL1 or PD1
inhibitor. In certain embodiments, the immunotherapeutic agent can
be selected from CTLA4 inhibitor such as ipilimumab, a PD1
inhibitor such as pembrolizumab or nivolumab or a PDL1 inhibitor
such as atezolizumab or durvalumab. In certain embodiments, the
immunotherapeutic agent is pembrolizumab. In other embodiments, the
immunogenic chemotherapeutic agent is a compound selected from
anthracycline, doxorubicin, cyclophosphamide, paclitaxel,
docetaxel, cisplatin, oxaliplatin or carboplatin. In certain
embodiments, provided herein is a combination comprising a compound
described herein and a lipoxygenase inhibitor. In certain
embodiments, the lipoxygenase inhibitor is selected from PD147176
and/or ML351. In certain embodiments, the lipoxygenase inhibitor
may be a 15-lipoxygenase inhibitor (see, e.g., Sadeghian et al.,
Expert Opinion on Therapeutic Patents, 2015, 26:1, 65-88).
[0409] In certain embodiments, the second chemotherapeutic agent is
selected from an alkylating agent, including, but not limiting to,
adozelesin, altretamine, bendamustine, bizelesin, busulfan,
carboplatin, carboquone, carmofur, carmustine, chlorambucil,
cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid,
fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven,
lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol,
nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine,
procarbazine, ranimustine, satraplatin, semustine, streptozocin,
temozolomide, thiotepa, treosulfan, triaziquone,
triethylenemelamine, triplatin tetranitrate, trofosphamide, and
uramustine; an antibiotic, including, but not limiting to,
aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,
doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril,
mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin,
valrubicin, and zorubicin; an antimetabolite, including, but not
limiting to, aminopterin, azacitidine, azathioprine, capecitabine,
cladribine, clofarabine, cytarabine, decitabine, floxuridine,
fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea,
mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed,
tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and
vidarabine; an immunotherapy, an antibody therapy, including, but
not limiting to, alemtuzumab, bevacizumab, cetuximab, galiximab,
gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab,
tositumomab, trastuzumab, 90 Y ibritumomab tiuxetan, ipilimumab,
tremelimumab and anti-CTLA-4 antibodies; a hormone or hormone
antagonist, including, but not limiting to, anastrozole, androgens,
buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant,
goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene,
tamoxifen, and toremifene; a taxane, including, but not limiting
to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel,
DHA-paclitaxel, and tesetaxel; a retinoid, including, but not
limiting to, alitretinoin, bexarotene, fenretinide, isotretinoin,
and tretinoin; an alkaloid, including, but not limiting to,
demecolcine, homoharringtonine, vinblastine, vincristine,
vindesine, vinflunine, and vinorelbine; an antiangiogenic agent,
including, but not limiting to, AE-941 (GW786034, Neovastat),
ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a
topoisomerase inhibitor, including, but not limiting to, amsacrine,
belotecan, edotecarin, etoposide, etoposide phosphate, exatecan,
irinotecan (also active metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,
pixantrone, rubitecan, teniposide, topotecan, and
9-aminocamptothecin; a kinase inhibitor, including, but not liming
to, axitinib (AG 013736), dasatinib (BMS 354825), erlotinib,
gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib
diphosphate (AMG 706), nilotinib (AMN107), seliciclib, sorafenib,
sunitinib malate, AEE-788, BMS-599626, UCN-01
(7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib,
paradox breakers (such as PLX8394 or PLX7904), LGX818, BGB-283,
pexidartinib (PLX3397) and vatalanib; a targeted signal
transduction inhibitor including, but not limiting to bortezomib,
geldanamycin, and rapamycin; a biological response modifier,
including, but not limiting to, imiquimod, interferon-.alpha., and
interleukin-2; and other chemotherapeutics, including, but not
limiting to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone),
altrasentan, aminoglutethimide, anagrelide, asparaginase,
bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389),
ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen,
sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g.
sirolimus, temsirolimus, everolimus, deforolimus, INK28, AZD8055,
PI3K inhibitors (e.g. BEZ235, GDC-0941, XL147, XL765, BMK120),
cyclin dependent kinase (CDK) inhibitors (e.g., a CDK4 inhibitor or
a CDK6 inhibitor, such as Palbociclib (PD-0332991), Ribocyclib
(LEE011), Abemaciclib (LY2835219), P1446A-05, Abemaciclib
(LY2835219), Trilaciclib (G1T28), etc.), AKT inhibitors, Hsp90
inhibitors (e.g. geldanamycin, radicicol, tanespimycin),
farnesyltransferase inhibitors (e.g. tipifarnib), Aromatase
inhibitors (anastrozole letrozole exemestane); an MEK inhibitor
including, but are not limited to, AS703026, AZD6244 (Selumetinib),
AZD8330, BIX 02188, CI-1040 (PD184352), GSK1120212 (also known as
trametinib or JTP-74057), cobimetinib, PD0325901, PD318088,
PD98059, RDEA119(BAY 869766), TAK-733 and U0126-EtOH; tyrosine
kinase inhibitors, including, but are not limited to, AEE788,
AG-1478 (Tyrphostin AG-1478), AG-490, Apatinib (YN968D1), AV-412,
AV-951(Tivozanib), Axitinib, AZD8931, BIBF1120 (Vargatef), BIBW2992
(Afatinib), BMS794833, BMS-599626, Brivanib (BMS-540215), Brivanib
alaninate (BMS-582664), Cediranib (AZD2171), Chrysophanic acid
(Chrysophanol), Crenolanib (CP-868569), CUDC-101, CYC116, Dovitinib
Dilactic acid (TKI258 Dilactic acid), E7080, Erlotinib
Hydrochloride (Tarceva, CP-358774, OSI-774, NSC-718781), Foretinib
(GSK1363089, XL880), Gefitinib (ZD-1839 or Iressa), Imatinib
(Gleevec), Imatinib Mesylate, Ki8751, KRN 633, Lapatinib (Tykerb),
Linifanib (ABT-869), Masitinib (Masivet, AB1010), MGCD-265,
Motesanib (AMG-706), MP-470, Mubritinib (TAK 165), Neratinib
(HKI-272), NVP-BHG712, OSI-420 (Desmethyl Erlotinib, CP-473420),
OSI-930, Pazopanib HCl, PD-153035 HCl, PD173074, Pelitinib
(EKB-569), PF299804, Ponatinib (AP24534), PP121, RAF265 (CHIR-265),
Raf265 derivative, Regorafenib (BAY 73-4506), Sorafenib Tosylate
(Nexavar), Sunitinib Malate (Sutent), Telatinib (BAY 57-9352),
TSU-68 (SU6668), Vandetanib (Zactima), Vatalanib dihydrochloride
(PTK787), WZ3146, WZ4002, WZ8040, quizartinib, Cabozantinib, XL647,
EGFR siRNA, FLT4 siRNA, KDR siRNA, Antidiabetic agents such as
metformin, PPAR agonists (rosiglitazone, pioglitazone, bezafibrate,
ciprofibrate, clofibrate, gemfibrozil, fenofibrate, indeglitazar),
DPP4 inhibitors (sitagliptin, vildagliptin, saxagliptin,
dutogliptin, gemigliptin, alogliptin) or an EGFR inhibitor,
including, but not limited to, AEE-788, AP-26113, BIBW-2992
(Tovok), CI-1033, GW-572016, Iressa, LY2874455, RO-5323441, Tarceva
(Erlotinib, OSI-774), CUDC-101 and WZ4002.
[0410] In certain embodiments, the second chemotherapeutic agent is
selected from afatinib, afuresertib, alectinib, alisertib,
alvocidib, amsacrine, amonafide, amuvatinib, axitinib, azacitidine,
azathioprine, bafetinib, barasertib, bendamustine, bleomycin,
bosutinib, bortezomib, busulfan, cabozantinib, camptothecin,
canertinib, capecitabine, cabazitaxel, carboplatin, carmustine,
cenisertib, ceritinib, chlorambucil, cisplatin, cladribine,
clofarabine, crenolanib, crizotinib, cyclophosphamide, cytarabine,
dabrafenib, dacarbazine, dacomitinib, dactinomycin, danusertib,
dasatinib, daunorubicin, decitabine, dinaciclib, docetaxel,
dovitinib, doxorubicin, epirubicin, epitinib, eribulin mesylate,
errlotinib, etirinotecan, etoposide, everolimus, exemestane,
floxuridine, fludarabine, fluorouracil, gefitinib, gemcitabine,
hydroxyurea, ibrutinib, icotinib, idarubicin, idelalisib,
ifosfamide, imatinib, imetelstat, ipatasertib, irinotecan,
ixabepilone, lapatinib, lenalidomide, lestaurtinib, lomustine,
lucitanib, masitinib, mechlorethamine, melphalan, mercaptopurine,
methotrexate, midostaurin, mitomycin, mitoxantrone, mubritinib,
nelarabine, neratinib, nilotinib, nintedanib, omacetaxine
mepesuccinate, olaparib, orantinib, oxaliplatin, paclitaxel,
palbociclib, palifosfamide tris, pazopanib, pelitinib, pemetrexed,
pentostatin, plicamycin, ponatinib, poziotinib, pralatrexate,
procarbazine, quizartinib, raltitrexed, regorafenib, ruxolitinib,
seliciclib, sorafenib, streptozocin, sulfatinib, sunitinib,
tamoxifen, tandutinib, temozolomide, temsirolimus, teniposide,
theliatinib, thioguanine, thiotepa, topotecan, uramustine,
valrubicin, vandetanib, vemurafenib (Zelboraf), vincristine,
vinblastine, vinorelbine, vindesine, and the like. In certain
embodiments, the compounds herein are administered prior to,
concurrently with, or subsequent to the treatment with the
chemotherapeutic agent.
[0411] In certain embodiments, the method of treating a cancer
comprises administering a therapeutically effective amount of a
compound described herein and a therapeutically effective amount a
biologic agent used to treat cancer. In certain embodiments, the
biologic agent is selected from anti-BAFF (e.g., belimumab);
anti-CCR4 (e.g., mogamulizumab); anti-CD19/CD3 (e.g.,
blinatumomab); anti-CD20 (e.g., obinutuzumab, rituximab,
ibritumomab tiuxetan, ofatumumab, tositumomab); anti-CD22 (e.g.,
moxetumomab pasudotox); anti-CD30 (e.g., brentuximab vedotin);
anti-CD33 (e.g., gemtuzumab); anti-CD37 (e.g., otlertuzumab);
anti-CD38 (e.g., daratumumab); anti-CD52 (e.g., alemtuzumab);
anti-CD56 (e.g., lorvotuzumab mertansine); anti-CD74 (e.g.,
milatuzumab); anti-CD105; anti-CD248 (TEM1) (e.g., ontuxizumab);
anti-CTLA4 (e.g., tremelimumab, ipilimumab); anti-EGFL7 (e.g.,
parsatuzumab); anti-EGFR (HER1/ERBB1) (e.g., panitumumab,
nimotuzumab, necitumumab, cetuximab, imgatuzumab, futuximab);
anti-FZD7 (e.g., vantictumab); anti-HER2 (ERBB2/neu) (e.g.,
margetuximab, pertuzumab, ado-trastuzumab emtansine, trastuzumab);
anti-HER3 (ERBB3); anti-HGF (e.g., rilotumumab, ficlatuzumab);
anti-IGF-1R (e.g., ganitumab, figitumumab, cixutumumab,
dalotuzumab); anti-IGF-2R; anti-KIR (e.g., lirilumab, onartuzumab);
anti-MMP9; anti-PD-1 (e.g., nivolumab, pidilizumab, lambrolizumab);
anti-PD-L1 (e.g. Atezolizumab); anti-PDGFRa (e.g., ramucirumab,
tovetumab); anti-PD-L2; anti-PIGF (e.g., ziv-aflibercept);
anti-RANKL (e.g., denosumab); anti-TNFRSF 9 (CD 137/4-1 BB) (e.g.,
urelumab); anti-TRAIL-RI/DR4,R2/D5 (e.g., dulanermin);
anti-TRAIL-R1/D4 (e.g., mapatumumab); anti-TRAIL-R2/D5 (e.g.,
conatumumab, lexatumumab, apomab); anti-VEGFA (e.g., bevacizumab,
ziv-aflibercept); anti-VEGFB (e.g., ziv-aflibercept); and
anti-VEGFR2 (e.g., ramucirumab).
5. Formulations and Administration
[0412] In certain embodiments, the pharmaceutical compositions of
the compounds can be formulated by standard techniques using one or
more physiologically acceptable carriers or excipients. Suitable
pharmaceutical carriers are described herein and in Remington: The
Science and Practice of Pharmacy, 21 Ed. (2005). The therapeutic
compounds and their physiologically acceptable salts, hydrates and
solvates can be formulated for administration by any suitable
route, including, among others, topically, nasally, orally,
parenterally, rectally or by inhalation. In certain embodiments,
the administration of the pharmaceutical composition may be made by
intradermal, subdermal, intravenous, intramuscular, intranasal,
intracerebral, intratracheal, intraarterial, intraperitoneal,
intravesical, intrapleural, intracoronary or intratumoral
injection, with a syringe or other devices. Transdermal
administration is also contemplated, as are inhalation or aerosol
administration. Tablets, capsules, and solutions can be
administered orally, rectally or vaginally.
[0413] For oral administration, a pharmaceutical composition can
take the form of, for example, a tablet or a capsule prepared by
conventional means with a pharmaceutically acceptable excipient.
Tablets and capsules comprising the active ingredient can be
prepared together with excipients such as: (a) diluents or fillers,
e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose
(e.g., ethyl cellulose, microcrystalline cellulose), glycine,
pectin, polyacrylates and/or calcium hydrogen phosphate, calcium
sulfate; (b) lubricants, e.g., silica, talcum, stearic acid, its
magnesium or calcium salt, metallic stearates, colloidal silicon
dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate,
sodium acetate and/or polyethyleneglycol; (c) binders, e.g.,
magnesium aluminum silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose,
polyvinylpyrrolidone and/or hydroxypropyl methylcellulose; (d)
disintegrants, e.g., starches (including potato starch or sodium
starch), glycolate, agar, alginic acid or its sodium salt, or
effervescent mixtures; (e) wetting agents, e.g., sodium lauryl
sulphate, and/or (f) absorbents, colorants, flavors and sweeteners.
The compositions are prepared according to conventional mixing,
granulating or coating methods.
[0414] In certain embodiments, the carrier is a cyclodextrin, such
as to enhance solubility and/or bioavailability of the compounds
herein. In certain embodiments, the cyclodextrin for use in the
pharmaceutical compositions can be selected from
.alpha.-cyclodextrin, .beta.-cyclodextrin, .gamma.-cyclodextrin,
derivatives thereof, and combinations thereof. In certain
embodiments, the cyclodextrin is selected from .beta.-cyclodextrin,
.gamma.-cyclodextrin, derivatives thereof, and combinations
thereof.
[0415] In certain embodiments, the compounds can be formulated with
a cyclodextrin or derivative thereof selected from carboxyalkyl
cyclodextrin, hydroxyalkyl cyclodextrin, sulfoalkylether
cyclodextrin, and an alkyl cyclodextrin. In various embodiments,
the alkyl group in the cyclodextrin is methyl, ethyl, propyl,
butyl, or pentyl.
[0416] When used in a formulation with the compound of the present
disclosure, the cyclodextrin can be present at about 0.1 w/v to
about 30% w/v, about 0.1 w/v to about 20% w/v, about 0.5% w/v to
about 10% w/v, or about 1% w/v to about 5% w/v. In certain
embodiments, the cyclodextrin is present at about 0.1% w/v, about
0.2% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 3% w/v,
about 4% w/v, about 5% w/v, about 6% w/v, about 7% w/v, about 8%
w/v, about 9% w/v, about 10% w/v, about 12% w/v, about 14% w/v,
about 16% w/v, about 18% w/v, about 20% w/v, about 25% w/v, or
about 30% w/v or more.
[0417] Tablets may be either film coated or enteric coated
according to methods known in the art. Liquid preparations for oral
administration can take the form of, for example, solutions,
syrups, or suspensions, or they can be presented as a dry product
for reconstitution with water or other suitable vehicle before use.
Such liquid preparations can be prepared by conventional means with
pharmaceutically acceptable carriers and additives, for example,
suspending agents, e.g., sorbitol syrup, cellulose derivatives, or
hydrogenated edible fats; emulsifying agents, for example, lecithin
or acacia; non-aqueous vehicles, for example, almond oil, oily
esters, ethyl alcohol, or fractionated vegetable oils; and
preservatives, for example, methyl or propyl-p-hydroxybenzoates or
sorbic acid. The preparations can also contain buffer salts,
flavoring, coloring, and/or sweetening agents as appropriate. If
desired, preparations for oral administration can be suitably
formulated to give controlled release of the active compound.
[0418] The compounds can be formulated for parenteral
administration, for example by bolus injection or continuous
infusion. Formulations for injection can be presented in unit
dosage form, for example, in ampoules or in multi-dose containers,
with an optionally added preservative. Injectable compositions can
be aqueous isotonic solutions or suspensions. In certain
embodiments for parenteral administration, the compounds can be
prepared with a surfactant, such as Cremaphor, or lipophilic
solvents, such as triglycerides or liposomes. The compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers.
Alternatively, the compound can be in powder form for
reconstitution with a suitable vehicle, for example, sterile
pyrogen-free water, before use. In addition, they may also contain
other therapeutically effective substances.
[0419] For administration by inhalation, the compound may be
conveniently delivered in the form of an aerosol spray presentation
from pressurized packs or a nebulizer, with the use of a suitable
propellant, for example, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide,
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit can be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, for example, gelatin
for use in an inhaler or insufflator can be formulated containing a
powder mix of the compound and a suitable powder base, for example,
lactose or starch.
[0420] Suitable formulations for transdermal application include an
effective amount of a compound with a carrier. Preferred carriers
include absorbable pharmacologically acceptable solvents to assist
passage through the skin of the subject. For example, transdermal
devices are in the form of a bandage or patch comprising a backing
member, a reservoir containing the compound optionally with
carriers, optionally a rate controlling barrier to deliver the
compound to the skin of the host at a controlled and predetermined
rate over a prolonged period of time, and a means to secure the
device to the skin. Matrix transdermal formulations may also be
used.
[0421] Suitable formulations for topical application, e.g., to the
skin and eyes, are preferably aqueous solutions, ointments, creams
or gels well-known in the art. The formulations may contain
solubilizers, stabilizers, tonicity enhancing agents, buffers and
preservatives.
[0422] In certain embodiments, the compound can also be formulated
as a rectal composition, for example, suppositories or retention
enemas, for example, containing conventional suppository bases, for
example, cocoa butter or other glycerides, or gel forming agents,
such as carbomers.
[0423] In certain embodiments, the compound can be formulated as a
depot preparation. Such long-acting formulations can be
administered by implantation (for example, subcutaneously or
intramuscularly) or by intramuscular injection. The compound can be
formulated with suitable polymeric or hydrophobic materials (for
example as an emulsion in an acceptable oil), ion exchange resins,
biodegradable polymers, or as sparingly soluble derivatives, for
example, as a sparingly soluble salt.
[0424] The pharmaceutical compositions can, if desired, be
presented in a pack or dispenser device that can contain one or
more unit dosage forms containing the active ingredient. The pack
can, for example, comprise metal or plastic foil, for example, a
blister pack. The pack or dispenser device can be accompanied by
instructions for administration.
6. Effective Amount and Dosing
[0425] In certain embodiments, a pharmaceutical composition of the
compound is administered to a subject, preferably a human, at a
therapeutically effective dose to prevent, treat, or control a
condition or disease as described herein. The pharmaceutical
composition is administered to a subject in an amount sufficient to
elicit an effective therapeutic response in the subject. An
effective therapeutic response is a response that at least
partially arrests or slows the symptoms or complications of the
condition or disease. An amount adequate to accomplish this is
defined as "therapeutically effective dose" or "therapeutically
effective amount." The dosage of compounds can take into
consideration, among others, the species of warm-blooded animal
(mammal), the body weight, age, condition being treated, the
severity of the condition being treated, the form of
administration, route of administration. The size of the dose also
will be determined by the existence, nature, and extent of any
adverse effects that accompany the administration of a particular
therapeutic compound in a particular subject.
[0426] In certain embodiments, a suitable dosage of the compounds
of the disclosure or a composition thereof is from about 1 ng/kg to
about 1000 mg/kg, from 0.01 mg/kg to 900 mg/kg, 0.1 mg/kg to 800
mg/kg, from about 1 mg/kg to about 700 mg/kg, from about 2 mg/kg to
about 500 mg/kg, from about 3 mg/kg to about 400 mg/kg, 4 mg/kg to
about 300 mg/kg, or from about 5 mg/kg to about 200 mg/kg. In
certain embodiments, the suitable dosages of the compound can be
about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30
mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg,
80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200
mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700
mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg. In certain embodiments,
the dose of the compound can be administered once per day or
divided into subdoses and administered in multiple doses, e.g.,
twice, three times, or four times per day.
[0427] In certain embodiments, the compounds can be administered
with one or more of a second compound, sequentially or
concurrently, either by the same route or by different routes of
administration. When administered sequentially, the time between
administrations is selected to benefit, among others, the
therapeutic efficacy and/or safety of the combination treatment. In
certain embodiments, the compounds herein can be administered first
followed by a second compound, or alternatively, the second
compound administered first followed by the compounds of the
present disclosure. By way of example and not limitation, the time
between administrations is about 1 hr, about 2 hr, about 4 hr,
about 6 hr, about 12 hr, about 16 hr or about 20 hr. In certain
embodiments, the time between administrations is about 1, about 2,
about 3, about 4, about 5, about 6, or about 7 more days. In
certain embodiments, the time between administrations is about 1
week, 2 weeks, 3 weeks, or 4 weeks or more. In certain embodiments,
the time between administrations is about 1 month or 2 months or
more.
[0428] When administered concurrently, the compound can be
administered separately at the same time as the second compound, by
the same or different routes, or administered in a single
composition by the same route. In certain embodiments, the amount
and frequency of administration of the second compound can used
standard dosages and standard administration frequencies used for
the particular compound. See, e.g., Physicians' Desk Reference,
70th Ed., PDR Network, 2015; incorporated herein by reference.
[0429] In certain embodiments where the compounds of the present
disclosure is administered in combination with a second compound,
the dose of the second compound is administered at a
therapeutically effective dose. In certain embodiments, a suitable
dose can be from about 1 ng/kg to about 1000 mg/kg, from about 0.01
mg/kg to about 900 mg/kg, from about 0.1 mg/kg to about 800 mg/kg,
from about 1 mg/kg to about 700 mg/kg, from about 2 mg/kg to about
500 mg/kg, from about 3 mg/kg to about 400 mg/kg, from about 4
mg/kg to about 300 mg/kg, or from about 5 mg/kg to about 200 mg/kg.
In certain embodiments, the suitable dosages of the second compound
can be about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25
mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg,
70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175
mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600
mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg. In certain
embodiments, guidance for dosages of the second compound is
provided in Physicians' Desk Reference, 70.sup.th Ed, PDR Network
(2015), incorporated herein by reference.
[0430] It to be understood that optimum dosages, toxicity, and
therapeutic efficacy of such compounds may vary depending on the
relative potency of individual compound and can be determined by
standard pharmaceutical procedures in cell cultures or experimental
animals, for example, by determining the LD.sub.50 (the dose lethal
to 50% of the population) and the ED.sub.50 (the dose
therapeutically effective in 50% of the population). The dose ratio
between toxic and therapeutic effects is the therapeutic index and
can be expressed as the ratio, LD.sub.50/ED.sub.50. compounds or
combinations thereof that exhibit large therapeutic indices are
preferred. While certain agents that exhibit toxic side effects can
be used, care should be used to design a delivery system that
targets such agents to the site of affected tissue to minimize
potential damage to normal cells and, thereby, reduce side
effects.
[0431] The data obtained from, for example, cell culture assays and
animal studies can be used to formulate a dosage range for use in
humans. The dosage of such small molecule compounds lies preferably
within a range of circulating concentrations that include the
ED.sub.50 with little or no toxicity. The dosage can vary within
this range depending upon the dosage form employed and the route of
administration. For any compounds used in the methods disclosed
herein, the therapeutically effective dose can be estimated
initially from cell culture assays. A dose can be formulated in
animal models to achieve a circulating plasma concentration range
that includes the IC.sub.50 (the concentration of the test compound
that achieves a half-maximal inhibition of symptoms) as determined
in cell culture. Such information can be used to more accurately
determine useful doses in humans. Levels in plasma can be measured,
for example, by high performance liquid chromatography (HPLC).
7. Methods of Preparation
[0432] The following examples are provided to further illustrate
the methods of the present disclosure, and the compounds and
compositions for use in the methods. The examples described are
illustrative only and are not intended to limit the scope of the
invention(s) in any way. The disclosures of all articles and
references mentioned in this application, including patents, are
incorporated herein by reference in their entirety.
[0433] The compounds of the present disclosure can be synthesized
in view of the guidance provided herein, incorporating known
chemical reactions and related procedures such as separation and
purification. Representative methods and procedures for preparation
of the compounds in this disclosure are described below and in the
Examples. Acronyms are abbreviations are used per convention which
can be found in literature and scientific journals.
[0434] In certain embodiments, provided is a process for preparing
a compound of Formula I, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or salt thereof:
##STR00158##
[0435] wherein each of ring A, X, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, p, and q are independently as defined herein, comprising
contacting a compound of Formula 1-5 with a compound of Formula
1-6:
##STR00159##
[0436] under reaction conditions sufficient to provide the compound
of Formula I, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or salt thereof.
[0437] In certain embodiments, provided is a process for preparing
a compound of Formula I-5, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or salt thereof:
##STR00160##
[0438] wherein each of ring A, X, R.sup.1, R.sup.3, R.sup.4, p, and
q are independently as defined herein, comprising cyclizing a
compound of Formula 1-3:
##STR00161##
[0439] under reaction conditions sufficient to provide the compound
of Formula 1-5, or a tautomer, stereoisomer, mixture of
stereoisomers, isotopically enriched analog, or salt thereof.
[0440] It is understood that the starting materials and reaction
conditions may be varied, the sequence of the reactions altered,
and additional steps employed to produce compounds encompassed by
the present disclosure, as demonstrated by the following examples.
General references for known chemical reactions useful for
synthesizing the disclosed compounds are available (see, e.g.,
Smith and March, March's Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, Fifth Edition, Wiley Interscience, 2001;
or Carey and Sundberg, Advanced Organic Chemistry, Part B. Reaction
and Synthesis; Fifth Edition, Springer, 2007; or Li, J. J. Name
Reactions, A Collection of Detailed Mechanisms and Synthetic
Applications; Fifth Edition, Springer, 2014).
[0441] It will be appreciated that where typical or preferred
process conditions (i.e., reaction temperatures, times, mole ratios
of reactants, solvents, pressures, etc.) are given, other process
conditions can also be used unless otherwise stated. Optimum
reaction conditions may vary with the particular reactants or
solvent used, but such conditions can be determined by one skilled
in the art by routine optimization procedures.
[0442] Additionally, conventional protecting groups may be
necessary to prevent certain functional groups from undergoing
undesired reactions. Suitable protecting groups for various
functional groups as well as suitable conditions for protecting and
deprotecting particular functional groups are well known in the
art. For example, numerous protecting groups are described in Wuts,
P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's
protective groups in organic synthesis. Hoboken, N.J.,
Wiley-Interscience, and references cited therein.
[0443] Furthermore, the compounds of this disclosure may contain
one or more chiral centers. Accordingly, if desired, such compounds
can be prepared or isolated as pure stereoisomers, i.e., as
individual enantiomers or diastereomers or as stereoisomer-enriched
mixtures. All such stereoisomers (and enriched mixtures) are
included within the scope of this disclosure, unless otherwise
indicated. Pure stereoisomers (or enriched mixtures) may be
prepared using, for example, optically active starting materials or
stereoselective reagents well-known in the art. Alternatively,
racemic mixtures of such compounds can be separated using, for
example, chiral column chromatography, chiral resolving agents, and
the like.
[0444] The starting materials for the following reactions are
generally known compounds or can be prepared by known procedures or
obvious modifications thereof. For example, many of the starting
materials are available from commercial suppliers such as Aldrich
Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif.,
USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). Others may be
prepared by procedures or obvious modifications thereof, described
in standard reference texts such as Fieser and Fieser's Reagents
for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991),
Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and
Supplementals (Elsevier Science Publishers, 1989) organic
Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's
Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition,
2001), and Larock's Comprehensive Organic Transformations (VCH
Publishers Inc., 1989).
[0445] General Synthesis
[0446] In certain embodiments, compounds disclosed herein can be
according to the general schemes shown below. For example,
compounds of Formula I can be prepared according to the general
syntheses outlined below in Scheme 1, where suitable reagents can
be purchased form commercial sources or synthesized via known
methods or methods adapted from the examples provided herein. In
Scheme 1, each of ring A, X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, p,
and q are independently as defined herein.
##STR00162##
[0447] In Scheme 1, compound 1-3 can be provided by coupling amine
1-1 with acid 1-2 under standard amide bond forming reaction
conditions. Cyclization of compound 1-3 to provide compound 1-5 can
be achieved by first forming compound 1-4 followed by reduction
using a hydride (e.g., NaBH.sub.4, LiAlH.sub.4, etc.).
Alternatively, compound 1-5 can be provided directly from compound
1-3 under suitable conditions, such as an aprotic solvent in the
presence of an acid catalyst. Compounds of Formula I can then be
provided by coupling compound 1-5 with compound 1-6 under reaction
conditions suitable to provide compounds of Formula I. Upon each
reaction completion, each of the intermediate or final compounds
can be recovered, and optionally purified, by conventional
techniques such as neutralization, extraction, precipitation,
chromatography, filtration and the like.
[0448] Appropriate starting materials and reagents for use in
Scheme 1 can be purchased or prepared by methods known to one of
skill in the art. As shown in Scheme 2, chiral or enantiomerically
enriched starting materials can be provided for use in the method
of Scheme 1 by converting a chiral or enantiomerically enriched
amino alcohol to a oxathiazolidine dioxide 2-2. In Scheme 2, X,
R.sup.1, R.sup.4, and p are independently as defined herein, M is a
metal halide (e.g., MgBr) and PG is a protecting group (e.g.,
Boc).
##STR00163##
[0449] Referring to Scheme 2, compound 2-1 is coupled to compound
2-2 under standard coupling conditions to produce compound 2-3. The
reaction is typically conducted in the presence of suitable
catalyst (e.g., CuI) using suitable solvents/solvent mixtures.
Deprotection of compound 2-3 provides compound 2-4. Upon reaction
completion, each intermediate can be recovered by conventional
techniques such as neutralization, extraction, precipitation,
chromatography, filtration and the like.
[0450] In some embodiments of the methods of Scheme 1 and Scheme 2,
the various substituents on the starting compound (e.g., compound
I-1 and compound I-2, (e.g., ring A, R.sup.1, R.sup.2, R.sup.3,
etc.) are as defined for Formula I. However, it should also be
appreciated that chemical derivatization and/or functional group
interconversion, can be used to further modify of any of the
compounds of Scheme 1 or Scheme 2 in order to provide the various
compounds of Formula I.
[0451] Other compounds of the disclosure can be synthesized using
the synthetic routes above and adapting chemical synthetic
procedures available to the skilled artisan. Exemplary methods of
synthesis are provided in the Examples. It is to be understood that
each of the procedures describing synthesis of exemplary compounds
are part of the specification, and thus incorporated herein into
the Detailed Description of this disclosure.
SYNTHETIC EXAMPLES
Intermediate 1: Synthesis of intermediate
(S)-1-(3-methoxyphenyl)hexan-2-amine
##STR00164##
[0453] (S)-2-aminohexan-1-ol: To a solution of (S)-2-aminohexanoic
acid (30.0 g, 228.6 mmol, 1 eq) in THF (300 mL) at 0.degree. C. was
added lithium aluminumhydride (1M in THF, 458 mL, 457.3 mmol, 2 eq)
over a period of 1 h. Reaction mixture was warm to room
temperature, then the mixture was stirred at 70.degree. C. for 14 h
under N2 atmosphere. Reaction mixture was cooled to room
temperature, the reaction was diluted with Diethyl ether (50 mL),
after fisher--workup, reaction mixture was filtered through
sintered funnel, using diethyl ether, filtrate was concentrated
under reduced pressure to get the product, without further
purification crude product was forward to next step. .sup.1H NMR
(400 MHz, CDCl3) .delta. ppm 0.89 (s, 3H), 1.29-1.39 (m, 6H), 2.00
(s, 3H), 2.81 (s, 1H), 3.23-3.25 (m, 1H), 3.55-3.56 (m, 1H).
[0454] tert-butyl (S)-(1-hydroxyhexan-2-yl)carbamate: To a solution
of (S)-2-aminohexan-1-ol (24.5 g, 209.06 mmol, 1 eq) in DCM (250
mL) was added TEA (58.76 mL, 418.12 mmol, 2 eq) at 0.degree. C.
drop wise, it was stirred for 5 mins, then di-tert-butyl
dicarbonate (57.63 mL, 250.87 mmol, 1.2 eq). After stirring at room
temperature for 14 h, diluted with water (30 mL), extracted with
DCM (2.times.150 mL). Combined organic layer was washed with water,
then with aq NaHCO.sub.3 solution (.about.30 mL) and finally with
brine solution (75 mL), dried over Na.sub.2SO.sub.4, and
concentrated in-vacuo. The residue was subjected to Combiflash
silica gel chromatography equipped MeOH in DCM as an eluent to give
the tert-butyl (S)-(1-hydroxyhexan-2-yl)carbamate. .sup.1H NMR (400
MHz, CDCl3) .delta. ppm 0.90 (s, 3H), 1.25-1.33 (m, 6H), 1.38-1.41
(m, 9H), 3.48-3.55 (m, 1H), 3.62-3.68 (m, 2H), 4.57 (bs, 1H).
[0455] 1H-imidazole (25 g, 368.1 mmol, 4 equiv) and triethlamine
(39 mL, 276.1 mmol, 3 eq) were dissolved in anhydrous
dichloromethane (200 mL, commercial dry solvent) at rt and the
mixture was cooled to 0.degree. C. (external temp, maintained with
ice). Then thionyl chloride (7.3 mL, 101.2 mmol, 1.1 eq) was added
slowly dropwise through an additional funnel over a period of
.about.30 minutes while maintaining the bath temperature at
0.degree. C. The reaction mixture was then stirred for additional
10 mins at 0.degree. C. Then the reaction mixture was cooled
-78.degree. C. Then a solution of tert-butyl
(S)-(1-hydroxyhexan-2-yl)carbamate (20 g, 92.03 mmol, 1 eq) made in
anhydrous dichloromethane (100 mL, commercial dry solvent) at rt
was added through an additional funnel dropwise to the reaction
mixture stirred at -78.degree. C. over a period of 45 mins. The
reaction mixture was stirred at -78.degree. C. for additional 3
hours. Then the dry ice-acetone bath was removed and the reaction
mixture was allowed to stir at room temperature for 16 h. After
completion of the reaction (TLC, 10% EA in hexane) the mixture was
diluted with DCM, washed with water (200 mL.times.3) and brine (200
mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure at rotavapor to
obtain the crude product. The crude was purified by silica gel
column chromatography using ethyl acetate in hexane as eluent.
Product was eluted at 10-25% of EA in hexane to give the tert-butyl
(4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide. .sup.1H
NMR (400 MHz, CDCl3) .delta. ppm 0.91 (t, J=6.8 Hz, 3H), 1.27-1.38
(m, 4H), 1.52 (s, 9H), 1.67-1.73 (m, 1H), 1.99-2.10 (m, 1H),
3.97-4.02 (m, 1H), 4.70-4.78 (m, 2H).
[0456] tert-butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide: This reaction was performed 20 g.times.2 batches.
Ruthenium(III)chloride (0.463 g, 2.23 mmol, 0.014 eq), was added to
a stirred solution of tert-butyl
(4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (42.0 g,
159.48 mmol, 1 eq), in acetonitrile (400 mL) and water (200 mL) at
0.degree. C., followed by portion wise addition of sodium
metaperiodate (37.43 g, 175.43 mmol, 1.1 eq). The biphasic mixture
was stirred at rt for 2 hours. Reaction mixture was filtered
through sintered, washed with ethyl acetate. Water (250 mL) was
added and the mixture was extracted in to ethyl acetate
(2.times.150 mL). The combined organics were washed with water (150
mL), brine (150 mL), dried over with Na2SO4, filtered and
concentrated under reduced pressure to obtain the crude product,
which was purified by column chromatography using 10% ethylacetate
in hexane as an eluent to give the tert-butyl
(S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.
.sup.1H NMR (400 MHz, CDCl3) .delta. ppm 0.89-0.92 (m, 3H),
1.24-1.37 (m, 4H), 1.53 (s, 9H), 1.77-1.83 (m, 1H), 1.88-1.89 (m,
1H), 4.26-4.30 (m, 2H), 4.59-4.63 (m, 1H).
[0457] tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate: To
a solution of copper iodide (0.95 g, 5.017 mmol, 0.1 eq) in diethyl
ether (150 mL) was added (3-methoxyphenyl)magnesium bromide (1M in
THF) (98.5 mL, 100.35 mmol, 2 eq) drop wise over a period of 15 min
at -20.degree. C. (salt & Ice mixture bath). The reaction
mixture stirred for 30 min at -20.degree. C. (salt & Ice
mixture bath). After this time, a solution of tert-butyl
(S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (14 g,
50.172 mmol, 1 eq) in diethyl ether (100 mL) was added at
-20.degree. C. (salt & Ice mixture bath) drop wise over a
period of 25 min to the reaction mass. The resulting mixture
stirred for 4 h at -20.degree. C. Finally, the reaction quenched
with 10% aqueous citric acid solution (70 mL) at -20.degree. C.
(salt & Ice mixture bath). The mixture was allowed to warm to
RT and stirred for 10 min. The mixture was filtered through celite
pad, washed with ethyl acetate thoroughly. The filtrate was washed
with water (100 mL), brine (100 mL), dried over anhydrous sodium
sulfate, filtered and concentrated to give the crude product, which
was purified by flash column chromatography using 15% ethyl acetate
in n-hexane as an eluent to obtain tert-butyl
(S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate. LCMS (ES) m/z=208.2
[M+H].sup.+ without boc mass observed. .sup.1H NMR (400 MHz, CDCl3)
.delta. ppm 0.86-0.87 (m, 3H), 1.25-1.28 (m, 6H), 1.40 (s, 9H),
2.73 (bs, 2H), 3.79 (s, 3H), 4.29 (bs, 1H), 6.71-6.76 (m, 3H),
7.17-7.21 (m, 1H), amide NH was not observed.
[0458] (S)-1-(3-methoxyphenyl)hexan-2-amine: To a solution of
tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (12.0 g,
39.033 mmol, 1 eq) in dichloromethane (50 mL) was added 4M HCl in
1,4-dioxane (150 mL) slowly at 0.degree. C. The mixture was allowed
to stir at room temperature for 5 h. Progress of the reaction was
monitored by TLC, after completion of reaction; the reaction
mixture was concentrated under reduced pressure. The obtained crude
was basified by saturated aqueous solution of NaHCO.sub.3. The
compound was extracted with EtOAc (3.times.200 mL). Organic layer
was washed with brine (100 mL), dried over anhydrous sodium
sulfate, filtered and concentrated to get
(S)-1-(3-methoxyphenyl)hexan-2-amine. LCMS (ES) m/z=208.1
[M+H].sup.+
Procedure 1: Synthesis of Compound 1
##STR00165## ##STR00166##
[0460] To a stirred mixture of (R)-2-methyloxirane (10 g, 172 mmol,
1 eq) in dry tetrahydrofuran (100 mL) was added phenyl magnesium
bromide (3M in diethyl ether) (63 mL, 183 mmol, 1.1 eq) at
-10.degree. C. under nitrogen atmosphere. The resulting mixture was
allowed to warm to room temperature gradually and stirred for 16 h.
The progress of the reaction was monitored by TLC (15% Ethyl
acetate in hexane). The reaction mixture was quenched with
saturated ammonium chloride solution. The crude product was
extracted with ethyl acetate (3.times.300 mL), the combined
organics were washed with water (200 mL), brine (100 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to provide the crude product, which was purified
by flash column chromatography using 15% of ethyl acetate in hexane
as eluent to obtain (R)-1-phenylpropan-2-ol. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.23 (d, J=2.0 Hz, 3H), 1.48 (s, 1H),
2.66-2.71 (m, 1H), 2.77-2.80 (m, 1H), 4.02 (bs, 1H), 7.21-7.31 (m,
5H).
[0461] To a stirred mixture of (R)-1-phenylpropan-2-ol (0.5 g,
3.671 mmol, 1 eq) and triethyl amine (1.54 mL, 11 mmol, 3 eq) in
dichloromethane (10 mL) was added methane sulfonyl chloride (0.42
mL, 5.5 mmol, 1.5 eq) at 0.degree. C. under nitrogen atmosphere.
The resulting mixture was allowed to warm to room temperature
gradually and stirred for 2 h. The progress of the reaction was
monitored by TLC (50% dichloromethane in hexane). The reaction
mixture was quenched with water. The crude product was extracted
with dichloromethane (3.times.30 mL), the combined organics were
washed with water (50 mL), brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to provide
crude product (R)-1-phenylpropan-2-yl methanesulfonate, which was
taken as such without purification to next step. 1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.47 (d, J=6.4 Hz, 3H), 2.51 (s, 3H),
2.89-2.99 (m, 2H), 4.85-4.95 (m, 1H), 7.16-7.40 (m, 5H).
[0462] To a stirred solution of (R)-1-phenylpropan-2-yl
methanesulfonate (0.5 g crude, 2 mmol, 1 eq) in N,N-dimethyl
formamide (10 mL) was added sodium azide (0.18 g, 2.80 mmol, 1.2
eq) at room temperature under nitrogen atmosphere. The resulting
mixture was heated to 80.degree. C. and stirred for 16 h. The
progress of the reaction was monitored by TLC (5% ethyl acetate in
hexane). After completion of reaction, the reaction mixture was
allowed to cool to room temperature and quenched with water. The
mixture was extracted with ethyl acetate (3.times.30 mL), the
combined organics were washed with water (4.times.30 mL), brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4, concentrated under
reduced pressure to crude product, which was purified by flash
column chromatography using 5% of ethyl acetate in hexane as eluent
to obtain (S)-(2-azidopropyl)benzene. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.29 (d, J=6.8 Hz, 3H), 2.69-2.74 (m, 1H),
2.81-2.86 (m, 1H), 3.66-3.72 (m, 1H), 7.18-7.32 (m, 5H).
[0463] To a stirred solution of (S)-(2-azidopropyl)benzene (0.24 g,
1.5 mmol, 1 eq) in ethyl acetate (10 mL) was added Palladium, (10%
on activated carbon powder, 50% water wet) (0.05 g) at room
temperature under nitrogen atmosphere. The resulting mixture was
subjected to hydrogenation by using hydrogen pressure (balloon, if
large scale parr apparatus is suitable) stirred for 8 h. The
progress of the reaction was monitored by TLC (10% ethyl acetate in
hexane). After completion of reaction, the reaction mixture was
filtered through celite pad, washed the celite pad with ethyl
acetate, the filtrated was concentrated under reduced pressure to
obtain (S)-1-phenylpropan-2-amine. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.12 (d, J=6.8 Hz, 3H), 2.49-2.59 (m, 1H),
2.68-2.77 (m, 1H), 3.12-3.20 (m, 1H), 4.68 (s, 2H), 7.09-7.31 (m,
5H).
[0464] To a solution of (S)-1-phenylpropan-2-amine (0.2 g, 1.5
mmol, 1 eq) and 4-morpholinobenzaldehyde (0.28 g, 1.5 mmol, 1 eq)
in toluene (10 mL) was added MgSO.sub.4 anhydrous (0.2 g) at room
temperature. The reaction mixture was stirred at 110.degree. C. for
4 h. TLC (70% ethyl acetate in hexane) showed the reaction was
completed. The solid portion was removed from reaction mixture by
filtration and filtrate was concentrated under reduced pressure.
The obtained crude
(S)-1-(4-morpholinophenyl)-N-(1-phenylpropan-2-yl)methanimine was
carried to next step without further purification.
[0465] To a solution of
(S)-1-(4-morpholinophenyl)-N-(1-phenylpropan-2-yl)methanimine (0.5
g crude) in triflic acid (0.5 mL) was stirred at 130.degree. C. for
24 h. TLC 5% (methanol in dichloromethane) showed the reaction was
completed. The reaction was cooled to room temperature and was
diluted with ice cold water (5 mL), and then basified with 10%
aqueous sodium hydroxide solution up to pH=12. The product was
extracted in to ethyl acetate (30 mL), the organic layer dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain the crude product. The obtained crude product
was purified by flash chromatography using 5% methanol in
dichloromethane as an eluent. The isolated product was re-purified
by preparative HPLC [Analytical conditions: Column: Inertsil ODS 3V
(250 mm.times.4.6 mm.times.5 .mu.m), mobile phase (A): 0.1% ammonia
in water, mobile phase (B): CH.sub.3CN, flow rate: 1.0 mL/min,
composition of B: 0/10, 12/80, 25/90, 27/10, 30/10] to obtain
4-(4-((3S)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)morpholine.
LCMS (ES) m/z=309.2 [M+H]+; 1H NMR (400 MHz, CDCl3): .delta. ppm
1.24 (d, J=4.4 Hz, 3H), 2.69-2.81 (m, 2H), 3.14-3.20 (m, 5H), 3.85
(bs, 4H), 5.05 (s, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.87 (d, J=6.8 Hz,
2H), 6.99 (s, 1H), 7.09 (s, 2H), 7.21-7.25 (m, 2H).
[0466] To a solution of
4-(4-((3S)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)morpholine
(0.04 g, 0.129 mmol, 1 eq) in chloroform (5 mL) was added sodium
bicarbonate (0.021 g, 0.259 mmol, 2.0 eq) at 0.degree. C., followed
by 2-chloroacetyl chloride (0.015 mL, 0.194 mmol, 1.5 eq). The
mixture was allowed to warm to room temperature and stirred for 3 h
under N.sub.2 atmosphere. TLC (40% ethyl acetate in hexane) showed
the reaction was completed. Then the reaction was diluted with
dichloromethane (20 mL) and washed with water (20 mL), brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to obtain the crude product.
The crude product was purified by flash column chromatography using
50% EtOAc in n-hexane as mobile phase to obtain
2-chloro-1-((3S)-3-methyl-1-(4-morpholinophenyl)-3,4-dihydroisoquinolin-2-
(1H)-yl)ethan-1-one. LCMS (ES) m/z=385.3 [M+H].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. ppm 1.25 (bs, 3H), 2.3-2.5 (m, 1H),
2.75-2.95 (m, 1H), 3.14 (bs, 4H), 3.85 (bs, 4H), 4.16-4.26 (m, 3H),
5.97 (bs, 1H), 6.83 (bs, 2H), 7.07 (bs, 2H), 7.19-7.25 (m, 4H).
chiral HPLC purity: 48.93 (trans): 47.12% (cis).
Procedure 2: Synthesis of Compounds 2 and 3
##STR00167##
[0468] methyl D-phenylalaninate hydrochloride (0.3 g, 1.391 mmol, 1
eq) was portioned between ethyl acetate and sodium bicarbonate
solution and stirred for 15 min, the ethyl acetate layer was
separated and the aqueous layer was extracted with ethyl acetate
(2.times.50 mL). The combined ethyl acetate fractions were washed
with water (50 mL), brine (50 mL), dried over anhydrous sodium
sulfate, and concentrated under reduced pressure to obtain methyl
D-phenylalaninate. LCMS (ES) m/z=180.1 [M+H].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm, 2.83-2.88 (m, 1H), 3.07-3.11 (m,
1H), 3.71-3.75 (m, 4H), 7.18-7.32 (m, 5H).
[0469] To a solution of methyl D-phenylalaninate (0.1 g, 0.557
mmol, 1 eq) in toluene (10 mL) was added methyl 4-formylbenzoate
(0.0.09 g, 0.557 mmol, 1 eq). The reaction mixture was heated to
120.degree. C. and stirred for 1 h. The mixture was concentrated
under reduced pressure to obtain methyl
(R,E)-4-(((1-methoxy-1-oxo-3-phenylpropan-2-yl)imino)methyl)benzoate
and the obtained crude product was carried to next step without any
further purification.
[0470] methyl
(R,E)-4-(((1-methoxy-1-oxo-3-phenylpropan-2-yl)imino)methyl)benzoate
(0.3 g crude) was mixed with triflic acid (2 mL) and the mixture
was heated to 130.degree. C. and stirred for 18 h and the mixture
was analyzed by LCMS (LCMS showed hydrolyzed product
(3R)-1-(4-carboxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid). The mixture was cooled to 0.degree. C. and 10 mL of
anhydrous methanol was added. The resulting mixture was heated to
80.degree. C. and stirred for 2 h. The mixture was cooled to
0.degree. C. and neutralized with triethylamine and concentrated
under reduced pressure. The obtained crude was dissolved with ethyl
acetate, washed with water (3.times.20 mL), brine (20 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The crude product was purified by flash
chromatography using 20% ethyl acetate in hexane as the eluent to
provide methyl
(3R)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carbo-
xylate. LCMS (ES) m/z=326.2 [M+H].sup.+.
[0471] To a stirred mixture of methyl
(3R)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carbo-
xylate (0.12 g, 0.368 mmol, 1 eq) and sodium bicarbonate (0.06 g,
0.737 mmol, 2 eq) in chloroform (5 mL), was added 2-chloroacetyl
chloride (0.044 mL, 0.553 mmol, 1.5 eq) at 0.degree. C. under
nitrogen atmosphere. The resulting mixture was allowed to warm to
room temperature and stirred for 2 h. The progress of the reaction
was monitored by TLC (20% ethyl acetate in hexane). After
completion of reaction, the mixture was diluted with
dichloromethane (50 mL), washed with water (2.times.20 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to obtain the crude product. The crude product was
purified by preparative HPLC [Analytical Conditions:--Column:
Inertsil ODS 3V (250 mm.times.4.6 mm.times.5 .mu.m), mobile phase
(A): 0.1% ammonia in water, mobile phase (B): CH.sub.3CN, flow
rate: 1.0 mL/min, composition of B: 0/20, 12/80, 25/90, 27/20,
30/20] to obtain methyl
(1S,3R)-2-(2-chloroacetyl)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahyd-
roisoquinoline-3-carboxylate (3). In TLC, polar spot compared to
corresponding to the other isomer. LCMS (ES) m/z=402 [M+H]+; 1H NMR
(400 MHz, DMSO-d6) .delta. ppm 3.04-3.15 (m, 1H), 3.30 (m, 1H),
3.46 (m, 3H), 3.78-3.79 (s, 3H), 3.98, 4.30 (m, 0.5H, 0.5H),
4.67-4.73 (m, 1H), 5.21, 5.37 (m, 0.5H, 0.5H), 6.28, 6.52 (s, 0.5H,
0.5H), 7.11-7.21 (m, 3H), 7.51-7.60 (m, 3H), 7.88-7.89 (m, 2H).
Chiral HPLC purity with 2 peaks with 61.1% & 36.7%;
[0472] and methyl
(1R,3R)-2-(2-chloroacetyl)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahyd-
roisoquinoline-3-carboxylate (2). In TLC, non-polar spot compared
to corresponding to the other isomer. LCMS (ES) m/z=402 [M+H]+; 1H
NMR (400 MHz, DMSO-d6) .delta. ppm 2.98-3.02 (m, 0.5H), 3.07-3.12
(m, 1H), 3.21-3.22 (m, 0.5H), 3.27 (s, 1H), 3.66 (s, 2H), 3.80 (s,
3H), 4.22-4.26 (m, 1H), 4.31-4.40 (m, 1H), 4.65-4.75, 5.02 (m, 1H),
6.42, 6.77 (m, 0.8H, 0.3H), 7.11-7.38 (m, 4H), 7.63 (d, J=7.2 Hz,
2H), 7.83-7.89 (m, 2H). Chiral HPLC purity with 2 peaks with 74.37%
& 25.6%.
Procedure 3: Synthesis of Compounds 4 and 5
##STR00168##
[0474] To a solution of compound methyl
4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate
(0.35 g, 1.12 mmol, 1.0 eq) in DCM (10 mL) was added triethylamine
(0.45 g, 4.49 mmol, 4.0 eq) and di-tert-butyl dicarbonate (0.715 g,
2.24 mmol, 2.0 eq) at room temperature and the mixture was stirred
for 16 h. TLC (50% EtOAc in hexane) showed the reaction was
completed. The reaction mixture was concentrated under reduced
pressure, and the crude was diluted with EtOAc (50 mL), washed with
water (2.times.50 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to crude
product tert-butyl
(1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate. LC-MS (m/z): 356.0
[M-.sup.tBu+H].sup.+.
[0475] To a solution of compound tert-butyl
(1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate (0.650 g, 1.57 mmol, 1.0 eq) in a mixture
of THF:MeOH:H.sub.2O (9 mL:1 mL) were added lithium hydroxide
(0.331 g, 7.89 mmol, 5.0 eq) and allowed to stirrer at room
temperature for 16 h. TLC (50% EtOAc in hexane) showed the reaction
was completed. The reaction mixture was concentrated under reduced
pressure, and the crude was acidified with 5% citric acid solution
(pH=9). Reaction mixture was diluted with EtOAc (50 mL) and the
organic layer was separated and dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to give crude
4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroi-
soquinolin-1-yl)benzoic acid. LC-MS (m/z): 396.0 [M+H].sup.+.
[0476] To a solution of compound
4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroi-
soquinolin-1-yl)benzoic acid (0.38 g, 0.957 mmol, 1.0 eq) in DCM
(10 mL) was added triethylamine (0.4 mL, 2.87 mmol, 3.0 eq) and
cyclopropanamine (0.65 g, 1.14 mmol, 1.2 eq) at 0.degree. C. and
the mixture was stirred for 15 min. To the above reaction mixture
T3P (50% wt in EtOAc) (1.4 mL, 1.97 mmol, 1.2 eq) was added at the
same temperature and stirred for 16 h. TLC (50% EtOAc in hexane)
showed the reaction was completed. The reaction mixture was
concentrated under reduced pressure, and the crude was diluted with
EtOAc (50 mL), washed with water (2.times.50 mL). The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, and concentrated under
reduced pressure to give crude tert-butyl
(1S,3S)-1-(4-(cyclopropylcarbamoyl)phenyl)-6-methoxy-3-methyl-3,4-dihydro-
isoquinoline-2(1H)-carboxylate. LC-MS (m/z): 381.0
[M-.sup.tBu+H].sup.+.
[0477] To a solution of compound tert-butyl
(1S,3S)-1-(4-(cyclopropylcarbamoyl)phenyl)-6-methoxy-3-methyl-3,4-dihydro-
isoquinoline-2(1H)-carboxylate (0.27 g, 0.61 mmol, 1.0 eq) in DCM
(10 mL) was added trifluoroacetic acid (0.084 g, 0.74 mmol, 1.2 eq)
at 0.degree. C. and the mixture was stirred for 2 h. TLC (50% EtOAc
in hexane) showed the reaction was completed. The reaction mixture
was concentrated under reduced pressure to give crude
N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2-
,3,4-tetrahydro-2.lamda..sup.4-isoquinolin-1-yl)benzamide. LC-MS
(m/z): 337.0 [M+H].sup.+.
[0478] To a solution of
N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2-
,3,4-tetrahydro-2.lamda..sup.4-isoquinolin-1-yl)benzamide (0.2 g,
0.59 mmol, 1.0 eq) in DCM (8.0 mL) was added TEA (0.12 g, 1.18
mmol, 2.0 eq) at 0.degree. C., stirred for 15 mins and then and
2-chloroacetyl chloride (0.08 g, 0.71 mmol, 1.2 eq) was added at
0.degree. C. The mixture was allowed to stir at room temperature
for 1 hr. LCMS and TLC (50% EtOAc in hexane) showed the reaction
was completed. The reaction mixture was diluted with saturated
NaHCO.sub.3 solution (10 mL) and was extracted with DCM (2.times.50
mL). The organic layers were dried over Na.sub.2SO.sub.4 and
concentrated to give the crude product. The crude product was
purified by flash column chromatography using 15% EtOAc/hexane as
an eluent followed by preparative TLC with 30% EtOAc in hexane as
eluent to give
4-((1S,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoqui-
nolin-1-yl)-N-cyclopropylbenzamide. LC-MS (m/z): 413.3 [M+H].sup.+,
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.49-0.52 (m, 2H),
0.52-0.64 (m, 2H), 0.66 (bs, 3H), 2.65-2.66 (m, 1H), 2.77-2.81 (m,
1H), 3.71 (s, 3H), 4.37-4.74 (bs, 3H), 6.13 (s, 1H), 6.74-6.75 (m,
1H), 6.79-6.81 (m, 1H), 7.320-7.302 (m, 2H), 7.48 (d, J=8.4 Hz,
1H), 7.64 (s, 2H), 8.13 (s, 1H).
[0479] To a solution of
N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2-
,3,4-tetrahydro-2.lamda..sup.4-isoquinolin-1-yl)benzamide (0.2 g,
0.59 mmol, 1.0 eq) in DCM (10.0 mL) was added triethylamine (0.162
g, 1.42 mmol, 2.4 eq) and propiolic acid (0.041 mL, 0.59 mmol, 1.0
eq) and stirred for 15 minutes. To the above reaction mixture
2-chloro-1-methylpyridin-1-iumiodide (0.182 g, 0.71 mmol, 1.2 eq)
was added and stirred for 16 hours. LCMS and TLC (5% MeOH in DCM)
showed the reaction was completed. The reaction mixture was diluted
with water (10 mL) and organic layer was separated, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
the crude product. The crude product was purified by preparative
TLC with 70% EtOAc in hexane as an eluent to give
N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-propioloyl-1,2,3,4-tetrahyd-
roisoquinolin-1-yl)benzamide. LC-MS (m/z): 389.0 [M+H].sup.+,
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.49-0.51 (m, 2H),
0.52-0.65 (m, 2H), 0.66 (bs, 3H), 2.65-2.66 (m, 1H), 2.78-2.82 (m,
1H), 3.71 (s, 3H), 4.37-4.74 (bs, 3H), 6.13 (s, 1H), 6.75-6.78 (m,
1H), 6.79-6.81 (m, 1H), 7.32-7.30 (m, 2H), 7.48 (d, J=8.4 Hz, 1H),
7.64 (s, 2H), 8.13 (s, 1H).
Procedure 4: Synthesis of Compounds 6 and 7
##STR00169##
[0481] To a solution of (R)-2-methyloxirane (3.0 g, 51.72 mmol, 1.0
eq) in THF (30 mL) was added (3-methoxyphenyl)magnesium bromide (62
mL, 62.06 mmol, 1.2 eq) drop wise at 0.degree. C. The reaction
mixture was stirred at room temperature for 6 hours. After this
time, the reaction mixture was quenched with aqueous ammonium
chloride solution (10 mL) and product was extracted in to ethyl
acetate (100 mL). The organic layer was washed with water
(2.times.20 mL), brine (15 mL), dried over anhydrous MgSO.sub.4,
filtered and concentrated under reduced pressure to obtain the
crude product which was purified by silica gel flash column
chromatography (n-hexane/EtOAc=8:1, R.sub.f=0.24) to give
(R)-1-(3-methoxyphenyl)propan-2-ol. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.00 (d, J=6.4 Hz, 3H), 2.49-2.51 (m,
1H), 2.61-2.66 (m, 1H), 3.70 (s, 3H), 3.76-3.81 (m, 1H), 4.51 (d,
J=4.8 Hz, 1H), 6.71-6.74 (m, 3H), 7.14 (t, J=7.8 Hz, 1H).
[0482] To a solution of (R)-1-(3-methoxyphenyl)propan-2-ol (2.8 g,
16.86 mmol, 1.0 eq) in DCM (30 mL) was added triethyl amine (5.1 g,
50.58 mmol, 3.0 eq) at 0.degree. C., followed by mesylchloride (2.8
g, 25.30 mmol, 1.5 eq). The mixture was stirred at 0.degree. C. for
1.0 h under a N.sub.2 atmosphere. TLC (30% EtOAc in n-hexane)
showed the reaction was completed. The reaction was diluted with
saturated aqueous solution of NaHCO.sub.3 (15 mL) and was extracted
with DCM (50 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give (R)-1-(3-methoxyphenyl)propan-2-ylmethanesulfonate. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.47 (d, J=6.0 Hz, 3H), 2.56
(s, 3H), 2.84-2.89 (m, 1H), 2.93-2.99 (m, 1H), 3.79 (s, 3H),
4.87-4.92 (m, 1H), 6.77-6.82 (m, 3H), 7.21-7.23 (m, 1H).
[0483] To a solution of
(R)-1-(3-methoxyphenyl)propan-2-ylmethanesulfonate (3.8 g, 15.57
mmol, 1.0 eq) in DMF (38 mL) was added sodium azide (1.2 g, 18.68
mmol, 1.2 eq) at room temperature. The mixture was stirred at
80.degree. C. for 16 h. TLC (5% EtOAc in n-hexane) showed the
reaction was completed. The reaction was diluted with water (15 mL)
and EtOAc (50 mL), the organic layer was separated, washed with
water (5.times.25 mL), brine (10 mL), dried over anhydrous
MgSO.sub.4, filtered and concentrated under reduced pressure to
provide the crude product. The crude product was purified by silica
gel flash column chromatography (n-hexane/EtOAc=9.7:0.2,
R.sub.f=0.6) to give (S)-1-(2-azidopropyl)-3-methoxybenzene.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.26 (d, J=6.0 Hz,
3H), 2.66-2.71 (m, 1H), 2.78-2.83 (m, 1H), 3.62-3.71 (m, 1H), 3.80
(s, 3H), 6.74-6.79 (m, 3H), 7.20-7.22 (m, 1H).
[0484] To a solution of (S)-1-(2-azidopropyl)-3-methoxybenzene
(2.37 g, 12.40 mmol, 1.0 eq) in ethyl acetate (23 mL) was added
Pd/C (150 mg of 10 percent Pd) at room temperature. The resulting
reaction mixture was hydrogenated at 100 PSI in parr shaker at room
temperature for 20 h. After this time, catalyst was removed by
filtration through Celite, filtrate was concentrated under reduced
pressure to provide (S)-1-(3-methoxyphenyl)propan-2-amine. LCMS
(ES) m/z=343.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 1.13 (d, J=6.0 Hz, 3H), 2.44-2.54 (m, 1H), 2.67-2.72
(m, 1H), 3.16-3.21 (m, 1H), 3.79 (s, 3H), 6.74-6.78 (m, 3H), 7.21
(t, J=7.8 Hz, 1H). NH.sub.2 Protons were not observed in .sup.1H
NMR.
[0485] To a solution of (S)-1-(3-methoxyphenyl)propan-2-amine (0.3
g, 1.81 mmol, 1.0 eq) and methyl 4-formylbenzoate (0.36 g, 2.18
mmol, 1.2 eq) in toluene (4 mL) was irradiated in microwave at
90.degree. C. for 20 min. After this time, the volatile portion was
concentrated under reduced pressure to provide methyl
(S)-4-(((1-(3-methoxyphenyl)propan-2-yl)imino)methyl)benzoate. This
product was taken forward for cyclization step as such.
[0486] To a solution of methyl
(S)-4-(((1-(3-methoxyphenyl)propan-2-yl)imino)methyl)benzoate
(previous step product) in TFA (2 mL) was irradiated in microwave
at 140.degree. C. for 45 min. After this time, the volatile portion
was concentrated under reduced pressure and diluted with saturated
aqueous solution of NaHCO.sub.3 (10 mL) and EtOAc (40 mL). The
organic layer was separated, washed with brine (10 mL), dried over
anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure to obtain the crude product. The obtained crude product
was purified by silica gel flash column chromatography
(n-hexane/EtOAc=3:2, R.sub.f=0.4--for non-polar spot,
R.sub.f=0.3--for polar spot) to give methyl
4-((1R,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate
(less polar spot) and methyl
4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate
(polar spot).
[0487] methyl
4-((1R,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate-
: LCMS (ES) m/z=312.2 [M+H].sup.+, .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.26 (d, J=6.0 Hz, 3H), 2.74-2.76 (m, 2H),
3.19-3.20 (m, 1H), 3.76 (s, 3H), 3.90 (s, 3H), 5.12 (s, 1H),
6.49-6.64 (m, 3H), 7.41 (d, J=8.0 Hz, 2H), 8.00 (d, J=7.6 Hz, 2H).
NH Proton was not observed in .sup.1H NMR.
[0488] methyl
4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate-
: LCMS (ES) m/z=312.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 1.11 (d, J=6.4 Hz, 3H), 2.53-2.60 (m, 1H),
2.82-2.87 (m, 1H), 3.04-3.07 (m, 1H), 3.80 (s, 3H), 3.89 (s, 3H),
5.24 (s, 1H), 6.67-6.69 (m, 2H), 6.79 (d, J=8.8 Hz, 1H), 7.20 (d,
J=8.4 Hz, 2H), 7.94 (d, J=8.0 Hz, 2H). NH Proton was not observed
in .sup.1H NMR.
[0489] To a solution of methyl
4-((1R,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate
(0.2 g, 0.64 mmol, 1 eq) in DCM (5.0 mL) was added triethyl amine
(0.19 g, 1.92 mmol, 3.0 eq) at 0.degree. C., followed by
2-chloroacetyl chloride (0.095 g, 0.83 mmol, 1.3 eq). The mixture
was stirred at 0.degree. C. for 2.0 h under N.sub.2 atmosphere. TLC
(35% EtOAc in n-hexane) showed the reaction was completed. Then the
reaction was diluted with saturated aqueous solution of NaHCO.sub.3
(5 mL) and was extracted with DCM (25 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude product was purified by
preparative TLC using 40% EtOAc in n-hexane as mobile phase to give
methyl
4-((1R,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoqui-
nolin-1-yl)benzoate (6): LCMS (ES) m/z=388.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) (at 70.degree. C.) .delta. ppm 1.10 (d,
J=5.6 Hz, 3H), 3.00 (bs, 2H), 3.77 (m, 3H), 3.82 (s, 3H), 4.21 (bs,
1H), 4.47 (q, J=13.6 Hz, 2H), 6.45 (bs, 1H), 6.83-6.85 (m, 2H),
7.16 (bs, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H).
[0490] To a solution of methyl
4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate
(0.11 g, 0.35 mmol, 1 eq) in DCM (4.0 mL) was added triethyl amine
(0.1 g, 1.05 mmol, 3.0 eq) at 0.degree. C., followed by
2-chloroacetyl chloride (0.05 g, 0.45 mmol, 1.3 eq). The mixture
was stirred at 0.degree. C. for 2.0 h under N.sub.2 atmosphere. TLC
(35% EtOAc in n-hexane) showed the reaction was completed. Then the
reaction was diluted with saturated aqueous solution of NaHCO.sub.3
(5 mL) and was extracted with DCM (25 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude product was purified by
preparative TLC using 40% EtOAc in n-hexane as mobile phase to give
methyl
4-((1S,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoqui-
nolin-1-yl)benzoate (7): LCMS (ES) m/z=388.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) (at 70.degree. C.) .delta. ppm 0.97
(bs, 3H), 2.65 (bs, 2H), 3.71 (s, 3H), 3.79 (s, 3H), 4.40 (bs, 1H),
4.75 (bs, 2H), 6.17 (bs, 1H), 6.76-6.82 (m, 2H), 7.40-7.49 (m, 3H),
7.81 (bs, 2H).
Procedure 5: Compounds 8, 9, and 10
##STR00170##
[0492] Compounds 8, 9, and 10 were synthesized according to the
procedure provided in Examples 6 and 7 using the appropriate
starting material.
[0493] Compound 8: LC-MS (m/z): 348.3 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.95 (d, J=5.2 Hz, 3H), 2.58-2.65
(m, 1H), 3.02-3.12 (m, 1H), 3.71 (s, 3H), 4.41-4.72 (m, 3H), 6.11
(s, 1H), 6.76 (s, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.04 (bs, 2H), 7.27
(dd, J=8.4, 5.6 Hz, 2H), 7.45 (d, J=8.4 Hz, 1H). This NMR was
recorded at 60.degree. C.
[0494] Compound 9: LC-MS (m/z): 324.0 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 0.92 (d, J=6.0 Hz, 1H), 1.07 (d,
J=6.0 Hz, 2H), 2.57-2.73 (m, 1H), 2.82-2.90 (m, 1H), 3.72-3.73 (m,
3H), 4.22 (s, 0.4H), 4.49 (s, 0.6H), 4.70 (bs, 0.5H), 4.92 (bs,
0.5H), 6.09 (s, 0.6H), 6.31 (s, 0.4H), 6.78-6.85 (m, 2H), 7.01 (t,
J=9.0 Hz, 1H), 7.08 (t, J=8.4 Hz, 1H), 7.21-7.23 (m, 2H), 7.40 (d,
J=8.0 Hz, 0.6H), 7.57 (d, J=8.4 Hz, 0.4H). This NMR was recorded at
60.degree. C.
[0495] Compound 10: LC-MS (m/z): 324.3 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.09-1.13 (m, 3H), 2.21-2.28
(m, 0.5H), 2.90-2.94 (m, 0.5H), 3.07-3.08 (m, 1H), 3.77 (s, 3H),
4.07 (bs, 0.5H), 4.49-4.57 (m, 1.5H), 6.53-6.56 (m, 1H), 6.82-6.88
(m, 2H), 7.02-7.14 (m, 4.5H), 7.32-7.36 (m, 0.5H). This NMR was
recorded at 60.degree. C.
Procedure 6: Synthesis of Compound 11
##STR00171## ##STR00172##
[0497] To a solution of (S)-2-aminohexanoic acid (5 g, 38.14 mmol,
1 eq) in THF (140 mL) at 0.degree. C. was added 1 M LAH solution in
THF (76.28 mL, 76.28 mmol, 2 eq). Reaction mixture was warmed to
room temperature, then the mixture was stirred at 65.degree. C. for
7 h under N2 atmosphere. TLC (10% MeOH in DCM) showed the reaction
was completed. Reaction mixture was cooled to room temperature, the
reaction was diluted with diethyl ether (50 mL), after
fisher-workup, reaction mixture was filtered through sintered
funnel, using diethyl ether, the filtrate was concentrated under
reduced pressure and without further purification, the crude
(S)-2-aminohexan-1-ol was forward to next step. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 0.83-0.91 (m, 3H), 1.2-1.42 (m, 6H),
2.82-2.83 (m, 1H), 3.24-3.29 (m, 1H), 3.57-3.61 (m, 1H).
[0498] To a solution of (S)-2-aminohexan-1-ol (4.2 g, 35.83 mmol, 1
eq) in DCM (40 mL) was added TEA (10 mL, 71.67 mmol, 2 eq) at
0.degree. C. dropwise, it was stirred for 5 mins, then
di-tert-butyl dicarbonate (9.86 mL, 43.00 mmol, 1.2 eq). After
stirring at room temperature for 18 h, washed with water (75 mL)
and brine (75 mL), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo. The residue was subjected to combiflash silica gel
chromatography MeOH in DCM as an eluent to give tert-butyl
(S)-(1-hydroxyhexan-2-yl)carbamate. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 0.89 (s, 3H), 1.32-1.43 (m, 6H), 1.44 (s,
9H), 3.50-3.54 (m, 1H), 3.61-3.67 (m, 2H), 4.59 (bs, 1H).
[0499] To a solution of 1H-imidazole (5.1 g, 75.57 mmol, 4 eq) and
triethylamine (7.9 mL, 56.68 mmol, 3 eq) in anhydrous
dichloromethane (30 mL) at -78.degree. C. was added thionyl
chloride (1.5 mL, 20.78 mmol, 1.1 eq) dropwise. The reaction
mixture was stirred for 5 min while cooling -78.degree. C. and
tert-butyl (S)-(1-hydroxyhexan-2-yl)carbamate (4.1 g, 18.89 mmol, 1
eq) in anhydrous dichloromethane (30 mL) was added dropwise over 30
min. The reaction mixture was stirred at -78.degree. C. for 3
hours. The reaction mixture was stirred while warming to room
temperature overnight. Water was added (100 mL) and phase
separated. The aqueous phase was further extracted into
dichloromethane (150 mL), the combined organics were washed with
water (100 mL), dried over with anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The tert-butyl
(4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide was taken
on to the next step without further purification.
[0500] Ruthenium(III)chloride hydrate (0.002 g, 0.013 mmol, 0.007
eq), was added to a stirred solution of tert-butyl
(4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (5 g, 19
mmol, 1 eq), in acetonitrile (50 mL) and water (50 mL) at 0.degree.
C., followed by portion-wise addition of sodium periodate (4.4 g,
20.91 mmol, 1.1 eq). The biphasic mixture was stirred at 20.degree.
C. for 2 hours. Water (250 mL) was added and the mixture was
extracted into ethyl acetate (2.times.150 mL). The combined
organics were washed with water (150 mL), brine (150 mL), dried
over with Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to obtain the crude product, crude product was purified by
column chromatography using 10% ethylacetate in hexane as an eluent
to give the tert-butyl
(S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.90-1.25 (m, 3H),
1.31-1.38 (m, 6H), 1.48 (s, 9H), 1.75-1.95 (m, 2H), 4.27-4.32 (m,
2H), 4.61-4.65 (m, 1H).
[0501] To a solution of copper iodide (0.238 g, 1.25 mmol, 0.1 eq)
in diethyl ether (25 mL) was added (3-methoxyphenyl)magnesium
bromide (1M in THF) (25 mL, 25.08 mmol, 2.0 eq) dropwise over a
period of 10 min at -12.degree. C. The reaction mixture was stirred
for 30 min at -12.degree. C. After this time, a solution of
tert-butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide (3.5 g, 12.54 mmol, 1.0 eq) in diethyl ether (15 mL)
was added at -12.degree. C. dropwise to the reaction. The resulting
mixture was stirred for 4 h at -12.degree. C. Finally, the reaction
was quenched with 10% aqueous citric acid solution (15 mL) at
-12.degree. C. and diluted with ethyl acetate (100 mL). The organic
layer was separated and washed with brine (20 mL), dried over
anhydrous sodium sulfate, filtered and concentrated to give the
crude product, which was purified by flash column chromatography
using 15% ethyl acetate in n-hexane as an eluent to obtain
tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate. LC-MS
(m/z)=252.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 0.86-0.87 (m, 3H), 1.23-1.35 (m, 6H), 1.40 (s, 9H), 2.73 (bs,
2H), 3.78 (s, 3H), 4.29 (bs, 1H), 6.71-6.76 (m, 3H), 7.19 (t, J=7.8
Hz, 1H). Amide NH was not observed.
[0502] To a solution of tert-butyl
(S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (3.7 g, 12.05 mmol, 1
eq) in dichloromethane (30 mL) was added trifluoroacetic acid (2.7
g, 24.10 mmol, 2 eq) at 0.degree. C. The mixture was allowed to
stir at room temperature for 16 h. The progress of the reaction was
monitored by TLC, after completion of reaction; the reaction
mixture was concentrated under reduced pressure. The obtained
product was dissolved with ice cold water (10 mL) and basified with
saturated aqueous solution of NaHCO.sub.3. The compound was
extracted with EtOAc (100 mL). The Organic layer was washed with
brine (10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to obtain (S)-1-(3-methoxyphenyl)hexan-2-amine. LC-MS
(m/z)=208.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 0.82-0.90 (m, 3H), 1.23-1.42 (m, 4H), 1.57-1.62 (m, 2H),
2.69-2.91 (m, 2H), 3.25-3.58 (m, 1H), 3.80 (s, 3H), 6.69-6.78 (m,
3H), 7.21 (t, J=8.0 Hz, 1H). NH.sub.2 protons not observed.
[0503] To a solution of 4-fluorobenzoic acid (1.62 g, 11.59 mmol,
1.2 eq) in DCM (25 mL) was added TEA (3.9 g, 38.64 mmol, 4 eq), the
reaction stirred for 15 min and then T3P (50 wt % in EtOAc) (4.6 g,
14.49 mmol, 1.5 eq) was added at 0.degree. C. and stirred for
another 5 min. (S)-1-(3-methoxyphenyl)hexan-2-amine (2.0 g, 9.66
mmol, 1 eq) was added to the reaction mixture and then reaction
mixture was stirred at room temperature. The progress of the
reaction was monitored by TLC (20% ethyl acetate in hexane). After
16 h, the reaction mixture was diluted with DCM (50 mL) and
saturated sodium bicarbonate solution (20 mL). The organic layer
was separated, washed with brine solution (20 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain
(S)-4-fluoro-N-(1-(3-methoxyphenyl)hexan-2-yl)benzamide. LC-MS
(m/z)=330.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm 0.88-0.89 (m, 3H), 1.26-1.48 (m, 6H), 2.83-2.93 (m, 2H), 3.76
(s, 3H), 4.36-4.38 (m, 1H), 5.74 (d, J=7.6 Hz, 1H), 6.69-6.80 (m,
3H), 7.08 (t, J=8.4 Hz, 2H), 7.21 (t, J=7.6 Hz, 1H), 7.68 (t, J=6.4
Hz, 2H).
[0504] Trifluoromethanesulfonic anhydride (2.5 mL, 14.89 mmol, 2.0
eq) was added via syringe over 1 min to a stirred mixture of amide
(S)-4-fluoro-N-(1-(3-methoxyphenyl)hexan-2-yl)benzamide (2.45 g,
7.44 mmol, 1 eq) and 2-chloropyridine (1.4 mL, 14.89 mmol, 2.0 eq)
in dichloromethane (25 mL) at -78.degree. C. After 5 min, the
reaction mixture was placed in an ice-water bath and warmed to
0.degree. C. After 5 min, the resulting solution was allowed to
warm to 23.degree. C. After 1 h, aqueous sodium hydroxide solution
(5 mL, 1N) was introduced to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (50 mL) was added
to dilute the mixture and the layers were separated. The organic
layer was washed with brine (2 mL), was dried over anhydrous sodium
sulfate, and was filtered. The volatiles were removed under reduced
pressure to give the
(S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline.
LC-MS (m/z)=312.0 [M+H].sup.+.
[0505] A solution of the
(S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline
(0.8 g, 2.57 mmol, 1 eq) in anhydrous THF (5 mL) was added drop
wise to a mixture of lithium aluminum hydride 1M in THF (25.7 mL,
25.72 mmol, 10 eq) and trimethylaluminum 25% w/w in hexane (3.7 mL,
12.85 mmol, 5 eq) in THF (20 mL) at -78.degree. C. under nitrogen.
The suspension was stirred at -78.degree. C. for 1 h, and warmed to
0.degree. C. over 3 h. The reaction mixture was quenched with
saturated aqueous sodium chloride (5 mL) followed by diluted with
EtOAc (30 mL) and the precipitate was filtered off. Finally,
filtrate was dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was purified by
silica gel flash chromatography (EtOAc/n-hexane=75/25) to give the
(1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoli-
ne (trans confirmed by nOe experiment).
[0506] The isolated pure product was treated with metal scavenger
Quadrasil.RTM. TA (compound was dissolved in THF (5 mL) and
Quadrasil.RTM. TA (100 mg) was added, the mixture was stirred for
0.5 h, filtered. This was repeated one more time and concentrated).
LC-MS (m/z)=314.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 0.85 (bs, 3H), 1.26 (bs, 4H), 1.45 (bs, 2H), 2.60-2.69
(m, 1H), 2.87-2.92 (m, 2H), 3.80 (s, 3H), 5.20 (s, 1H), 6.69 (s,
2H), 6.79-6.81 (m, 1H), 6.97-7.05 (m, 2H), 7.13 (s, 2H).
[0507] To a solution of
(1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoli-
ne (0.1 g, 0.31 mmol, 1 eq) in DCM (4 mL) was added triethyl amine
(0.08 g, 0.77 mmol, 2.5 eq) at 0.degree. C., followed by
2-chloroacetyl chloride (0.054 g, 0.47 mmol, 1.5 eq). The mixture
was stirred at 0.degree. C. for 1 h under N.sub.2 atmosphere. TLC
(25% EtOAc in hexane) showed the reaction was completed. Then the
reaction was diluted with saturated aqueous solution of NaHCO.sub.3
(5 mL) and product was extracted with DCM (25 mL). The organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to obtain the crude product.
The obtained crude product was purified by preparative TLC using
25% EtOAc in n-hexane as mobile phase to give
1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(-
1H)-yl)-2-chloroethan-1-one. LC-MS (m/z)=390.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): (recorded at 70.degree. C. due to
rotameric behavior was seen with RT NMR) .delta. 0.79-0.81 (m, 3H),
1.00 (bs, 1H), 1.20 (bs, 4H), 1.40 (bs, 1H), 2.78-2.83 (m, 1H),
2.87-2.90 (m, 2H), 3.71 (s, 3H), 4.50 (bs, 2H), 6.09 (s, 1H),
6.77-6.80 (m, 2H), 7.03 (bs, 2H), 7.28 (t, J=6.6 Hz, 2H), 7.41 (d,
J=8.0 Hz, 1H).
Procedure 7: Synthesis of Compound 12
##STR00173##
[0509] To a solution of 3-(trimethylsilyl)propiolic acid (0.1 g,
0.7 mmol, 1.0 eq) in DMF (0.003 mL, 0.0038 mmol, 0.04 eq) was added
oxalyl chloride (0.066 mL, 0.77 mmol, 1.1 eq) at room temperature
and stirred for 30 minutes. After this time, reaction mixture was
concentrated under reduced pressure to provide
3-(trimethylsilyl)propioloyl chloride, which was carried to next
step without any further purification.
[0510] To a solution of
(1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoli-
ne (0.15 g, 0.47 mmol, 1.0 eq) in acetonitrile (3.5 mL) was added
sodium bicarbonate (0.3 g, 3.57 mmol, 7.5 eq) at 0.degree. C. After
stirring for 5 minutes, a solution of 3-(trimethylsilyl)propioloyl
chloride (0.113 g, 0.69 mmol, 1.5 eq) in acetonitrile (1.5 mL) was
added. The resulting mixture was stirred at 0.degree. C. for 15
min, and progress of the reaction was monitored by TLC (20% ethyl
acetate in n-hexane). After this time, the solid portion from the
reaction mass was removed by passing through a Celite pad, which
was washed with acetonitrile. The obtained filtrate was
concentrated under reduced pressure to provide
1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(-
1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one which was carried to next
step without any further purification. LC-MS (m/z)=438.2
[M+H].sup.+.
[0511] To a solution of
1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(-
1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.2 g, 0.45 mmol, 1 eq)
in THF (4.0 mL) was added tetra-butyl ammonium fluoride (1M in
solution THF) (0.5 mL, 0.5 mmol, 1.1 eq) at -78.degree. C. This
reaction mixture was stirred at -78.degree. C. for 15 minutes. The
progress of the reaction was monitored by TLC (20% ethyl acetate in
n-hexane). After this time, the reaction mixture was diluted with
water (5 mL) and the product was extracted with ethyl acetate (25
mL). Combined organic layers were dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to obtain
crude product, which was purified by preparative TLC using 20%
ethyl acetate in n-hexane as an eluent to provide
1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(-
1H)-yl)prop-2-yn-1-one. LC-MS (m/z)=366.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.81-0.88 (m, 3H), 1.20-1.24
(m, 5H), 1.50 (bs, 1H), 2.78-2.89 (s, 2H), 3.72 (s, 3H), 4.18 (s,
0.3H), 4.54 (s, 0.5H), 4.50 (bs, 0.5H), 4.70 (bs, 0.7H), 6.05 (s,
0.6H), 6.31 (s, 0.4H), 6.77-6.84 (m, 2H), 6.98-7.10 (m, 2H),
7.23-7.24 (m, 2H), 7.36 (d, J=8.0 Hz, 0.7H), 7.53 (d, J=7.6 Hz,
0.3H).
Procedure 8: Synthesis of Compound 13
##STR00174##
[0513] To a solution of (S)-1-(3-methoxyphenyl)hexan-2-amine (1.0
g, 1.27 mmol, 1 eq) and N-cyclobutyl-4-formylbenzamide (1.17 g,
5.79 mmol, 1.2 eq) in toluene (4 mL) was irradiated in microwave at
90.degree. C. for 20 min. After this time, volatile portion was
concentrated under reduced pressure and taken forward for
cyclization step in TFA (4 mL) and irradiated in microwave at
140.degree. C. for 45 min. After this time, volatile portion was
concentrated under reduced pressure and the obtained crude was
diluted with saturated aqueous solution of NaHCO.sub.3 (10 mL) and
EtOAc (40 mL). The organic layer was separated, washed with brine
(10 mL), dried over anhydrous MgSO.sub.4, filtered and concentrated
under reduced pressure to obtain the crude product. The obtained
crude product was purified by silica gel flash column
chromatography (n-hexane/EtOAc) to give
4-((1S,3S)-3-butyl-2-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydr-
oisoquinolin-1-yl)-N-cyclobutylbenzamide. LC-MS (m/z): 393.3
[M+H].sup.+.
[0514] To a solution of
4-((3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobuty-
lbenzamide (0.5 g, 1.27 mmol, 1 eq) in DCM (10 mL) was TEA (0.4 g,
3.18 mmol, 2.5 eq) followed by the addition 2-chloroacetyl chloride
(0.091 mL, 1.14 mmol, 0.9 eq) stirred at 0.degree. C. for 6 h. TLC
30% (ethylacetate in hexane) showed the reaction was completed. The
reaction mixture was concentrated under reduced pressure, and the
crude was diluted with EtOAc (50 mL), washed with water (2.times.50
mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
concentrated under reduced pressure to give crude product. The
obtained crude product was purified by Prep HPLC purification
[Analytical conditions: Column: Inertsil ODS 3V (250 mm.times.4.6
mm.times.5 .mu.m), mobile phase (A): 0.1% Ammonia in water, mobile
phase (B): CH.sub.3CN, flow rate: 1.0 mL/min, composition of B:
0/10,12/80,25/90,27/10,30/10] to obtain
4-((1S,3S)-3-butyl-2-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquin-
olin-1-yl)-N-cyclobutylbenzamide. LCMS (ES) m/z: 469.0 [M+H].sup.+,
HPLC Purity: 99.8%, Chiral HPLC Purity: 99.92%. .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. ppm 0.78-0.81 (m, 3H), 1.22-1.41 (m, 6H),
1.60-1.69 (m, 2H), 1.99-2.06 (m, 2H), 2.18-2.20 (m, 2H), 2.80-2.84
(m, 2H), 3.09-3.10 (m, 1H), 3.71 (s, 3H), 4.31-4.37 (m, 1H), 4.55
(bs, 2H), 6.13 (s, 1H), 6.77-6.81 (m, 2H), 7.32-7.34 (m, 2H), 7.43
(m, 1H), 7.66 (s, 1H).
Procedure 9: Synthesis of Compound 14
##STR00175## ##STR00176## ##STR00177##
[0516] To a solution of copper iodide (0.510 g, 2.68 mmol, 0.1 eq)
in diethyl ether (50 mL) was added (3-methoxyphenyl)magnesium
bromide (1M in THF) (53 mL, 53.76 mmol, 2 eq) drop wise over a
period of 10 min at -12.degree. C. The reaction mixture was stirred
for 30 min at -12.degree. C. After this time, a solution of
tert-butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate
2,2-dioxide (7.5 g, 26.88 mmol, 1 eq) in diethyl ether (15 mL) was
added at -12.degree. C. drop wise to the reaction mass. The
resulting mixture was stirred for 4 h at -12.degree. C. Finally,
the reaction was quenched with 10% aqueous citric acid solution (15
mL) at -12.degree. C. and diluted with ethyl acetate (100 mL). The
organic layer was separated and washed with brine (50 mL), dried
over anhydrous sodium sulfate, filtered and concentrated to give
the crude product, which was purified by flash column
chromatography using 15% ethyl acetate in n-hexane as an eluent to
obtain tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate.
LC-MS (m/z): 252.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. ppm 0.86-0.87 (m, 3H), 1.23-1.35 (m, 6H), 1.40 (s, 9H),
2.73 (bs, 2H), 3.78 (s, 3H), 4.29 (bs, 1H), 6.71-6.76 (m, 3H), 7.19
(t, J=7.8 Hz, 1H) Amide NH was not observed.
[0517] To a solution of tert-butyl
(S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (10 g, 32.57 mmol, 1
eq) in dichloromethane (50 mL) was added 4M HCl in 1,4-Dioxane (20
mL, 64.10 mmol, 2 eq) at 0.degree. C. The mixture was allowed to
stir at room temperature for 16 h. The progress of the reaction was
monitored by TLC, after completion of reaction; the reaction
mixture was concentrated under reduced pressure. The obtained crude
was dissolved with ice cold water (10 mL) and was basified by
saturated aqueous solution of NaHCO.sub.3. The compound was
extracted with EtOAc (100 mL). Organic layer was washed with brine
(10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to obtain (S)-1-(3-methoxyphenyl)hexan-2-amine. LC-MS
(m/z): 208.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. ppm 0.82-0.90 (m, 3H), 1.23-1.42 (m, 4H), 1.57-1.62 (m,
2H), 2.69-2.91 (m, 2H), 3.25-3.58 (m, 1H), 3.80 (s, 3H), 6.69-6.78
(m, 3H), 7.21 (t, J=8.0 Hz, 1H) (NH.sub.2 protons not
observed).
[0518] To a solution of (S)-1-(3-methoxyphenyl)hexan-2-amine (0.7
g, 3.37 mmol, 1 eq) and methyl 4-formylbenzoate (0.664 g, 4.05
mmol, 1 eq) in toluene (4 mL) was irradiated in microwave at
90.degree. C. for 20 min. After this time, volatile portion was
concentrated under reduced pressure and taken forward for
cyclization step as such in TFA (4 mL) and irradiated in microwave
at 140.degree. C. for 45 min. After this time, volatile portion was
concentrated under reduced pressure and obtained crude was diluted
with saturated aqueous solution of NaHCO.sub.3 (10 mL) and EtOAc
(40 mL). The organic layer was separated, washed with brine (10
mL), dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure to obtain the crude product. The obtained crude
product was purified by silica gel flash column chromatography
(n-hexane/EtOAc) to give methyl
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate.
LC-MS (m/z): 208.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. ppm 0.84-0.86 (m, 3H), 1.23-1.24 (m, 6H), 2.55-2.59 (m,
1H), 2.85-2.88 (m, 2H), 3.75 (s, 3H), 3.80 (s, 3H), 5.29 (s, 3H),
6.67-6.69 (m, 2H), 6.70-6.80 (m, 1H), 7.21-7.26 (s, 2H), 7.94-8.0
(m, 2H).
[0519] To a solution of compound methyl
4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate
(0.35 g, 1.12 mmol, 1 eq) in DCM (10 mL) was added triethylamine
(0.45 g, 4.49 mmol, 4 eq) and di-tert-butyl dicarbonate (0.715 g,
2.24 mmol, 2 eq) at room temperature and the mixture was stirred
for 16 h. TLC (50% EtOAc in hexane) showed the reaction was
completed. The reaction mixture was concentrated under reduced
pressure, and the crude was diluted with EtOAc (50 mL), washed with
water (2.times.50 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to crude
product tert-butyl
(1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate. LC-MS (m/z): 356.0 [M-Bu+H].sup.+.
[0520] To a solution of compound tert-butyl
(1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate (0.650 g, 1.57 mmol, 1 eq) in a mixture
of THF:MeOH:H.sub.2O (9 mL:1 mL) were added Lithium hydroxide
(0.331 g, 7.89 mmol, 5 eq) and allowed to stirrer at room
temperature for 16 h. TLC (50% EtOAc in hexane) showed the reaction
was completed. The reaction mixture was concentrated under reduced
pressure, and the crude was acidified with 5% citric acid solution
(pH=9). Reaction mixture was diluted with EtOAc (50 mL) and the
organic layer was separated and dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to give crude
product
4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tet-
rahydroisoquinolin-1-yl)benzoic acid. LC-MS (m/z): 396.0
[M+H].sup.+.
[0521] To a solution of compound
4-((1S,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydrois-
oquinolin-1-yl)benzoic acid (0.520 g, 1.18 mmol, 1 eq) in DCM (10
mL) was added triethylamine (0.6 mL, 4.73 mmol, 4 eq) and
2-methoxyethan-1-amine (0.106 g, 1.42 mmol, 1.2 eq) at 0.degree. C.
and the mixture was stirred for 15 min. To the above reaction
mixture T3P (50% wt in EtOAc) (1.4 mL, 1.7 mmol, 1.5 eq) was added
at the same temperature and stirred for 16 h. TLC (30% EtOAc in
hexane) showed the reaction was completed. The reaction mixture was
concentrated under reduced pressure, and the crude was diluted with
EtOAc (50 mL), washed with water (2.times.50 mL). The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, concentrated under
reduced pressure to give crude product tert-butyl
(1S,3S)-3-butyl-6-methoxy-1-(4-((2-methoxyethyl)carbamoyl)phenyl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate. LC-MS (m/z): 497.0
[M-Bu+H].sup.+.
[0522] To a solution of tert-butyl
(1S,3S)-3-butyl-6-methoxy-1-(4-((2-methoxyethyl)carbamoyl)phenyl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate (0.380 g, 0.76 mmol, 1 eq) in
dichloromethane (50 mL) was added 4M HCl in 1,4-Dioxane (10 mL,
1.52 mmol, 2 eq) at 0.degree. C. The mixture was allowed to stir at
room temperature for 16 h. The progress of the reaction was
monitored by TLC, after completion of reaction; the reaction
mixture was concentrated under reduced pressure. The obtained crude
was dissolved with ice cold water (20 mL) and was basified by
saturated aqueous solution of NaHCO.sub.3. The compound was
extracted with EtOAc (100 mL). Organic layer was washed with brine
(10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to obtain
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-met-
hoxyethyl)benzamide. LC-MS (m/z): 397.0 [M+H].sup.+.
[0523] To 3-(trimethylsilyl)propiolic acid (0.172 g, 1.20 mmol, 1
eq), DMF (0.003 g, 0.048 mmol, 0.04 eq) and oxalyl chloride (0.114
mL, 1.33 mmol, 1.1 eq) was added and stirred for 30 mins. After
this time reaction mixture was concentrated under reduced pressure
to obtain crude 3-(trimethylsilyl)propioloyl chloride and this
crude was diluted with ACN (1 mL) and added to a reaction mixture
containing a stirred solution of
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-met-
hoxyethyl)benzamide (0.320 g, 0.807 mmol, 1 eq) and NaHCO.sub.3
(0.508 g, 6.05 mmol, 7.5 eq) in ACN (5 mL) at 0.degree. C. and
stirred for 15 mins. LCMS and TLC (70% EtOAc in hexane) showed the
reaction was completed. The reaction was filtered and concentrated
under reduced pressure to give the crude product
4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4-tet-
rahydroisoquinolin-1-yl)-N-(2 methoxyethyl)benzamide which was
taken to next step without further purification. LC-MS (m/z): 521.0
[M+H].sup.+.
[0524] To
4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,-
2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-methoxyethyl)benzamide
(0.360 g, 0.69 mmol, 1 eq) in THF (10.0 mL) TBAF (1M solution in
THF) (0.48 mL, 0.48 mmol, 2 eq) was added and stirred for 30 mins.
After this time reaction mixture was concentrated under reduced
pressure, diluted with ethylacetate (100 mL) and was washed with
water (2.times.10 mL). The organic layers were dried over
Na.sub.2SO.sub.4 and concentrated to give to obtain the crude
product which was further purified by preparative TLC
chromatography using 70% EtOAc in hexane as an eluent to
4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinolin-1-
-yl)-N-(2 methoxyethyl)benzamide. LC-MS (m/z): 449.2 [M+H].sup.+;
HPLC Purity: 98.6%, Chiral HPLC Purity: 99.98%. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 0.80-0.83 (m, 3H), 0.92-1.24 (m, 5H),
1.50 (bs, 1H), 2.80-2.90 (m, 2H), 3.10 (s, 1H), 3.24 (s, 3H),
3.38-3.42 (m, 4H), 3.71-3.72 (m, 2H), 4.16-4.46 (s, 1H), 4.58-4.75
(bs, 1H), 6.07-6.34 (s, 1H), 6.77-6.84 (m, 2H), 7.29-7.31 (m, 2H),
7.38-7.58 (m, 1H), 7.64-7.73 (m, 2H), 8.13-8.19 (m, 1H).
Procedure 10: Synthesis of Compound 15
##STR00178## ##STR00179##
[0526] To a solution of (S)-1-(3-methoxyphenyl)hexan-2-amine (0.890
g, 4.29 mmol, 1 eq) and methyl 5-formylpicolinate (0.850 g, 5.15
mmol, 1.2 eq) in toluene (4 mL) was irradiated in microwave at
90.degree. C. for 20 min. After this time, volatile portion was
concentrated under reduced pressure and taken forward for
cyclization step as such in TFA (4 mL) and irradiated in microwave
at 140.degree. C. for 45 min. After this time, volatile portion was
concentrated under reduced pressure and obtained crude was diluted
with saturated aqueous solution of NaHCO.sub.3 (10 mL) and EtOAc
(40 mL). The organic layer was separated, washed with brine (10
mL), dried over anhydrous MgSO.sub.4, filtered and concentrated
under reduced pressure to obtain the crude product. The obtained
crude product was purified by silica gel flash column
chromatography (n-hexane/EtOAc) to give methyl
5-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)picolinat-
e. LC-MS (m/z): 355.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. ppm 0.83-0.87 (s, 3H), 1.23-1.25 (m, 6H),
2.58-2.62 (m, 1H), 2.81-2.91 (m, 2H), 3.80 (s, 3H), 3.99 (s, 3H),
5.31 (s, 1H), 6.69-6.71 (m, 2H), 6.67-6.80 (m, 1H), 7.54-7.55 (m,
1H), 8.01-8.03 (m, 1H), 8.67 (s, 1H).
[0527] To a solution of compound methyl
5-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)picolinat-
e (0.320 g, 0.18 mmol, 1 eq) in DCM (10 mL) was added triethylamine
(0.50 g, 3.61 mmol, 4 eq) and di-tert-butyl dicarbonate (0.394 g,
1.80 mmol, 2 eq) at room temperature and the mixture was stirred
for 16 h. TLC (50% EtOAc in hexane) showed the reaction was
completed. The reaction mixture was concentrated under reduced
pressure, and the crude was diluted with EtOAc (50 mL), washed with
water (2.times.50 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to crude
product tert-butyl
(1R,3S)-3-butyl-6-methoxy-1-(6-(methoxycarbonyl)pyridin-3-yl)-3,4-dihydro-
isoquinoline-2(1H)-carboxylate. LC-MS (m/z): 455.0
[M-Bu+H].sup.+.
[0528] To a solution of compound tert-butyl
(1R,3S)-3-butyl-6-methoxy-1-(6-(methoxycarbonyl)pyridin-3-yl)-3,4-dihydro-
isoquinoline-2(1H)-carboxylate (0.450 g, 0.99 mmol, 1 eq) in a
mixture of THF:MeOH:H.sub.2O (9 mL:1 mL) were added Lithium
hydroxide (0.208 g, 4.96 mmol, 5 eq) and allowed to stirrer at room
temperature for 16 h. TLC (50% EtOAc in hexane) showed the reaction
was completed. The reaction mixture was concentrated under reduced
pressure, and the crude was acidified with 5% citric acid solution
(pH=9). Reaction mixture was diluted with EtOAc (50 mL) and the
organic layer was separated and dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to give crude
product
5-((1R,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetr-
ahydroisoquinolin-1-yl)picolinic acid. LC-MS (m/z): 441.0
[M+H].sup.+.
[0529] To a solution of compound
5-((1R,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydrois-
oquinolin-1-yl)picolinic acid (0.300 g, 0.68 mmol, 1 eq) in DCM (10
mL) was added triethylamine (0.38 mL, 2.72 mmol, 4 eq) and
cyclobutanamine (0.058 g, 0.817 mmol, 1.2 eq) at 0.degree. C. and
the mixture was stirred for 15 min. To the above reaction mixture
T3P (50% wt in EtOAc) (0.72 mL, 0.81 mmol, 1.5 eq) was added at the
same temperature and stirred for 16 h. TLC (30% EtOAc in hexane)
showed the reaction was completed. The reaction mixture was
concentrated under reduced pressure, and the crude was diluted with
EtOAc (50 mL), washed with water (2.times.50 mL). The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, concentrated under
reduced pressure to give crude product tert-butyl
(1R,3S)-3-butyl-1-(6-(cyclobutylcarbamoyl)pyridin-3-yl)-6-methoxy-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate. LC-MS (m/z): 494.0
[M-Bu+H].sup.+.
[0530] To a solution of tert-butyl
(1R,3S)-3-butyl-1-(6-(cyclobutylcarbamoyl)pyridin-3-yl)-6-methoxy-3,4-dih-
ydroisoquinoline-2(1H)-carboxylate (0.220 g, 0.445 mmol, 1 eq) in
dichloromethane (50 mL) was added 4M HCl in 1,4-dioxane (10 mL,
0.89 mmol, 2 eq) at 0.degree. C. The mixture was allowed to stir at
room temperature for 16 h. The progress of the reaction was
monitored by TLC, after completion of reaction; the reaction
mixture was concentrated under reduced pressure. The obtained crude
was dissolved with ice cold water (20 mL) and was basified by
saturated aqueous solution of NaHCO.sub.3. The compound was
extracted with EtOAc (100 mL). Organic layer was washed with brine
(10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to obtain
5-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclob-
utylpicolinamide. LC-MS (m/z): 394.0 [M+H].sup.+.
[0531] To 3-(trimethylsilyl)propiolic acid (0.084 g, 0.59 mmol, 1
eq), DMF (0.003 g, 0.048 mmol, 0.04 eq) and oxalyl chloride (0.055
mL, 0.64 mmol, 1.1 eq) was added and stirred for 30 mins. After
this time reaction mixture was concentrated under reduced pressure
to obtain crude 3-(trimethylsilyl)propioloyl chloride which was
diluted with ACN (1 mL) and added to a reaction mixture containing
a stirred solution of
5-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclob-
utylpicolinamide (0.155 g, 0.394 mmol, 1 eq) and NaHCO.sub.3 (0.248
g, 2.95 mmol, 7.5 eq) in ACN (5 mL) at 0.degree. C. and stirred for
15 mins. LCMS and TLC (70% EtOAc in hexane) showed the reaction was
completed. The reaction was filtered and concentrated under reduced
pressure to give the crude product
5-((1R,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4-tet-
rahydroisoquinolin-1-yl)-N-cyclobutylpicolinamide which was taken
to next step without further purification. LC-MS (m/z): 518.0
[M+H].sup.+.
[0532] To
5-((1R,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,-
2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylpicolinamide (0.210
g, 0.405 mmol, 1 eq) in THF (10.0 mL) TBAF (1M solution in THF)
(0.81 mL, 0.81 mmol, 2 eq) was added and stirred for 30 mins. After
this time reaction mixture was concentrated under reduced pressure,
diluted with Ethylacetate (100 mL) and was washed with water
(2.times.10 mL). The organic layers were dried over
Na.sub.2SO.sub.4 and concentrated to give to obtain the crude
product, which was further purified by preparative TLC
chromatography using 70% EtOAc in hexane as an eluent to
5-((1R,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinolin-1-
-yl)-N-cyclobutylpicolinamide. LC-MS (m/z): 446.2 [M+H].sup.+; HPLC
Purity: 99.45%, Chiral HPLC Purity: 99.8%. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 0.79-0.83 (m, 3H), 1.20-1.24 (m, 5H), 1.46
(bs, 1H), 1.57-1.63 (m, 2H), 2.09-2.16 (m, 4H), 2.81-2.95 (m, 1H),
3.15-3.19 (m, 1H), 4.35-4.41 (m, 1H), 4.63 (s, 1H), 4.77 (bs, 1H),
6.15 (s, 0.7H), 6.47 (s, 0.39H), 6.78-6.83 (m, 2H), 7.42-7.44 (m,
1H), 7.78-7.88 (m, 3H), 8.56-8.60 (m, 1H), 8.68-8.70 (m, 1H).
Procedure 11: Synthesis of Compounds 40 and 41
##STR00180##
[0534] To a solution of 40-1 (200 mg, 1.02 mmol, 1 eq) in MeOH (8
mL) was added SOCl.sub.2 (609.43 mg, 5.12 mmol, 371.60 .mu.L, 5 eq)
in DCM (1 mL) at 40.degree. C. Then the mixture was stirred at
40.degree. C. for 3 h to give a yellow solution. TLC (quenched with
water, eluting with: PE/MeOH=20/1) showed the reaction was
completed. The mixture was concentrated under reduced pressure to
give 40-2.
[0535] To a solution of 40-2 (80 mg, 382.33 umol, 1 eq), 4A MS (700
mg, 382.33 umol, 1 eq) and methyl 4-formylbenzoate (62.76 mg,
382.33 umol, 1 eq) in DCM (15 mL) at 20.degree. C. with stirring
for 0.5 h to give a yellow solution. TLC (eluting with: PE/EA=3/1)
showed the reaction was completed. The reaction solution was
diluted with DCM (10 mL), washed with water (10 mL*3). The organic
layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under
reduced pressure to give 40-3.
[0536] To a solution of 40-3 (150 mg, 422.08 umol, 1 eq) in TFA
(4.81 g, 42.21 mmol, 3.13 mL, 100 eq) was stirred at 80.degree. C.
for 16 h to give a yellow solution. TLC (quenched with water,
eluting with: PE/EA=3/1) showed the reaction was completed. The
reaction solution was diluted with DCM (10 mL), washed with
NaHCO.sub.3 solution until pH=8. The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to
give 40-4.
[0537] To a solution of 40-4 (150 mg, 422.08 umol, 1 eq) and
Et.sub.3N (85.42 mg, 844.16 umol, 117.50 .mu.L, 2 eq) in DCM (5 mL)
was added 2-chloroacetyl chloride (71.51 mg, 633.12 umol, 50.36
.mu.L, 1.5 eq) at 0.degree. C. for 1 h to give a yellow solution.
TLC (quenched with water, eluting with: PE/EA=3/1) showed the
reaction was completed. The reaction was purified by prep-TLC to
give 40 and 41.
[0538] Compound 40: LC-MS (m/z): 432.0[M].sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 3.08-3.13 (m, 1H) 3.28 (br s, 1H)
3.59 (s, 4H) 3.77 (s, 4H) 3.85-3.90 (m, 5H) 3.93-3.99 (m, 1H) 4.07
(br s, 1H) 4.11-4.18 (m, 1H) 5.17 (br s, 1H) 5.28 (br s, 1H) 6.13
(s, 1H) 6.42 (s, 1H) 6.61-6.69 (m, 2H) 6.77-6.86 (m, 2H) 7.28-7.36
(m, 5H) 7.91 (br d, J=8.28 Hz, 1H) 7.98 (br d, J=8.03 Hz, 2H).
[0539] Compound 41: LC-MS (m/z): 432.0[M].sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 2.59-2.71 (m, 1H) 2.99 (br dd,
J=14.81, 4.52 Hz, 1H) 3.20 (br s, 1H) 3.33 (br s, 1H) 3.79 (s, 3H)
3.77-3.80 (m, 1H) 3.83 (s, 4H) 3.89 (s, 4H) 4.07-4.26 (m, 3H) 4.40
(br dd, J=12.92, 4.64 Hz, 1H) 4.68-4.77 (m, 1H) 4.73 (br s, 1H)
6.10 (s, 1H) 6.76-6.85 (m, 2H) 6.89 (br d, J=8.53 Hz, 1H) 7.00 (br
d, J=7.28 Hz, 1H) 7.35 (br d, J=8.28 Hz, 1H) 7.63 (br d, J=8.28 Hz,
2H) 7.89 (br d, J=7.53 Hz, 1H) 7.99 (br d, J=8.28 Hz, 2H).
Procedure 12: Synthesis of Compounds 42 and 43
##STR00181##
[0541] To a solution of 42-1 (150 mg, 552.83 umol, 1 eq) in MeOH (4
mL) was added SOCl.sub.2 (65.77 mg, 552.83 umol, 40.10 .mu.L, 1 eq)
in DCM (1 mL). The mixture was stirred at 30.degree. C. for 16 h to
give a colorless solution. TLC showed the reaction was completed.
The reaction mixture was distilled (40.degree. C.) to give 42-3
(HCl salt). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.25
(br s, 5H) 3.44 (br d, J=4.52 Hz, 2H) 3.75 (s, 3H) 4.40 (br s, 1H)
6.97 (br d, J=4.52 Hz, 1H) 7.28 (br s, 1H) 7.33 (br s, 1H) 8.61 (br
s, 3H)
[0542] To a solution of 42-3 (50 mg, 269.92 umol, 1 eq) and methyl
4-formylbenzoate (44.31 mg, 269.92 umol, 1 eq) in toluene (3 mL)
was added TFA (15.39 mg, 134.96 umol, 9.99 .mu.L, 0.5 eq) at
20.degree. C. The mixture was stirred at 80.degree. C. for 16 h to
give a yellow solution. TLC showed the reaction was completed. The
reaction mixture was purified by prep-TLC to give 42-4 and 42-5.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 2.96-3.05 (m, 1H)
3.10-3.18 (m, 1H) 3.73 (s, 3H) 3.83-3.88 (m, 1H) 3.86 (dd, J=7.15,
5.65 Hz, 1H) 3.91 (s, 3H) 5.44 (s, 1H) 6.85 (d, J=5.02 Hz, 1H) 7.19
(d, J=5.02 Hz, 1H) 7.40 (d, J=8.28 Hz, 2H) 8.00 (d, J=8.28 Hz,
2H).
[0543] To a solution of 42-4 (40 mg, 120.71 umol, 1 eq) and TEA
(18.32 mg, 181.06 umol, 25.20 .mu.L, 1.5 eq) in DCM (3 mL) was
added 2-chloroacetyl chloride (20.45 mg, 181.06 umol, 14.40 .mu.L,
1.5 eq) at 0.degree. C. The mixture was stirred at 30.degree. C.
for 1 h to give a yellow solution. TLC (quenched with water,
eluting with: PE/EA=0/1) showed the reaction was completed. The
reaction was purified by prep-TLC to give 42. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 3.02-3.59 (m, 2H) 3.60-3.70 (m, 3H) 3.88
(br d, J=5.52 Hz, 3H) 4.06 (br d, J=13.30 Hz, 1H) 5.03-5.27 (m, 1H)
6.27 (br s, 1H) 6.77 (d, J=5.02 Hz, 1H) 7.09-7.20 (m, 1H) 7.32-7.52
(m, 2H) 7.88-8.10 (m, 2H). LC-MS (m/z): 407.9[M].sup.+.
[0544] To a solution of 42-5 (60.00 mg, 181.06 umol, 1 eq) and TEA
(27.48 mg, 271.59 umol, 37.80 .mu.L, 1.5 eq) in DCM (3 mL) was
added 2-chloroacetyl chloride (30.67 mg, 271.59 umol, 21.60 .mu.L,
1.5 eq) at 0.degree. C. The mixture was stirred at 30.degree. C.
for 1 h to give a yellow solution. TLC (quenched with water,
eluting with: PE/EA=3/1) showed the reaction was completed. The
mixture was re-purified by prep-TLC to give 43. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 2.01 (s, 1H) 2.99-3.17 (m, 5H) 3.56
(br d, J=16.06 Hz, 1H) 3.89 (s, 4H) 4.18 (d, J=12.30 Hz, 1H) 4.30
(br s, 1H) 4.87 (br s, 1H) 6.88-7.05 (m, 2H) 7.28 (br s, 1H) 7.39
(br s, 2H) 7.94 (br s, 2H). LC-MS (m/z): 407.9[M].sup.+.
Procedure 13: Synthesis of Compounds 44 and 45
##STR00182##
[0546] To this solution of 2-methylpropane-2-sulfinamide (6.24 g,
51.49 mmol, 2 eq) in THF (120 mL) was added Ti(OEt).sub.4 (58.72 g,
257.43 mmol, 53.38 mL, 10 eq), 44-1 (5 g, 25.74 mmol, 1 eq) in THF
(100 mL). The brown solution was heated to 75.degree. C. and
monitored by TLC. After 5 hrs the reaction was allowed to cool to
25.degree. C. to give crude 44-2. The reaction was then cooled down
to -20.degree. C., NaBH.sub.4 (973.93 mg, 25.74 mmol, 1 eq) was
added and the reaction was stirred for 3 hr at -20.degree. C., then
warmed to 25.degree. C. and stirred for 12 hrs. LCMS showed the
reaction was completed. An equal volume of sat. aq. NaCl (60 mL)
was added to precipitate titanium salts. After stirring for 5 min,
the suspension was filtered through celite and the filter cake was
washed with EtOAc (100 mL.times.2). The organic layers were
separated, and the aqueous layer was extracted with EtOAc
(2.times.100 mL). The combined organic layers were dried over
anhydrous sodium sulfate, and concentrated to yield a residue. The
residue was purified by flash chromatography (silica) eluting with
ethyl acetate in petroleum ether (0% to 80%) to give 44-3. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.=6.77-6.62 (m, 3H), 3.80 (d, J=4.8
Hz, 6H), 3.64-3.49 (m, 1H), 3.18 (br d, J=4.8 Hz, 1H), 2.78-2.59
(m, 2H), 1.14-1.05 (m, 12H).
[0547] To a mixture of 44-3 (2 g, 6.68 mmol, 1 eq) in MeOH (20 mL)
was added HCl/dioxane (4 M, 20 mL, 11.98 eq) dropwise. The mixture
was stirred at 20.degree. C. for 12 h to give brown mixture. LCMS
showed the reaction was completed. The reaction mixture was diluted
with 60 mL HCl (0.1 M). The resulting mixture was extracted with
ethyl acetate (30 mL.times.2). The aqueous phase was adjust pH=8.
The aqueous phase was extracted with ethyl acetate (30 mL.times.3).
The combined organic phase dried with anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to afford 44-4. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.=6.78-6.83 (m, 1H), 6.70-6.75 (m, 2H),
3.86 (d, J=4.4 Hz, 6H), 3.07-3.21 (m, 1H), 2.78-2.59 (m, 2H), 2.67
(m, 1H), 2.44 (m, 1H), 1.64 (brs, 2H), 1.12 (d, J=6.4 Hz, 3H).
[0548] 4A molecular sieve (3 g, 2.56 mmol, 1 eq) was added to a
solution of 44-4 (500 mg, 2.56 mmol, 1 eq) and
4-morpholinobenzaldehyde (489.68 mg, 2.56 mmol, 1 eq) in toluene
(20 mL), the mixture was stirred at 120.degree. C. for 4 hr. LCMS
showed starting material was not consumed completely. The reaction
mixture was stirred at 120.degree. C. for another 4 h. LCMS showed
starting material was consumed completely. The reaction mixture was
filtered and the filter was concentrated in vacuum. The residue was
dissolved in TFA (32.58 g, 285.73 mmol, 21.16 mL, 111.58 eq) and
the solution was heated at 120.degree. C. for 20 h. LC-MS showed
starting material was consumed completely. The reaction mixture was
concentrated under reduced pressure. The mixture was adjust to pH=9
by 2N NaOH aqueous solution and extracted with EtOAc (30
mL.times.3). The combined organic layers were washed with brine (30
mL), dried over anhydroussodium sulfate, filtered and concentrated
under reduced pressure to give a residue. The residue was purified
by column chromatography (SiO.sub.2, Dichloromethane:Methanol=100:1
to 100:5) to afford N136-6 and 44-5. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.25 (d, J=6.4 Hz, 3H), 2.58-2.80 (m,
2H), 3.12-3.22 (m, 5H), 3.57-3.64 (m, 3H), 3.84-3.91 (m, 7H), 5.01
(s, 1H), 6.18-6.25 (m, 1H), 6.57-6.66 (m, 1H), 6.89 (d, J=8.8 Hz,
2H), 7.23 (d, J=8.8 Hz, 2H).
[0549] To a mixture of 44-6 (122 mg, 331.10 umol, 1 eq) and TEA
(335.04 mg, 3.31 mmol, 460.85 .mu.L, 10 eq) in DCM (6 mL) was added
2-chloroacetyl chloride (112.19 mg, 993.30 umol, 79.00 .mu.L, 3 eq)
at 0.degree. C. The mixture was stirred at 0.degree. C. for 30 min
to give a brown mixture. LCMS showed starting material was consumed
completely. The reaction mixture was concentrated in reduced
pressure to give a residue. The residue was purified by prep-TLC
and then dried by lyophilization to afford 44 and 45.
[0550] Compound 44: LC-MS (m/z): 445.0 [M+H].sup.+
[0551] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 0.99 (br s, 3H),
2.41 (br d, J=14.8 Hz, 1H), 2.80-3.28 (m, 5H), 3.60-4.57 (m, 12H),
4.83 (br s, 1H), 5.74 (br s, 1H), 6.57 (s, 1H), 6.65-6.90 (m, 3H),
7.03 (d, J=8.8 Hz, 2H)
[0552] Compound 45: LC-MS (m/z): 445.0 [M+H].sup.+
[0553] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 0.99 (br s, 3H),
2.41 (br d, J=14.8 Hz, 1H), 2.80-3.28 (m, 5H), 3.60-4.57 (m, 12H),
4.83 (br s, 1H), 5.74 (br s, 1H), 6.57 (s, 1H), 6.65-6.90 (m, 3H),
7.03 (d, J=8.8 Hz, 2H)
Procedure 14: Synthesis of Compound 46
##STR00183##
[0555] To a solution of 46-1a (5 g, 26.73 mmol, 3.38 mL, 1 eq) in
THF (150 mL) at -78.degree. C. was added n-BuLi (2.5 M, 16.04 mL,
1.5 eq) dropwise. After stirring 30 min, 46-1 (1.71 g, 29.41 mmol,
2.06 mL, 1.1 eq) was added all at once. The mixture was stirred at
-78.degree. C. for 1 hr, then warmed to 25.degree. C. and stirred
for 12 hr. TLC showed the reaction was completed. The reaction was
quenched by adding saturated NH.sub.4Cl (50 mL) aqueous solution.
The aqueous phase was extracted with ethyl acetate (3.times.50 mL)
and the combined organic layers were washed with brine (100 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (silica) eluting with ethyl acetate in petroleum
ether (0% to 30%) to give 46-2. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.=7.15 (t, J=8.0 Hz, 1H), 6.79-6.59 (m, 3H), 3.99-3.89 (m,
1H), 3.72 (s, 3H), 2.74-2.53 (m, 2H), 1.63 (br s, 1H), 1.19-1.14
(m, 1H), 1.17 (d, J=6.0 Hz, 2H).
[0556] To a solution of 46-2 (1 g, 6.02 mmol, 1 eq) and Et.sub.3N
(1.83 g, 18.05 mmol, 2.51 mL, 3 eq) in DCM (20 mL) at 0.degree. C.
was added MsCl (1.03 g, 9.02 mmol, 698.48 .mu.L, 1.5 eq). The
mixture was stirred at 25.degree. C. for 1 h. TLC showed the
reaction was completed. The reaction was poured into sat. aq.
NaHCO.sub.3 (50 mL) solution, the mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic layers were
washed with brine (50 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to give 46-3,
which was used for next step directly without further purification.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.22-7.12 (m, 1H),
6.82-6.62 (m, 3H), 4.89-4.73 (m, 1H), 3.73 (s, 3H), 2.95-2.74 (m,
2H), 2.49 (s, 3H), 1.40 (d, J=6.0 Hz, 3H).
[0557] To a solution of 46-3 (1.5 g, 6.14 mmol, 1 eq) in DMF (8 mL)
was added NaN.sub.3 (798.30 mg, 12.28 mmol, 2 eq). The mixture was
heated at 80.degree. C. for 2 h. TLC showed the reaction was
completed. 90 mL of water was added, the mixture was extracted with
120 mL of EtOAc/hexane (1:1) mixture. The extract was dried over
anhydrous Na.sub.2SO.sub.4 and evaporated to give crude 46-4, which
was used for next step directly without further purification.
[0558] To a solution of 46-4 (1.1 g, 5.75 mmol, 1 eq) in EtOAc (100
mL) was added Pd/C (500 mg, 10% purity) under N.sub.2. The
suspension was degassed under vacuum and purged with H.sub.2
several times. The mixture was stirred under H.sub.2 (15 psi) at
25.degree. C. for 1 hours. TLC showed the reaction was completed.
The reaction mixture was filtered and the filter was concentrated.
The crude product was purified by flash chromatography (silica)
eluting with MeOH in CH.sub.2Cl.sub.2 (0% to 20%) to give 46-5.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.20-7.08 (m, 1H),
6.74-6.61 (m, 3H), 3.72 (s, 3H), 3.17-3.03 (m, 1H), 2.62 (dd,
J=5.6, 13.6 Hz, 1H), 2.42 (dd, J=8.0, 13.2 Hz, 1H), 1.42 (s, 2H),
1.05 (d, J=6.4 Hz, 3H).
[0559] 4A MS (600 mg) was added to a solution of 46-5 (100 mg,
605.21 umol, 1 eq) and 4-morpholinobenzaldehyde (115.73 mg, 605.21
umol, 1 eq) in toluene (4 mL) and the mixture was stirred at
120.degree. C. for 4 hrs. The reaction mixture was filtered and the
filter was concentrated in vacuum. The residue was dissolved in TFA
(5.00 mL) and the solution was heated at 120.degree. C. for 20 hrs.
TLC showed the reaction was completed. The reaction mixture was
concentrated under reduced pressure. The mixture was basified by 2N
NaOH aqueous solution and extracted with EtOAc (30 mL.times.3). The
combined organic layers were washed with brine (30 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to give 46-6, which was used for next step directly
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.=7.19-7.13 (m, 2H), 6.80 (d, J=8.4 Hz, 2H), 6.58-6.47 (m,
3H), 4.93 (s, 1H), 3.80-3.77 (m, 4H), 3.69 (s, 3H), 3.16-3.11 (m,
1H), 3.10-3.05 (m, 4H), 2.71-2.63 (m, 2H), 1.97 (s, 1H), 1.16 (d,
J=6.0 Hz, 3H)
[0560] To a solution of 46-6 (250.00 mg, 738.68 umol, 1 eq) and
Et.sub.3N (224.24 mg, 2.22 mmol, 308.45 .mu.L, 3 eq) in DCM (5 mL)
at 0.degree. C. was added 2-chloroacetyl chloride (166.86 mg, 1.48
mmol, 117.51 .mu.L, 2 eq). The mixture was stirred at 25.degree. C.
for 1 h. LCMS showed the reaction was completed. The reaction was
poured into sat. NaHCO.sub.3 (50 mL) solution, the mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The combined
organic layers were washed with brine (50 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica) eluting
with ethyl acetate in petroleum ether (0% to 40%) to give 46.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.=7.15 (br d, J=8.8 Hz,
1H), 7.00 (d, J=8.4 Hz, 2H), 6.90-6.79 (m, 4H), 6.31 (br s, 1H),
4.53-4.35 (m, 2H), 4.28-4.18 (m, 1H), 3.79 (s, 3H), 3.76-3.70 (m,
2H), 3.76-3.70 (m, 1H), 3.76-3.70 (m, 1H), 3.12-3.08 (m, 4H),
3.01-2.93 (m, 1H), 2.49-2.37 (m, 1H), 1.14 (d, J=6.4 Hz, 3H).
Procedure 15: Synthesis of Compound 47
##STR00184##
[0562] To a solution of 47-1a (5 g, 26.73 mmol, 3.38 mL, 1 eq) in
THF (150 mL) at -78.degree. C. was added n-BuLi (2.5 M, 16.04 mL,
1.5 eq) dropwise. After stirring 30 min, 47-1 (1.71 g, 29.41 mmol,
2.06 mL, 1.1 eq) was added all at once. The mixture was stirred at
-78.degree. C. for 1 hr, then warmed to 25.degree. C. and stirred
for 12 hr. TLC showed the reaction was completed. The reaction was
quenched by adding saturated NH.sub.4Cl (50 mL) aqueous solution.
The aqueous phase was extracted with ethyl acetate (3.times.50 mL)
and the combined organic layers were washed with brine (100 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (silica) eluting with ethyl acetate in petroleum
ether (0% to 30%) to give 47-2. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.=7.15 (t, J=8.0 Hz, 1H), 6.79-6.59 (m, 3H), 3.99-3.89 (m,
1H), 3.72 (s, 3H), 2.74-2.53 (m, 2H), 1.63 (br s, 1H), 1.19-1.14
(m, 1H), 1.17 (d, J=6.0 Hz, 2H).
[0563] To a solution of 47-2 (1 g, 6.02 mmol, 1 eq) and Et.sub.3N
(1.83 g, 18.05 mmol, 2.51 mL, 3 eq) in DCM (20 mL) at 0.degree. C.
was added MsCl (1.03 g, 9.02 mmol, 698.48 .mu.L, 1.5 eq). The
mixture was stirred at 25.degree. C. for 1 h. TLC showed the
reaction was completed. The reaction was poured into sat. aq.
NaHCO.sub.3 (50 mL) solution, the mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic layers were
washed with brine (50 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to give 47-3,
which was used for next step directly without further purification.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.22-7.12 (m, 1H),
6.82-6.62 (m, 3H), 4.89-4.73 (m, 1H), 3.73 (s, 3H), 2.95-2.74 (m,
2H), 2.49 (s, 3H), 1.40 (d, J=6.0 Hz, 3H).
[0564] To a solution of 47-3 (1.5 g, 6.14 mmol, 1 eq) in DMF (8 mL)
was added NaN.sub.3 (798.30 mg, 12.28 mmol, 2 eq). The mixture was
heated at 80.degree. C. for 2 h. TLC showed the reaction was
completed. 90 mL of water was added, the mixture was extracted with
120 mL of EtOAc/hexane (1:1) mixture. The extract was dried over
anhydrous Na.sub.2SO.sub.4 and evaporated to give crude 47-4, which
was used for next step directly without further purification.
[0565] To a solution of 47-4 (1.1 g, 5.75 mmol, 1 eq) in EtOAc (100
mL) was added Pd/C (500 mg, 10% purity) under N.sub.2. The
suspension was degassed under vacuum and purged with H.sub.2
several times. The mixture was stirred under H.sub.2 (15 psi) at
25.degree. C. for 1 hours. TLC showed the reaction was completed.
The reaction mixture was filtered and the filter was concentrated.
The crude product was purified by flash chromatography (silica)
eluting with MeOH in CH.sub.2Cl.sub.2 (0% to 20%) to give 47-5.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.20-7.08 (m, 1H),
6.74-6.61 (m, 3H), 3.72 (s, 3H), 3.17-3.03 (m, 1H), 2.62 (dd,
J=5.6, 13.6 Hz, 1H), 2.42 (dd, J=8.0, 13.2 Hz, 1H), 1.42 (s, 2H),
1.05 (d, J=6.4 Hz, 3H).
[0566] 4A molecular sieve (3 g, 3.03 mmol, 1.00 eq) was added to a
solution of 47-5 (500 mg, 3.03 mmol, 1 eq) and
4-morpholinobenzaldehyde (578.66 mg, 3.03 mmol, 1 eq) in toluene
(25 mL), the mixture was stirred at 120.degree. C. for 4 hr. LCMS
showed the reaction was completed. After cooling to room
temperature, the mixture was filtered and the filtrate to
concentrated to a small volume under vacuum to give crude N135-6A,
which was used for next step directly without further
purification.
[0567] 47-6A (1 g, 2.95 mmol, 1 eq) was dissolved in TFA (46.20 g,
405.19 mmol, 30.00 mL, 137.13 eq), the solution was heated at
120.degree. C. for 20 hrs to give a brown solution. LCMS showed the
reaction was completed. The reaction mixture was concentrated under
reduced pressure. The mixture was basified by 2N NaOH aqueous
solution and extracted with EtOAc (50 mL.times.3). The combined
organic layers were washed with brine (50 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (silica) eluting
with MeOH in CH.sub.2Cl.sub.2(0% to 5%). The crude product was
purified by prep-TLC (DCM/MeOH=10/1, Rf1=0.5, Rf2=0.45) to give
cis-product as major product.
[0568] Trace trans-product was obtained by further prep-TLC
purification (95% purity) and the structure was confirmed by 2D NMR
clearly.
[0569] To a solution of 47-6B (10 mg, 29.55 umol, 1 eq) and
Et.sub.3N (8.97 mg, 88.64 umol, 12.34 .mu.L, 3 eq) in DCM (2 mL) at
0.degree. C. was added 2-chloroacetyl chloride (6.67 mg, 59.09
umol, 4.70 .mu.L, 2 eq). The mixture was stirred at 25.degree. C.
for 1 h to give brown solution. LCMS showed the reaction was
completed.
[0570] The reaction was concentrated under reduced pressure. The
residue was purified by prep-TLC (PE/EA=2/1, Rf=0.4) to give 47.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.24 (br d, J=8.0 Hz,
1H), 7.02 (d, J=8.4 Hz, 2H), 6.78-6.69 (m, 3H), 6.61 (s, 1H), 5.78
(br s, 1H), 4.84 (br s, 1H), 4.04 (br d, J=12.4 Hz, 1H), 3.81 (br
d, J=12.4 Hz, 1H), 3.77-3.73 (m, 4H), 3.72 (s, 3H), 3.06-2.99 (m,
4H), 2.96 (br s, 1H), 2.44 (br d, J=16.0 Hz, 1H), 0.97 (br d, J=5.6
Hz, 3H).
Procedure 16: Synthesis of Compound 39
##STR00185##
[0572]
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)cyclohexanecarboxamide: To a
solution of cyclohexanecarboxylic acid (0.78 g, 6.11 mmol, 1.15 eq)
in DCM (15 mL) was added TEA (2.14 g, 21.24 mmol, 4 eq), stirred
for 5 minutes, and then T3P (50 wt. % in EtOAc) (2.53 g, 7.96 mmol,
1.5 eq) was added at 0.degree. C. and stirred for another 5
minutes. (S)-1-(3-methoxyphenyl)hexan-2-amine (1.1 g, 5.31 mmol, 1
eq) was added to the reaction mixture and the reaction mixture was
stirred at room temperature for 16 hours. The progress of the
reaction was monitored by TLC (20% ethyl acetate in hexane). The
reaction mixture was diluted with DCM (50 mL) and saturated sodium
bicarbonate solution (20 mL), the organic layer was separated,
washed with brine solution (20 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to obtain
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)cyclohexanecarboxamide. LC-MS
(m/z)=318.3 [M+H].sup.+.
[0573] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.84-0.92 (m,
3H), 1.16-1.38 (m, 9H), 1.49-1.51 (m, 1H), 1.65-1.80 (m, 6H),
1.92-2.03 (m, 1H), 2.70-2.79 (m, 2H), 3.78 (s, 3H), 4.12-4.17 (m,
1H), 5.11 (d, J=8.4 Hz, 1H), 6.70-6.75 (m, 3H), 7.18 (t, J=7.8 Hz,
1H).
[0574] (S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinoline:
Trifluoromethanesulfonic anhydride (1.45 mL, 8.64 mmol, 2.0 eq) was
added via syringe over a period of 1 minute to a stirred mixture of
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)cyclohexanecarboxamide (1.37
g, 4.32 mmol, 1 eq) and 2-chloropyridine (0.81 mL, 8.64 mmol, 2.0
eq) in dichloromethane (13 mL) at -78.degree. C. After 5 minutes,
the reaction mixture was placed in an ice-water bath and warmed to
0.degree. C. After 5 minutes, the resulting solution was allowed to
warm to 23.degree. C. After 1 h, aqueous sodium hydroxide solution
(5 mL, 1N) was introduced to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (50 mL) was added
to dilute the mixture and the layers were separated. The organic
layer was washed with brine (10 mL), was dried over anhydrous
sodium sulfate, and was filtered. The volatiles were removed under
reduced pressure to give the crude product. The obtained crude
product was taken forward to next step without further
purification. LC-MS (m/z)=300.3 [M+H].sup.+.
[0575]
(1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquinoli-
ne: A solution of the
(S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinoline (1.37 g,
4.58 mmol, 1 eq) in anhydrous THF (20 mL) was added drop wise to a
mixture of lithium aluminum hydride 1M in THF (22.9 mL, 22.90 mmol,
5.0 eq) and trimethylaluminum 2M solution in toluene (11.45 mL,
22.90 mmol, 5 eq) in THF (20 mL) at -78.degree. C. under nitrogen
atmosphere. The suspension was stirred at -78.degree. C. for 1 h,
and warmed to 0.degree. C. over 30 minutes. The reaction mixture
was quenched with saturated aqueous sodium chloride (5 mL) followed
by diluted with EtOAc (30 mL) and the obtained precipitate was
filtered off. Finally, filtrate was dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography (EtOAc/n-hexane=20/80)
to give the
(1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquin-
oline (trans isomer confirmed by nOe experiment). The isolated pure
product was treated with metal scavenger QuadraSil.RTM. AP
(compound was dissolved in THF (10 mL) and QuadraSil.RTM. AP (1 g)
was added, the mixture was stirred for 0.5 h, filtered. This is
repeated one more time and concentrated). LC-MS (m/z)=302.3
[M+H].sup.+
[0576] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.90-0.93 (m,
3H), 1.02-1.04 (m, 1H), 1.17 (bs, 3H), 1.25-1.29 (m, 1H), 1.34-1.35
(s, 3H), 1.36-1.42 (m, 3H), 1.66-1.68 (m, 3H), 1.68-1.77 (m, 3H),
2.41-2.47 (m, 1H), 2.80-2.85 (m, 1H), 3.10 (bs, 1H), 3.58 (d, J=6.4
Hz, 1H), 3.76 (s, 3H), 6.60 (s, 1H), 6.66 (d, J=8.4 Hz, 1H), 6.98
(d, J=8.4 Hz, 1H).
[0577]
1-((1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(-
1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First step:--To a
solution of 3-(trimethylsilyl)propiolic acid (141 mg, 0.99 mmol,
1.5 eq) in DMF (1.9 mg, 0.026 mmol, 0.04 eq) was added oxalyl
chloride (0.13 g, 1.05 mmol, 1.6 eq) at room temperature and
stirred for 30 minutes. After this time, reaction mixture was
concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. This acid chloride was
carried to next step without any further purification.
[0578] Second step:--To a solution of
(1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline
(0.2 g, 0.66 mmol, 1.0 eq) in acetonitrile (5.0 mL) was added
sodium bicarbonate (0.42 g, 4.98 mmol, 7.5 eq) at 0.degree. C.
After stirring for 5 minutes, a solution of
3-(trimethylsilyl)propioloyl chloride in acetonitrile (2.0 mL) was
added to the above reaction mass. The resulting mixture stirred at
0.degree. C. for 15 min, progress of the reaction was monitored by
TLC (15% ethyl acetate in n-hexane). After this time, reaction mass
was diluted with EtOAc (30 mL) and water (5 mL). Organic layer was
separated, washed with brine solution (10 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. This crude product was carried to next
step without any further purification. LC-MS (m/z)=426.7
[M+H].sup.+
[0579]
1-((1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(-
1H)-yl)prop-2-yn-1-one: To a solution of
1-((1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl-
)-3-(trimethylsilyl)prop-2-yn-1-one (0.29 g, 0.68 mmol, 1.0 eq) in
THF (5.0 mL) was added TBAF (1M solution in THF) (0.75 mL, 0.75
mmol, 1.1 eq) at -78.degree. C. This reaction mixture was stirred
at -78.degree. C. for 15 minutes. Progress of the reaction was
monitored by TLC (15% ethyl acetate in n-hexane). After this time,
the reaction mixture was quenched with saturated aqueous
NaHCO.sub.3 solution (5 mL) and product was extracted with ethyl
acetate (30 mL). Organic layers were dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. The
obtained crude product was purified by preparative TLC using 15%
ethyl acetate in n-hexane as an eluent to get
1-((1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl-
)prop-2-yn-1-one. LC-MS (m/z)=354.6 [M+H].sup.+
[0580] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.54-0.68
(m, 1H), 0.76-0.77 (m, 3H), 0.82-0.99 (m, 3H), 1.08-1.14 (m, 6H),
1.38-1.66 (m, 7H), 2.74-2.78 (m, 1H), 2.96-3.08 (m, 1H), 3.72 (s,
3H), 4.16 (bs, 0.5H), 4.35-4.38 (m, 0.5H), 4.50-4.52 (m, 1H),
4.75-4.78 (m, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.84 (d, J=12.8 Hz, 1H),
7.01-7.08 (m, 1H).
Procedure 17: Synthesis of Compound 28
##STR00186## ##STR00187##
[0582] ethyl 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoate: To a
stirred solution of ethyl 4-iodobenzoate (6.0 g, 21.73 mmol, 1 eq)
and (3s,5s,7s)-adamantan-1-amine (3.93 g, 26.08 mmol, 1.2 eq) in
1,4-dioxane was added XPhos (0.51 g, 1.08 mmol, 0.05 eq) and
Cs.sub.2CO.sub.3 (14.26 g, 43.26 mmol, 2 eq) at room temperature.
The reaction mixture was purged under argon for 15 mins, then added
Pd.sub.2(dba).sub.3 (0.516 g, 0.65 mmol, 0.03 eq) to the reaction
and stirred at 110.degree. C. for 16 h. The progress of the
reaction was monitored by TLC (15% ethyl acetate in hexane). After
completion of reaction, the reaction mixture was filtered through
celite bed and the celite bed was washed with ethyl acetate (150
mL). The filtrate was concentrated under reduced pressure to obtain
crude. The obtained crude product was purified by flash
chromatography using ethyl acetate in hexane as an eluent to obtain
ethyl 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoate. LC-MS
(m/z)=300.0 [M+H].sup.+
[0583] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.34 (t, J=7.0
Hz, 3H), 1.67-1.74 (m, 6H), 1.97 (s, 6H), 2.14 (s, 3H), 4.29 (q,
J=6.9 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H).
[0584] 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoic acid: To a
solution of ethyl 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoate (1.6
g, 5.37 mmol, 1 eq) in EtOH (29 mL) and water (11 mL) was added
sodium hydroxide (0.43 g, 10.70 mmol, 2 eq) and stirrer at
80.degree. C. for 6 h. TLC (15% ethyl acetate in hexane) showed the
reaction was completed. The reaction mixture was concentrated under
reduced pressure and the obtained crude was acidified with 5%
aqueous citric acid solution (pH=4). Finally, the product was
extracted with EtOAc (75 mL) from aqueous layer, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure to get the product
4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoic acid. LC-MS (m/z)=272.0
[M+H].sup.+
[0585] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.61-1.68
(m, 6H), 1.91 (s, 6H), 2.06 (s, 3H), 5.87 (bs, 1H), 6.72 (d, J=8.8
Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 12.00 (bs, 1H).
[0586]
4-(((3R,5R,7R)-adamantan-1-yl)amino)-N--((S)-1-(3-methoxyphenyl)hex-
an-2-yl)benzamide: To a solution of
4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoic acid (1.05 g, 3.88
mmol, 1.2 eq) in DCM (20 mL) was added TEA (1.3 g, 12.92 mmol, 4
eq), stirred for 5 min and then T3P (50 wt. % in EtOAc) (1.53 g,
4.84 mmol, 1.5 eq) was added at 0.degree. C. and stirred for
another 5 mins. Then (S)-1-(3-methoxyphenyl)hexan-2-amine (0.67 g,
3.23 mmol, 1 eq) was added to the reaction mixture and then
reaction mixture was stirred at room temperature for 16 h. The
progress of the reaction was monitored by TLC (30% ethyl acetate in
hexane). The reaction mixture was diluted with DCM (50 mL) and
saturated sodium bicarbonate solution (20 mL) Organic layer was
separated, washed with brine solution (20 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. The obtained crude product was purified
by flash chromatography using ethyl acetate in hexane as an eluent
to get
4-(((3R,5R,7R)-adamantan-1-yl)amino)-N--((S)-1-(3-methoxyphenyl)hexan-2-y-
l)benzamide. LC-MS (m/z)=461.0 [M+H].sup.+
[0587] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80 (bs,
3H), 1.22 (bs, 4H), 1.45 (bs, 2H), 1.64 (s, 6H), 1.89 (s, 6H), 2.05
(s, 3H), 2.65-2.76 (m, 2H), 3.16 (d, J=4.0 Hz, 1H), 3.66 (s, 3H),
4.07 (bs, 1H), 5.49 (s, 1H), 6.68-6.75 (m, 4H), 7.11-7.12 (m, 1H),
7.50 (d, J=7.2 Hz, 2H), 7.57-7.64 (m, 1H).
[0588]
(3R,5R,7R)--N-(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl-
)phenyl)adamantan-1-amine: Trifluoromethanesulfonic anhydride
(0.547 mL, 3.26 mmol, 3.0 eq) was added via syringe over a period
of 1 min to a stirred mixture of
4-(((3R,5R,7R)-adamantan-1-yl)amino)-N--((S)-1-(3-methoxyphenyl)hexan-2-y-
l)benzamide (0.5 g, 1.08 mmol, 1 eq) and 2-chloropyridine (0.3 mL,
3.26 mmol, 3.0 eq) in dichloromethane (3.6 mL) at -78.degree. C.
After 5 min, the reaction mixture was placed in an ice-water bath
and warmed to 0.degree. C. After 5 min, the resulting solution was
allowed to warm to 23.degree. C. After 1 h, aqueous sodium
hydroxide solution (5 mL, 1N) was introduced to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (50 mL) was added
to dilute the mixture and the layers were separated. The organic
layer was washed with brine (7 mL), was dried over anhydrous sodium
sulfate, and was filtered. The volatiles were removed under reduced
pressure to give the crude product. The obtained crude product was
purified by flash chromatography using ethyl acetate in hexane as
an eluent to get the desired product
((3R,5R,7R)--N-(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phen-
yl)adamantan-1-amine. LC-MS (m/z)=443.3 [M+H].sup.+
[0589]
(3R,5R,7R)--N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoqu-
inolin-1-yl)phenyl)adamantan-1-amine: A solution of the
(3R,5R,7R)--N-(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)pheny-
l)adamantan-1-amine (0.5 g, 1.13 mmol, 1 eq) in methanol (9 mL) was
added sodium borohydride (0.128 g, 33.93 mmol, 3 eq) at 0.degree.
C. The suspension was stirred at room temperature for 16 h. After
this time, the reaction mixture was concentrated and obtained crude
was diluted with EtOAc (30 mL) and water (10 mL). Organic layer was
separated, washed with brine solution (10 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. The obtained crude product was purified
by flash chromatography using ethyl acetate in hexane as an eluent
to get
(3R,5R,7R)--N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-
-1-yl)phenyl)adamantan-1-amine. The isolated pure product was
treated with metal scavenger QuadraSil.RTM. AP (compound was
dissolved in THF (5 mL) and QuadraSil.RTM. AP (50 mg) was added,
the mixture was stirred for 0.5 h, filtered. This is repeated one
more time and concentrated). LC-MS (m/z)=445.3 [M+H].sup.+
[0590] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.84-088 (m,
3H), 1.22-1.30 (m, 4H), 1.42-1.43 (m, 2H), 1.60-1.70 (m, 6H), 1.85
(s, 6H), 2.09 (bs, 3H), 2.53-2.60 (m, 1H), 2.82-2.86 (m, 1H),
2.87-2.97 (m, 1H), 3.78 (s, 3H), 5.13 (s, 1H), 6.66-6.70 (m, 4H),
6.84-6.90 (m, 3H).
[0591]
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-
-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-on-
e: First step:--To a solution of 3-(trimethylsilyl)propiolic acid
(11.8 mg, 0.083 mmol, 1.0 eq) in DMF (0.24 mg, 0.003 mmol, 0.04 eq)
was added oxalyl chloride (11.5 mg, 0.091 mmol, 1.1 eq) at room
temperature and stirred for 30 minutes. After this time, reaction
mixture was concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. This acid chloride was
carried to next step without any further purification.
[0592] Second step:--To a solution of
(3R,5R,7R)--N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-
-1-yl)phenyl)adamantan-1-amine (37 mg, 0.083 mmol, 1.0 eq) in
acetonitrile (1.0 mL) was added sodium bicarbonate (52.5 mg, 0.62
mmol, 7.5 eq) at 0.degree. C. After stirring for 5 minutes, a
solution of 3-(trimethylsilyl)propioloyl chloride in acetonitrile
(1.0 mL) was added to the above reaction mass. The resulting
mixture stirred at 0.degree. C. for 15 min, progress of the
reaction was monitored by TLC (70% ethyl acetate in n-hexane).
After this time, reaction mass was diluted with EtOAc (30 mL) and
water (10 mL). Organic layer was separated, washed with brine
solution (10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain the crude product.
This crude product was carried to next step without any further
purification. LC-MS (m/z)=569.4 [M+H].sup.+
[0593]
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-
-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To a
solution of
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-metho-
xy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one
(48 mg, 0.084 mmol, 1.0 eq) in THF (1.5 mL) was added TBAF (1M
solution in THF) (0.092 mL, 0.092 mmol, 1.1 eq) at -78.degree. C.
This reaction mixture was stirred at -78.degree. C. for 15 minutes.
Progress of the reaction was monitored by TLC (25% ethyl acetate in
n-hexane). After this time, the reaction mixture was quenched with
saturated aqueous NaHCO.sub.3 solution (5 mL) and product was
extracted with ethyl acetate (25 mL). Organic layers were dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The obtained crude product was purified by
preparative TLC using 25% ethyl acetate in n-hexane as an eluent to
get
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-metho-
xy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LC-MS
(m/z)=497.3 ([M+H].sup.+
[0594] .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.79-0.80 (m,
3H), 1.18-1.24 (m, 6H), 1.51 (bs, 1H), 1.61 (s, 5H), 1.79 (s, 6H),
2.01 (s, 3H), 2.71-2.83 (m, 1H), 3.00-3.09 (m, 2H), 3.72-3.73 (m,
3H), 4.15 (bs, 0.3H), 4.40 (bs, 1H), 4.61 (bs, 0.7H), 5.95 (s,
0.5H), 6.16 (s, 0.5H), 6.59-6.66 (m, 2H), 6.76-6.85 (m, 4H), 7.29
(d, J=8.4 Hz, 0.5H), 7.40 (d, J=7.6 Hz, 0.5H).
Procedure 18: Synthesis of Compound 55
##STR00188## ##STR00189## ##STR00190##
[0596] tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate: To
a solution of copper iodide (0.510 g, 2.68 mmol, 0.1 eq) in diethyl
ether (50 mL) was added (3-methoxyphenyl)magnesium bromide (1M in
THF) (53 mL, 53.76 mmol, 2 eq) drop wise over a period of 10 min at
-12.degree. C. The reaction mixture was stirred for 30 min at
-12.degree. C. After this time, a solution of tert-butyl
(S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (7.5 g,
26.88 mmol, 1 eq) in diethyl ether (15 mL) was added at -12.degree.
C. drop wise to the reaction mass. The resulting mixture was
stirred for 4 h at -12.degree. C. Finally, the reaction was
quenched with 10% aqueous citric acid solution (15 mL) at
-12.degree. C. and diluted with ethyl acetate (100 mL). The organic
layer was separated and washed with brine (50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated to give the
crude product, which was purified by flash column chromatography
using 15% ethyl acetate in n-hexane as an eluent to obtain
tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate. LC-MS
(m/z): 252.0 [M+H].sup.+
[0597] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 0.86-0.87 (m,
3H), 1.23-1.35 (m, 6H), 1.40 (s, 9H), 2.73 (bs, 2H), 3.78 (s, 3H),
4.29 (bs, 1H), 6.71-6.76 (m, 3H), 7.19 (t, J=7.8 Hz, 1H) Amide NH
was not observed.
[0598] (S)-1-(3-methoxyphenyl)hexan-2-amine: To a solution of
tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (10 g,
32.57 mmol, 1 eq) in dichloromethane (50 mL) was added 4M HCl in
1,4-Dioxane (20 mL, 64.10 mmol, 2 eq) at 0.degree. C. The mixture
was allowed to stir at room temperature for 16 h. The progress of
the reaction was monitored by TLC, after completion of reaction;
the reaction mixture was concentrated under reduced pressure. The
obtained crude was dissolved with ice cold water (10 mL) and was
basified by saturated aqueous solution of NaHCO.sub.3. The compound
was extracted with EtOAc (100 mL). Organic layer was washed with
brine (10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to obtain (S)-1-(3-methoxyphenyl)hexan-2-amine. LC-MS
(m/z): 208.1 [M+H].sup.+.
[0599] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 0.82-0.90 (m,
3H), 1.23-1.42 (m, 4H), 1.57-1.62 (m, 2H), 2.69-2.91 (m, 2H),
3.25-3.58 (m, 1H), 3.80 (s, 3H), 6.69-6.78 (m, 3H), 7.21 (t, J=8.0
Hz, 1H) NH.sub.2 protons was not observed.
[0600] methyl
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate:
To a solution of (S)-1-(3-methoxyphenyl)hexan-2-amine (0.7 g, 3.37
mmol, 1 eq) and methyl 4-formylbenzoate (0.664 g, 4.05 mmol, 1 eq)
in toluene (4 mL) was irradiated in microwave at 90.degree. C. for
20 min. After this time, volatile portion was concentrated under
reduced pressure and taken forward for cyclization step as such in
TFA (4 mL) and irradiated in microwave at 140.degree. C. for 45
min. After this time, volatile portion was concentrated under
reduced pressure and obtained crude was diluted with saturated
aqueous solution of NaHCO.sub.3 (10 mL) and EtOAc (40 mL). The
organic layer was separated, washed with brine (10 mL), dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure
to obtain the crude product. The obtained crude product was
purified by silica gel flash column chromatography (n-hexane/EtOAc)
to give methyl
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate.
LC-MS (m/z): 208.1 [M+H].sup.+.
[0601] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 0.84-0.86 (m,
3H), 1.23-1.24 (m, 6H), 2.55-2.59 (m, 1H), 2.85-2.88 (m, 2H), 3.75
(s, 3H), 3.80 (s, 3H), 5.29 (s, 3H), 6.67-6.69 (m, 2H), 6.70-6.80
(m, 1H), 7.21-7.26 (s, 2H), 7.94-8.0 (m, 2H).
[0602]
tert-butyl-(1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-
-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a solution of
compound methyl
4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)b-
enzoate (0.35 g, 1.12 mmol, 1 eq) in DCM (10 mL) was added
triethylamine (0.45 g, 4.49 mmol, 4 eq) and di-tert-butyl
dicarbonate (0.715 g, 2.24 mmol, 2 eq) at room temperature and the
mixture was stirred for 16 h. TLC (50% EtOAc in hexane) showed the
reaction was completed. The reaction mixture was concentrated under
reduced pressure, and the crude was diluted with EtOAc (50 mL),
washed with water (2.times.50 mL). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to
crude product tert-butyl
(1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate. LC-MS (m/z): 356.0 [M-Bu+H].sup.+.
[0603]
4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetra-
hydroisoquinolin-1-yl)benzoic acid: To a solution of compound
tert-butyl
(1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoqu-
inoline-2(1H)-carboxylate (0.650 g, 1.57 mmol, 1 eq) in a mixture
of THF:MeOH:H.sub.2O (9 mL:1 mL) were added lithium hydroxide
(0.331 g, 7.89 mmol, 5 eq) and allowed to stirrer at room
temperature for 16 h. TLC (50% EtOAc in hexane) showed the reaction
was completed. The reaction mixture was concentrated under reduced
pressure, and the crude was acidified with 5% citric acid solution
(pH=9). Reaction mixture was diluted with EtOAc (50 mL) and the
organic layer was separated and dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to give crude
product
4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tet-
rahydroisoquinolin-1-yl)benzoic acid. LC-MS (m/z): 396.0 [M+H].
[0604] tert-butyl
(1S,3S)-3-butyl-1-(4-(((E)-1-(hydroxyimino)ethyl)carbamoyl)phenyl)-6-meth-
oxy-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a solution of
4-((1S,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydrois-
oquinolin-1-yl)benzoic acid (0.2 g, 0.45 mmol, 1 eq) in DMF (10 mL)
was added DIPEA (0.15 mL, 0.91 mmol, 2 eq) and HATU (0.207 g, 5.46
mmol, 1.2 eq) at room temperature, stirred for 15 mins and then
(E)-N'-hydroxyacetimidamide (0.043 g, 0.591 mmol, 1.3 eq) was added
and the reaction mixture was stirred at room temperature for 3 h.
The progress of the reaction was monitored by TLC (30% EtOAc in
hexane). After the completion of the reaction, the reaction mixture
was poured to crushed ice and then extracted with EtOAc (2.times.50
mL). Combined organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to obtain
tert-butyl
(1S,3S)-3-butyl-1-(4-(((E)-1-(hydroxyimino)ethyl)carbamoyl)phenyl)-6-meth-
oxy-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m/z)=496.0
[M+H].sup.+.
[0605]
tert-butyl(1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol--
5-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a
solution of tert-butyl
(1S,3S)-3-butyl-1-(4-(((E)-1-(hydroxyimino)ethyl)carbamoyl)phenyl)-6-meth-
oxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.3 g, 0.606 mmol, 1
eq) in ACN (10 mL) was added 4 A MS (0.1 g) and the reaction
mixture was stirred at 120.degree. C. for 3 h in a sealed tube. The
progress of the reaction was monitored by TLC (50% EtOAc in
hexane). After the completion of the reaction, the reaction mixture
was filtered through sintered funnel and the filtrate obtained was
concentrated under reduced pressure to obtain the crude. It was
purified by silica gel column chromatography using 25-30% EtOAc in
hexane as an eluent to afford tert-butyl
(1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-
-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m/z)=478.0
[M+H].sup.+.
[0606]
5-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-
phenyl)-3-methyl-1,2,4-oxadiazole: To a solution of tert-butyl
(1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-
-dihydroisoquinoline-2(1H)-carboxylate (0.185 g, 0.387 mmol, 1 eq)
in dichloromethane (20 mL) was added 4 M HCl in 1,4-Dioxane (10 mL,
1.52 mmol, 2 eq) at 0.degree. C. The mixture was allowed to stir at
room temperature for 16 h. The progress of the reaction was
monitored by TLC, after completion of reaction; the reaction
mixture was concentrated under reduced pressure. The obtained crude
was dissolved with ice cold water (20 mL) and was basified by
saturated aqueous solution of NaHCO.sub.3. The compound was
extracted with EtOAc (100 mL). Organic layer was washed with brine
(10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to obtain
5-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl-
)-3-methyl-1,2,4-oxadiazole. LC-MS (m/z): 378.0 [M+H].sup.+.
[0607]
1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)ph-
enyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one:
To 3-(trimethylsilyl)propiolic acid (0.090 g, 0.260 mmol, 1 eq),
DMF (0.0008 g, 0.010 mmol, 0.04 eq) and oxalyl chloride (0.05 mL,
0.969 mmol, 1.1 eq) was added and stirred for 30 mins. After this
time reaction mixture was concentrated under reduced pressure to
obtain crude 3-(trimethylsilyl)propioloyl chloride and this crude
was diluted with ACN (1 mL) and added to a reaction mixture
containing a stirred solution of
5-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl-
)-3-methyl-1,2,4-oxadiazole (0.160 g, 0.424 mmol, 1 eq) and
NaHCO.sub.3 (0.267 g, 3.181 mmol, 7.5 eq) in ACN (5 mL) at
0.degree. C. and stirred for 15 mins. LCMS and TLC (30% EtOAc in
hexane) showed the reaction was completed. The reaction was
filtered and concentrated under reduced pressure to give the crude
product
1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)--
3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one
which was taken to next step without further purification. LC-MS
(m/z): 502.0 [M+H].sup.+.
[0608]
1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)ph-
enyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To
1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)--
3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one
(0.100 g, 0.199 mmol, 1 eq) in THF (10.0 mL) TBAF (1M solution in
THF) (0.104 mL, 0.399 mmol, 2 eq) was added and stirred for 30
mins. After this time reaction mixture was concentrated under
reduced pressure, diluted with Ethylacetate (100 mL) and was washed
with water (2.times.10 mL). The organic layers were dried over
Na.sub.2SO.sub.4 and concentrated to give to obtain the crude
product, which was further purified by preparative TLC
chromatography using 20% EtOAc in hexane as an eluent to
1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)--
3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LC-MS (m/z): 430.1
[M+H].sup.+.
[0609] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.80-0.81 (m,
3H), 0.83-1.49 (m, 6H), 2.31 (s, 3H), 2.81-2.92 (m, 1H), 2.93-3.13
(m, 1H), 3.71 (s, 3H), 4.35 (s, 0.5H), 4.59 (s, 0.5H), 4.65-4.77
(bs, 1H), 6.13 (s, 0.7H), 6.41 (s, 0.5H), 6.78-6.86 (m, 2H),
7.49-7.53 (m, 2H), 7.68-7.70 (m, 1H), 7.92-8.00 (m, 2H).
Procedure 19: Synthesis of Compound 38
##STR00191## ##STR00192##
[0611]
tert-butyl(1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)carbamoyl)phenyl-
)-3-butyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a
solution of
4-((1S,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydrois-
oquinolin-1-yl)benzoic acid (0.2 g, 0.45 mmol, 1 eq) in DCM (10 mL)
was added TEA (0.2 mL, 1.36 mmol, 3 eq),
(3s,5s,7s)-adamantan-1-amine (0.068 g, 0.45 mmol, 1 eq) and HOBt
(0.092 g, 0.682 mmol, 1.5 eq) at room temperature, stirred for 15
mins and then EDC.HCl (0.13 g, 0.682 mmol, 1.5 eq) was added and
the reaction mixture was stirred at room temperature for 16 h. The
progress of the reaction was monitored by TLC (30% EtOAc in
hexane). After the completion of the reaction, the reaction mixture
was diluted with water and then extracted with DCM (2.times.50
mL).
[0612] Combined organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to obtain
tert-butyl(1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)carbamoyl)phenyl)-3-bu-
tyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS
(m/z): 517.3 [M+H].sup.+.
[0613] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 0.81 (s,
3H), 0.98-1.40 (m, 15H), 1.62 (s, 6H), 2.00 (s, 9H), 2.75 (s, 1H),
3.03 (s, 1H), 3.68 (s, 3H), 4.30-4.44 (m, 1H), 5.87 (s, 1H), 6.73
(s, 2H), 7.28 (s, 2H), 7.41 (s, 2H), 7.59 (s, 2H).
[0614]
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4--
tetrahydroisoquinolin-1-yl)benzamide: To a solution of
tert-butyl(1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)carbamoyl)phenyl)-3-bu-
tyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.23 g,
0.401 mmol, 1 eq) in dichloromethane (10 mL) was added 4M HCl in
1,4-dioxane (7 mL) at 0.degree. C. The mixture was allowed to stir
at room temperature for 3 h. The progress of the reaction was
monitored by TLC, after completion of reaction; the reaction
mixture was concentrated under reduced pressure. The obtained crude
was dissolved with ice cold water (10 mL) and was basified by
saturated aqueous solution of NaHCO.sub.3. The compound was
extracted with EtOAc (30 mL). Organic layer was washed with brine
(10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated to obtain
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrah-
ydroisoquinolin-1-yl)benzamide. LC-MS (m/z): 473.7 [M+H].sup.+.
[0615]
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-(3-(tr-
imethylsilyl)propioloyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide:
To 3-(trimethylsilyl)propiolic acid (0.085 g, 0.59 mmol, 1 eq), DMF
(0.001 mL, 0.023 mmol, 0.04 eq) and oxalyl chloride (0.061 mL,
0.717 mmol, 1.2 eq) was added and stirred for 30 mins. After this
time reaction mixture was concentrated under reduced pressure to
obtain crude 3-(trimethylsilyl)propioloyl chloride, which was
diluted with ACN (1 mL) and added to a reaction mixture containing
a stirred solution of
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrah-
ydroisoquinolin-1-yl)benzamide (0.19 g, 0.401 mmol, 1 eq) and
NaHCO.sub.3 (0.253 g, 3.01 mmol, 7.5 eq) in ACN (5 mL) at 0.degree.
C. and stirred for 15 mins. LCMS and TLC (40% EtOAc in hexane)
showed the reaction was completed. The reaction was filtered and
concentrated under reduced pressure to give the crude product
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethy-
lsilyl)propioloyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide
which was taken to next step without further purification. LC-MS
(m/z): 597.3 [M+H].sup.+.
[0616]
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-propio-
loyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide: To
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethy-
lsilyl)propioloyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide
(0.17 g, 0.284 mmol, 1 eq) in THF (10.0 mL) TBAF (1M solution in
THF) (0.081 mL, 0.313 mmol, 1.1 eq) was added and stirred for 15
mins. After this time reaction mixture was concentrated under
reduced pressure, diluted with Ethylacetate (30 mL) and was washed
with water (2.times.10 mL). The organic layers were dried over
Na.sub.2SO.sub.4 and concentrated to give to obtain the crude
product, which was further purified by flash column chromatography
using 20% EtOAc in hexane as an eluent to get
N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1-
,2,3,4-tetrahydroisoquinolin-1-yl)benzamide. LC-MS (m/z): 525.8
[M+H].sup.+.
[0617] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.81 (t, J=6.0
Hz, 3H), 1.22 (s, 6H), 1.48-1.61 (m, 7H), 2.00 (s, 8H), 2.85-2.89
(m, 1H), 3.10-3.13 (m, 1H), 3.69 (d, J=6.0 Hz, 3H), 4.29 (s, 1H),
4.59 (bs, 1H), 6.06 (s, 1H), 6.76-6.84 (m, 2H), 7.25-7.29 (m, 2H),
7.41-7.47 (m, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz,
1H).
Procedure 20: Synthesis of Compound 48
##STR00193##
[0619]
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)-2-methylisonicotinamide: To
a solution of 2-methylisonicotinic acid (0.654 g, 4.77 mmol, 1.1
eq) in DCM (15 mL) was added TEA (2.5 mL, 17.36 mmol, 4 eq),
stirred for 15 min and then T3P (50 wt. % in EtOAc) (4.2 mL, 6.51
mmol, 1.5 eq) was added at 0.degree. C. and stirred for another 5
mins. Then (S)-1-(3-methoxyphenyl)hexan-2-amine (0.900 g, 4.34
mmol, 1 eq) was added to the reaction mixture and then reaction
mixture was stirred at room temperature for 16 h. The progress of
the reaction was monitored by TLC (40% ethyl acetate in hexane).
The reaction mixture was diluted with DCM (30 mL) and saturated
sodium bicarbonate solution (15 mL) Organic layer was separated,
washed with brine solution (12 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to obtain
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)-2-methylisonicotinamide.
LCMS (ES) (m/z)=327.3 [M+H].sup.+
[0620] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.87-0.89 (m,
3H), 1.36-1.46 (m, 4H), 1.60-1.69 (m, 2H), 2.59 (s, 3H), 2.81-2.93
(m, 2H), 3.76 (s, 3H), 4.36-4.37 (m, 1H), 5.83 (d, J=7.2 Hz, 1H),
6.74-6.78 (m, 3H), 7.21 (t, J=7.6 Hz, 2H), 7.37 (s, 1H), 8.57 (d,
J=4.8 Hz, 1H).
[0621]
(S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinol-
ine: Trifluoromethanesulfonic anhydride (1.28 mL, 7.65 mmol, 2 eq)
was added via syringe over a period of 1 min to a stirred mixture
of (S)--N-(1-(3-methoxyphenyl)hexan-2-yl)-2-methylisonicotinamide
(1.25 g, 3.82 mmol, 1 eq) and 2-chloropyridine (0.72 mL, 7.65 mmol,
2 eq) in dichloromethane (10 mL) at -78.degree. C. After 5 min, the
reaction mixture was placed in an ice-water bath and warmed to
0.degree. C. After 5 min, the resulting solution was allowed to
warm to 23.degree. C. TLC (5% MeOH in DCM) showed the reaction was
completed. After 1 h, aqueous sodium hydroxide solution (12 mL, 1N)
was introduced to neutralize the trifluoromethanesulfonate salts.
Dichloromethane (70 mL) was added to dilute the mixture and the
layers were separated. The organic layer was washed with brine (10
mL), was dried over anhydrous sodium sulfate, and was filtered. The
volatiles were removed under reduced pressure to give the crude
product. The obtained crude product was purified by flash
chromatography using ethyl acetate in hexane as an eluent to get
the desired product
(S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinoline.
LCMS (ES) m/z=309.4 [M+H].sup.+
[0622]
(1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahyd-
roisoquinoline: A solution of the
(S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinoline
(0.54 g, 1.78 mmol, 1 eq) in anhydrous THF (4 mL) was added drop
wise to a mixture of lithium aluminum hydride 1M in THF (17.8 mL,
17.8 mmol, 10 eq) and trimethylaluminum (2M in THF) (4.46 mL, 12.85
mmol, 5 eq) at -78.degree. C. under nitrogen. The suspension was
stirred at -78.degree. C. for 1 h, and warmed to 0.degree. C. over
1 h. TLC (5% MeOH in DCM) showed the reaction was completed. The
reaction mixture was quenched with saturated aqueous sodium
chloride (8 mL) followed by diluted with EtOAc (30 mL) and the
precipitate was filtered off. Finally, filtrate was dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified by silica gel flash
chromatography using ethyl acetate in hexane as an eluent to give
the
(1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoq-
uinoline. LCMS (ES) m/z=311.3 [M+H].sup.+
[0623]
1-((1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydrois-
oquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First
step:--To a solution of 3-(trimethylsilyl)propiolic acid (206 mg,
1.44 mmol, 3 eq) in DMF (0.014 mL, 0.05 mmol, 0.04 eq) was added
oxalyl chloride (0.13 mL, 1.59 mmol, 1.1 eq) at room temperature
and stirred for 30 minutes. After this time, reaction mixture was
concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. This acid chloride was
carried to next step without any further purification.
[0624] Second step:--To a solution of
(1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoq-
uinoline (0.15 g, 0.48 mmol, 1.0 eq) in acetonitrile (5.0 mL) was
added sodium bicarbonate (0.30 g, 3.62 mmol, 7.5 eq) at 0.degree.
C. After stirring for 5 minutes, a solution of
3-(trimethylsilyl)propioloyl chloride in acetonitrile (3.0 mL) was
added to the above reaction mass. The resulting mixture stirred at
0.degree. C. for 15 min, progress of the reaction was monitored by
TLC (55% ethyl acetate in n-hexane). After this time, reaction mass
was diluted with EtOAc (15 mL) and water (5 mL). Organic layer was
separated, washed with brine solution (5 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. This crude product was carried to next
step without any further purification. LCMS (ES) m/z=435.3
[M+H].sup.+
[0625]
1-((1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydrois-
oquinolin-2(1H)-yl)prop-2-yn-1-one: To a solution of
1-((1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquino-
lin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.25 g, 0.576
mmol, 1 eq) in THF (5.0 mL) was added TBAF (1M solution in THF)
(0.63 mL, 0.63 mmol, 1.1 eq) at -78.degree. C. This reaction
mixture was stirred at -78.degree. C. for 15 minutes. Progress of
the reaction was monitored by TLC (60% ethyl acetate in n-hexane).
After this time, the reaction mixture was quenched with saturated
aqueous NaHCO.sub.3 solution (8 mL) and product was extracted with
ethyl acetate (25 mL). Organic layers were dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The obtained crude product was purified by preparative TLC using
55% ethyl acetate in n-hexane as an eluent to obtain
1-((1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquino-
lin-2(1H)-yl)prop-2-yn-1-one. LCMS (ES) m/z=363.4 [M+H].sup.+.
[0626] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm .delta. 0.80 (d,
3H), 1.24 (s, 4H), 1.50 (s, 2H), 2.38 (s, 3H), 2.80-2.88 (m, 1H),
3.12-3.15 (m, 1H), 3.72 (s, 3H), 4.38 (s, 1H), 4.57-4.74 (m, 1H),
5.97 (s, 1H), 6.78 (s, 2H), 6.99-7.07 (m, 2H), 7.40-7.55 (m, 1H),
8.23-8.29 (m, 1H).
Procedure 21: Synthesis of Compound 49
##STR00194##
[0628] (S)--N-(1-(3-methoxyphenyl)hexan-2-yl)picolinamide: To a
solution of picolinic acid (0.68 g, 5.54 mmol, 1.15 eq) in DCM (15
mL) was added TEA (2.7 mL, 19.29 mmol, 4 eq), stirred for 15 min
and then T3P (50 wt. % in EtOAc) (4.6 mL, 7.23 mmol, 1.5 eq) was
added at 0.degree. C. and stirred for another 5 mins. Then
(S)-1-(3-methoxyphenyl)hexan-2-amine (1.0 g, 4.82 mmol, 1 eq) was
added to the reaction mixture and then reaction mixture was stirred
at room temperature for 16 h. The progress of the reaction was
monitored by TLC (40% ethyl acetate in hexane). The reaction
mixture was diluted with DCM (30 mL) and saturated sodium
bicarbonate solution (15 mL) Organic layer was separated, washed
with brine solution (12 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)picolinamide. LC-MS
(m/z)=313.4 [M+H].sup.+
[0629] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.84 (t, J=6.8
Hz, 3H), 1.23-1.60 (m, 6H), 2.81-2.94 (m, 2H), 3.74 (s, 3H),
4.35-4.36 (m, 1H), 6.73-6.82 (m, 3H), 7.17 (t, J=8.0 Hz, 1H), 7.39
(t, J=6.0 Hz, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H),
8.17 (d, J=7.6 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H).
[0630]
(S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoline:
Trifluoromethanesulfonic anhydride (1.55 mL, 9.28 mmol, 2.0 eq) was
added via syringe over a period of 1 min to a stirred mixture of
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)picolinamide (1.4 g, 4.64
mmol, 1 eq) and 2-chloropyridine (0.87 mL, 9.28 mmol, 2.0 eq) in
dichloromethane (15 mL) at -78.degree. C. After 5 min, the reaction
mixture was placed in an ice-water bath and warmed to 0.degree. C.
After 5 min, the resulting solution was allowed to warm to
23.degree. C. TLC (40% ethyl acetate in n-hexane) showed the
reaction was completed. After 1 h, aqueous sodium hydroxide
solution (12 mL, 1N) was introduced to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (50 mL) was added
to dilute the mixture and the layers were separated. The organic
layer was washed with brine (10 mL), was dried over anhydrous
sodium sulfate, and was filtered. The volatiles were removed under
reduced pressure to give the crude product. The obtained crude
product was purified by flash chromatography using ethyl acetate in
hexane as an eluent to get the desired product
(S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoline.
LC-MS (m/z)=295.1 [M+H].sup.+
[0631] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.93 (t, J=7.2
Hz, 3H), 1.26-1.43 (m, 4H), 1.65-1.88 (m, 2H), 2.58-2.65 (m, 1H),
2.79-2.87 (m, 1H), 3.58 (bs, 1H), 3.83 (s, 3H), 6.73-6.75 (m, 2H),
7.32-7.37 (m, 2H), 7.77-7.83 (m, 2H), 8.64-8.70 (m, 1H).
[0632]
(1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-1,2,3,4-tetrahydroisoqui-
noline: A solution of the
(S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoline (0.1
g, 0.34 mmol, 1 eq) in anhydrous THF (4 mL) was added drop wise to
a mixture of lithium aluminum hydride 1M in THF (3.4 mL, 3.40 mmol,
10 eq) and trimethylaluminum (2M in toluene) (0.85 mL, 1.70 mmol, 5
eq) at -78.degree. C. under nitrogen. The suspension was stirred at
-78.degree. C. for 1 h, and warmed to 0.degree. C. over 1 h. TLC
(5% MeOH in DCM) showed the reaction was completed. The reaction
mixture was quenched with saturated aqueous sodium chloride (4 mL)
followed by diluted with EtOAc (15 mL) and the precipitate was
filtered off. Finally, filtrate was dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by silica gel flash chromatography using ethyl
acetate in hexane as an eluent to give the
(1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-
. LC-MS (m/z)=311.3 [M+H].sup.+
[0633]
1-((1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoli-
n-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First step:--To a
solution of 3-(trimethylsilyl)propiolic acid (0.10 g, 0.709 mmol,
3.0 eq.) in DMF (0.0007 mL 0.009 mmol, 0.04 equiv.), oxalyl
chloride (0.02 mL, 0.26 mmol, 1.1 eq.) was added at room
temperature and reaction was stirred for 30 minutes. After this
time, the reaction mixture was concentrated under reduced pressure
to yield 3-trimethylsilyl)propioloyl chloride. This acid chloride
was carried to next step without further purification.
[0634] Second step:--To a solution of
(1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoq-
uinoline (0.07 g, 0.236 mmol, 1.0 eq.) in acetonitrile (3.0 mL) was
added sodium bicarbonate (0.149 g, 1.77 mmol, 7.5 eq.) at 0.degree.
C. After stirring for 5 minutes, a solution of
3-(trimethylsilyl)propioloyl chloride in acetonitrile (2.0 mL) was
added to the above reaction mass. The resulting mixture stirred at
0.degree. C. for 15 min, progress of the reaction was monitored by
TLC (60% ethyl acetate in n-hexane). After this time, reaction mass
was diluted with EtOAc (15 mL) and water (5 mL). Organic layer was
separated, washed with brine solution (5 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. This crude product was carried to next
step without any further purification. LC-MS (m/z)=421.3
[M+H].sup.+
[0635]
1-((1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoli-
n-2(1H)-yl)prop-2-yn-1-one: To a solution of
1-((1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H-
)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.07 g, 0.166 mmol, 1.0
equiv.) in THF (4.0 mL) was added TBAF (1M solution in THF) (0.183
mL, 0.183 mmol, 1.1 equiv.) at -78.degree. C. This reaction mixture
was stirred at -78.degree. C. for 15 minutes. Progress of the
reaction was monitored by TLC (50% ethyl acetate in n-hexane).
After this time, the reaction mixture was quenched with saturated
aqueous NaHCO.sub.3 solution (2 mL) and product was extracted with
ethyl acetate (25 mL). Organic layers were dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The obtained crude product was purified by preparative TLC using
50% ethyl acetate in n-hexane as an eluent to get
1-((1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H-
)-yl)prop-2-yn-1-one. LC-MS (m/z)=349.4 [M+H].sup.+
[0636] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.80 (t, J=6.8
Hz, 3H), 1.20-1.44 (m, 6H), 2.71-2.83 (m, 1H), 3.03 (s, 1H),
3.43-3.47 (m, 1H), 3.67-3.69 (m, 3H), 4.56-4.70 (m, 2H), 6.01-6.28
(m, 2H), 6.72-6.79 (m, 1H), 7.09-7.18 (m, 1H), 7.35-7.44 (m, 1H),
7.56-7.69 (m, 1H), 8.32-8.42 (m, 1H).
Procedure 22: Synthesis of Compound 50
##STR00195##
[0638] ethyl 1-methyl-1H-pyrazole-3-carboxylate: To a solution of
ethyl 1H-pyrazole-5-carboxylate (4.0 g, 28.5 mmol, 1.0 eq) in DMF
(40 mL), potassium carbonate (7.89 g, 57.1 mmol, 2 eq) and methyl
iodide (3.55 mL, 57.1 mmol, 2 eq) were added at room temperature.
The reaction mixture was stirred for 16 h at room temperature. The
progress of the reaction was monitored by TLC (30% ethyl acetate in
n-hexane). After this time, the reaction mixture was diluted with
ice cold water (30 mL) and extracted with ethyl acetate (100 mL).
The organic layer was separated, dried over anhydrous sodium
sulphate, filtered and concentrated under reduced pressure to get
crude product of ethyl 1-methyl-1H-pyrazole-3-carboxylate. LCMS
(ES) m/z=155.1 [M+H].sup.+
[0639] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.38 (t, J=7.2
Hz, 3H), 3.97 (s, 3H), 4.38 (q, J=6.8 Hz, 2H), 6.79 (d, J=1.6 Hz,
1H), 7.37 (d, J=1.2 Hz, 1H).
[0640] 1-methyl-1H-pyrazole-3-carboxylic acid: To a solution of
ethyl 1-methyl-1H-pyrazole-3-carboxylate (2.0 g, 13.0 mmol, 1 eq)
in THF (10 mL) and methanol (10 mL), 2 M sodium hydroxide solution
(15 mL) was added. The reaction mixture was stirred at room
temperature for 16 h. The progress of the reaction was monitored by
TLC (70% ethyl acetate in n-hexane). After reaction completion, the
reaction mixture was concentrated to remove solvents. The reaction
mixture was acidified using 1N HCl solution (pH 3) and extracted
with ethyl acetate (120 mL). The organic layer was dried over
anhydrous sodium sulphate, filtered and concentrated under reduced
to yield crude 1-methyl-1H-pyrazole-5-carboxylic acid. LCMS
(m/z)=127.1 [M+H]+
[0641] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 3.87 (s,
3H), 6.63-6.64 (m, 1H), 7.75 (s, 1H), 12.54 (s, 1H).
[0642]
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)-1-methyl-1H-pyrazole-3-carbo-
xamide: To a solution of (2S)-1-(3-methoxyphenyl)hexan-2-amine (1.6
g, 7.72 mmol, 1.0 eq) in DCM (10 mL) was added
1-methyl-1H-pyrazole-3-carboxylic acid (1.17 g, 9.26 mmol, 1.2 eq)
and triethylamine (4.3 mL, 30.9 mmol, 4.0 eq). To this
propanephosphonic acid anhydride (7.37 mL, 11.6 mmol, 1.5 eq) was
added at 0.degree. C. After the addition, the reaction mixture was
stirred at room temperature for 16 h. The progress of the reaction
was monitored by TLC (70% ethyl acetate in n-hexane). After
reaction completion, the reaction mixture was quenched with aqueous
NaHCO.sub.3 solution (15 mL) and extracted with DCM (70 mL).
Organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to get crude
N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide-
. LCMS (m/z)=316.2 [M+H].sup.+
[0643]
(3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoq-
uinoline: Trifluoromethanesulfonic anhydride (3.19 mL, 19.0 mmol,
2.0 eq) was added via syringe over a period of 10 minutes to a
stirred mixture of
N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-1-methyl-1H-pyrazole-3-carboxamide
(3.0 g, 9.51 mmol, 1.0 eq) and 2-chloropyridine (1.8 mL, 19.0 mmol,
2.0 eq) in dichloromethane (20 mL) at -78.degree. C. After 5 min,
the reaction mixture was placed in an ice-water bath and warmed to
0.degree. C. After 5 min, the resulting solution was allowed to
warm to 23.degree. C. The progress of the reaction was monitored by
TLC (70% ethyl acetate in n-hexane). After 15 minutes aqueous
sodium hydroxide solution (12 mL, 1N) was added to reaction mixture
at 0.degree. C. to neutralize the trifluoromethanesulfonate salts.
Dichloromethane (50 mL) was added to dilute the mixture and the
layers were separated. The organic layer was washed with brine (10
mL), was dried over anhydrous sodium sulfate, and was filtered. The
volatiles were removed under reduced pressure to give the crude
product. The obtained crude product was purified by flash
chromatography using ethyl acetate in hexane as an eluent to get
the desired product
(3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinoli-
ne. LCMS (m/z)=298.1 [M+H].sup.+
[0644] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm: 0.88 (t,
J=6.4 Hz, 3H), 1.24-1.44 (m, 4H), 1.54-2.03 (m, 2H), 2.76-2.88 (m,
1H), 3.01-3.20 (m, 1H), 3.92 (s, 3H), 4.04 (s, 4H), 6.85 (d, J=1.2
Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 7.10 (s, 1H), 7.56 (s, 1H), 8.13
(d, J=8.8 Hz, 1H).
[0645]
(1R,3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetr-
ahydroisoquinoline: To a solution of trimethylaluminium (7.82 mL,
15.6 mmol, 5 eq) in tetrahydrofuran (8 mL) at -78.degree. C. was
added lithium aluminium hydride (31.3 mL, 31.3 mmol, 10 eq) at
-78.degree. C. followed by the addition of
(3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinoli-
ne (0.93 g, 3.13 mmol, 1 eq) in THF (3 mL). The reaction was
stirred at -78.degree. C. for 1 h. The progress of the reaction was
monitored by TLC (70% ethyl acetate in n-hexane). After 1 h, the
reaction was completed. The reaction mixture was quenched with
brine solution (10 mL) at 0.degree. C., diluted with ethyl acetate
(15 mL). It was then filtered through celite bed and washed with
ethyl acetate (20 mL). Organic layer was separated from aqueous
layer and concentrated under reduced pressure to get crude. The
crude was purified by flash column chromatography on silica gel
with an increasing polarity of 2-3% MeOH in DCM as solvent to get
(1R,3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrah-
ydroisoquinoline (mixture of cis and trans). LCMS (m/z)=300.2
[M+H].sup.+
[0646]
1-[(3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetr-
ahydroisoquinolin-2-yl]-3-(trimethylsilyl)prop-2-yn-1-one: First
step: To a solution of 3-(trimethylsilyl)propiolic acid (0.2 g,
1.41 mmol, 1 eq) in DMF (0.004 mL, 0.056 mmol, 0.04 eq), oxalyl
chloride (0.13 mL, 1.55 mmol, 1.1 eq) was added at room temperature
and reaction was stirred for 30 minutes. After this time, the
reaction mixture was concentrated under reduced pressure to yield
3-trimethylsilyl)propioloyl chloride. This acid chloride was
carried to next step without further purification.
[0647] Second step: To a solution of
(1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoq-
uinoline (0.42 g, 1.40 mmol, 1 eq) in acetonitrile (3.0 mL) was
added sodium bicarbonate (0.88 g, 10.5 mmol, 7.5 eq) at 0.degree.
C. After stirring for 5 minutes, a solution of
3-(trimethylsilyl)propioloyl chloride in acetonitrile (2 mL) was
added to the above reaction mass. The resulting mixture stirred at
0.degree. C. for 15 min, progress of the reaction was monitored by
TLC (60% ethyl acetate in n-hexane). After this time, reaction mass
was diluted with EtOAc (20 mL) and water (5 mL). Organic layer was
separated, washed with brine solution (5 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. This crude product was carried to next
step without any further purification. LCMS (m/z)=424.3
[M+H].sup.+.
[0648]
1-[(1R,3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-t-
etrahydroisoquinolin-2-yl]prop-2-yn-1-one: To a solution of
-[(3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydroi-
soquinolin-2-yl]-3-(trimethylsilyl)prop-2-yn-1-one (0.5 g, 1.18
mmol, 1 eq) in THF (8.0 mL) was added TBAF (1M solution in THF
(1.30 mL, 1.30 mmol, 1.1 eq) at -78.degree. C. This reaction
mixture was stirred at -78.degree. C. for 15 minutes. Progress of
the reaction was monitored by TLC (50% ethyl acetate in n-hexane).
After this time, the reaction mixture was quenched with saturated
aqueous NaHCO.sub.3 solution (2 mL) and product was extracted with
ethyl acetate (25 mL). Organic layers were dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The obtained crude product was purified by preparative TLC using
50% ethyl acetate in n-hexane as an eluent to get
1-[(1R,3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahy-
droisoquinolin-2-yl]prop-2-yn-1-one. LCMS (m/z)=352.4
[M+H].sup.+.
[0649] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.79 (t, J=6.0
Hz, 3H), 0.94-1.43 (m, 6H), 2.71-2.83 (m, 1H), 2.93-2.98 (m, 0.5H),
3.25-3.26 (m, 0.5H), 3.64-3.70 (m, 6H), 4.30-4.56 (m, 2H),
5.91-6.20 (m, 2H), 6.73-6.79 (m, 2H), 7.26-7.47 (m, 2H).
Procedure 23: Synthesis of Compound 76
##STR00196## ##STR00197##
[0651] tert-butyl
(S)-(3-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-y-
l)carbamate: To a solution of
3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic
acid (2.19 g, 9.62 mmol, 1.05 eq) in DCM (10.0 mL) was added TEA
(3.71 g, 36.7 mmol, 4 eq), stirred for 5 min and then T3P (50 wt. %
in EtOAc) (4.37 g, 13.70 mmol, 1.5 eq) was added at 0.degree. C.
and stirred for another 30 min. Then a solution of
(S)-1-(3-methoxyphenyl)hexan-2-amine (1.90 g, 9.16 mmol, 1 eq) in
DCM (5.0 mL) was added to the reaction mixture at 0.degree. C. and
then reaction mixture was stirred at room temperature for 16 h.
Progress of the reaction was monitored by TLC (40% ethyl acetate in
n-hexane). After this time, the reaction mixture was diluted with
DCM (75 mL), organic layer was separated, washed with saturated
aqueous solution of sodium bicarbonate (2.times.15 mL), water (15
mL), brine solution (15 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude product. The resulting residue was used in the next reaction
without any further purification. LCMS (ES) m/z=417.3 [M+H]+.
[0652] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.86 (bs, 3H),
1.25-1.28 (m, 6H), 1.43 (s, 9H), 2.17 (s, 6H), 2.68-2.81 (m, 2H),
3.86 (s, 3H), 4.11-4.13 (m 1H), 4.93 (bs, 1H), 5.16 (d, J=8.4 Hz,
1H), 6.67-6.76 (m, 3H), 7.19 (t, J=8.0 Hz, 1H).
[0653] tert-butyl
(S)-(3-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)bicyclo[1.1.1]penta-
n-1-yl)carbamate: To stirred solution of tert-butyl
(S)-(3-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-y-
l)carbamate (3.2 g, 7.68 mmol, 1 eq) and 2-chloropyridine (1.31 g,
11.50 mmol, 1.5 eq) in dichloromethane (32 mL) was added
trifluoromethanesulfonic anhydride (1.94 mL, 11.50 mmol, 1.5 eq)
via syringe slowly dropwise at -78.degree. C. After 10 minutes,
aqueous sodium hydroxide solution (10 mL, 1N) was introduced to
neutralize the trifluoromethanesulfonate salts. Dichloromethane (75
mL) was added to dilute the mixture and the layers were separated.
The organic layer was washed with brine (15 mL), was dried over
anhydrous sodium sulfate, and was filtered. The volatiles were
removed under reduced pressure to give crude product. The resulting
residue was used in the next reaction without any further
purification. LCMS (ES) m/z=399.3 [M+H]+.
[0654] tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[-
1.1.1]pentan-1-yl)carbamate & tert-butyl
(3-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[-
1.1.1]pentan-1-yl)carbamate: To a solution of tert-butyl
(S)-(3-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)bicyclo[1.1.1]penta-
n-1-yl)carbamate (3.0 g, 7.53 mmol, 1 eq) in methanol (30 mL) was
added sodium borohydride (0.854 mg, 22.60 mmol, 3 eq) portion wise
at 0.degree. C. The suspension was stirred at room temperature for
1 h. Progress of the reaction was monitored by TLC (50% EtOAc in
n-hexane). After this time, the reaction mixture was concentrated
under reduced pressure and obtained crude was diluted with EtOAc
(100 mL) and water (20 mL). Organic layer was separated, washed
with brine solution (20 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude product. The obtained crude product was purified by flash
column chromatography on silica gel using ethyl acetate in n-hexane
as an eluent. Desired products were eluted with 30-70% ethyl
acetate in n-hexane. Fractions containing products were combined
and concentrated under reduced pressure to get tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[-
1.1.1]pentan-1-yl)carbamate (1,3-trans isomer) and tert-butyl
(3-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[-
1.1.1]pentan-1-yl)carbamate (1,3-cis isomer).
[0655] Cis-isomer: LCMS (ES) m/z=401.3 [M+H]+.
[0656] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.92 (t, J=6.8
Hz, 3H), 1.23-1.29 (m, 3H), 1.36-1.37 (m, 3H), 1.43 (s, 9H),
1.93-2.04 (m, 6H), 2.37-2.44 (m, 1H), 2.64-2.68 (m, 1H), 2.76 (bs,
1H), 3.77 (s, 3H), 4.20 (s, 1H), 4.91 (bs, 1H), 6.59 (s, 1H), 6.68
(d, J=8.4 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H).
[0657] Trans-isomer: LCMS (ES) m/z=401.3 [M+H]+.
[0658] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.93-0.94 (m,
3H), 1.25-1.28 (m, 5H), 1.36-1.47 (m, 10H), 1.93-1.98 (m, 6H),
2.43-2.50 (m, 1H), 2.69-2.72 (m, 1H), 3.13 (bs, 1H), 3.77 (s, 3H),
4.13 (s, 1H), 4.90 (bs, 1H), 6.60 (s, 1H), 6.65 (d, J=8.4 Hz, 1H),
6.89 (d, J=8.8 Hz, 1H).
[0659] To a solution of tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[-
1.1.1]pentan-1-yl)carbamate (0.3 g, 0.749 mmol, 1 eq) in THF (4 mL)
was added QuadraSil.RTM. AP extent of labeling: 1.5-2.0 mmol/g
loading (480 mg) (calculated by amount of QuadraSil.RTM. required
(for 1.0 eq)=mmol of copper catalyst used in the previous
steps/mmol of scavenger loading) at room temperature and stirred
for 1 h. After this time, solid portion was removed by passing
through filter paper and filtrate was concentrated under reduced
pressure to get tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[-
1.1.1]pentan-1-yl)carbamate. LCMS (ES) m/z=401.3 [M+H]+.
[0660] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.93-0.94 (m,
3H), 1.25-1.28 (m, 5H), 1.36-1.47 (m, 10H), 1.93-1.98 (m, 6H),
2.43-2.50 (m, 1H), 2.69-2.72 (m, 1H), 3.13 (bs, 1H), 3.77 (s, 3H),
4.13 (s, 1H), 4.90 (bs, 1H), 6.60 (s, 1H), 6.65 (d, J=8.4 Hz, 1H),
6.89 (d, J=8.8 Hz, 1H).
[0661] tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4-te-
trahydroisoquinolin-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate: First
step: To a solution of 3-(trimethylsilyl)propiolic acid (155 mg,
1.09 mmol, 1.0 eq) in DMF (3.2 mg, 0.04 mmol, 0.04 eq) was added
oxalyl chloride (152 mg, 1.2 mmol, 1.1 eq) at room temperature and
stirred for 30 minutes. After this time, reaction mixture was
concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. This acid chloride was
carried to next step without any further purification.
[0662] Second step: To a solution of tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[-
1.1.1]pentan-1-yl)carbamate (285 mg, 0.711 mmol, 1.0 eq) in
acetonitrile (3.0 mL) was added sodium bicarbonate (448 mg, 5.34
mmol, 7.5 eq.) at 0.degree. C. After stirring for 5 minutes, a
solution of 3-(trimethylsilyl)propioloyl chloride (171 mg, 1.07
mmol, 1.5 eq) in acetonitrile (1 mL) was added to the above
reaction mass at 0.degree. C. The resulting mixture stirred at
0.degree. C. for 15 min, progress of the reaction was monitored by
TLC (50% ethyl acetate in n-hexane). After this time, reaction mass
was diluted with EtOAc (40 mL) and water (10 mL). Organic layer was
separated, washed with brine solution (7 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. The obtained crude product was purified
by preparative TLC by using 25% EtOAc in n-hexane as mobile phase
to get tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4-te-
trahydroisoquinolin-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate. LCMS
(ES) m/z=525.3 [M+H]+.
[0663] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.25-0.28 (m,
9H), 0.80-0.84 (m, 3H), 1.16-1.26 (m, 6H), 1.39 (s, 9H), 1.73-1.82
(m, 6H), 2.67-2.71 (m, 1H), 2.92-2.96 (m, 1H), 3.02-3.11 (m, 1H),
3.80-3.81 (m, 3H), 4.44 (bs, 1H), 5.28 (s, 1H), 6.67-6.74 (m, 2H),
6.92 (d, J=8.4 Hz, 1H).
[0664] tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinolin--
1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate: To a solution of
tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4-te-
trahydroisoquinolin-1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (145
mg, 0.276 mmol, 1 eq) in DCM (16 mL)/MeOH (3.3 mL) were added
K.sub.2CO.sub.3 (232 mg, 1.66 mmol, 6.0 eq) at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 3 hr to give a
white solution. Progress of the reaction was monitored by TLC (30%
ethyl acetate in n-hexane). After this time, the reaction mixture
was diluted with DCM (50 mL) and water (10 mL). Organic layer was
separated, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure to give tert-butyl
3-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinolin-1-
-yl)bicyclo[1.1.1]pentan-1-yl)carbamate. The resulting residue was
used in the next reaction without any further purification. LCMS
(ES) m/z=397.3 [M+H]+-56.
[0665] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.80-0.82 (m,
3H), 1.18-1.25 (m, 6H), 1.38-1.39 (m, 9H), 1.75-1.84 (m, 6H),
2.68-2.72 (m, 1H), 2.92-3.11 (m, 2H), 3.80-3.81 (m, 3H), 4.45 (bs,
1H), 4.84 (s, 1H), 5.27 (s, 1H), 6.67-6.73 (m, 2H), 6.92 (d, J=8.4
Hz, 1H).
[0666]
1-((1S,3S)-1-(3-aminobicyclo[1.1.1]pentan-1-yl)-3-butyl-6-methoxy-3-
,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To a solution of
tert-butyl
(3-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinolin--
1-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (120 mg, 0.265 mmol, 1.0
eq) in DCM (10 mL) was added TFA (2.42 g, 21.2 mmol, 80 eq) at
0.degree. C. The mixture was stirred at 0.degree. C. for 1.5 hr.
LCMS showed the reaction was completed. Then, the reaction mixture
was concentrate under reduced pressure. Obtained residue was
dissolved in water (5 mL) followed by lyophilize to give
1-((1S,3S)-1-(3-aminobicyclo[1.1.1]pentan-1-yl)-3-butyl-6-methoxy-3,4-dih-
ydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LCMS (ES) m/z=353.3
[M+H]+.
[0667] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.77 (bs,
3H), 0.88-0.95 (m, 1H), 1.16-1.17 (m, 4H), 1.34 (bs, 1H), 1.58-1.77
(m, 6H), 2.78-2.89 (m, 2H), 3.73 (s, 3H), 4.32-4.43 (m, 1H),
4.57-4.62 (m, 1H), 5.19-5.29 (m, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.87
(s, 1H), 6.05-7.14 (m, 1H), 8.37-8.44 (m, 3H).
Procedure 24: Synthesis of Compound 94
##STR00198## ##STR00199##
[0669] ethyl 4-[(pyridin-3-yl)amino]benzoate: To a solution of
ethyl 4-iodobenzoate (5.0 g, 18.1 mmol, 1.0 eq) and
pyridine-3-amine (2.05 g, 21.7 mmol, 1.2 eq) in Toluene (100 mL)
was added cesium carbonate (11.8 g, 36.2 mmol, 2 eq) and binap
(0.226 g, 0.362 mmol, 0.02 eq) at room temperature, purged the
reaction mixture with nitrogen for 20 mins and then Pd(OAc).sub.2
(0.081 g, 0.362 mmol, 0.02 eq) added. Then reaction mixture was
stirred under reflux condition for 30 h. The reaction mixture was
cooled to room temperature, filtered through celite bed, washed the
bed with EtOAc (200 mL) and the filtrate was concentrated under
reduced pressure to get crude product. The obtained crude product
was purified by flash column chromatography on silica gel using
EtOAc in n-hexane. Product was isolated at 40-45% ethyl acetate in
hexane as an eluent to afford ethyl 4-(pyridin-3-ylamino)benzoate.
LCMS (ES) m/z=243.1 [M+H]+.
[0670] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 1.27 (t,
J=6.8 Hz, 3H), 4.23 (q, J=7.2 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H),
7.29-7.32 (m, 1H), 7.59 (d, J=6.8 Hz, 1H), 7.81 (d, J=8.4 Hz, 2H),
8.15-8.16 (m, 1H), 8.41-8.42 (m, 1H), 8.91 (s, 1H).
[0671] 4-[(pyridin-3-yl)amino]benzoic acid hydrochloride: To a
stirred solution of ethyl 4-[(pyridin-3-yl)amino]benzoate (2.5 g,
10.3 mmol, 1.0 eq) in ethanol (30 mL) was added sodium hydroxide
(0.84 g, 20.6 mmol, 2.0 eq) in water (10 mL). The reaction mixture
was stirred at 75.degree. C. for 16 h. The progress of the reaction
was monitored by TLC (70% ethyl acetate in n-hexane). After
reaction completion, the reaction mixture was concentrated.
Obtained crude was acidified with 1N HCl (pH .about.2) and
evaporated under reduced pressure to get hydrochloride salt of
crude product. Product was dried and taken for next step as
hydrochloride salt. LCMS (ES) m/z=215.1 [M+H]+free amine mass.
[0672]
N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-4-[(pyridin-3-yl)amino]benza-
mide: To a stirred solution of 4-(pyridin-3-ylamino)benzoic acid
hydrochloride (3.10 g, 12.3 mmol, 1.6 eq) in DMF (30 mL) was added
DIPEA (8.1 mL, 46.3 mmol, 6 eq) and stirred for 5 minutes, then
EDC.HCl (2.2 g, 11.6 mmol, 1.5 eq) followed by
(S)-1-(3-methoxyphenyl)hexan-2-amine (1.6 g, 7.72 mmol, 1 eq) was
added at 0.degree. C. After stirring for 5 minutes HOBt (1.56 g,
11.6 mmol, 1.5 eq) was added to the reaction mixture at 0.degree.
C. and then reaction mixture was stirred at room temperature for 16
h. After this time, the reaction mixture was diluted with EtOAc (60
mL), organic layer was washed with saturated sodium bicarbonate
solution (20 mL), water (10 mL), brine solution (10 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography using 5% MeOH in DCM as an eluent to obtain
N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-4-[(pyridin-3-yl)amino]benzamide.
LCMS(ES) m/z=404.4 [M+H]+.
[0673] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 0.91 (bs,
3H), 1.23 (s, 4H), 1.49 (s, 2H), 2.71-2.81 (m, 2H), 3.66 (s, 3H),
4.11-4.12 (m, 1H), 6.69 (d, J=8.0 Hz, 1H), 6.76 (s, 2H), 7.04 (d,
J=8.0 Hz, 2H), 7.11-7.13 (m, 1H), 7.26-7.28 (m, 1H), 7.52-7.53 (m,
1H), 7.71 (d, J=8.0 Hz, 2H), 7.92 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.0
Hz, 1H), 8.37 (s, 1H), 8.66 (s, 1H).
[0674]
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}pyr-
idin-3-amine: To stirred solution of
N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-4-[(pyridin-3-yl)amino]benzamide
(2.4 g, 5.95 mmol, 1 eq) and 2-chloropyridine (1.69 mL, 17.8 mmol,
3.0 eq) in dichloromethane (30 mL) was added
trifluoromethanesulfonic anhydride (3.0 mL, 17.8 mmol, 3.0 eq) via
syringe slowly dropwise at -78.degree. C. After 5 min, the reaction
mixture was placed in an ice-water bath and warmed to 0.degree. C.
After 5 min, the resulting solution was allowed to warm to
23.degree. C. Progress of the reaction was monitored by TLC (5%
MeOH in DCM). After 1 h, reaction was quenched with aqueous sodium
hydroxide solution (25 mL, 1N) to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (150 mL) was added
to dilute the mixture and the layers were separated. The aqueous
layer was extracted with DCM (100 mL). The combined organic layer
was washed with brine (25 mL), was dried over anhydrous sodium
sulfate, and was filtered. The volatiles were removed under reduced
pressure to give the crude product. The obtained crude product was
purified by flash chromatography using 5% MeOH in DCM as an eluent
to get the desired product
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}pyridin-3-
-amine. LCMS (ES) m/z=386.2 [M+H]+.
[0675]
N-{4-[(3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phe-
nyl}pyridin-3-amine: To a stirred solution of
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}pyridin-3-
-amine (1.9 g, 4.93 mmol, 1 eq) in methanol (45 mL) was added
sodium borohydride (0.559 g, 14.8 mmol, 3 eq) portion wise at
0.degree. C. The suspension was stirred at room temperature for 1
h. The reaction mixture was concentrated and obtained crude was
diluted with EtOAc (300 mL) and water (100 mL). Organic layer was
separated, washed with brine solution (100 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain the crude product. The obtained crude product
was purified by flash chromatography using 5% methanol in DCM as an
eluent to get
N-{4-[(3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}py-
ridin-3-amine. LCMS (ES) m/z=388.4 [M+H]+.
[0676]
1-[(3S)-3-butyl-6-methoxy-1-{4-[(pyridin-3-yl)amino]phenyl}-1,2,3,4-
-tetrahydroisoquinolin-2-yl]-3-(trimethylsilyl)prop-2-yn-1-one: To
a stirred solution of
N-{4-[(3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}py-
ridin-3-amine (0.400 g, 1.03 mmol, 1.0 eq) in DCM (12.0 mL) was
added triethylamine (0.363 mL, 2.58 mmol, 2.5 eq),
3-(trimethylsilyl)propiolic acid (0.176 g, 1.24 mmol, 1.2 eq) and
2-Chloro-1-methylpyridinium iodide (0.316 g, 1.24 mmol, 1.2 eq) at
room temperature and the reaction was stirred at room temperature
for 1 h. The reaction mixture was diluted with DCM (25 mL), washed
with water (10 mL) and brine (10 mL), dried over anhydrous sodium
sulfate. Organic layer was filtered and concentrated under reduced
pressure to get
1-[(3S)-3-butyl-6-methoxy-1-{4-[(pyridin-3-yl)amino]phenyl}-1,2,3,4-tetra-
hydroisoquinolin-2-yl]-3-(trimethylsilyl)prop-2-yn-1-one. LCMS (ES)
m/z=512.3 [M+H]+.
[0677]
1-[(1S,3S)-3-butyl-6-methoxy-1-{4-[(pyridin-3-yl)amino]phenyl}-1,2,-
3,4-tetrahydroisoquinolin-2-yl]prop-2-yn-1-one: To a stirred
solution of
1-[(3S)-3-butyl-6-methoxy-1-{4-[(pyridin-3-yl)amino]phenyl}-1,2,3,4-tetra-
hydroisoquinolin-2-yl]-3-(trimethylsilyl)prop-2-yn-1-one (0.640 g,
1.25 mmol, 1.0 eq) in MeOH:DCM (1:5) (12 mL) mixture at 0.degree.
C., potassium carbonate (1.04 g, 7.50 mmol, 6.0 eq) was added. Then
reaction mixture was stirred at 0.degree. C. for 50 minutes. Then
reaction mixture was diluted with DCM (25.0 mL), washed with water
(10.0 mL). Organic layer was separated and dried over anhydrous
sodium sulphate. Organic layer was filtered and concentrated under
reduced pressure to get crude product, which was purified by flash
column chromatography using ethyl acetate in hexane as eluent.
Isolated mixture was further purified by preparative TLC using 60%
ethyl acetate in hexane as eluent by running two times. Product
fraction collected and concentrated under reduced pressure to get
pure product. Obtained pure product kept under lyophilization by
dissolving acetonitrile (1.0 mL) and water (2.0 mL) mixture for 16
h to get
1-[(1S,3S)-3-butyl-6-methoxy-1-{4-[(pyridin-3-yl)amino]phenyl}-1,2,3,4-te-
trahydroisoquinolin-2-yl]prop-2-yn-1-one. LCMS (ES) m/z=440.5
[M+H]+.
[0678] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.79-0.80
(m, 3H), 1.21 (bs, 4H), 1.49 (s, 2H), 2.77-2.87 (m, 1.5H),
3.06-3.10 (m, 0.5H), 3.70-3.72 (m, 3H), 4.31 (s, 0.5H), 4.48 (s,
0.5H), 4.58 (s, 0.5H), 4.66 (s, 0.5H), 6.00 (s, 0.5H), 6.24 (s,
0.5H), 6.77-6.83 (m, 2H), 6.92-6.99 (m, 2H), 7.05-7.13 (m, 2H),
7.15-7.17 (m, 1H), 7.35-7.39 (m, 1.5H), 7.52-7.54 (m, 0.5H),
7.94-7.98 (m, 1H), 8.24-8.29 (m, 2H).
Procedure 25: Synthesis of Compound 100
##STR00200## ##STR00201## ##STR00202##
[0680] methyl 4-[({bicyclo[1.1.1]pentan-1-yl}amino)methyl]benzoate:
To a stirred solution of bicyclo[1.1.1]pentan-1-amine hydrochloride
(2.1 g, 17.6 mmol, 1.0 eq) in DMF (30.0 mL) at 0.degree. C.,
potassium carbonate (7.3 g, 52.7 mmol, 3.0 eq) added. After
stirring for 5 minutes methyl 4-(bromomethyl)benzoate (3.22 g, 14.0
mmol, 0.8 eq) added. Then reaction mixture was allowed to stir at
room temperature for 30 minutes. Reaction mixture was diluted with
water (30 mL), extracted in to ethyl acetate (2.times.30 mL).
Combined organic layer was washed with cool water (40 mL), brine
(20 mL), dried over anhydrous sodium sulphate. Organic layer was
filtered and concentrated under reduced pressure to get crude
product, which was purified by flash column chromatography on
silica gel using ethyl acetate in hexane as eluent. Product was
isolated at 15-18% ethyl acetate in hexane. Product fractions
collected and concentrated under reduced pressure to get methyl
4-((bicyclo[1.1.1]pentan-1-ylamino)methyl)benzoate. LCMS (ES)
m/z=232.2 [M+H]+.
[0681] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 1.64 (s,
6H), 2.28 (s, 1H), 3.69 (s, 2H), 3.74 (s, 3H), 7.45-7.48 (m, 2H),
7.86-7.88 (m, 2H).
[0682] methyl
4-[({bicyclo[1.1.1]pentan-1-yl}[(tert-butoxy)carbonyl]amino)methyl]benzoa-
te: To a stirred solution of methyl
4-((bicyclo[1.1.1]pentan-1-ylamino)methyl)benzoate (2.2 g, 9.51
mmol, 1 eq) in THF (30 mL) at 0.degree. C. added DIPEA (5 mL, 28.5
mmol, 3 eq) followed by boc anhydride (6.6 mL, 28.5 mmol, 3 eq).
Then reaction mixture was allowed to stir at room temperature for
16 h. Reaction mixture was diluted with water (25 mL), extracted
with ethyl acetate (2.times.30 mL). Combined organic layer was
washed with water (20 mL), brine (20 mL), dried over anhydrous
sodium sulphate. Organic layer was filtered and concentrated under
reduced pressure to get crude product, which was purified by flash
column chromatography on silica gel using ethyl acetate in hexane
as eluent. Product was isolated at 12-16% ethyl acetate in hexane.
Product fractions collected and concentrated under reduced pressure
to get methyl
4-((bicyclo[1.1.1]pentan-1-yl(tert-butoxycarbonyl)amino)methyl)benzoate.
LCMS (ES) m/z=332.2 [M+H]+ but observed 276.2 without tert butyl
group.
[0683]
4-[({bicyclo[1.1.1]pentan-1-yl}[(tert-butoxy)carbonyl]amino)methyl]-
benzoic acid: To a solution of methyl
4-((bicyclo[1.1.1]pentan-1-yl(tert-butoxycarbonyl)amino)methyl)benzoate
(2.75 g, 8.30 mmol, 1 eq) in MeOH (20 mL) and water (10 mL) was
added sodium hydroxide (0.680 g, 16.6 mmol, 2 eq) at room
temperature and the reaction mixture was stirred at 60.degree. C.
for 2 h. Progress of the reaction was monitored by TLC (5% MeOH in
DCM). After completion of the reaction, the reaction mixture was
concentrated under reduced pressure to remove methanol from
reaction mass and the remaining aqueous layer was acidified with 5%
citric acid (pH.about.4) and then product was extracted with EtOAc
(100 mL). Organic layer was dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to get
4-((bicyclo[1.1.1]pentan-1-yl(tert-butoxycarbonyl)amino)methyl)benzoic
acid. LCMS (ES) m/z=318.1 [M+H]+ but observed 262.1 without tert
butyl group.
[0684] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 1.38 (s,
9H), 1.92 (s, 6H), 2.33 (s, 1H), 4.41 (s, 2H), 7.26 (d, J=8.4 Hz,
2H), 7.88 (d, J=8.4 Hz, 2H), 12.40 (bs, 1H).
[0685] tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-[(4-{[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-
carbamoyl}phenyl)methyl]carbamate: To a solution of
4-((bicyclo[1.1.1]pentan-1-yl(tert-butoxycarbonyl)amino)methyl)benzoic
acid (1.99 g, 6.27 mmol, 1 eq) in DCM (20 mL) was added TEA (2.64
mL, 18.8 mmol, 3 eq), stirred for 5 min and then T3P (50 wt. % in
EtOAc) (6 mL, 9.41 mmol, 1.5 eq) was added at 0.degree. C. and
stirred for another 30 min. Then a solution of
(S)-1-(3-methoxyphenyl)hexan-2-amine (1.3 g, 6.27 mmol, 1 eq) in
DCM (10 mL) was added to the reaction mixture at 0.degree. C. and
then reaction mixture was stirred at room temperature for 2 h.
Progress of the reaction was monitored by TLC (20% ethyl acetate in
hexane). After this time, the reaction mixture was diluted with DCM
(100 mL), washed with saturated sodium bicarbonate solution (40
mL), water (40 mL), brine solution (20 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. The obtained crude product was purified
by flash chromatography on silica gel. Desired product was eluted
with 16-18% ethyl acetate in n-hexane. Fractions containing product
were combined and concentrated under reduced pressure to get
tert-butyl
(S)-bicyclo[1.1.1]pentan-1-yl(4-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl-
)benzyl)carbamate. LCMS (ES) m/z=507.3 [M+H]+.
[0686] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 0.81 (s,
3H), 1.25-1.26 (m, 4H), 1.39 (s, 9H), 1.50 (s, 2H), 1.93 (s, 6H),
2.33 (s, 1H), 2.75 (bs, 2H), 3.65 (s, 3H), 4.12 (bs, 1H), 4.39 (s,
2H), 6.69 (d, J=8.0 Hz, 1H), 6.77 (s, 2H), 7.11-7.15 (m, 1H),
7.20-7.21 (m, 2H), 7.71 (d, J=7.2 Hz, 2H), 8.04 (bs, 1H).
[0687] tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(3S)-3-butyl-6-methoxy-3,4-dihydrois-
oquinolin-1-yl]phenyl}methyl)carbamate: To stirred solution of
tert-butyl
(S)-bicyclo[1.1.1]pentan-1-yl(4-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl-
)benzyl)carbamate (2.3 g, 4.54 mmol, 1 eq) and 2-chloropyridine
(1.30 mL, 13.6 mmol, 3.0 eq) in dichloromethane (25 mL) was added
trifluoromethanesulfonic anhydride (2.3 mL, 13.6 mmol, 3 eq) via
syringe slowly drop wise at -78.degree. C. After 5 min, the
reaction mixture was placed in an ice-water bath and warmed to
0.degree. C. After 5 minutes reaction mixture was quenched with
aqueous sodium hydroxide solution (1N, 20 mL) to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (150 mL) was added
to dilute the mixture and the layers were separated. The aqueous
layer was extracted with DCM (100 mL). The combined organic layer
was washed with brine (25 mL), was dried over anhydrous sodium
sulfate, filtered and concentrated under pressure to obtain the
crude product, which was purified by flash column chromatography on
silica gel using ethyl acetate in hexane as eluent. Product was
isolated at 12-15% ethyl acetate in hexane. Product fractions
collected and concentrated under reduced pressure to get tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(3S)-3-butyl-6-methoxy-3,4-dihydrois-
oquinolin-1-yl]phenyl}methyl)carbamate. In Column purification
N-({4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}methyl)b-
icyclo[1.1.1]pentan-1-amine also isolated. LCMS (ES) m/z=489.3
[M+H]+.
[0688] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.87-0.91
(m, 3H), 1.32-1.40 (m, 12H), 1.56-1.67 (m, 3H), 1.95 (s, 6H),
2.30-2.34 (m, 1H), 2.41-2.48 (m, 2H), 2.74-2.78 (m, 1H), 3.78 (s,
3H), 4.42 (s, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 7.07 (d,
J=8.4 Hz, 1H), 7.23 (d, J=7.6 Hz, 2H), 7.45-7.46 (m, 2H).
[0689] tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-te-
trahydroisoquinolin-1-yl]phenyl}methyl)carbamate: To a solution of
tert-butyl
(S)-bicyclo[1.1.1]pentan-1-yl(4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-
-1-yl)benzyl)carbamate (0.850 g, 1.74 mmol, 1 eq) in methanol (10
mL) was added sodium borohydride (0.197 g, 5.22 mmol, 3 eq) portion
wise at 0.degree. C. The suspension was stirred at room temperature
for 1 h. Progress of the reaction was monitored by TLC (20% EA in
hexane). After this time, the reaction mixture was concentrated and
obtained crude was diluted with EtOAc (20 mL) and water (10 mL).
Organic layer was separated, washed with brine solution (10 mL),
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure to obtain the crude product. The obtained
crude product was purified by Preparative TLC using 20% ethyl
acetate in n-hexane. Product fraction collected and concentrated
under reduced pressure to get tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-te-
trahydroisoquinolin-1-yl]phenyl}methyl)carbamate. LCMS (ES)
m/z=491.3 [M+H]+.
[0690] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.75-0.78
(m, 3H), 1.08-1.17 (m, 6H), 1.36 (bs, 9H), 1.90 (s, 6H), 2.30 (s,
1H), 2.37 (s, 1H), 2.73-2.75 (m, 2H), 3.70 (s, 3H), 4.30 (s, 2H),
5.04 (bs, 1H), 6.64-6.69 (m, 2H), 6.75-6.77 (m, 1H), 7.04 (s,
4H).
[0691] tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-2-[3-(trim-
ethylsilyl)prop-2-ynoyl]-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}methyl)-
carbamate: First step: To a solution of 3-(trimethylsilyl)propiolic
acid (35 mg, 0.246 mmol, 1.0 eq) in DMF (0.001 mL, 0.009 mmol, 0.04
eq) was added oxalyl chloride (0.023 mL, 0.271 mmol, 1.1 eq) at
room temperature and stirred for 30 minutes. Then reaction mixture
was concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. This acid chloride was
carried to next step without any further purification.
[0692] Second step: To a solution of tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-te-
trahydroisoquinolin-1-yl]phenyl}methyl)carbamate (0.085 g, 0.173
mmol, 1 eq) in acetonitrile (3 mL) was added sodium bicarbonate
(0.118 g, 1.39 mmol, 8.0 eq) at 0.degree. C. After stirring for 5
minutes, a solution of 3-(trimethylsilyl)propioloyl chloride (0.031
g, 0.191 mmol, 1.1 eq) in acetonitrile (2.0 mL) was added to the
above reaction mass. The resulting mixture stirred at 0.degree. C.
for 1 h. Then reaction mixture was diluted with EtOAc (10 mL) and
water (5 mL). Organic layer was separated, washed with brine
solution (5 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain the crude product.
This crude product was carried to next step without any further
purification. LCMS (ES) m/z=615.3 [M+H]+ but observed 559.3 without
tert butyl group
[0693] tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2--
ynoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}methyl)carbamate:
To a solution of tert-butyl
bicyclo[1.1.1]pentan-1-yl(4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsil-
yl)propioloyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzyl)carbamate
(85 mg, 0.138 mmol, 1 eq) in DCM (5 mL)/MeOH (1 mL) was added K2CO3
(115 mg, 0.829 mmol, 6 eq) at 0.degree. C. The mixture was stirred
at 0.degree. C. for 45 minutes. Then reaction mixture was diluted
with DCM (10 mL) and added water (2 mL). The organic layer was
extracted with DCM (2.times.5 mL) and dried over anhydrous Na2SO4.
Organic layer was filtered and concentrated to obtain the crude
product, which product was purified by preparative TLC using 20%
ethyl acetate in hexane as mobile phase. Product fraction collected
and concentrated under reduced pressure to get tert-butyl
bicyclo[1.1.1]pentan-1-yl(4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3-
,4-tetrahydroisoquinolin-1-yl)benzyl)carbamate. LCMS (ES) m/z=543.3
[M+H]+ but observed without boc group.
[0694]
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-2-(p-
rop-2-ynoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}methyl)-2,2,2-trifl-
uoroacetamide: To a stirred solution of tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2--
ynoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}methyl)carbamate
(0.040 g, 0.073 mmol, 1.0 eq) in DCM (1.0 mL) at 0.degree. C. TFA
(0.150 mL) was added. Then reaction mixture was stirred at
0.degree. C. for 1.5 h. Reaction mixture was evaporated under
reduced pressure keeping water bath temperature at 30.degree. C.
The obtained crude product kept under lyophilization by adding
water (1.5 mL) and acetonitrile (0.5 mL) mixture for 16 h. Obtained
product taken for analysis. LCMS (ES) m/z=443.3 [M+H]+ (observed
free amine mass).
[0695] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.79-0.82
(m, 3H), 1.13-1.21 (m, 4H), 1.47 (bs, 2H), 1.97-1.98 (m, 6H), 2.65
(s, 1H), 2.77 (bs, 1H), 2.85-2.89 (m, 0.5H), 3.14-3.15 (m, 0.5H),
3.69-3.70 (m, 3H), 3.98 (s, 2H), 4.29 (s, 0.5H), 4.60 (s, 1H), 4.74
(s, 0.5H), 6.04 (s, 0.5H), 6.33 (s, 0.5H), 6.75-6.83 (m, 2H),
7.28-7.32 (m, 3H), 7.37-7.42 (m, 1.5H), 7.60-7.62 (m, 0.5H), 9.42
(bs, 2H).
Procedure 26: Synthesis of Compound 98
##STR00203## ##STR00204##
[0697] pentan-1-ol: To a solution of pentanal (8.0 g, 92.9 mmol,
1.0 eq) in methanol (50 mL) was added sodium borohydride (10.5 g,
279 mmol, 3.0 eq) at 0.degree. C. portion wise. The reaction
mixture was stirred at room temperature for 1 h. The progress of
the reaction was monitored by TLC (20% ethyl acetate in n-hexane).
After reaction completion, the reaction mixture was quenched with
few drops of acetone, concentrated, diluted with water (35 mL) and
extracted with ethyl acetate (2.times.50 mL). The organic layer was
dried over anhydrous sodium sulphate, filtered and concentrated
under reduced pressure to get crude pentan-1-ol.
[0698] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.84 (t,
J=6.0 Hz, 3H), 1.13-1.24 (m, 4H), 1.37-1.42 (m, 2H), 3.31-3.37 (m,
2H), 4.30 (t, J=4.8 Hz, 1H).
[0699] methyl 4-{[(pentyloxy)carbonyl]amino}benzoate: To a solution
of pentan-1-ol (5.0 g, 56.7 mmol, 1.0 eq) in DCM (75 mL) was added
methyl-4-aminobenzoate (10.3 g, 68.1 mmol, 1.2 eq) and
triethylamine (39.5 mL, 284 mmol, 5.0 eq). To this triphosgene
(11.8 g, 23.8 mmol, 0.7 eq) was added at 0.degree. C. portion wise.
The reaction mixture was stirred at rt for 1 h. The progress of the
reaction was monitored by TLC (15% ethyl acetate in n-hexane).
After reaction completion, the reaction mixture was quenched with
aqueous sodium bicarbonate solution (80 mL) and extracted with
ethyl acetate (140 mL). The organic layer was dried over anhydrous
sodium sulphate, filtered and concentrated under reduced pressure
to get crude. The crude was purified by flash column chromatography
on silica gel with an increasing polarity of 5-10% ethyl acetate in
n-hexane to get methyl 4-(((pentyloxy)carbonyl)amino)benzoate.
[0700] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.86 (s,
3H), 1.31 (s, 4H), 1.60 (s, 2H), 3.78 (s, 3H), 4.07 (t, J=6.0 Hz,
2H), 7.57 (d, J=8.0 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 10.0 (s,
1H).
[0701] 4-{[(pentyloxy)carbonyl]amino}benzoic acid: To a solution of
methyl 4-(((pentyloxy)carbonyl)amino)benzoate (6.6 g, 24.9 mmol, 1
eq) in methanol (70 mL) was added sodium hydroxide (1.53 g, 37.3
mmol, 1.5 eq.) and water (35 mL). The reaction mixture was stirred
at 65.degree. C. for 16 h. The progress of the reaction was
monitored by TLC (40% ethyl acetate in n-hexane). After reaction
completion, the reaction mixture was acidified with 10% citric acid
solution up to pH=4 and extracted with ethyl acetate (160 mL). The
organic layer was dried over anhydrous sodium sulphate, filtered
and concentrated under reduced pressure to get crude
4-(((pentyloxy)carbonyl)amino)benzoic acid.
[0702] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.86 (t,
J=7.2 Hz, 3H), 1.30-1.38 (m, 4H), 1.59-1.62 (m, 2H), 4.07 (t, J=6.4
Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 9.97 (s,
1H), 12.54 (s, 1H).
[0703] pentyl
(S)-(4-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)phenyl)carbamate:
To a solution of 4-(((pentyloxy)carbonyl)amino)benzoic acid (2.06
g, 8.20 mmol, 1.0 eq) in DCM (35 mL) was added (4.61 mL, 32.8 mmol,
4 eq), stirred for 15 min and then T3P (50 wt. % in EtOAc) (7.8 mL,
12.3 mmol, 1.5 eq) was added at 0.degree. C. and stirred for
another 5 mins. Then (S)-1-(3-methoxyphenyl)hexan-2-amine (1.70 g,
8.20 mmol, 1.0 eq) was added to the reaction mixture and then
reaction mixture was stirred at room temperature for 16 h. The
progress of the reaction was monitored by TLC (40% ethyl acetate in
hexane). The reaction mixture was diluted with DCM (70 mL) and
saturated sodium bicarbonate solution (30 mL) Organic layer was
separated, washed with brine solution (12 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain pentyl
(S)-(4-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)phenyl)carbamate.
LCMS (ES) m/z=441.2 [M+H].sup.+
[0704] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80-0.86
(m, 6H), 1.21-1.31 (m, 8H), 1.47-1.72 (m, 4H), 2.65-2.79 (m, 2H),
3.65 (s, 3H), 4.06-4.13 (m, 3H), 6.67-6.77 (m, 3H), 7.12 (t, J=7.6
Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.98 (d,
J=8.0 Hz, 1H), 9.81 (s, 1H).
[0705] pentyl
(S)-(4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)carbamate:
Trifluoromethanesulfonic anhydride (1.91 mL, 11.3 mmol, 2 eq) was
added via syringe over a period of 1 min to a stirred mixture of
pentyl
(S)-(4-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)phenyl)carbamate
(2.50 g, 5.67 mmol, 1 eq) and 2-chloropyridine (1.07 mL, 11.3 mmol,
2 eq) in dichloromethane (20 mL) at -78.degree. C. After 5 min, the
reaction mixture was placed in an ice-water bath and warmed to
0.degree. C. After 5 min, the resulting solution was allowed to
warm to 23.degree. C. TLC (20% ethyl acetate in n-hexane) showed
the reaction was completed. After 1 h, aqueous sodium hydroxide
solution (30 mL, 1N) was introduced to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (120 mL) was added
to dilute the mixture and the layers were separated. The organic
layer was washed with brine (20 mL), was dried over anhydrous
sodium sulfate, and was filtered. The volatiles were removed under
reduced pressure to give the crude product. The obtained crude
product was purified by flash chromatography using ethyl acetate in
hexane as an eluent to get the desired product pentyl
(S)-(4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)carbamate.
LCMS (ES) m/z=423.3 [M+H].sup.+.
[0706] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.79-0.89
(m, 6H), 1.32-1.60 (m, 8H), 1.61-1.96 (m, 4H), 2.30-2.48 (m, 2H),
2.65-2.76 (m, 1H), 3.78 (s, 3H), 4.07 (t, J=6.4 Hz, 2H), 6.80 (d,
J=8.4 Hz, 1H), 6.89 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.8
Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 9.74 (s, 1H).
[0707] pentyl
N-{4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl-
}carbamate: To a solution of pentyl
(S)-(4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)carbamate
(0.300 g, 0.710 mmol, 1 eq) in methanol (6 mL) was added sodium
borohydride (0.081 g, 2.13 mmol, 3 eq) portion wise at 0.degree. C.
The suspension was stirred at room temperature for 1 h. After this
time, the reaction mixture was concentrated and obtained crude was
diluted with EtOAc (30 mL) and water (10 mL). Organic layer was
separated, washed with brine solution (10 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. The obtained crude product was purified
by preparative TLC using 30% ethyl acetate in n-hexane as eluent.
Product fraction collected and concentrated under reduced pressure
to get pentyl
(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)c-
arbamate. LCMS (ES) m/z=425.3 [M+H]+
[0708] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.79-0.85
(m, 6H), 1.17-1.35 (m, 10H), 1.58 (s, 2H), 2.77 (bs, 2H), 3.14-3.15
(m, 1H), 3.70 (s, 3H), 4.00-4.02 (m, 2H), 5.04 (s, 1H), 6.64-6.74
(m, 3H), 6.99 (d, J=8.0 Hz, 2H), 7.31 (d, J=7.6 Hz, 2H), 9.50 (s,
1H).
[0709] pentyl
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-[3-(trimethylsilyl)prop-2-ynoyl]-1,2,3,-
4-tetrahydroisoquinolin-1-yl]phenyl}carbamate: First step: To a
solution of 3-(trimethylsilyl)propiolic acid (15 mg, 0.105 mmol,
1.0 eq) in DMF (0.0003 mL, 0.004 mmol, 0.04 eq) was added oxalyl
chloride (0.010 mL, 0.116 mmol, 1.1 eq) at room temperature and
stirred for 30 minutes. Then reaction mixture was concentrated
under reduced pressure to get 3-(trimethylsilyl)propioloyl
chloride. This acid chloride was carried to next step without any
further purification.
[0710] Second step: To a solution of pentyl
N-{4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl-
}carbamate (0.035 g, 0.082 mmol, 1.0 eq) in acetonitrile (3 mL) was
added sodium bicarbonate (0.057 g, 0.659 mmol, 8.0 eq) at 0.degree.
C. After stirring for 5 minutes, a solution of
3-(trimethylsilyl)propioloyl chloride (0.015 g, 0.090 mmol, 1.1 eq)
in acetonitrile (2.0 mL) was added to the above reaction mass. The
resulting mixture was stirred at 0.degree. C. for 30 minutes,
progress of the reaction was monitored by TLC (20% ethyl acetate in
n-hexane). After this time, reaction mass was diluted with EtOAc
(15 mL) and water (5 mL). Organic layer was separated, washed with
brine solution (5 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude product. This crude product was carried to next step without
any further purification. LC-MS (ES) m/z=549.4 [M+H]+.
[0711] pentyl
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2-ynoyl)-1,2,3,4-tetrahydroisoqui-
nolin-1-yl]phenyl}carbamate: To a stirred solution of pentyl
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-[3-(trimethylsilyl)prop-2-ynoyl]-1,2,3,-
4-tetrahydroisoquinolin-1-yl]phenyl}carbamate (0.045 g, 0.082 mmol,
1 eq) in MeOH:DCM (1:5) (6 mL) mixture at 0.degree. C., potassium
carbonate (0.068 g, 0.492 mmol, 6 eq) was added. Then reaction
mixture was stirred at 0.degree. C. for 30 minutes. Then reaction
mixture was diluted with DCM (15.0 mL), washed with water (3.0 mL).
Organic layer was separated and dried over anhydrous sodium
sulphate. Organic layer was filtered and concentrated under reduced
pressure to get crude product, which was purified by preparative
TLC using 20% ethyl acetate in hexane as eluent. Product fraction
collected and concentrated under reduced pressure to get pure
product. Obtained pure product kept under lyophilization by
dissolving acetonitrile (1.0 mL) and water (2.0 mL) mixture for 16
h to get pentyl
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2-ynoyl)-1,2,3,4-tetrahydroisoqui-
nolin-1-yl]phenyl}carbamate. LCMS (ES) m/z: 477.3 [M+H]+.
[0712] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 0.78-0.85
(m, 6H), 1.21-1.29 (m, 9H), 1.46-1.56 (m, 3H), 2.65 (s, 1H),
2.82-2.86 (m, 0.5H), 3.06-3.09 (m, 0.5H), 3.69-3.70 (m, 3H),
3.98-4.01 (m, 2H), 4.30 (s, 0.5H), 4.49 (s, 0.5H), 4.60 (s, 0.5H),
4.68 (s, 0.5H), 5.97 (s, 0.5H), 6.22 (s, 0.5H), 6.75-6.81 (m, 2H),
7.07-7.12 (m, 2H), 7.25-7.27 (m, 1H), 7.31-7.36 (m, 1.5H),
7.53-7.55 (m, 0.5H), 9.46 (s, 0.5H), 9.53 (s, 0.5H).
Procedure 27: Synthesis of Compound 101
##STR00205##
[0714]
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-
-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one
hydrochloride: To a solution of
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-metho-
xy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one (10 mg, 0.02
mmol, 1 eq) in ACN (1.0 mL) was added 1M HCl (aqueous solution)
(0.04 mL, 0.04 mmol, 2 eq) at 0.degree. C. and the mixture was
stirred at 0.degree. C. for 15 min. After this time, reaction
mixture was diluted with water (2 mL), followed by cooled to
-78.degree. C. and lyophilize to get
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-metho-
xy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one hydrochloride.
LCMS (ES) m/z=497.3 [M+H]+excluding HCl salt mass.
[0715] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80 (t,
J=6.4 Hz, 3H), 1.19-1.21 (m, 6H), 1.47-1.60 (m, 7H), 1.75 (s, 5H),
2.07 (s, 3H), 2.64 (bs, 1H), 2.86-2.90 (m, 1H), 3.06-3.09 (m, 1H),
3.69-3.71 (m, 3H), 4.35 (s, 0.5H), 4.55 (bs, 0.5H), 4.65 (s, 0.5H),
4.72 (bs, 0.5H), 6.09 (s, 1H), 6.35 (bs, 0.5H), 6.78-6.84 (m, 2H),
7.15-7.30 (m, 2H), 7.41-7.47 (m, 2H), 7.60 (bs, 0.5H), 10.50-10.60
(m, 1H).
Procedure 28: Synthesis of Compound 97
##STR00206##
[0717]
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)quinoline-6-carboxamide: To a
solution of isoquinoline-6-carboxylic acid (0.735 g, 4.24 mmol, 1
eq) in DCM (10 mL) under nitrogen atmosphere was added
1-(3-methoxyphenyl)hexan-2-amine (0.968 g, 4.67 mmol, 1.1 eq) at
0.degree. C., stirred for 10 mins and then Propanephosphonic acid
anhydride (4.18 mL, 6.37 mmol, 1.5 eq) was added at 0.degree. C. to
the reaction mixture, stirred at 0.degree. C. for 15 mins and then
triethylamine (2.20 mL, 17 mmol, 4 eq) dissolved in DCM (10 mL) was
added to the reaction mixture at 0.degree. C. and then the reaction
mixture was stirred at room temperature for 2 h. TLC (40% EtOAc in
hexane) showed the reaction was completed after 2 h. The reaction
mixture was diluted with ethyl acetate (100 mL), washed with
saturated sodium bicarbonate solution (20 mL) and water (30 mL).
Organic layer was dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure to get
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)quinoline-6-carboxamide
crude. LCMS (ES) m/z=363 [M+H]+.
[0718]
(S)-6-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)quinolone: To
a solution of
N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]quinoline-6-carboxamide (1 g,
2.76 mmol, 1 eq) in DCM (10 mL) under nitrogen atmosphere was added
2-Chloropyridine (0.783 mL, 8.28 mmol, 3 eq) at room temperature.
Then trifluoromethanesulfonic anhydride (1.39 mL, 8.28 mmol, 3 eq)
was added at -78.degree. C., stirred for 5 mins, then warmed to
0.degree. C., stirred for 30 mins at 0.degree. C. and then the
reaction mixture was stirred at room temperature for 1 h. TLC (5%
MeOH in DCM) showed starting material along with new spots.
Reaction was monitored by LCMS. The reaction mass was concentrated
under reduced pressure to obtain the crude residue, obtained
residue was quenched with 10% sodium hydroxide solution (15 mL),
extracted with (2.times.150 mL) DCM, combined organic layers were
dried with anhydrous Na2SO4, filtered and concentrated under
reduced pressure to get crude product, which was purified by flash
column chromatography using 5% MeOH in DCM as an eluent to obtain
6-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]quinoline.
LCMS (ES) m/z=345 [M+H]+.
[0719] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.90 (t,
J=7.2 Hz, 3H), 1.46 (s, 1H), 1.61 (t, J=6.4 Hz, 3H), 1.73 (s, 2H),
2.65 (s, 1H), 2.80-2.83 (m, 1H), 3.42 (d, J=11.2 Hz, 1H), 3.80 (s,
3H), 6.83 (d, J=8.8 Hz, 1H), 6.95 (s, 1H), 7.17 (d, J=8.8 Hz, 1H),
7.54-7.57 (m, 1H), 7.91-8.10 (m, 3H), 8.45 (d, J=7.6 Hz, 1H), 8.93
(d, J=2.8 Hz, 1H).
[0720]
6-((3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)quinol-
one: To a stirred solution of
(S)-6-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)quinoline (0.5
g, 1.45 mmol, 1 eq) in MeOH (10 mL) was added sodium borohydride
(0.165 g, 4.35 mmol, 3 eq) at 0.degree. C. and the reaction was
stirred at room temperature for 1 h. Reaction was monitored by TLC
(70% EtOAc in hexane). Reaction was completed after this time. The
reaction was concentrated under reduced pressure to remove methanol
and the crude obtained was dissolved in EtOAc (100 mL) and was
washed with water (10 mL). Organic layer was dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
afford
6-((3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)quinoline.
LCMS (ES) m/z=347.2 [M+H]+.
[0721]
1-((3S)-3-butyl-6-methoxy-1-(quinolin-6-yl)-3,4-dihydroisoquinolin--
2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: Step 1: To
3-(trimethylsilyl)propiolic acid (0.195 g, 1.37 mmol, 1 eq) in DMF
(0.004 mL, 0.054 mmol, 0.04 eq) was added oxalyl chloride (0.13 mL,
1.51 mmol, 1.1 eq) at room temperature and the reaction was stirred
at room temperature for 30 mins. After this time the reaction
mixture was concentrated under reduced pressure to afford
3-(trimethylsilyl)propioloyl chloride and the same was taken for
the next step.
[0722] Step 2: To a stirred solution of
6-((3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)quinoline
(0.35 g, 1.01 mmol, 1 eq) in ACN (8.0 mL) was added sodium
bicarbonate (0.64 g, 7.58 mmol, 7.5 eq) at 0.degree. C., stirred at
0.degree. C. for 15 mins and then 3-(trimethylsilyl)propioloyl
chloride (0.19 g, 1.21 mmol, 1.2 eq) in ACN (2.0 mL) was added at
0.degree. C. and the reaction was stirred at room temperature for
30 mins. Reaction was monitored by TLC (70% EtOAc in hexane). After
this time the reaction mixture was diluted with EtOAc (100 mL) and
was washed with water (10 mL). Organic layer was dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to afford
1-((3S)-3-butyl-6-methoxy-1-(quinolin-6-yl)-3,4-dihydroisoquinolin-2(1H)--
yl)-3-(trimethylsilyl)prop-2-yn-1-one. LCMS (ES) m/z=471.3
[M+H]+.
[0723]
1-((1S,3S)-3-butyl-6-methoxy-1-(quinolin-6-yl)-3,4-dihydroisoquinol-
in-2(1H)-yl)prop-2-yn-1-one: To a stirred solution of
1-((3S)-3-butyl-6-methoxy-1-(quinolin-6-yl)-3,4-dihydroisoquinolin-2(1H)--
yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.53 g, 1.13 mmol, 1 eq) in
methanol (4 mL) and DCM (30 mL) was added potassium carbonate (0.93
g, 6.76 mmol, 6 eq) at 0.degree. C. and the reaction was stirred at
0.degree. C. for 1 h. Reaction was monitored by TLC (50% EtOAc in
hexane). After this time, the reaction mixture was diluted with
water (10 mL) and extracted with DCM (150 mL). Organic layer was
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure to get crude. The crude was purified twice
by preparative TLC using 50% EtOAc in hexane as an eluent (eluted
twice) to afford
1-((1S,3S)-3-butyl-6-methoxy-1-(quinolin-6-yl)-3,4-dihydroisoquinolin-2(1-
H)-yl)prop-2-yn-1-one. LCMS (ES) m/z=399.2 [M+H]+.
[0724] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.82 (t,
J=7.0 Hz, 3H), 1.20-1.21 (m, 4H), 1.53 (bs, 2H), 2.80-2.84 (m, 1H),
2.90-2.94 (m, 1H), 3.68-3.70 (m, 3H), 4.25 (s, 0.38H), 4.62 (s,
0.73H), 4.68 (bs, 0.6H), 4.82 (bs, 0.8H), 6.21 (s, 0.6H), 6.49 (s,
0.4H), 6.77-6.86 (m, 2H), 7.44-7.52 (m, 2H), 7.71 (t, J=7.2 Hz,
1.5H), 7.79-7.91 (m, 2.5H), 8.28-8.36 (m, 1H), 8.78-8.82 (m,
1H).
Procedure 29: Synthesis of Compound 27
##STR00207## ##STR00208##
[0726] ethyl 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoate: To a
solution of ethyl 4-iodobenzoate (30 g, 109 mmol, 1 eq) in
1,4-Dioxane (500 mL) was added adamantan-1-amine (19.7 g, 130 mmol,
1.2 eq), cesium carbonate (70.8 g, 217 mmol, 2 eq),
dicyclohexyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane
(2.59 g, 5.43 mmol, 0.05 eq) at room temperature and the reaction
mixture was purged under nitrogen atmosphere for 30 min. Then
tris(dibenzylideneacetone)dipalladium (2.99 g, 3.26 mmol, 0.03 eq)
was added to the mixture at room temperature. Then reaction mixture
was allowed to warm to 110.degree. C. for 16 h in a sealed tube.
Progress of the reaction was monitored by TLC (10% EtOAc in
n-hexane). After completion of the reaction, reaction mixture was
cooled to room temperature and passed through celite bed and the
filtrate was concentrated under reduced pressure to get crude.
Obtained crude was extracted with EtOAc (500 mL) and washed with
water (100 mL) and brine solution (100 mL). Organic layer was dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to get crude product. The obtained crude product
was purified by flash column chromatography on silica gel using
6-7% ethyl acetate in hexane. Fractions containing product was
combined and concentrated under reduced pressure to get ethyl
4-[(adamantan-1-yl)amino]benzoate. LCMS (ES) m/z=300.2 [M+H]+.
[0727] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.25 (t, J=8
Hz, 3H), 1.48 (s, 6H), 1.90 (s, 6H), 2.04 (s, 3H), 4.15-4.22 (m,
2H), 5.95 (s, 1H), 6.73 (d, J=8 Hz, 2H), 7.59 (d, J=8 Hz, 2H).
[0728] 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoic acid: To a
solution of ethyl 4-[(adamantan-1-yl)amino]benzoate (8.20 g, 27.4
mmol, 1 eq) in ethanol (140 mL) was added sodium hydroxide (2.25 g,
54.8 mmol, 2 eq) in water (52 mL) at 0.degree. C. Then reaction
mixture was allowed to warm to 80.degree. C. and stirred for 6 h.
Progress of the reaction was monitored by TLC (5% Methanol in DCM).
After completion of the reaction, reaction mixture was cooled to
room temperature and organic solvent was removed under reduced
pressure. Then, the resulting residue was acidified with 1 N HCl
(pH=2) and extracted with DCM (200 mL). Organic layer was dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to get 4-[(adamantan-1-yl)amino]benzoic acid. LCMS
(ES) m/z=272.2 [M+H]+.
[0729] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.60-1.67
(m, 6H), 1.89 (d, J=9.2 Hz, 6H), 2.04 (s, 3H), 5.91 (s, 1H), 6.71
(d, J=8 Hz 2H), 7.57 (d, J=8.8 Hz, 2H), 12.21 (s, 1H).
[0730]
4-(((3R,5R,7R)-adamantan-1-yl)amino)-N--((S)-1-(3-methoxyphenyl)hex-
an-2-yl)benzamide: To a solution of
4-[(adamantan-1-yl)amino]benzoic acid (3.6 g, 13.5 mmol, 1 eq) in
DCM (25 mL) was added triethylamine (7.5 mL, 54.0 mmol, 4 eq) and
the reaction mixture was cooled to 0.degree. C.
Tripropyl-1,3,5,2.lamda..sup.5,4.lamda..sup.5,6.lamda..sup.5-trioxatripho-
sphinane-2,4,6-trione (12.0 mL, 20.3 mmol, 1.5 eq) was added to the
reaction mixture at 0.degree. C. and stirred for 30 min. Then a
solution of (2S)-1-(3-methoxyphenyl)hexan-2-amine (2.8 g, 13.5
mmol, 1 eq) in DCM (5 mL) was added to the reaction mixture.
Followed by the addition, reaction mixture was warmed to room
temperature then stirred for 16 h. Progress of the reaction was
monitored by TLC (5% MeOH in DCM). After completion of the
reaction, reaction mixture was diluted with DCM (400 mL) and
saturated sodium bicarbonate (50 mL). Organic layer was separated,
washed with brine solution (25 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. The
obtained crude product was purified by flash column chromatography
on silica gel using 20-27% ethyl acetate in hexane. Fractions
containing product was combined and concentrated under reduced
pressure to get
4-[(adamantan-1-yl)amino]-N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]benzamide-
. LCMS (ES) m/z=461.3 [M+H]+.
[0731] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80 (s,
3H), 1.13-1.22 (m, 4H), 1.46 (s, 2H), 1.64 (s, 5H), 1.89 (s, 5H),
2.05 (s, 4H), 2.65-2.78 (m, 2H), 3.57 (s, 3H), 4.00-4.09 (m, 2H),
5.53 (s, 1H), 5.74 (s, 1H), 6.71 (t, J=4 Hz, 4H), 7.13 (d, J=8 Hz,
1H), 7.57 (d, J=4 Hz, 2H), 7.65 (d, J=8 Hz, 1H).
[0732]
(3R,5R,7R)--N-(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl-
)phenyl)adamantan-1-amine: To a solution of
4-[(adamantan-1-yl)amino]-N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]benzamide
(1.92 g, 4.17 mmol, 1 eq) in DCM (25 mL) was added 2-chloropyridine
(1.18 mL, 12.5 mmol, 3 eq) at room temperature and the reaction
mixture was cooled to -78.degree. C. and trifluoromethanesulfonyl
trifluoromethanesulfonate (2.97 mL, 12.5 mmol, 3 eq) was added to
the mixture at -78.degree. C. and stirred. After 10 min, reaction
mixture was placed in an ice-water bath and warmed to 0.degree. C.
for 10 min. Then resulting solution was allowed to warm to room
temperature and stirred for 1 hr. Progress of the reaction was
monitored by TLC (70% EtOAc in n-hexane). After completion of the
reaction, reaction mixture was quenched with 1M NaOH (10 mL) at
0.degree. C. and then diluted with DCM (50 mL) and extracted with
DCM (100 mL) and washed with water (5 mL). Organic layer was dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to get crude product. The obtained crude product
was purified by flash column chromatography on silica gel using
56-65% ethyl acetate in hexane. Fractions containing product was
combined and concentrated under reduced pressure to afford
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}adamantan-
-1-amine. LCMS (ES) m/z=443.3 [M+H]+.
[0733]
(3R,5R,7R)--N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoqu-
inolin-1-yl)phenyl)adamantan-1-amine: To a solution of
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}adamantan-
-1-amine (0.4 g, 0.904 mmol, 1 eq) in methanol (10 mL) was added
sodium borohydride (0.103 g, 2.71 mmol, 3 eq) portion wise at
0.degree. C. The suspension was stirred at room temperature for 30
min. Progress of the reaction was monitored by TLC (5% MeOH in
DCM). Then the reaction mixture was concentrated and obtained crude
was diluted with EtOAc (50 mL) and water (10 mL). Organic layer was
separated, washed with brine solution (10 mL), and dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain the crude product. The obtained crude product
was purified by preparative TLC using 60% ethyl acetate in n-hexane
as eluent to get
N-{4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]cycloh-
exyl}adamantan-1-amine. LCMS (ES) m/z=445.3 [M+H]+.
[0734] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.12-1.31
(m, 9H), 1.59 (s, 6H), 1.80 (s, 6H), 2.03 (d, J=3H), 3.27 (s, 1H),
3.69 (s, 3H), 6.62 (t, J=8 Hz 4H), 6.74 (t, J=8.8 Hz, 3H).
[0735]
1-((1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)amino)phenyl)-3-butyl-6-
-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-chloroethan-1-one: To a
solution of
N-{4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl-
}adamantan-1-amine (0.030 g, 0.067 mmol, 1 eq) in DCM (5 mL) was
added sodium bicarbonate (8.5 mg, 0.101 mmol, 1.5 eq) and cooled to
0.degree. C. and stirred for 10 minutes. After that 2-Chloro acetyl
chloride (0.003 mL, 0.067 mmol, 1 eq) was added at 0.degree. C. and
warmed to room temperature stirred for 30 minutes. Progress of the
reaction was monitored by TLC (70% EtOAc in n-hexane). After
completion of the reaction, reaction mixture was quenched with 1M
NaOH (5 mL) at 0.degree. C. and then diluted with DCM (5 mL) and
extracted with DCM (100 mL) and washed with water (5 mL).
[0736] Organic layer was dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to get crude
product. The obtained crude product was purified by preparative TLC
using 70% ethyl acetate in n-hexane as an eluent. Product fraction
was collected and concentrated under reduced pressure to get
1-[(1S,3S)-1-{4-[(adamantan-1-yl)amino]phenyl}-3-butyl-6-methoxy-1,2,3,4--
tetrahydroisoquinolin-2-yl]-2-chloroethan-1-one. LCMS (ES)
m/z=521.5 [M+H]+.
[0737] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.78 (s,
3H), 1.29 (d, J=6.8 Hz, 6H), 1.40 (bs, 2H), 1.58 (s, 3H), 1.78 (s,
3H), 1.99 (s, 2H), 2.15 (bs, 1H), 2.65-2.83 (m, 3H), 3.69 (s, 3H),
3.79-3.82 (m, 1H), 4.47-4.93 (m, 5H), 5.89-5.93 (m, 1H), 6.56-6.65
(m, 2H), 6.76 (d, J=8 Hz, 2H), 6.87 (s, 2H), 7.36 (d, J=8 Hz,
1H).
Procedure 30: Synthesis of Compound 102
##STR00209## ##STR00210##
[0739] methyl 4-(cyclobutanecarboxamido)benzoate: To a solution of
Cyclobutanecarboxylic acid (3.64 g, 36.4 mmol, 1.1 eq) in DCM (15
mL) was added TEA (18.4 mL, 132 mmol, 4 eq.), stirred for 5 min and
then T3P (50 wt. % in EtOAc) (15.0 mL, 49.6 mmol, 1.5 eq) was added
at 0.degree. C. and stirred for another 30 min. Then a solution of
methyl 4-aminobenzoate (5.0 g, 33.1 mmol, 1 eq) in DCM (10 mL) was
added to the reaction mixture at 0.degree. C. and then reaction
mixture was stirred at room temperature for 16 h. Progress of the
reaction was monitored by TLC (30% ethyl acetate in n-hexane).
After this time, the reaction mixture was diluted with DCM
(2.times.100 mL) and saturated sodium bicarbonate solution (15 mL).
Organic layer was separated, washed with water (10 mL), brine
solution (10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to get methyl
4-cyclobutaneamidobenzoate. LCMS (ES) m/z=234.1 [M+H]+.
[0740] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.77-1.97
(m, 2H), 2.07-2.17 (m, 2H), 2.22-2.47 (m, 2H), 3.10-3.22 (m, 1H),
3.78 (s, 3H), 7.10 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 10.05
(s, 1H).
[0741] 4-(cyclobutanecarboxamido)benzoic acid: To a solution of
methyl 4-cyclobutaneamidobenzoate (3.50 g, 15 mmol, 1 eq) in EtOH
(15.0 mL) and water (7.5 mL) was added sodium hydroxide (1.20 g,
30.0 mmol, 2 eq) at room temperature and the reaction mixture was
stirred at 80.degree. C. for 16 h. Progress of the reaction was
monitored by TLC (30% ethyl acetate in hexane). After completion of
the reaction, the reaction mixture was concentrated under reduced
pressure to remove ethanol from reaction mass and the remaining
aqueous layer was extracted with EtOAc (20 mL). Finally, the
aqueous layer was acidified with 5% citric acid (pH .about.4) and
then product was extracted with EtOAc (2.times.80 mL). Organic
layer was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to get the product which was
triturated with n-pentane (10 mL) for 5 minutes, decanted the
pentane layer and dried under high vacuum to afford
4-cyclobutaneamidobenzoic acid. LCMS (ES) m/z=220.3 [M+H]+.
[0742]
(S)-4-(cyclobutanecarboxamido)-N-(1-(3-methoxyphenyl)hexan-2-yl)ben-
zamide: To a solution of 4-cyclobutaneamidobenzoic acid (2.12 g,
9.65 mmol, 1 eq) in DCM (15 mL) under nitrogen atmosphere was added
triethylamine (5.42 mL, 38.6 mmol, 4 eq) at 0.degree. C., stirred
for 10 mins and then propanephosphonic acid anhydride (50 wt. % in
ethyl acetate) (4.6 g, 14.5 mmol, 1.5 eq) was added at 0.degree. C.
to the reaction mixture, stirred at 0.degree. C. for 15 mins and
then (2S)-1-(3-methoxyphenyl)hexan-2-amine (2 g, 9.65 mmol, 1 eq)
dissolved in DCM (5 mL) was added to the reaction mixture at
0.degree. C. and then the reaction mixture was stirred at room
temperature for 16 h. TLC (50% EtOAc in hexane) showed the reaction
was completed after 16 h. The reaction mixture was diluted with DCM
(80 mL), washed with saturated sodium bicarbonate solution (20 mL)
and water (10 mL). Organic layer was dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure to get
4-cyclobutaneamido-N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]benzamide-
. LCMS (ES) m/z=409.3 [M+H]+.
[0743]
(S)--N-(4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)cyc-
lobutanecarboxamide: To a solution of
4-cyclobutaneamido-N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]benzamide
(0.1 g, 0.245 mmol, 1 eq) in DCM (5 mL) was added 2-chloropyridine
(0.046 mL, 0.490 mmol, 2 eq) at room temperature and the reaction
mixture was cooled to -78.degree. C. and trifluoromethanesulfonyl
trifluoromethanesulfonate (0.082 mL, 0.49 mmol, 2 eq) was added to
the mixture at -78.degree. C. and stirred. After 10 min, reaction
mixture was placed in an ice-water bath and warmed to 0.degree. C.
for 10 min. Then resulting solution was allowed to warm to room
temperature and stirred for 1 h. Progress of the reaction was
monitored by TLC (70% EtOAc in n-hexane). After completion of the
reaction, reaction mixture was quenched with 1M NaOH (5 mL) at
0.degree. C. and then diluted with DCM (5 mL) and extracted with
DCM (25 mL) and washed with water (5 mL). Organic layer was dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to afford
(S)--N-(4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)cy-
clobutanecarboxamide. LCMS (ES) m/z=391.3 [M+H]+.
[0744]
N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-
phenyl)cyclobutanecarboxamide: To a solution of
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}cyclobuta-
necarboxamide (1.40 g, 3.58 mmol, 1 eq) in MeOH (20 mL) under
nitrogen atmosphere was added sodium borohydride (0.396 g, 10.8
mmol, 3 eq) at 0.degree. C. and then the reaction mixture was
stirred at room temperature for 1 h. Reaction was monitored by TLC
(70% EtOAc in hexane) and LC-MS. After completion of the reaction,
reaction mixture was quenched with acetone and concentrated under
reduced pressure then extracted with EtOAc (50 mL) and washed with
water (10 mL). Organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to get
crude product. The obtained crude product was purified by flash
column chromatography with 45-55% ethyl acetate in hexane as an
eluent. Fractions containing product was combined and concentrated
under reduced pressure to get a crude of cis and trans mixture.
Again the crude was purified by preparative TLC using 60% ethyl
acetate in n-hexane as eluent to get
N-{4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl-
}cyclobutanecarboxamide. LCMS (ES) m/z=393.3 [M+H]+.
[0745]
N-(4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,-
2,3,4-tetrahydroisoquinolin-1-yl)phenyl)cyclobutanecarboxamide:
Step 1: To a solution of 3-(trimethylsilyl)propiolic acid (0.1 g,
0.703 mmol, 1 eq) in DMF (0.002 mL, 0.028 mmol, 0.04 eq) was added
oxalyl chloride (0.072 mL, 0.844 mmol, eq) at room temperature and
stirred for 30 minutes. Then reaction mixture was concentrated
under reduced pressure to get 3 (trimethylsilyl)propioloyl
chloride.
[0746] Step 2: To a solution of
N-{4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl-
}cyclobutanecarboxamide (0.2 g, 0.509 mmol, 1 eq) in acetonitrile
(7.0 mL) was added sodium bicarbonate (0.325 g, 3.82 mmol, 7.5 eq)
at 0.degree. C. After stirring for 5 minutes, a solution of
3-(trimethylsilyl)propioloyl chloride (0.123 g, 0.764 mmol, 1.5
equiv.) in acetonitrile (3 mL) was added to the above reaction mass
at 0.degree. C. The resulting mixture was stirred at 0.degree. C.
for 45 min, progress of the reaction was monitored by TLC (25%
ethyl acetate in n-hexane). After this time, reaction mass was
diluted with EtOAc (20 mL) and water (5 mL). Organic layer was
separated, washed with brine solution (7.0 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain the crude product. LCMS (ES) m/z=517.3
[M+H]+.
[0747]
N-(4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoq-
uinolin-1-yl)phenyl)cyclobutanecarboxamide: To a solution of
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-[3-(trimethylsilyl)prop-2-ynoyl]-1,2,3,-
4-tetrahydroisoquinolin-1-yl]phenyl}cyclobutanecarboxamide (0.2 g,
0.387 mmol, 1 eq) in THF (5 mL) was added TBAF (1M solution in THF)
(0.968 mL, 0.968 mmol, 2.5 eq) at -78.degree. C. This reaction
mixture was stirred at -78.degree. C. for 15 minutes. Progress of
the reaction was monitored by TLC (25% ethyl acetate in n-hexane).
After this time, the reaction mixture was quenched with saturated
aqueous NaHCO.sub.3solution (10 mL) at -78.degree. C. and product
was extracted with ethyl acetate (2.times.50 mL). Combined organic
layers was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The obtained crude product was
purified by preparative TLC using 30% ethyl acetate in n-hexane as
an eluent. Product fraction was collected and concentrated under
reduced pressure to get
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2-ynoyl)-1,2,3,4-tetrahydroisoqui-
nolin-1-yl]phenyl}cyclobutanecarboxamide. LCMS (ES) m/z=445.2
[M+H]+.
[0748] .sup.1H NMR (400 MHZ, DMSO-d.sub.6) .delta. ppm: rotamer
pattern observed along with additional peaks (minor impurity).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.65-0.68 (m, 3H),
0.75 (bs, 1H), 1.09-1.11 (m, 4H), 1.25 (s, 1H), 1.54 (s, 1H),
1.78-1.86 (m, 1H), 1.89-1.93 (m, 1H), 2.05-2.07 (m, 2H), 2.20-2.25
(m, 2H), 2.63-2.66 (m, 0.5H), 2.99-3.01 (m, 0.5H), 3.13-3.18 (m,
1H), 3.74-3.76 (m, 3H), 4.04 (s, 0.5H), 4.53-4.59 (m, 1.5H),
6.50-6.55 (m, 1H), 6.77-6.79 (m, 0.5H), 6.84 (s, 1H), 6.90-6.94 (m,
2H), 7.03 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 0.5H), 7.47-7.54
(m, 2H), 9.67-9.72 (m, 1H).
Procedure 31: Synthesis of Compound 96
##STR00211## ##STR00212##
[0750] tert-butyl
(S)-(3-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-y-
l)carbamate: To a solution of
3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylic
acid (2.3 g, 10.1 mmol, 1.05 eq) in DCM (30 mL) was added TEA (4.04
mL, 28.9 mmol, 3 eq), stirred for 5 min and then T3P (50 wt. % in
EtOAc) (4.85 mL, 14.5 mmol, 1.5 eq) was added at 0.degree. C. and
stirred for another 30 min. Then a solution of
(S)-1-(3-methoxyphenyl)hexan-2-amine (2 g, 9.65 mmol, 1 eq) in DCM
(10 mL) was added to the reaction mixture at 0.degree. C. and then
reaction mixture was stirred at room temperature for 16 h. Progress
of the reaction was monitored by TLC (40% ethyl acetate in
n-hexane). After this time, the reaction mixture was diluted with
DCM (50 mL), organic layer was washed with saturated aqueous
solution of sodium bicarbonate (2.times.10 mL), water (10 mL),
brine solution (10 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude product. Obtained crude was purified by flash chromatography
using 0-30% EtOAc in n-hexane as an eluent to give tert-butyl
(S)-(3-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-y-
l)carbamate. LCMS (ES) m/z=417.5 [M+H]+.
[0751] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.84 (bs, 3H),
1.27 (bs, 6H), 1.42 (s, 9H), 2.16 (s, 6H), 2.67-2.79 (m, 2H), 3.77
(s, 3H), 4.11 (bs, 1H), 4.92 (bs, 1H), 5.15 (d, J=8.4 Hz, 1H),
6.66-6.57 (m, 3H), 7.18 (t, J=8.0 Hz, 1H).
[0752]
(S)-3-amino-N-(1-(3-methoxyphenyl)hexan-2-yl)bicyclo[1.1.1]pentane--
1-carboxamide hydrochloride: To a solution of tert-butyl
(S)-(3-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)bicyclo[1.1.1]pentan-1-y-
l)carbamate (3 g, 7.20 mmol, 1 eq) in dichloromethane (50 mL) was
added 4 M HCl in 1,4-dioxane (5 mL) at 0.degree. C. The mixture was
allowed to warm at room temperature and stirred for 12 h. The
progress of the reaction was monitored by TLC (60% EtOAc in
hexane), after completion of the reaction, the reaction mixture was
concentrated under reduced pressure to obtain the crude, which was
triturated with mixture of diethyl ether (10 mL) and n-pentane (10
mL) and decanted the solvent, dried under reduced pressure to
obtain
(S)-3-amino-N-(1-(3-methoxyphenyl)hexan-2-yl)bicyclo[1.1.1]pentane-1-carb-
oxamide hydrochloride. LCMS (ES) m/z=317 [M+H]+.
[0753] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.81 (s,
3H), 1.09-1.21 (m, 4H), 1.37-1.40 (m, 2H), 2.05 (s, 6H), 2.56-2.64
(m, 2H), 3.7 (s, 3H), 3.84 (bs, 1H), 6.70-6.72 (m, 3H), 7.13 (t,
J=7.6 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 8.73 (bs, 3H).
[0754]
(S)--N-(3-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)bicyclo[1.1.1]p-
entan-1-yl)isonicotinamide: To a solution of
3-amino-N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]bicyclo[1.1.1]pentane-1-car-
boxamide hydrochloride (0.6 g, 1.70 mmol, 1 eq) &
pyridine-4-carboxylic acid (0.251 g, 2.04 mmol, 1.2 eq) in DCM (10
mL) was added triethylamine (1.32 mL, 10.2 mmol, 6 eq), stirred for
5 min and then T3P (50 wt. % in EtOAc) (2.03 mL, 3.40 mmol, 2 eq)
was added at 0.degree. C. and stirred for another 30 min and then
reaction mixture was stirred at room temperature for 3 h. Progress
of the reaction was monitored by TLC (60% ethyl acetate in
n-hexane). After this time, the reaction mixture was diluted with
DCM (20 mL), organic layer was washed with saturated aqueous
solution of sodium bicarbonate (2.times.10 mL), water (10 mL),
brine solution (10 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude product. The crude was purified by silica gel column
chromatography using 35-40% EtOAc in hexane as an eluent to afford
N-(3-{[(2S)-1-(3-methoxyphenyl)hexan-2-yl]carbamoyl}bicyclo[1.1.1]pentan--
1-yl)pyridine-4-carboxamide. LCMS (ES) m/z=422.3 [M+H]+
[0755]
(S)--N-(3-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)bicyclo[1.-
1.1]pentan-1-yl)isonicotinamide: To a stirred solution of
N-(3-{[(2S)-1-(3-methoxyphenyl)hexan-2-yl]carbamoyl}bicyclo[1.1.1]pentan--
1-yl)pyridine-4-carboxamide (0.4 g, 0.949 mmol, 1 eq) in DCM (10
mL) under nitrogen atmosphere was added 2-chloropyridine (0.18 mL,
1.90 mmol, 2 eq) at room temperature and the resulting reaction
mixture was cooled to -78.degree. C. and then trifluoromethane
sulfonic anhydride (0.32 mL, 1.90 mmol, 2 eq) was added dropwise.
The reaction mixture was then stirred at -78.degree. C. for 5 mins,
then warmed to 0.degree. C. and stirred for 10 mins, then warmed to
room temperature and stirred for 1.5 h. Reaction was monitored by
TLC (5% MeOH/DCM). After this time the reaction was neutralized
with 1N NaOH solution and was extracted with DCM (2.times.50 mL).
Combined organic layer was washed with water (10 mL), separated the
layers. Organic layer was dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude. Obtained crude was purified by flash chromatography using
15-20% EtOAc in n-hexane as an eluent to give to afford
N-{3-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]bicyclo[1.1.1]pe-
ntan-1-yl}pyridine-4-carboxamide. LCMS (ES) m/z=404.3 [M+H]+.
[0756]
N-(3-((3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bic-
yclo[1.1.1]pentan-1-yl)isonicotinamide: To a solution of
N-{3-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]bicyclo[1.1.1]pe-
ntan-1-yl}pyridine-4-carboxamide (0.27 g, 0.669 mmol, 1 eq) in
methanol (10 mL) was added sodium borohydride (0.076 g, 2.01 mmol,
3 eq) at 0.degree. C. portion wise. The suspension was stirred at
0.degree. C. for 3 h. After this time, the reaction mixture was
concentrated and obtained crude was diluted with EtOAc (50 mL) and
water (10 mL). Organic layer was separated, washed with brine
solution (5 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to afford
N-(3-((3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)bicyclo[1-
.1.1]pentan-1-yl)isonicotinamide. LCMS (ES) m/z=406.2 [M+H]+.
[0757]
N-(3-((3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3-
,4-tetrahydroisoquinolin-1-yl)bicyclo[1.1.1]pentan-1-yl)isonicotinamide:
Step 1: To a solution of 3-(trimethylsilyl)propiolic acid (0.05 g,
0.352 mmol, 1 eq) in DMF (0.001 mL, 0.014 mmol, 0.04 eq) was added
oxalyl chloride (0.033 mL, 0.387 mmol, 1.1 eq) at room temperature
and stirred for 30 minutes. After this time, reaction mixture was
concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride.
[0758] Step 2: To a solution of
N-{3-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]bicycl-
o[1.1.1]pentan-1-yl}pyridine-4-carboxamide (0.220 g, 0.542 mmol, 1
eq) in acetonitrile (3.0 mL) was added sodium bicarbonate (0.346 g,
4.07 mmol, 7.5 eq) at 0.degree. C. After stirring for 5 minutes, a
solution of 3-(trimethylsilyl)propioloyl chloride (0.131 g, 0.814
mmol, 1.5 eq) in acetonitrile (1.0 mL) was added to the above
reaction mass at 0.degree. C. The resulting mixture stirred at
0.degree. C. for 15 min, progress of the reaction was monitored by
TLC (5% MeOH/DCM). Desired product mass was observed in LCMS. After
this time, the reaction was quenched with saturated sodium
bicarbonate solution (10 ml), diluted with EtOAc (20 mL), stirred
at room temperature for 5 mins. Then the layers were separated.
Aqueous layer was extracted with EtOAc (2.times.50 mL). Combined
organic layer was washed with water (15 mL), separated the layers.
Then the organic layer was dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain product
N-{3-[(1S,3S)-3-butyl-6-methoxy-2-[3-(trimethylsilyl)prop-2-ynoyl]-1,2,3,-
4-tetrahydroisoquinolin-1-yl]bicyclo[1.1.1]pentan-1-yl}pyridine-4-carboxam-
ide. LCMS (ES) m/z=530.2 [M+H]+.
[0759]
N-(3-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoq-
uinolin-1-yl)bicyclo[1.1.1]pentan-1-yl)isonicotinamide: To a
stirred solution of
N-(3-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4--
tetrahydroisoquinolin-1-yl)bicyclo[1.1.1]pentan-1-yl)isonicotinamide
(0.25 g, 0.47 mmol, 1 eq) in Methanol (3 mL) and DCM (20 mL) was
added potassium carbonate (0.39 g, 2.83 mmol, 6 eq) at 0.degree. C.
and the reaction was stirred at 0.degree. C. for 1 h. Reaction was
monitored by TLC (5% MeOH-DCM) After this time, the reaction
mixture was diluted with water (10.0 mL) and extracted with DCM
(150 mL). Organic layer was dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to get crude. The
crude was purified twice by preparative TLC using 4% MeOH-DCM as an
eluent (eluted thrice) to isolate the desired product. It was
re-purified by preparative HPLC using the following condition.
(Analytical Conditions: Column: X-BridgeC-18 (250 mm.times.4.6
mm.times.5 .mu.m); mobile phase (A): 0.1% ammonia in water; mobile
phase (B): acetonitrile; flow rate: 1.0 mL/min; gradient B: 0/10,
12/60, 22/95, 25/95, 27/10, 30/10). Fractions obtained from
preparative HPLC was concentrated under reduced pressure and
lyophilized to afford
N-(3-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinoli-
n-1-yl)bicyclo[1.1.1]pentan-1-yl)isonicotinamide. LCMS (ES)
m/z=458.3 [M+H]+.
Procedure 32: Synthesis of Compound 54
##STR00213##
[0761]
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)-1-methylpiperidine-4-carboxa-
mide: To a solution of 1-methylpiperidine-4-carboxylic acid (0.64
g, 3.76 mmol, 1.2 eq) in DCM (20 mL) was added TEA (1.75 mL, 12.56
mmol, 4 eq), stirred for 15 min and then T3P (50 wt. % in EtOAc)
(9.9 mL, 4.71 mmol, 1.5 eq) was added at 0.degree. C. and stirred
for another 5 mins. Then (S)-1-(3-methoxyphenyl)hexan-2-amine (0.65
g, 3.14 mmol, 1 eq) was added to the reaction mixture and then
reaction mixture was stirred at room temperature for 16 h. The
progress of the reaction was monitored by TLC (70% ethyl acetate in
hexane). The reaction mixture was diluted with DCM (50 mL) and
saturated sodium bicarbonate solution (20 mL) Organic layer was
separated, washed with brine solution (20 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product, which was purified by silica gel flash
chromatography using 70% EtOAc/n-hexane as an eluent to give the
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)-1-methylpiperidine-4-carboxamide.
LCMS (ES) m/z=333 [M+H].sup.+
[0762] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80-0.90
(m, 3H), 1.18-1.30 (m, 6H), 1.39-1.52 (m, 4H), 1.73-1.82 (m, 2H),
1.92-1.96 (m, 1H), 2.12 (s, 3H), 2.58-2.65 (m, 2H), 2.70-2.75 (m,
2H), 3.69 (s, 3H), 3.86 (bs, 1H), 6.70-6.71 (m, 3H), 7.11-7.15 (m,
1H), 7.48 (d, J=7.6 Hz, 1H).
[0763]
(S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-3,4-dihydroisoquin-
oline: To a stirred solution of
(S)--N-(1-(3-methoxyphenyl)hexan-2-yl)-1-methylpiperidine-4-carboxamide
(0.3 g, 0.90 mmol, 1 eq) in POCl3 (0.1 mL, 1.08 mmol, 1.2 eq) was
stirred at 80.degree. C. for 1 hour, reaction progress was checked
by TLC monitoring, after completion of the reaction, reaction was
cooled to room temperature, reaction mass was concentrated under
reduced pressure to obtain the crude residue obtained residue was
basified with 10% aq NaOH solution (pH=8), aqueous layer was
extracted with (2.times.20) mL of Ethylacetate, combined organic
layers were dried with anhydrous Na2SO4, filtered and concentrated
under reduced pressure to get the
(S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinoline.
LC-MS (m/z)=315 [M+H].sup.+
[0764]
(3S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydr-
oisoquinoline: To a solution of tert-butyl
(S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinoline
(0.2 g, 0.63 mmol, 1.0 eq) in methanol (10 mL) was added sodium
borohydride (0.07 g, 1.91 mmol, 3 eq) portion wise at 0.degree. C.
The suspension was stirred at room temperature for 15 mins.
Progress of the reaction was monitored by TLC (10% MeOH in DCM).
After this time, the reaction mixture was concentrated and obtained
crude was diluted with EtOAc (15 mL) and water (8 mL). Organic
layer was separated, washed with brine solution (7 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain the crude product, which was purified by flash
column chromatography using 8% MeOH in DCM as mobile phase to get
(3S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoqu-
inoline. LCMS (ES) m/z=317 [M+H]+.
[0765] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.87 (bs,
3H), 1.21-1.45 (m, 10H), 2.11-2.14 (m, 3H), 1.76 (bs, 2H),
2.60-2.80 (m, 4H), 3.48 (bs, 1H), 3.67 (s, 3H), 3.91 (s, 1H), 6.30
(bs, 1H), 6.59-6.69 (m, 2H), 7.02-7.04 (m, 2H).
[0766]
1-((3S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-3,4-dihydroiso-
quinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First step:
To a solution of 3-(trimethylsilyl)propiolic acid (0.1 g, 0.70
mmol, 1.0 eq) in DMF (0.002 mL, 0.028 mmol, 0.04 eq) was added
oxalyl chloride (0.065 mL, 0.77 mmol, 1.1 eq) at room temperature
and stirred for 30 minutes. After this time, reaction mixture was
concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. Obtained acid chloride was
carried to next step without any further purification.
[0767] Second step: To a solution of
(3S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoqu-
inoline (0.18 g, 0.5696 mmol, 1.0 eq) in acetonitrile (10 mL) was
added sodium bicarbonate (0.35 g, 4.27 mmol, 7.5 eq) at 0.degree.
C. After stirring for 5 minutes, a solution of
3-(trimethylsilyl)propioloyl chloride (0.109 g, 0.62 mmol, 1.2 eq)
in acetonitrile (5 mL) was added to the above reaction mass at
0.degree. C. The resulting mixture stirred at 0.degree. C. for 15
min, progress of the reaction was monitored by TLC (5% MeOH in
DCM). After this time, reaction mass was diluted with EtOAc (40 mL)
and water (8 mL). Organic layer was separated, washed with brine
solution (7 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to obtain the crude product, it
was carried to next step without any further purification. LCMS
(ES) m/z=441 [M+H]+.
[0768]
1-((3S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-3,4-dihydroiso-
quinolin-2(1H)-yl)prop-2-yn-1-one: To a solution of
1-((3S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-3,4-dihydroisoquinol-
in-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.2 g, 0.45 mmol,
1.0 eq) in MeOH (15 mL) was added K.sub.2CO.sub.3 (0.187 g, 1.36
mmol, 3 eq) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 15 mins to give a white solution. Progress of the
reaction was monitored by TLC (10% MeOH in DCM). After this time,
the reaction mixture was diluted with DCM (5 mL) and water (5 mL).
Organic layer was separated, dried over Na2SO4 and concentrated
under reduced pressure to obtain the crude product, which was
purified by following preparative HPLC conditions. Analytical
Conditions: column: X-BridgeC-18 (250 mm.times.4.6 mm.times.5
.mu.m); mobile phase (A): 0.1% ammonia in water; mobile phase (B):
CAN; flow rate: 1.0 mL/min.
[0769] Product fractions collected and concentrated under reduced
pressure to get
1-((3S)-3-butyl-6-methoxy-1-(1-methylpiperidin-4-yl)-3,4-dihydrois-
oquinolin-2(1H)-yl)prop-2-yn-1-one. LCMS (ES) m/z=369 [M+H]+.
[0770] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.80-0.87 (m,
3H), 1.15-1.20 (m, 2H), 1.22-1.32 (m, 4H), 1.60-1.66 (m, 3H),
1.72-1.77 (m, 2H), 1.95-2.04 (m, 1H), 2.07-2.08 (m, 3H), 2.73-2.80
(m, 2H), 3.06-3.17 (m, 2H), 3.71 (s, 3H), 3.90 (bs, 1H), 4.08 (bs,
1H), 4.53-4.55 (m, 1H), 4.91-4.93 (m, 1H), 6.67-6.72 (m, 1H), 6.81
(s, 1H), 7.00-7.05 (m, 1H).
Procedure 33: Synthesis of Compound 99
##STR00214## ##STR00215## ##STR00216##
[0772] methyl 4-((((3s,5s,7s)-adamantan-1-yl)amino)methyl)benzoate:
To a stirred solution of (3s,5s,7s)-adamantan-1-amine (1.98 g, 13.1
mmol, 1.0 eq) in DMF (30.0 mL) at 0.degree. C., potassium carbonate
(2.71 g, 19.6 mmol, 1.5 eq) added. After stirring for 5 minutes
methyl 4-(bromomethyl)benzoate (2.7 g, 11.8 mmol, 0.9 eq) added.
Then reaction mixture was allowed to stirred at 80.degree. C. for 2
h. After completion of the reaction, reaction mixture was cool to
room temperature, Reaction mixture was diluted with water (30 mL),
extracted in to ethyl acetate (2.times.30 mL). Combined organic
layer was washed with cool water (40 mL), brine (20 mL), dried over
anhydrous sodium sulphate. Organic layer was filtered and
concentrated under reduced pressure to get crude product, which was
purified by flash column chromatography on silica gel using ethyl
acetate in hexane as eluent. Product was isolated at 15-20% ethyl
acetate in hexane. Product fractions collected and concentrated
under reduced pressure to get methyl
4-((((3s,5s,7s)-adamantan-1-yl)amino)methyl)benzoate. LCMS (ES)
m/z=300 [M+H]+.
[0773] methyl
4-{[(adamantan-1-yl)[(tert-butoxy)carbonyl]amino]methyl}benzoate:
To a solution of methyl 4-{[(adamantan-1-yl)amino]methyl}benzoate
(3 g, 10.0 mmol, 1 eq) in THF (30 mL) was added
N,N-diisopropylethylamine (5.25 mL, 30.1 mmol, 3 eq) and
di-tert-butyl dicarbonate (6.91 mL, 30.1 mmol, 3 eq) at 0.degree.
C. The reaction was stirred at room temperature for 16 h. TLC (30%
EtOAc in hexane) showed the reaction was completed. After this
time, reaction mixture was concentrated under reduced pressure and
obtained crude was diluted with saturated aqueous NaHCO.sub.3
solution (15 mL) and ethyl acetate (30 mL). Organic layer was
separated, washed with water (20 mL), brine solution (10 mL), dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure to get crude (9 g), which was purified by flash
chromatography using 0-25% EtOAc in hexane as an eluent to give
methyl
4-{[(adamantan-1-yl)[(tert-butoxy)carbonyl]amino]methyl}benzoate.
LCMS (ES) m/z=300 [M+H]+, Boc group cleaved mass was observed.
[0774] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.42 (s, 9H),
1.52-1.72 (m, 6H), 1.98-2.03 (m, 3H), 1.52-1.72 (m, 6H), 2.16-2.19
(m, 3H), 4.62-4.67 (m, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.97 (d, J=6.8
Hz, 2H).
[0775]
4-((((3s,5s,7s)-adamantan-1-yl)(tert-butoxycarbonyl)amino)methyl)be-
nzoic acid: To a solution of methyl
4-((((3s,5s,7s)-adamantan-1-yl)(tert-butoxycarbonyl)amino)methyl)benzoate
(3 g, 7.51 mmol, 1 eq) in MeOH (30 mL) and water (15 mL) was added
sodium hydroxide (0.616 g, 15 mmol, 2.0 eq) at room temperature and
the reaction mixture was stirred at 80.degree. C. for 12 h.
Progress of the reaction was monitored by TLC (60% E.A in hexane).
After completion of the reaction, the reaction mixture was
concentrated under reduced pressure to remove Methanol from
reaction mass and the remaining aqueous layer was extracted with
EtOAc (50 mL). Finally the aqueous layer was acidified with 5%
citric acid (pH=4) and then product was extracted with EtOAc (250
mL). Organic layer was dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to get the product
which was triturated with n-pentane (20 mL), decanted the pentane
layer and dried under high vacuum to afford
4-((((3s,5s,7s)-adamantan-1-yl)(tert-butoxycarbonyl)amino)methyl)benzoic
acid. LCMS (ES) m/z=286 [M+H]+(without boc mass was observed).
[0776] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 1.33 (s,
9H), 1.88-2.20 (m, 9H), 4.58 (s, 2H), 7.28 (d, J=8 Hz, 2H), 7.87
(d, J=8 Hz, 2H), 12.79 (bs, 1H).
[0777]
4-((((1R,3R)-adamantan-1-yl)amino)methyl)-N--((S)-1-(3-methoxypheny-
l)hexan-2-yl)benzamide: To a solution of
4-((((3s,5s,7s)-adamantan-1-yl)(tert-butoxycarbonyl)amino)methyl)benzoic
acid (2.66 g, 6.27 mmol, 1.1 eq) in DCM (20 mL) was added TEA (2.63
mL, 18.8 mmol, 3 eq), stirred for 5 min and then T3P (50 wt. % in
EtOAc) (3.15 mL, 9.41 mmol, 1.5 eq) was added at 0.degree. C. and
stirred for another 30 min. Then a solution of
(S)-1-(3-methoxyphenyl)hexan-2-amine (1.3 g, 6.27 mmol, 1 eq) in
DCM (10 mL) was added to the reaction mixture at 0.degree. C. and
then reaction mixture was stirred at room temperature for 12 h.
Progress of the reaction was monitored by TLC (60% ethyl acetate in
n-hexane). After this time, the reaction mixture was diluted with
DCM (50 mL), organic layer was washed with saturated aqueous
solution of sodium bicarbonate (2.times.10 mL), water (10 mL),
brine solution (10 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude product, which was purified by flash chromatography using
25-30% EtOAc in n-hexane as an eluent to give
4-((((1R,3R)-adamantan-1-yl)amino)methyl)-N--((S)-1-(3-methoxyphenyl)hexa-
n-2-yl)benzamide. LCMS (ES) m/z=576 [M+H]+.
[0778] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80-0.87
(m, 3H), 1.12-1.35 (m, 9H), 1.52 (bs, 5H), 1.97-2.03 (m, 6H), 2.74
(bs, 1H), 3.64 (s, 3H), 4.11 (bs, 1H), 3.8 (bs, 1H), 4.11 (bs, 1H),
4.55 (bs, 2H), 6.70-6.76 (m, 2H), 7.13-7.22 (m, 3H), 7.71 (m, 1H),
8.09 (bs, 1H).
[0779]
N-({4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}me-
thyl)adamantan-1-amine: To stirred solution of
4-((((1R,3R)-adamantan-1-yl)amino)methyl)-N--((S)-1-(3-methoxyphenyl)hexa-
n-2-yl)benzamide (2.2 g, 3.83 mmol, 1 eq) and 2-chloropyridine (3.6
mL, 38.32 mmol, 10.0 eq) in dichloromethane (5 mL) was added
trifluoromethanesulfonic anhydride (1.9 mL, 11.49 mmol, 3.0 eq) via
syringe slowly dropwise at -78.degree. C. After 5 min, the reaction
mixture was placed in an ice-water bath and warmed to 0.degree. C.
After 5 min, the resulting solution was allowed to warm to
23.degree. C. for 1 h. Progress of the reaction was monitored by
TLC (30% EA in hexane). After 30 minutes, reaction was quenched
with aqueous sodium hydroxide solution (3 mL, 1N) to neutralize the
trifluoromethanesulfonate salts. Dichloromethane (15 mL) was added
to dilute the mixture and the layers were separated. The aqueous
layer was extracted with DCM (2.times.50 mL). The combined organic
layer was washed with brine (5 mL), was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to give
the crude product. LCMS (ES) m/z=457 [M+H]+.
[0780] tert-butyl
N-(adamantan-1-yl)-N-({4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-
-yl]phenyl}methyl)carbamate: To a stirred solution of
(1R,3R)--N-(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)benzyl)a-
damantan-1-amine (2.1 g, 4.60 mmol, 1.0 eq) in THF (20.0 mL) at
0.degree. C. was added DIPEA (2.46 mL, 13.8 mmol, 3.0 eq) followed
by boc anhydride (3.17 mL, 13.8 mmol, 3.0 eq). Then reaction
mixture was allowed to stir at room temperature for 16 h. Reaction
mixture was diluted with water (25 mL), extracted with ethyl
acetate (2.times.30 mL). Combined organic layer was washed with
water (20 mL), brine (20 mL), dried over anhydrous sodium sulphate.
Organic layer was filtered and concentrated under reduced pressure
to get crude product, which was purified by silica gel column
chromatography 30% ethylacetate in hexane as an eluent to give the
tert-butyl
((1R,3R)-adamantan-1-yl)(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin--
1-yl)benzyl)carbamate. LCMS (ES) m/z=557 [M+H]+
[0781] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.89 (t,
J=7.2 Hz, 3H), 1.3 (s, 9H), 1.54-1.65 (m, 9H), 1.99-2.10 (m, 9H),
2.4-2.6 (m, 2H), 2.74-2.77 (m, 1H), 3.78 (s, 3H), 4.58 (s, 2H),
6.79-6.81 (m, 1H), 6.90 (s, 1H), 7.07-7.09 (m, 1H), 7.23-7.25 (m,
2H), 7.44-7.46 (m, 1H).
[0782] tert-butyl
N-(adamantan-1-yl)-N-({4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroiso-
quinolin-1-yl]phenyl}methyl)carbamate: To a solution of tert-butyl
((1R,3R)-adamantan-1-yl)(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin--
1-yl)benzyl)carbamate (0.8 g, 1.44 mmol, 1 eq) in methanol (15 mL)
was added sodium borohydride (0.159 g, 4.31 mmol, 3 eq) portion
wise at 0.degree. C. The suspension was stirred at room temperature
for 30 mins. Progress of the reaction was monitored by TLC (20% EA
in hexane). After this time, the reaction mixture was quenched with
acetone (10 mL), concentrated and obtained crude was diluted with
EtOAc (20 mL) and water (5 mL). Organic layer was separated, washed
with brine solution (10 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to obtain the
crude product. The obtained crude product was purified by prep TLC
using 20% ethyl acetate in n-hexane as an eluent to get tert-butyl
((1R,3R)-adamantan-1-yl)(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroi-
soquinolin-1-yl)benzyl)carbamate (1,3 trans isomer). LCMS (ES)
m/z=559 [M+H]+.
[0783] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.8-0.9 (m,
3H), 1.1-1.3 (m, 5H), 1.39 (s, 9H), 1.59-1.70 (m, 9H), 2.02 (bs,
3H), 2.10 (s, 5H), 2.73 (bs, 2H), 2.88-2.99 (m, 2H), 3.79 (s, 3H),
4.55 (s, 2H), 5.29 (s, 2H), 6.68 (s, 2H), 6.84 (bs, 1H), 7.11 (bs,
3H).
[0784] tert-butyl
N-(adamantan-1-yl)-N-({4-[(1S,3S)-3-butyl-6-methoxy-2-[3-(trimethylsilyl)-
prop-2-ynoyl]-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}methyl)carbamate:
First step: To a solution of 3-(trimethylsilyl)propiolic acid
(0.043 g, 0.302 mmol, 1.0 eq) in DMF (0.00094 mL, 0.012 mmol, 0.04
eq) was added oxalyl chloride (0.028 mL, 0.33 mmol, 1.1 eq) at room
temperature and stirred for 30 minutes. Then the reaction mixture
was concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. This acid chloride crude was
carried to next step without any further purification.
[0785] Second step: To a solution of tert-butyl
((1R,3R)-adamantan-1-yl)(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroi-
soquinolin-1-yl)benzyl)carbamate (0.080 g, 0.143 mmol, 1.0 eq) in
acetonitrile (10 mL) was added sodium bicarbonate (0.091 g, 1.07
mmol, 7.5 eq) at 0.degree. C. After stirring for 5 minutes, a
solution of 3-(trimethylsilyl)propioloyl chloride (0.025 g, 0.157
mmol, 1.1 eq) in acetonitrile (5.0 mL) was added to the above
reaction mass. The resulting mixture stirred at 0.degree. C. for 1
h, progress of the reaction was monitored by TLC (20% ethyl acetate
in n-hexane). After this time, reaction mass was diluted with EtOAc
(100 mL) and water (50 mL). Organic layer was separated, washed
with brine solution (10 mL), dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. This crude
product was carried to next step without any further purification.
LCMS (ES) m/z=583 [M+H]+(without Boc group mass was observed).
[0786] tert-butyl
N-(adamantan-1-yl)-N-({4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2-ynoyl)-1,2,-
3,4-tetrahydroisoquinolin-1-yl]phenyl}methyl)carbamate: To a
solution of tert-butyl
((1R,3R)-adamantan-1-yl)(4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsily-
l)propioloyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzyl)carbamate
(171 mg, 0.25 mmol, 1 eq) in DCM (10 mL)/MeOH (2 mL) were added
K.sub.2CO.sub.3 (207 mg, 1.50 mmol, 6 eq) at 0.degree. C. The
mixture was stirred at 0.degree. C. for 2 h, after completion of
the reaction, the reaction mixture was diluted with DCM (5 mL) and
added H2O (3 mL). The organic layer was extracted with DCM
(3.times.10 mL) and dried over Na.sub.2SO.sub.4 and concentrated.
The residue was purified by prep-TLC, using 20% E.A in hexane to
give tert-butyl
((1R,3R)-adamantan-1-yl)(4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,-
4-tetrahydroisoquinolin-1-yl)benzyl)carbamate. LCMS (ES) m/z=511.2
[M+H]+. (without group mass was showing).
[0787] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.81-0.85 (m,
3H), 0.93-0.95 (m, 1H), 1.2-1.2 (m, 6H), 1.38-1.56 (m, 9H),
1.68-1.71 (m, 2H), 1.91-2.0 (m, 3H), 2.01 (bs, 5H), 2.17 (s, 1H),
2.67-2.82 (m, 2H), 2.88 (s, 1H), 3.80-3.81 (m, 3H), 4.48-4.61 (m,
4H), 6.29 (d, J=14 Hz, 1H), 6.69 (s, 1H), 6.78-6.84 (m, 1H),
6.93-7.08 (m, 4H), 7.33 (d, J=8.4 Hz, 1H).
[0788]
N-(adamantan-1-yl)-N-({4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2-ynoyl-
)-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}methyl)-2,2,2-trifluoroacetami-
de: To a stirred solution of tert-butyl
((1R,3R)-adamantan-1-yl)(4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,-
4-tetrahydroisoquinolin-1-yl)benzyl)carbamate (0.06 g, 0.098 mmol,
1 eq) in DCM (15 mL) was added TFA (0.2 mL) drop wise under cooling
(0.degree. C.) conditions, reaction mixture was stirred at
0.degree. C. for 2 h, reaction progress was checked by TLC (70% EA
in hexane), after completion of the reaction, reaction mixture was
concentrated under reduced pressure to obtain the crude product,
which was further purified by prep HPLC purification by using
following analytical condition to get the
1-((1S,3S)-1-(4-((((1R,3R)-adamantan-1-yl)(2,2,2-trifluoroacetyl)-14-azan-
eyl)methyl)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop--
2-yn-1-one. Analytical Conditions: column: X-BridgeC-18 (250
mm.times.4.6 mm.times.5 .mu.m); mobile phase(A): 0.1% TFA in water;
mobile phase (B): acetonitrile; flow rate: 1.0 mL/min; gradient B:
0/20, 12/60, 22/95, 25/95, 27/20, 30/20. LCMS (ES) m/z=511.1
[M+H]+.
[0789] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.80-0.84 (m,
3H), 0.90-1.2 (m, 7H), 1.5-1.67 (m, 6H), 1.86 (s, 4H), 1.90-2.1 (m,
2H), 2.76-2.90 (m, 2H), 3.0-3.16 (m, 1H), 3.70-3.80 (m, 4H), 4.01
(bs, 2H), 4.59-4.75 (m, 2H), 6.75-6.81 (m, 2H), 7.07-7.12 (m, 1H),
7.27-7.44 (m, 4H), 8.46 (bs, 2H).
Procedure 34: Synthesis of Compound 18
##STR00217## ##STR00218##
[0791] methyl 4-(cyclobutylsulfamoyl)benzoate: To a solution of
methyl 4-(chlorosulfonyl)benzoate (5.0 g, 21.3 mmol, 1.0 eq) in THF
(50 mL) was added triethylamine (8.92 mL, 63.9 mmol, 3.0 eq) and
cyclobutanamine (1.83 mL, 21.3 mmol, 1.0 eq) at room temperature
and the mixture was stirred at room temperature for 3 h, TLC (30%
EtOAc in hexane) showed the reaction was completed. The reaction
mixture was concentrated under reduced pressure and the obtained
crude was diluted with EtOAc (250 mL), washed with water
(2.times.50 mL). The organic layer was dried over anhydrous Na2SO4,
concentrated under reduced pressure to get crude product. The crude
was purified by flash chromatography using 15-20% EtOAc in hexane
as an eluent to give methyl 4-(N-cyclobutylsulfamoyl)benzoate. LCMS
(ES) m/z: 270.1 [M+H]+.
[0792] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.56-1.67 (m,
2H), 1.71-1.76 (m, 2H), 2.10-2.14 (m, 2H), 3.78-3.86 (m, 1H), 3.95
(s, 3H), 4.67-4.69 (m, 1H), 7.92 (d, J=8.4 Hz, 2H), 8.15 (d, J=8.4
Hz, 2H).
[0793] 4-(cyclobutylsulfamoyl)benzoic acid: To a stirred solution
of methyl 4-(cyclobutylsulfamoyl)benzoate (5 g, 18.6 mmol, 1 eq) in
EtOH (25 mL) and water (25 mL) was added sodium hydroxide (1.49 g,
37.1 mmol, 2 eq) at room temperature and the reaction was stirred
at 80.degree. C. for 6 h. TLC (70% in EtOAc in hexane) showed that
the reaction was completed after 6 h. The reaction mixture was
cooled to room temperature, concentrated the reaction mixture under
reduced pressure. The obtained aqueous layer was extracted with
EtOAc (2.times.20 mL) and then the aqueous layer was acidified with
2 N HCl (pH .about.5) and then extracted with EtOAc (50 mL).
Organic layer was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to afford the title compound
4-(cyclobutylsulfamoyl)benzoic acid. LCMS (ES) m/z=254 [M-H]-.
[0794] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.20-1.45
(m, 2H), 1.68-1.72 (m, 2H), 1.60-1.88 (m, 2H), 1.74-1.78 (m, 4H),
3.60-3.66 (m, 1H), 7.86-7.88 (m, 2H), 8.09-8.13 (m, 3H), 4.37 (bs,
1H), 13.5 (bs, 1H).
[0795]
4-(cyclobutylsulfamoyl)-N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]benza-
mide: To a solution of 4-(cyclobutylsulfamoyl)benzoic acid (3.69 g,
14.5 mmol, 1 eq) in DCM (30 mL) under nitrogen atmosphere was added
triethylamine (6.06 mL, 43.4 mmol, 3.0 eq) at 0.degree. C., stirred
for 10 mins and then propanephosphonic acid anhydride (50 wt. % in
ethyl acetate) (9.69 mL, 8.57 mmol, 2.0 eq) was added at 0.degree.
C. to the reaction mixture, stirred at 0.degree. C. for 15 mins and
then (2S)-1-(3-methoxyphenyl)hexan-2-amine (3.0 g, 14.5 mmol, 1 eq)
dissolved in DCM (20.0 mL) was added to the reaction mixture at
0.degree. C. and then the reaction mixture was stirred at room
temperature for 16 h. TLC (40% EtOAc in hexane) showed the reaction
was completed after 16 h. The reaction mixture was diluted with DCM
(150 mL), washed with saturated sodium bicarbonate solution (20 mL)
and water (30 mL). Organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to get
4-(cyclobutylsulfamoyl)-N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]benzamide.
LCMS (ES) m/z=445.2 [M+H]+.
[0796] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 0.87-0.89 (m,
3H), 1.32-1.36 (m, 4H), 1.49-1.54 (m, 1H), 1.74-1.78 (m, 4H), 2.1
(bs, 2H), 2.86-2.94 (m, 2H), 3.75-3.78 (m, 4H), 4.37 (bs, 1H), 4.76
(bs, 3H), 5.58-5.89 (m, 1H), 6.74-6.67 (m, 3H), 7.19-7.25 (m, 1H),
7.74-7.75 (m, 2H), 7.84-7.86 (m, 2H).
[0797]
(S)-4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)-N-cyclobutylb-
enzenesulfonamide: To a solution of
(S)-4-(N-cyclobutylsulfamoyl)-N-(1-(3-methoxyphenyl)hexan-2-yl)benzamide
(3 g, 6.75 mmol, 1 eq) in DCM (30 mL) under nitrogen atmosphere was
added 2-chloropyridine (1.28 mL, 13.5 mmol, 2 eq) at room
temperature. Then trifluoromethanesulfonic anhydride (2.27 mL, 13.5
mmol, 2 eq) was added at -78.degree. C., stirred for 5 mins, then
warmed to 0.degree. C., stirred for 30 mins at 0.degree. C. and
then the reaction mixture was stirred at room temperature for 3 h.
TLC (100% EtOAc) showed starting material along with new spots.
Reaction was monitored by LC-MS. The reaction mass was concentrated
under reduced pressure to obtain the crude residue, obtained
residue was quenched with 10% sodium hydroxide solution (15 mL),
extracted with (2.times.150 mL) of ethyl acetate, combined organic
layers were dried with anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to get crude product, which was
purified by flash column chromatography using 100% ethyl acetate in
hexane as an eluent to obtain
(S)-4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)-N-cyclobutylbenzene-
sulfonamide. LCMS (ES) m/z=427.1 [M+H]+.
[0798] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm: 7.88 (d,
J=7.6 Hz, 2H), 7.70 (d, J=8 Hz, 2H), 7.05 (d, J=8.8 Hz, 1H), 6.78
(s, 1H), 6.72 (d, J=8 Hz, 1H), 4.68-4.67 (m, 1H), 3.89 (s, 3H),
3.56-3.52 (m, 1H), 2.82-2.71 (m, 1H), 2.82-2.71 (m, 1H), 2.62-2.46
(m, 1H), 2.18-2.16 (m, 1H), 1.83-1.75 (m, 4H), 1.61-1.56 (m, 3H),
1.49-1.35 (m, 2H), 0.95-0.91 (m, 3H).
[0799]
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N--
cyclobutylbenzenesulfonamide: To a solution of
(S)-4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)-N-cyclobutylbenzene-
sulfonamide (1.5 g, 3.52 mmol, 1 eq) in methanol (15 mL) was added
sodium borohydride (0.388 g, 10.5 mmol, 3 eq) portion wise at
0.degree. C. The suspension was stirred at room temperature for 1
h. Progress of the reaction was monitored by TLC (50% EA in
hexane). After this time, the reaction mixture was quenched with
acetone (10 mL), concentrated and the obtained crude product was
diluted with EtOAc (30 mL) and water (20 mL). The organic layer was
separated, washed with brine solution (10 mL), dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude product. The obtained crude product was purified
by prep TLC using 50% ethyl acetate in n-hexane as an eluent to get
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-
-cyclobutylbenzenesulfonamide (1,3 trans isomer). LCMS (ES)
(m/z)=429 [M+H]+.
[0800]
4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3-
,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylbenzenesulfonamide:
First step: To a solution of 3-(trimethylsilyl)propiolic acid (0.2
g, 1.41 mmol, 1 eq) in DMF (0.04 mL, 0.56 mmol, 0.04 eq) was added
oxalyl chloride (0.15 mL, 1.69 mmol, 1.2 eq) at room temperature
and stirred for 30 minutes. Then the reaction mixture was
concentrated under reduced pressure to get
3-(trimethylsilyl)propioloyl chloride. This acid chloride crude was
carried to next step without any further purification.
[0801] Second step: To a solution of
4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclob-
utylbenzenesulfonamide (0.2 g, 0.467 mmol, 1 eq) in Acetonitrile
(10 mL) was added sodium hydrogen carbonate (0.298 g, 3.5 mmol, 7.5
eq) at 0.degree. C., followed by 3-(trimethylsilyl)propioloyl
chloride (0.09 g, 0.56 mmol, 1.2 eq) in Acetonitrile (5 mL). The
mixture was stirred at 0.degree. C. for 5 minutes then allowed to
stirred at room temperature for 1 h. Then the reaction mixture was
diluted water (5 mL) and was extracted with ethyl acetate
(2.times.15 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to obtain the crude of
4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4-tet-
rahydroisoquinolin-1-yl)-N-cyclobutylbenzenesulfonamide. LCMS (ES)
(m/z)=553 [M+H]+.
[0802]
4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquin-
olin-1-yl)-N-cyclobutylbenzenesulfonamide: Trans-isomer: To a
stirred solution of
4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4-tet-
rahydroisoquinolin-1-yl)-N-cyclobutylbenzenesulfonamide (0.200 g,
0.362 mmol, 1.0 eq) in THF (5.0 mL) was added tetra butyl ammonium
fluoride (1M in THF) (0.43 mL, 0.43 mmol, 1.2 eq) at -78.degree. C.
The reaction mixture was stirred at same temperature for 30
minutes. The reaction mixture was quenched with saturated sodium
bicarbonate solution (5 mL), extracted with ethyl acetate
(2.times.20 mL). Combined organic layer was washed with water (10
mL), brine (10 mL) and dried over with anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to get crude. The
obtained crude product was purified by flash chromatography using
60% ethyl acetate in n-hexane as an eluent to get the desired
product
4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoqu-
inolin-1-yl)-N-cyclobutylbenzenesulfonamide. LCMS (ES) m/z=481.3
[M+H]+.
[0803] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.80-0.81
(m, 3H), 0.90-0.95 (m, 1H), 1.20-1.39 (m, 4H), 1.40-1.49 (m, 3H),
1.71-1.76 (m, 2H), 1.88-1.90 (m, 2H), 2.81-2.94 (m, 1H), 3.06-3.17
(m, 1H), 3.55-3.57 (m, 1H), 3.77 (s, 3H), 4.44 (s, 1H), 4.75 (s,
1H), 6.06 (s, 1H), 6.77-6.83 (m, 2H), 7.37-7.43 (m, 2H), 7.60-7.69
(m, 3H).
Procedure 35: Synthesis of Compound 95
##STR00219## ##STR00220##
[0805] 2-methylpyridine-4-carbonyl chloride: To a solution of
2-methylpyridine-4-carboxylic acid (3.00 g, 21.9 mmol, 1.0 eq) in
N,N-dimethylformamide (0.067, 0.87 mmol, 0.04 eq) was added SOCl2
(40.0 mL) at 0.degree. C., This mixture was refluxed for 3 h at
80.degree. C., and the excess of thionyl chloride was concentrated
under reduced pressure to get 2-methylpyridine-4-carbonyl chloride.
This crude product carried to next step without any further
purification.
[0806] ethyl 4-(2-methylpyridine-4-amido)benzoate: To a stirred
solution of ethyl 4-aminobenzoate (3.19 g, 19.3 mmol, 1.0 eq) in
DCM (40.0 mL) was added triethylamine (15.0 mL, 116 mmol, 6 eq)
0.degree. C. and the reaction was stirred for 15 mins. Then
2-methylpyridine-4-carbonyl chloride (20 ml DCM) (3.00 g, 19.3
mmol, 1 eq) was added slowly. After this time, the reaction was
stirred at room temperature for 12 h. After completion of the
reaction, the reaction mixture was slowly quenched with water,
diluted with DCM (100 mL), stirred at room temperature for 5 mins.
Then the layers were separated. Aqueous layer was extracted with
DCM (2.times.100.0 mL). Combined organic layer was washed with
water (50.0 mL), separated the layers. Then the organic layer was
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure to obtain the crude. The crude was purified
by column chromatography using 10% MeOH/DCM as an eluent to afford
ethyl 4-(2-methylpyridine-4-amido)benzoate. LCMS (ES) m/z=285.2
[M+H]+.
[0807] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28-1.31
(m, 3H), 2.48 (s, 3H), 4.25-4.30 (m, 2H), 7.62 (d, J=4.8 Hz, 1H),
7.76 (s, 1H), 7.89-7.97 (m, 4H), 8.61 (d, J=5.2 Hz, 1H), 10.72 (s,
1H),
[0808] 4-(2-methylpyridine-4-amido)benzoic acid: To a stirred
solution of ethyl 4-(2-methylpyridine-4-amido)benzoate (2.50 g,
8.79 mmol, 1.0 eq) in MeOH (20.0 mL), THF (20.0 mL) and Water (15.0
mL) was added LiOH.H2O (0.76 g, 17.6 mmol, 2.0 eq) and the reaction
was stirred at rt for 16 h. Reaction was monitored by TLC (5%
MeOH/DCM). After this time reaction mixture was concentrated under
reduced pressure at rt and the aqueous layer was extracted with
EtOAc (2.times.50 mL). The aqueous layer was then acidified with 5%
citric acid (Ph=5), filtered and dried under reduced pressure to
get the 4-(2-methylpyridine-4-amido)benzoic acid. LC-MS (ES)
(m/z)=257.2 [M+H]+.
[0809] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.57-7.64
(m, 1H), 7.71 (s, 1H), 7.87-7.95 (m, 4H), 8.63 (d, J=4.8 Hz, 1H),
10.69 (s, 1H), 12.71 (s, 1H).
[0810]
N-(4-{[(2S)-1-(3-methoxyphenyl)hexan-2-yl]carbamoyl}phenyl)-2-methy-
lpyridine-4-carboxamide: To a solution of
(2S)-1-(3-methoxyphenyl)hexan-2-amine (1.0 g, 4.82 mmol, 1.0 eq),
4-(2-methylpyridine-4-amido)benzoic acid (1.48 g, 5.79 mmol, 1.2
eq) in DCM (20.0 mL) was added Triethylamine (2.69 mL, 19.3 mmol, 4
eq), stirred for 5 min and then T3P (50 wt. % in EtOAc) (2.15 ml,
7.24 mmol, 1.5 eq) was added at 0.degree. C. and stirred for
another 30 min. Progress of the reaction was monitored by TLC (5%
MeOH/DCM). After the completion of the reaction, the reaction
mixture was quenched with water (20.0 mL) and extracted with DCM
(2.times.25 mL). The combined organic extracts were washed with
water (15 mL) and brine solution (15 mL) and dried over anhydrous
Na.sub.2SO.sub.4, concentrated under reduced pressure to obtain the
crude compound. The crude was purified by flash column
chromatography using 3-5% methanol in DCM as an eluent to yield
ethyl
(S)--N-(4-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)phenyl)-2-methylisoni-
cotinamide. LC-MS (m/z)=446.3 [M+H]+.
[0811] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 0.82 (d,
J=6.8 Hz, 3H), 1.13-1.31 (m, 5H), 1.50 (d, J=6.0 Hz, 2H), 2.65 (s,
3H), 2.71-2.81 (m, 2H), 3.67 (s, 3H), 4.08-4.15 (m, 1H), 6.69 (d,
J=8.8 Hz, 1H), 6.78 (d, J=6.4 Hz, 2H), 7.13 (t, J=8.0 Hz, 1H), 7.63
(d, J=4.8 Hz, 1H), 7.72 (s, 1H), 7.80 (s, 4H), 8.09 (d, J=8.8 Hz,
1H), 8.62 (d, J=5.2 Hz, 1H), 10.59 (s, 1H).
[0812]
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}-2--
methylpyridine-4-carboxamide: To stirred solution of
(S)--N-(4-((1-(3-methoxyphenyl)hexan-2-yl)carbamoyl)phenyl)-2-methylisoni-
cotinamide (1.2 g, 2.69 mmol, 1 eq) and 2-chloropyridine (1.02 mL,
10.8 mmol, 4.0 eq) in dichloromethane (25.0 mL) was added
trifluoromethanesulfonic anhydride (1.81 mL, 10.8 mmol, 4.0 eq)
slowly dropwise at -78.degree. C. After 5 min, the reaction mixture
was placed in an ice-water bath and warmed to 0.degree. C. and the
resulting solution was allowed to stir at 0.degree. C. After 1.5 h,
reaction was quenched with aqueous 1.0 N sodium hydroxide solution
(15 mL) to neutralize the trifluoromethanesulfonate salts.
Dichloromethane (2.times.15 mL) was added to dilute the reaction
mixture and the layers were separated. The combined organic layer
was washed with brine (5 mL), dried over anhydrous sodium sulfate,
and was filtered. The volatiles were removed under reduced pressure
to give the crude product of
(S)--N-(4-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)-2-methyl-
isonicotinamide. LCMS (ES) m/z=428.3 [M+H]+.
[0813]
N-{4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl]-
phenyl}-2-methylpyridine-4-carboxamide: To a solution of
N-{4-[(3S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl]phenyl}-2-methyl-
pyridine-4-carboxamide (260 mg, 0.608 mmol, 1 eq) in methanol (10
mL) was added sodium borohydride (69.0 mg, 1.82 mmol, 3 eq) portion
wise at 0.degree. C. The suspension was stirred at room temperature
for 1 h. Progress of the reaction was monitored by TLC (5% methanol
in DCM). After this time, the reaction mixture was concentrated and
obtained crude was diluted with EtOAc (20 mL) and water (10 mL).
Organic layer was separated, washed with brine solution (10 mL),
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure to obtain the crude product. The obtained
crude product was purified by preparative TLC using 5% methanol in
DCM. Product fraction was collected and concentrated under reduced
pressure to get tert-butyl
N-{bicyclo[1.1.1]pentan-1-yl}-N-({4-[(1S,3S)-3-butyl-6-methoxy-1,2,3,4-te-
trahydroisoquinolin-1-yl]phenyl}methyl)carbamate.
[0814]
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-[3-(trimethylsilyl)prop-2-ynoyl]--
1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl}-2-methylpyridine-4-carboxamide:
First step: To a solution of 3-(trimethylsilyl)prop-2-ynoic acid
(20 mg, 0.0141 mmol, 1.0 eq) in DMF (0.00043 mL, 0.00562 mmol, 0.04
eq) was added oxalyl chloride (0.013 mL, 0.155 mmol, 1.1 eq) at
room temperature and stirred for 30 minutes. After this time,
reaction mixture was concentrated under reduced pressure to get
3-(trimethylsilyl)prop-2-ynoyl chloride. This acid chloride was
carried forward to the next step without any further
purification.
[0815] Second step: To a solution of
N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl-
)-2-methylisonicotinamide (40 mg, 0.093 mmol, 1 eq) in acetonitrile
(4.0 mL) was added sodium bicarbonate (59.4 mg, 0.698 mmol, 7.5 eq)
at 0.degree. C. After stirring for 5 minutes, a solution of
3-(trimethylsilyl)prop-2-ynoyl chloride (22.4 mg, 0.140 mmol, 1.5
eq) in acetonitrile (2.0 mL) was added to the above reaction mass
at 0.degree. C. The resulting mixture was stirred at 0.degree. C.
for 15 min. Progress of the reaction was monitored by TLC (50%
ethyl acetate in n-hexane). After this time, reaction mass was
diluted with EtOAc (20 mL) and water (10 mL). Organic layer was
separated, washed with brine solution (7.0 mL), dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure to obtain the crude of
N-(4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4--
tetrahydroisoquinolin-1-yl)phenyl)-2-methylisonicotinamide. LCMS
(ES) m/z=554.4 [M+H]+.
[0816]
N-{4-[(1S,3S)-3-butyl-6-methoxy-2-(prop-2-ynoyl)-1,2,3,4-tetrahydro-
isoquinolin-1-yl]phenyl}-2-methylpyridine-4-carboxamide: To a
solution of
N-(4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propioloyl)-1,2,3,4--
tetrahydroisoquinolin-1-yl)phenyl)-2-methylisonicotinamide (0.14 g,
0.253 mmol, 1 eq) in dichloromethane (10 mL) and methanol (2 mL)
was added potassium carbonate (0.213 g, 1.52 mmol, 6.0 eq) at
0.degree. C. This reaction mixture was stirred at 0.degree. C. for
30 minutes. Progress of the reaction was monitored by LC-MS. After
completion of starting material, the reaction mixture was diluted
with Dichloromethane (2.times.10.0 mL) and separated with water
(10.0 mL) and the combined organic layer was dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the crude compound. The obtained crude product was purified
by prep HPLC purification method by using following analytical
condition to afford
N-(4-((1S,3S)-3-butyl-6-methoxy-2-propioloyl-1,2,3,4-tetrahydroisoquinoli-
n-1-yl)phenyl)-2-methylisonicotinamide. Analytical Conditions:
Column: X-BridgeC-18 (250 mm.times.4.6 mm.times.5 .mu.m); mobile
phase (A): 0.1% ammonia in water; mobile phase (B): acetonitrile;
Flow rate: 1.0 mL/min; gradient B: 0/10, 12/60, 22/95, 25/95,
27/10, 30/10. LCMS (ES) m/z=482.5 [M+H]+.
[0817] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 0.81 (t,
J=6.8 Hz, 3H), 1.22 (bs, 5H), 1.50 (bs, 2H), 2.53 (s, 3H), 2.79 (s,
1H), 3.12 (s, 1H), 3.70 (d, J=5.6 Hz, 2H), 4.30 (s, 1H), 4.59 (s,
1H), 6.03 (s, 1H), 6.28 (s, 1H), 6.80 (t, J=8.0 Hz, 1H), 7.21 (t,
J=8.4 Hz, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.64
(d, J=8.8 Hz, 2H), 8.58 (d, J=4.8 Hz, 1H), 10.32 (s, 1H).
[0818] Compounds shown in Table 1, can be or were, synthesized
according to the procedures described above using the appropriate
reagents and starting materials. Select data are shown in Table
2.
TABLE-US-00002 TABLE 2 No. MS [M + H].sup.+ 1 385.3 2 402 3 402 4
389 5 413.3 6 388.1 7 388.1 8 348.3 9 324 10 324.3 11 390 12 365 13
469 14 448 15 445 18 481.3 27 521.5 28 497 33 415.93 34 418.89 35
358.83 36 428.93 38 525.8 39 354.6 40 432.83 42 408.87 48 363.4 49
349.4 50 352.4 54 369 55 429.5 57 349 76 353.3 93 434.95 94 440 95
482 96 458 97 399 98 477 99 610 100 541 101 498 102 445
BIOLOGICAL EXAMPLES
Example 1: Cell Proliferation (Alamar Blue) Assay
[0819] A cell viability assay was performed to assess the potency
of the compounds in human cancer cell lines 786-0 (renal cell
carcinoma), SJSA-1 (osteosarcoma), and/or A431 (epidermoid
carcinoma). Additional cell lines, such as pancreatic cancer cell
lines (e.g., Panc 02.13, BxPC-3, Panc 12, Panc 02.03, Panc 6.03,
PSN-1, HPAC, and Capan-1), prostate cancer cell lines (e.g., PC-3,
DU145, 22Rv1, NCI-H660, BPH1, LNCaP, BM-1604, and MDA PCa 2b),
etc., can be tested in a similar method.
[0820] Cells (SJSA-1, 786-0 and/or A431) were seeded (5000
cells/100 .mu.L/well) in 96-well tissue culture plate and incubated
at 37.degree. C./5% CO.sub.2 for 16-24 hours. The cells were then
treated with compounds (25 .mu.L of 5.times.). The compound
concentrations were 10-0.0005 .mu.M prepared in 3-fold serial
dilutions with final DMSO concentration of 1%. The plates were then
incubated for 24h at 37.degree. C./5% CO.sub.2 in a moist
environment. Then Alamar Blue.TM. reagent (final concentration
1.times.-12.5 .mu.L) was added to each well and incubated for 1.5
hours at 37.degree. C./5% CO.sub.2. The plates were read on
fluorescence reader at 540 nm excitation and 590 nm emission
wavelengths. The IC.sub.50 values were subsequently determined
using a sigmoidal dose-response curve (variable slope) in GraphPad
Prism.RTM. 5 software. Table 3 shows cell proliferation data for
exemplary compounds as described herein.
TABLE-US-00003 TABLE 3 IC.sub.50 (.mu.M) No. 786-O SJSA-1 A431 1 2
2.8 -- 2 0.742 0.855 8.7 3 0.512 0.736 >10 4 0.588 1 -- 5 0.212
0.382 -- 6 3 3.2 >10 7 0.137 0.22 7.8 8 0.181 0.183 7.9 9 0.223
0.436 4.9 10 0.164 0.278 8.6 11 0.016 0.018 >10 12 0.014 0.025
3.5 13 0.002 0.005 3.6 14 0.024 0.07 7.6 15 0.010 0.018 3.5 18
0.004 0.008 8.9 27 0.004 0.006 8.4 28 0.004 0.016 2.9 33 0.2591 --
-- 34 0.5917 -- -- 35 -- 2.56 -- 38 0.005 0.010 10 39 0.158 0.170
>10 44 0.592 0.599 -- 45 5.891 >3 -- 46 -- 2.56 -- 47 0.259
0.329 -- 48 0.053 0.050 5 49 0.023 0.040 6.6 50 0.065 0.101 >10
54 0.743 0.659 5.8 55 0.027 0.032 2.3 57 0.023 0.040 6.6 76 0.187
0.623 >10 94 0.108 0.047 >10 95 0.037 0.2 >10 96 0.163
0.368 >10 97 0.026 0.068 >10 98 0.024 0.053 8.92 99 0.002
0.002 2.77 100 0.013 0.021 4.06 101 0.008 0.0115 6.87 102 0.021
0.021 6.13
[0821] Selected compounds were also assayed (counter-screened) in a
human lung cancer cell line, A549, a less sensitive cell line to
GPX4 inhibitors, as a control to assess differential activity.
Cells at a density of 800-2,000 cells/well were seeded in 96-well
plates and incubated at 37.degree. C. overnight. A series of nine
different concentrations of compound stocks (500.times.) were
created by 3-fold serial dilution in DMSO. These compounds were
further diluted in culture media and then added to cells so that
the final DMSO concentration was equal to 0.25% or less. After 96
hours of incubation, 50 .mu.L of CellTiter Glo reagent (Promega)
was added to each well and luminescence was measured after 10
minutes using EnVision (PerkinElmer). RSL3 (a prototype GPX4
inhibitor, also known as RSL-3) was used as a reference compound
titrated from top concentration of up to 30 .mu.M. All compounds
were tested initially from 30 M as the top concentration in
duplicates (range of 4.6 nM-30 .mu.M). The top concentration was
then adjusted to higher (from up to 1000 .mu.M) or lower for
compounds that showed potency out of the initial range.
Luminescence from cells treated with DMSO alone was set as Max and
% of inhibition was calculated as follows: Inhibition %=(Max-Sample
value)/Max*100. Data was analyzed using XL-fit software (ID
Business Solutions Ltd.). IC.sub.50, relative IC.sub.50, or % of
top inhibition was calculated. Data shown in Table 4.
TABLE-US-00004 TABLE 4 IC.sub.50 (.mu.M) No. A549 KP4 40 6.238
(RSL3 3.078) 0.019 (RSL3 0.002) 41 1.315 (RSL3 3.078) 0.042 (RSL3
0.002) 42 5.05 (RSL3 3.078) 0.0618 (RSL3 0.002) 43 10.3 (RSL3
3.078) 0.525 (RSL3 0.003) 44 6.575 (RSL3 2.735) -- 45 4.742 (RSL3
2.735) -- 46 3.825 (RSL3 3.667) -- 47 6.575 (RSL3 2.735) --
Example 2: GPX4 Inhibition Assay
[0822] Table 5 shows that compounds provided herein are GPX4
inhibitors. Studies have shown that lipophilic antioxidants, such
as Ferrostatin, can rescue cells from GPX4 inhibition-induced
ferroptosis. For instance, mesenchymal state GPX4-knockout cells
can survive in the presence of Ferrostatin, however, when the
supply of Ferrostatin is terminated, these cells undergo
ferroptosis (see, e.g., Viswanathan et al., Nature 547:453-7,
2017). It has also been experimentally determined that that GPX4i
can be rescued by blocking other components of the ferroptosis
pathways, such as lipid ROS scavengers (Ferrostatin, Liproxstatin),
lipoxygenase inhibitors, iron chelators and caspase inhibitors,
which an apoptotic inhibitor does not rescue. These findings are
suggestive of non-apoptotic, iron-dependent, oxidative cell death
(i.e., ferroptosis). Accordingly, the ability of a molecule to
induce ferroptotic cancer cell death, and that such ability is
admonished by the addition of Ferrostatin, is clear indication that
the molecule is an GPX4 inhibitor. The data in Table 5 shows that
compounds provided herein lost inhibitory activity in the presence
of Ferrostatin and are thus effective GPX4 inhibitors.
TABLE-US-00005 TABLE 5 786-O (IC.sub.50, .mu.M) SJSA-1 (IC.sub.50,
.mu.M) Compound Without 2 .mu.M Without 2 .mu.M No. Ferrostatin
Ferrostatin Ferrostatin Ferrostatin 4 0.588 5.731 1 3.563 5 0.212
>10.00 0.382 >10.00 8 0.181 >10.00 0.183 >10.00 9 0.223
>10.00 0.436 3744
Example 3: Method and Results of Western Blot-Gel Mobility Shift of
GPX4
[0823] A mobility shift of GPX4 Western blot assay was established
to assess target engagement directly in cell-based assay after
incubation with compounds and in tumors from mice treated with
compounds. Mobility shift can be used as a pharmacodynamic marker
for GPX4 irreversible inhibitors. For cell-based assay, cells that
are sensitive to GPX4 inhibitors (e.g. MiaPaCa-2) were seeded in 10
cm (2-8.times.10.sup.6 cells) and grown overnight. Cell seeding
number can be adjusted proportionally based on the surface area if
smaller dishes are used. Next day, cells were treated with DMSO and
various compounds at indicated concentrations for a period of time
(e.g. 0.5, 1, 2, 4, 6, or up to 72 hours). Cells were then lysed in
0.3-0.5 mL of RIPA buffer (Sigma) supplemented with protease
inhibitors (Roche) and phosphatase inhibitors (Sigma). Lysates were
assayed for protein concentration using BCA kit (Pierce).
Normalized amount of lysates (20-40 g protein/lane) were run on
4-12% or 12% NuPage gel (Life Technologies) and the proteins were
transferred to the polyvinylidene fluoride (PVDF) or nitrocellulose
membrane using iBlot.RTM. Transfer Stack (Life Technologies). The
membranes were probed with primary antibodies shown in Table 6 at
4.degree. C. overnight after blocking with 1.times.TBST containing
5% non-fat milk for one hour at room temperature. Similar
antibodies from other vendors could also be used in Western blot
analysis. After washing 5 times with 1.times.TBS containing 0.1%
Tween20, the membranes were probed with a second application of
antibody (e.g. Anti-mouse-HRP, Anti-rabbit-HRP, Anti-Goat-HRP,
Anti-mouse IgG Dylight 800 conjugate or Anti-rabbit IgG DyLight 680
conjugate) (1:10000; Cell signaling or similar IR to the antibodies
from different vendors) at room temperature for one hour. After
washing 5 times, the membranes were scanned using
ImageQuant-LAS-4010 (chemiluminiscence) (GE Healthcare) if
HRP-conjugated secondary antibodies were used or Odyssey.RTM.
Imaging System (Licor Biosciences) if infrared conjugated secondary
antibodies were used.
TABLE-US-00006 TABLE 6 Primary antibodies used for Western blot
analysis Antibody Name Vendor Cat No. Species MW Dilution
.beta.-Actin Sigma A5441 Mouse 43 kd 1:10000 (loading control)
Vinculin Sigma V9131 Mouse 116 KD 1:2000 (loading control) GPX4
Abcam ab125066 Rabbit 22 kd 1:1000 GPX4 Abcam ab41787 Rabbit 22 kd
1:1000
[0824] Compound 40 was evaluated in cell-based Western blot
analysis of GPX4 and the result is shown in FIG. 1. In DMSO treated
sample, GPX4 ran as doublet--the major lower free or unbound GPX4
band and the minor upper band (likely glutathione-bound GPX4 (Cozza
et al., Free Radical Biology and Medicine, Vol 112, pages 1-11,
2017)). The amount of upper band can be reduced if samples were
boiled in excess amount of reducing agent dithiothreitol (DTT).
GPX4 in SDS-PAGE reducing gel moved slower (appear as a larger
molecular weight protein) when treated with covalent, irreversible
inhibitors of GPX4 (e.g. RSL-3 and ML162) but not reversible
inhibitors (e.g. ML210), presumably due to addition of the
covalently linked small molecule to GPX4. Unlike glutathione-bound
GPX4, the irreversible inhibitor bound GPX4 upper band cannot be
reduced by excess amount of DTT. Further, distance of the GPX4
mobility shift is correlated with the molecular weight of the
irreversible GPX4 inhibitor--shifted distance is bigger with larger
irreversible inhibitors. Thus, this simple mobility shift of GPX4
Western blot can be used to conveniently assess direct target
engagement in vitro, in cells and in tumors by irreversible
inhibitors. As shown in FIG. 1, treatment of MiaPaCa-2 cells with
Compound 40 resulted in dose-dependent mobility shift of GPX4 from
the lower unbound to upper bound bands. At concentrations greater
than 50 nM, Compound 40 converted nearly all GPX4 to the upper
bands.
Example 4: Kinact/Ki Determination for GPX4 Inhibitors
[0825] The following example shows that target engagement with GPX4
is very rapid.
[0826] Day 1--seed cells: Cells were seeded with 5.times.10.sup.5
Calu6 cells/well into 5.times.6-well plates.
[0827] Day 2--treat cells with Cmpd, prepare samples for gels:
Cells were treated with 1, 0.75, 0.5, 0.25 and 0.1 .mu.M
inhibitor+2 .mu.M Ferrostatin-1 for 0, 10, 20, 30, 45, 60 minutes.
10 .mu.L of 1000.times.DMSO stock solutions were prepared for each
compound dilution (1, 0.75, 0.5, 0.25, 0.1 mM). Complete cell
culture media (EMEM+10% FBS) was prepared with 2 .mu.M
Ferrostatin-1 final conc. Drug solutions were prepared by adding
1000.times. inhibitors to Ferrostatin-1-supplemented media at
1.times. final concentration (1, 0.75, 0.5, 0.25, 0.1 .mu.M) plus
DMSO for use as a negative control.
[0828] Cell lysis buffer was prepared by diluting 5.times. cell
lysis buffer (Cell Signaling Technology #9803) and 100.times.
protease/phosphatase inhibitor cocktail (Cell Signaling Technology
#5872) to 1.times. with deionized water.
[0829] Cells were treated with drug solutions in 1-hour time
course. One concentration of drug added to each 6-well plate at
t=60, 45, 30, 20, 10, 0 minutes. Media was aspirated from cells in
1 well of each 6-well plate and add 1 mL of media
w/drug+Ferrostatin (t=60 min). Cells were returned to incubator
between time points. Media was aspirated and drug added to cells at
each subsequent time point. At t=10 min DMSO was added negative
control to additional well.
[0830] At t=0 media was aspirated from cells, cells were washed
with ice cold PBS and aspirated, 75 .mu.L of 1.times. cell lysis
buffer was added per well, bottom of plates scraped with cell
scraper, and lysates transferred to 1.5 mL Eppendorf tubes at store
at -20 C.
[0831] SDS-PAGE running buffer was prepared (2 L of 1.times.MES
Bolt running buffer (ThermoFisher Scientific #B0002), Store at 4 C
overnight for use the next day).
[0832] Day 3--perform BCA assay and run gels: Lysates were thawed
on ice, centrifuged at 18,000.times.g at 4.degree. C. for 10
minutes, and BCA assay was performed on supernatant following
manufacturer protocol (ThermoFisher Scientific #23225).
3.6.times.LDS/BME sample buffer was prepared by mixing Bolt
4.times.LDS sample buffer (ThermoFisher Scientific #B0008) with
2-mercaptoethanol at a 10:1 ratio. In 96-well PCR plate 19 .mu.L
3.6.times.LDS/BME sample buffer was added and 50 .mu.L lysate
samples. Lysates diluted to 1 mg/mL with 1.times.LDS/BME, plates
heated at 95.degree. C. for 10 min in PCR machine, loaded 15
.mu.L/well (15 .mu.g total lysate) into 12% Bis-Tris Bolt gels, and
gels were run at 200V for -35 minutes (until dye front reaches
bottom of gel) with cold 1.times.MES running buffer. After which
time, gels were washed 5 minutes in water, 10 minutes in 20%
Ethanol/water, and transferred to membrane with iBlot2
(ThermoFisher Scientific). Membrane was blocked 1 h at RT with
Licor TBS blocking buffer (Licor #927-60001) and incubated with
1:1000 dilution of anti-GPX4 antibody (Abcam #ab125066) in Licor
TBS blocking buffer at 4.degree. C. overnight with gentle
rocking.
[0833] Day 4--develop blots, quantify gel shift: Membrane was
washed with 1.times.TBST for 30 minutes (change wash buffer 3-4
times), incubated with Licor secondary antibody (Licor #926-68021)
1:40,000 in Licor TBS blocking buffer for 1 h at RT with gentle
rocking, washed with 1.times.TBST for 30 minutes, scraped with
Licor imager and bands were quantized with Image studio.
[0834] Kinact/Ki data for RSL3 and Compounds 13 and 15 shown in
FIG. 2.
Example 5: Pharmacokinetics Studies
[0835] Institutional Animal Ethical Committee (IAEC) of Jubilant
Biosys (IAEC/JDC/2019/188R (for Mice) and IAEC/JDC/2019/189R (for
Rat) nominated by CPCSEA (Committee for the Purpose of Control and
Supervision of Experiments on Animals) approved the mice and rat
pharmacokinetic experiments. Male Balb/c mice (.about.6-8 weeks old
with body weight range of 22-25 g) and male SD rats (6-8 weeks old
with body weight range of 200-250 g) were procured from Vivo
Biotech, Hyderabad, India. Animals were quarantined in Jubilant
Biosys Animal House for a period of 7 days with a 12:12 h light:
dark cycles, and prior to the study the animals were stratified as
per body weight.
[0836] Housing: The animals were group housed in standard
polycarbonate cages, with stainless steel top grill where pelleted
food and drinking water bottle are placed; corn cob was used as
bedding material and changed at least twice a week or as
required.
[0837] Diet ad libitum: Rodent feed manufactured by Altromin
Spezialfutter GmbH & Co. KG., ImSeelenkamp20. D-32791 Lage, was
provided.
[0838] Water ad libitum: Purified water was provided ad libitum to
animals in polycarbonate bottles with stainless steel sipper
tubes.
[0839] A) Procedure for Mice: Intravenous, oral and intraperitoneal
pharmacokinetics study was done at doses of 5, 20 and 10 mg/kg
respectively at dose volume of 10 mL/Kg for PO and IP while 5 mL/kg
for IV route. Sparse sampling was done and at each time point three
mice were used for blood sampling (.about.100 .mu.L) were collected
from retro-orbital plexus at 0.083 (Only for IV), 0.25, 0.5, 1, 2,
4, 8, 10 (only for PO) and 24 h. Blood samples collected in tubes
containing K.sub.2.EDTA as anticoagulant and centrifuged for 5 min
at 10,000 rpm in a refrigerated centrifuge (Biofuge, Heraeus,
Germany) maintained at 4.degree. C. for plasma separation.
[0840] Group I (IV) received test compound intravenously by tail
vein at 5 mg/Kg in solution formulation prepared using 30%
Kolliphore EL in WFI; dose volume: 5 mL/Kg; strength: 1 mg/mL.
[0841] Group II (PO) received test compound by per oral route using
oral gavage needle at 20 mg/Kg in solution formulation prepared
using 30% Kolliphore EL in WFI; dose volume: 10 mL/Kg; strength: 2
mg/mL.
[0842] Group III (IP) received test compound by intraperitoneal
route at 10 mg/Kg in solution formulation prepared using 30%
Kolliphore EL in WFI; dose volume: 10 mL/Kg; strength: 1 mg/mL.
[0843] B) Procedure for rat: Intravenous and oral pharmacokinetics
study was done at a dose 2 and 10 mg/kg at dose volume of 2 and 10
mL/Kg. Serial blood sampling was done and at each time point
(.about.200 .mu.L) were collected from retro-orbital plexus at
0.083 (only for IV), 0.25, 0.5, 1, 2, 4, 8, 10 (only for PO) and 24
h. Blood samples collected in tubes containing K.sub.2.EDTA as
anticoagulant and centrifuged for 5 min at 10,000 rpm in a
refrigerated centrifuge (Biofuge, Heraeus, Germany) maintained at
4.degree. C. for plasma separation.
[0844] Group I (IV) received test compound intravenously by tail
vein at 2 mg/Kg in solution formulation prepared using 30%
Kolliphore EL in WFI; dose volume: 2 mL/Kg; strength: 1 mg/mL.
[0845] Group II (PO) received test compound using oral gavage
needle at 10 mg/Kg (solution formulation prepared using 30%
Kolliphore EL in WFI; dose volume: 10 mL/Kg: strength: 1 mg/mL.
[0846] Blood concentration-time data of test compound was analyzed
by non-compartmental method using Phoenix WinNonlin Version 8.1.
Data is shown below in Table 7.
TABLE-US-00007 TABLE 7 Compound 12 28 Mouse IV-PK T.sub.1/2: 0.5 h,
T.sub.1/2: 3.5 h, (5 mg/kg) C.sub.max: 882 ng/mL, C.sub.max: 5446
ng/mL, AUC: 181 ng*h/mL, AUC: 1635 ng*h/mL, CL: 454 mL/min/kg, CL:
49 mL/min/kg, Vd: 19.5 L/kg. Vd: 14.7 L/kg Rat IV-PK T.sub.1/2:
3.15 h, (2 mg/kg): C.sub.max: 3529 ng/mL, AUC: 1082 ng*h/mL, CL: 30
mL/min/kg, Vd: 8.2 L/kg
[0847] All publications, patents, patent applications and other
documents cited in this application are hereby incorporated by
reference in their entireties for all purposes to the same extent
as if each individual publication, patent, patent application or
other document were individually indicated to be incorporated by
reference for all purposes.
[0848] While various specific embodiments have been illustrated and
described, it will be appreciated that various changes can be made
without departing from the spirit and scope of the
invention(s).
* * * * *