U.S. patent application number 16/499075 was filed with the patent office on 2021-03-25 for ask1 inhibitor compounds and uses thereof.
The applicant listed for this patent is SEAL ROCK THERAPEUTICS, INC.. Invention is credited to Samuel David BROWN.
Application Number | 20210087167 16/499075 |
Document ID | / |
Family ID | 1000005292971 |
Filed Date | 2021-03-25 |
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United States Patent
Application |
20210087167 |
Kind Code |
A1 |
BROWN; Samuel David |
March 25, 2021 |
ASK1 INHIBITOR COMPOUNDS AND USES THEREOF
Abstract
Described herein are compounds, including pharmaceutically
acceptable salts, solvates, metabolites, prodrugs thereof, methods
of making such compounds, pharmaceutical compositions comprising
such compounds, and methods of using such compounds to treat
non-alcoholic steatohepatitis and other diseases characterized by
dysfunctional tissue healing and fibrosis.
Inventors: |
BROWN; Samuel David;
(Seattle, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SEAL ROCK THERAPEUTICS, INC. |
Seattle |
WA |
US |
|
|
Family ID: |
1000005292971 |
Appl. No.: |
16/499075 |
Filed: |
April 4, 2018 |
PCT Filed: |
April 4, 2018 |
PCT NO: |
PCT/US2018/026134 |
371 Date: |
September 27, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62482085 |
Apr 5, 2017 |
|
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|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 417/14 20130101;
A61P 1/16 20180101; C07D 487/04 20130101; C07D 498/08 20130101;
C07D 401/14 20130101; C07D 403/14 20130101; C07D 405/14
20130101 |
International
Class: |
C07D 401/14 20060101
C07D401/14; A61P 1/16 20060101 A61P001/16; C07D 405/14 20060101
C07D405/14; C07D 498/08 20060101 C07D498/08; C07D 487/04 20060101
C07D487/04; C07D 403/14 20060101 C07D403/14; C07D 417/14 20060101
C07D417/14 |
Claims
1. A compound that has the structure of Formula III, or a
pharmaceutically acceptable salt or solvate thereof: ##STR00268##
wherein ##STR00269## is ##STR00270## R.sup.1 is ##STR00271## Z is
O, S, C(.dbd.O), N(R.sup.8), or C(R.sup.9).sub.2; X is O or S;
R.sup.2 is C.sub.3-6cycloalkyl; R.sup.3 is selected from a group
consisting of hydrogen, C.sub.1-6alkyl, and C.sub.3-6cycloalkyl;
each R.sup.4 is independently selected from a group consisting of
hydrogen, halo, C.sub.1-6alkyl, and C.sub.3-6 cycloalkyl; or one
R.sup.4 and another R.sup.2, R.sup.3, or R.sup.4, together with the
atoms to which they are attached, form a 5- or 6-membered ring that
is optionally containing one or two heteroatoms selected from O, N,
and S; wherein the 5- or 6-membered ring is saturated, unsaturated,
or aromatic; and wherein the 5- or 6-membered ring is optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; each R.sup.5 is independently
selected from a group consisting of halogen and C.sub.1-6alkyl;
R.sup.5a is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; each R.sup.25 is independently selected from
a group consisting of halogen, --CN, --OH, --OR.sup.6, --SR.sup.6,
--S(.dbd.O)R.sup.7, --NO.sub.2, --N(R.sup.6).sub.2,
--S(.dbd.O).sub.2R.sup.7, --NHS(.dbd.O).sub.2R.sup.7,
--S(.dbd.O).sub.2N(R.sup.6).sub.2, --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6).sub.2, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; each R.sup.6 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, --C.sub.3-C.sub.8cycloalkyl-phenyl, and
C.sub.2-9heterocycle, wherein C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, --C.sub.3-C.sub.8cycloalkyl-phenyl, and
C.sub.2-9heterocycle are optionally substituted with one, two, or
three substituents selected from the group consisting of halo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; or two R.sup.6 on the same
heteroatom are taken together with that heteroatom to which they
are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl, wherein C.sub.2-9heterocycle or
C.sub.2-9heteroaryl are optionally substituted with one, two, or
three substituents selected from the group consisting of halo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; each R.sup.7 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle, wherein
C.sub.3-C.sub.8cycloalkyl and C.sub.2-9heterocycle are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, oxo, --OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, --C.sub.1-6alkyl, --O--C.sub.1-6alkyl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; each R.sup.8 is independently
selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; each R.sup.9 is independently selected from
the group consisting of hydrogen, halogen, and
C.sub.1-C.sub.6alkyl; each R.sup.13 is independently selected from
the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, and
C.sub.3-C.sub.8cycloalkyl; or two R.sup.13 on the same heteroatom
are taken together with that heteroatom to which they are attached
to form a C.sub.2-9heterocycle; each R.sup.14 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or
3; and q is 0, 1, or 2.
2. A compound that has the structure of Formula II, or a
pharmaceutically acceptable salt or solvate thereof: ##STR00272##
wherein ##STR00273## is ##STR00274## R.sup.1 is ##STR00275## Z is
O, S, C(.dbd.O), N(R.sup.8), or C(R.sup.9).sub.2; X is O or S;
R.sup.2 is C.sub.3-6cycloalkyl; R.sup.3 is selected from a group
consisting of hydrogen, C.sub.1-6alkyl, and C.sub.3-6cycloalkyl;
each R.sup.4 is independently selected from a group consisting of
hydrogen, halo, C.sub.1-6alkyl, and C.sub.3-6 cycloalkyl; or one
R.sup.4 and another R.sup.2, R.sup.3, or R.sup.4, together with the
atoms to which they are attached, form a 5- or 6-membered ring that
is optionally containing one or two heteroatoms selected from O, N,
and S; wherein the 5- or 6-membered ring is saturated, unsaturated,
or aromatic; and wherein the 5- or 6-membered ring is optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; each R.sup.5 is independently
selected from a group consisting of halogen and C.sub.1-6alkyl;
R.sup.5a is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; R.sup.2 is selected from a group consisting
of halogen, --CN, --OH, --OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7,
--NO.sub.2, --N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6).sub.2, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; each R.sup.6 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle; or two R.sup.6
on the same heteroatom are taken together with that heteroatom to
which they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl; each R.sup.7 is independently selected from
the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; R.sup.8 is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.9 is
independently selected from the group consisting of hydrogen,
halogen, and C.sub.1-C.sub.6alkyl; each R.sup.13 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; each R.sup.14 is independently selected from
the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or
3; and q is 0, 1, or 2.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl, wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
6. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
7. The compound of claim 6, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
8. The compound of claim 7, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is ##STR00276## wherein each
R.sup.11 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
9. The compound of claim 7, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is ##STR00277## wherein each
R.sup.12 is independently hydrogen, halo, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
10. The compound of claim 7, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
11. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is selected from a group
consisting of pyrimidine, pyrazine, and pyridazine; wherein
pyrimidine, pyrazine, and pyridazine are optionally substituted
with one or two substituents selected from the group consisting of
halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
12. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is selected from a group
consisting of halogen, --OR.sup.6, --N(R.sup.6).sub.2,
C.sub.1-6alkyl, pyrazole, imidazole, thiazole, and pyridine;
wherein pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
13. The compound of claim 12, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is selected from a group
consisting of halogen, --OR.sup.6, --N(R.sup.6).sub.2,
C.sub.1-6alkyl, and unsubstituted pyridine.
14. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is
--C(.dbd.O)N(R.sup.6).sub.2 and each R.sup.6 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
15. The compound of claim 14, or a pharmaceutically acceptable salt
or solvate thereof wherein R.sup.25 is ##STR00278##
##STR00279##
16. The compound of claim 14, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.23 is ##STR00280## wherein
R.sup.10 is a C.sub.2-9heteroaryl.
17. The compound of claim 1, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle or a C.sub.2-9heteroaryl, wherein
C.sub.2-9heterocycle or C.sub.2-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, --C.sub.1-6alkyl, --O--C.sub.1-6alkyl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14.
18. The compound of claim 17, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is ##STR00281##
19. The compound of claim 2, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 are taken together with that heteroatom to which
they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl.
20. The compound of claim 18 or 19, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.25 is
##STR00282##
21. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt or solvate thereof, wherein R.sup.25 is --OR.sup.6 and R.sup.6
is selected from the group consisting of C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, and
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle.
22. The compound of any one of claims 1-21, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is
##STR00283##
23. The compound of any one of claims 1-22, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is
##STR00284##
24. The compound of any one of claims 1-23, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is
##STR00285##
25. The compound of any one of claims 1-23, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is
##STR00286##
26. The compound of any one of claims 1-21, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is
##STR00287##
27. A compound that has the structure of Formula I, or a
pharmaceutically acceptable salt or solvate thereof: ##STR00288##
wherein ##STR00289## is ##STR00290## Z is O, S, C(.dbd.O),
N(R.sup.8), or C(R.sup.9).sub.2; R.sup.1 and R.sup.3 are each
independently selected from a group consisting of hydrogen,
halogen, --CN, --OH, --OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7,
--NO.sub.2, --N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--WC(.dbd.O)N(R.sup.6).sub.2, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.7, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6 alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; R.sup.2 is selected from a
group consisting of hydrogen, halogen, --CN, --OH, --SR.sup.6,
--S(.dbd.O)R.sup.7, --NO.sub.2, --N(R.sup.6).sub.2,
--S(.dbd.O).sub.2R.sup.7, --NHS(.dbd.O).sub.2R.sup.7,
--S(.dbd.O).sub.2N(R.sup.6).sub.2, --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6).sub.2, --WC(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.7, C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; wherein R.sup.2 and R.sup.3
are not both hydrogen; each R.sup.4 and each R.sup.5 are
independently selected from a group consisting of halogen, --CN,
and C.sub.1-6alkyl; R.sup.5a is selected from the group consisting
of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.6 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle; or two R.sup.6
on the same heteroatom are taken together with that heteroatom to
which they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl; each R.sup.7 is independently selected from
the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; R.sup.8 is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.9 is
independently selected from the group consisting of hydrogen,
halogen, and C.sub.1-C.sub.6alkyl; each R.sup.13 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; each R.sup.14 is independently selected from
the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; n is 0, 1, or 2; p is 0, 1, 2, or 3; and
q is 0, 1, or 2.
28. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
29. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
30. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
31. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
32. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
33. The compound of claim 32, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is ##STR00291## wherein
R.sup.11 is C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.6cycloalkyl.
34. The compound of claim 32, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is ##STR00292## wherein each
R.sup.12 is independently halo, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
35. The compound of claim 32, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
36. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.2 is
--C(.dbd.O)N(R.sup.6).sub.2and each R.sup.6 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9 heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
37. The compound of claim 36, or a pharmaceutically acceptable salt
or solvate thereof wherein R.sup.2 is ##STR00293## ##STR00294##
38. The compound of claim 36, or a pharmaceutically acceptable salt
or solvate thereof wherein R.sup.2 is ##STR00295## wherein R.sup.10
is a heteroaryl.
39. The compound of any one of the claims 27-38, or a
pharmaceutically acceptable salt or solvate thereof, wherein
R.sup.3 is hydrogen.
40. The compound of any one of claims 27-38, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.3 is
C.sub.1-C.sub.6alkyl.
41. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl, wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
42. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
43. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
44. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
45. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
46. The compound of claim 45, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is ##STR00296## wherein
R.sup.11 is C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.6cycloalkyl.
47. The compound of claim 43, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is ##STR00297## wherein each
R.sup.12 is independently halo, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
48. The compound of claim 43, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
49. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9 heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
50. The compound of claim 49, or a pharmaceutically acceptable salt
or solvate thereof wherein R.sup.3 is ##STR00298## ##STR00299##
51. The compound of claim 49, or a pharmaceutically acceptable salt
or solvate thereof wherein R.sup.3 is ##STR00300## wherein R.sup.10
is a heteroaryl.
52. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.3 is --OR.sup.6 and R.sup.6 is
selected from the group consisting of C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, and
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle.
53. The compound of any one of claims 41-52, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.2 is
hydrogen.
54. The compound of any one of claims 41-52, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.2 is
C.sub.1-C.sub.6alkyl.
55. The compound of any one of claims 27-54, or a pharmaceutically
acceptable salt or solvate thereof, wherein R.sup.1 is selected
from a group consisting of C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and a
fused C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
56. The compound of claim 55, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.1 is selected from a group
consisting of a C.sub.1-9heteroaryl and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein the C.sub.1-9heteroaryl and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6 alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
57. The compound of claim 55, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.1 is selected from a group
consisting of a C.sub.1-9heteroaryl and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein the C.sub.1-9heteroaryl and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one or two substituents selected from the group consisting of
halo, --CN, C.sub.1-6alkyl, --C.sub.1-6 alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
58. The compound of claim 57, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.1 is selected from a group
consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole,
and tetrazole; wherein triazole, imidazole, oxazole, isoxazole,
oxadiazole, and tetrazole are optionally substituted with one or
two substituents selected from the group consisting of halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
59. The compound of claim 58, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.1 is selected from a group
consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole,
and tetrazole; wherein triazole, imidazole, oxazole, isoxazole,
oxadiazole, and tetrazole are optionally substituted with one or
two substituents selected from the group consisting of halo,
C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
60. The compound of claim 59, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.1 is ##STR00301##
61. The compound of claim 60, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.1 is ##STR00302##
62. The compound of claim 57, or a pharmaceutically acceptable salt
or solvate thereof, wherein R.sup.1 is ##STR00303##
63. The compound of any one of claims 1-62, or a pharmaceutically
acceptable salt or solvate thereof, wherein ##STR00304## is
##STR00305##
64. The compound of any one of claims 1-63, or a pharmaceutically
acceptable salt or solvate thereof, wherein p is 0.
65. The compound of any one of claims 1-62, or a pharmaceutically
acceptable salt or solvate thereof, wherein ##STR00306## is
##STR00307##
66. The compound of any one of claims 1-62, or a pharmaceutically
acceptable salt or solvate thereof, wherein ##STR00308## is
##STR00309##
67. The compound of claims 65 or 66, or a pharmaceutically
acceptable salt or solvate thereof, wherein q is 0.
68. The compound of any one of claims 1-67, or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 0.
69. The compound of any one of claims 1-67, or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 1.
70. The compound of any one of claims 1-67, or a pharmaceutically
acceptable salt or solvate thereof, wherein n is 2.
71. The compound of any one of claims 1-70, or a pharmaceutically
acceptable salt or solvate thereof, wherein Z is
C(R.sup.9).sub.2.
72. The compound of any one of claims 1-71, or a pharmaceutically
acceptable salt or solvate thereof, wherein each R.sup.9 is H.
73. The compound of claim 27, or a pharmaceutically acceptable salt
or solvate thereof, wherein the compound has one of the following
structures: ##STR00310## ##STR00311## ##STR00312## ##STR00313##
##STR00314##
74. The compound of claim 1, 2, or 27, or a pharmaceutically
acceptable salt or solvate thereof, wherein the compound has one of
the following structures: ##STR00315## ##STR00316## ##STR00317##
##STR00318## ##STR00319##
75. The compound of claim 1, 2, or 27, or a pharmaceutically
acceptable salt or solvate thereof, wherein the compound has one of
the following structures: ##STR00320## ##STR00321## ##STR00322##
##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327##
##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332##
##STR00333##
76. A pharmaceutical composition comprising a compound of any one
of claims 1-75, or a pharmaceutically acceptable salt or solvate
thereof, and at least one pharmaceutically acceptable
excipient.
77. A method of treating non-alcoholic steatohepatitis in a subject
in need thereof, comprising administering to the subject a
therapeutically effective amount of a compound of any one of claims
1-75, or a pharmaceutically acceptable salt or solvate thereof.
Description
CROSS-REFERENCE
[0001] This application claims benefit of U.S. Provisional
Application No. 62/482,085, filed on Apr. 5, 2017, which is herein
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Non-alcoholic steatohepatitis (NASH) is an extreme form of
non-alcoholic fatty liver disease (NAFLD), a condition resembling
alcohol-induced liver injury associated with obesity and metabolic
syndrome rather than alcohol abuse. In NAFLD, triglycerides
accumulate within hepatocytes due to alterations in lipid
synthesis, storage, movement, or clearance processes causing
steatosis. While steatosis typically has no large risk implications
on its own, in a subset of NAFLD patients the steatosis progresses
to include inflammation (hepatitis), necrosis and fibrosis, a
condition known as NASH. These NASH patients have highly elevated
risks of both hepatocellular carcinoma (HCC, as high as 7.6% total
risk in one study) and cirrhosis (as high as 25% total risk),
ultimately leading to liver failure or death.
[0003] Current population-based studies indicate that at least 25%
of the US population has NAFLD and about 25% of NAFLD patients will
go on to develop NASH, making these conditions a significant
epidemiologic contributor to organ failure and cancer. As these
conditions are associated with obesity and metabolic disease, their
prevalence is likely to increase in the future.
SUMMARY OF THE INVENTION
[0004] In one aspect, described herein are compounds, or
pharmaceutically acceptable salts or solvates thereof that inhibit
ASK1.
[0005] In one aspect, presented herein are compounds of the
structure of Formula I, or a pharmaceutically acceptable salt or
solvate thereof:
##STR00001##
wherein
##STR00002##
is
##STR00003## [0006] Z is O, S, C(.dbd.O), N(R.sup.8), or
C(R.sup.9).sub.2; [0007] R.sup.1 and R.sup.3 are each independently
selected from a group consisting of hydrogen, halogen, --CN, --OH,
--OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7, --NO.sub.2,
--N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--WC(.dbd.O)N(R.sup.6).sub.2, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6 alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0008] R.sup.2 is selected
from a group consisting of hydrogen, halogen, --CN, --OH,
--SR.sup.6, --S(.dbd.O)R.sup.7, --NO.sub.2, --N(R.sup.6).sub.2,
--S(.dbd.O).sub.2R.sup.7, --NHS(.dbd.O).sub.2R.sup.7,
--S(.dbd.O).sub.2N(R.sup.6).sub.2, --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6).sub.2, --WC(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; wherein R.sup.2 and R.sup.3
are not both hydrogen; [0009] each R.sup.4 and each R.sup.5 are
each independently selected from a group consisting of halogen,
--CN, and C.sub.1-6alkyl; [0010] R.sup.5a is selected from the
group consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0011] each
R.sup.6 is independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle; or two R.sup.6
on the same heteroatom are taken together with that heteroatom to
which they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl; [0012] each R.sup.7 is independently selected
from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0013] R.sup.8 is selected from the
group consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0014] each
R.sup.9 is independently selected from the group consisting of
hydrogen, halogen, and C.sub.1-C.sub.6alkyl; [0015] each R.sup.13
is independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; [0016] each R.sup.14 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0017] n is 0, 1, or 2; [0018] p is 0,
1, 2, or 3; and [0019] q is 0, 1, or 2.
[0020] In some embodiments, R.sup.2 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0021] In some embodiments, R.sup.2 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0022] In some embodiments, R.sup.2 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0023] In some embodiments, R.sup.2 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0024] In some embodiments, R.sup.2 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl. In
some embodiments, R.sup.2 is
##STR00004##
wherein R.sup.11 is C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
[0025] In some embodiments, R.sup.2 is
##STR00005##
wherein R.sup.12 is halo, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
[0026] In some embodiments, R.sup.2 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
[0027] In some embodiments, R.sup.2 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
[0028] In some embodiments, R.sup.2 is
##STR00006##
[0029] In some embodiments, R.sup.2 is
##STR00007##
wherein R.sup.10 is a heteroaryl.
[0030] In some embodiments, R.sup.3 is hydrogen. In some
embodiments, R.sup.3 is C.sub.1-C.sub.6alkyl.
[0031] In some embodiments, R.sup.3 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl, wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0032] In some embodiments, R.sup.3 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0033] In some embodiments, R.sup.3 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0034] In some embodiments, R.sup.3 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0035] In some embodiments, R.sup.3 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0036] In some embodiments, R.sup.3 is
##STR00008##
wherein R.sup.11 is C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
[0037] In some embodiments, R.sup.3 is
##STR00009##
wherein each R.sup.12 is independently halo, C.sub.1-C.sub.6alkyl,
or C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
[0038] In some embodiments, R.sup.3 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
[0039] In some embodiments, R.sup.3 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
[0040] In some embodiments R.sup.3 is
##STR00010##
[0041] In some embodiments, R.sup.3 is
##STR00011##
wherein R.sup.10 is a heteroaryl.
[0042] In some embodiments, R.sup.3 is --OR.sup.6 and R.sup.6 is
selected from the group consisting of C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, and
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle. In some embodiments,
R.sup.2 is hydrogen. In some embodiments, R.sup.2 is
C.sub.1-C.sub.6alkyl.
[0043] In some embodiments, R.sup.1 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl, C.sub.2-6
alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0044] In some embodiments, R.sup.1 is selected from a group
consisting of a C.sub.1-9heteroaryl and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein the C.sub.1-9heteroaryl and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0045] In some embodiments, R.sup.1 is selected from a group
consisting of a C.sub.1-9heteroaryl and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein the C.sub.1-9heteroaryl and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one or two substituents selected from the group consisting of
halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0046] In some embodiments, R.sup.1 is selected from a group
consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole,
and tetrazole; wherein triazole, imidazole, oxazole, isoxazole,
oxadiazole, and tetrazole are optionally substituted with one or
two substituents selected from the group consisting of halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O)--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0047] In some embodiments, R.sup.1 is selected from a group
consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole,
and tetrazole; wherein triazole, imidazole, oxazole, isoxazole,
oxadiazole, and tetrazole are optionally substituted with one or
two substituents selected from the group consisting of halo,
C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0048] In some embodiments, R.sup.1 is
##STR00012##
[0049] In some embodiments, R.sup.1 is
##STR00013##
[0050] In some embodiments, R.sup.1 is
##STR00014##
[0051] In another aspect described herein are compounds of Formula
I, or a pharmaceutically acceptable salt or solvate thereof:
##STR00015##
wherein
##STR00016##
is
##STR00017## [0052] R.sup.1 is
[0052] ##STR00018## [0053] Z is O, S, C(.dbd.O), N(R.sup.8), or
C(R.sup.9).sub.2; [0054] X is O or S; [0055] R.sup.2 is
C.sub.3-6cycloalkyl; [0056] R.sup.3 is selected from a group
consisting of hydrogen, C.sub.1-6alkyl, and C.sub.3-6cycloalkyl;
[0057] each R.sup.4 is independently selected from a group
consisting of hydrogen, halo, C.sub.1-6alkyl, and C.sub.3-6
cycloalkyl; [0058] or one R.sup.4 and another R.sup.2, R.sup.3, or
R.sup.4, together with the atoms to which they are attached, form a
5- or 6-membered ring that is optionally containing one or two
heteroatoms selected from O, N, and S; wherein the 5- or 6-membered
ring is saturated, unsaturated, or aromatic; and wherein the 5- or
6-membered ring is optionally substituted with one, two, or three
substituents selected from the group consisting of halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0059] each R.sup.5 is
independently selected from a group consisting of halogen and
C.sub.1-6alkyl; [0060] R.sup.5a is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0061] R.sup.25 is
selected from a group consisting of halogen, --CN, --OH,
--OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7, --NO.sub.2,
--N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6), --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.7, C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0062] each R.sup.6 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle; or two R.sup.6
on the same heteroatom are taken together with that heteroatom to
which they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl; [0063] each R.sup.7 is independently selected
from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0064] R.sup.8 is selected from the
group consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0065] each
R.sup.9 is independently selected from the group consisting of
hydrogen, halogen, and C.sub.1-C.sub.6alkyl; [0066] each R.sup.13
is independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; [0067] each R.sup.14 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0068] n is 0, 1, 2, 3, or 4; [0069] p
is 0, 1, 2, or 3; and [0070] q is 0, 1, or 2.
[0071] In another aspect described herein are compounds of Formula
II, or a pharmaceutically acceptable salt or solvate thereof:
##STR00019##
wherein
##STR00020##
is
##STR00021## [0072] R.sup.1 is
[0072] ##STR00022## [0073] Z is O, S, C(.dbd.O), N(R.sup.8), or
C(R.sup.9).sub.2; [0074] X is O or S; [0075] R.sup.2 is
C.sub.3-6cycloalkyl; [0076] R.sup.3 is selected from a group
consisting of hydrogen, C.sub.1-6alkyl, and C.sub.3-6cycloalkyl;
each R.sup.4 is independently selected from a group consisting of
hydrogen, halo, C.sub.1-6alkyl, and C.sub.3-6 cycloalkyl; [0077] or
one R.sup.4 and another R.sup.2, R.sup.3, or R.sup.4, together with
the atoms to which they are attached, form a 5- or 6-membered ring
that is optionally containing one or two heteroatoms selected from
O, N, and S; wherein the 5- or 6-membered ring is saturated,
unsaturated, or aromatic; and wherein the 5- or 6-membered ring is
optionally substituted with one, two, or three substituents
selected from the group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0078] each R.sup.5 is
independently selected from a group consisting of halogen and
C.sub.1-6alkyl; [0079] R.sup.5a is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0080] each
R.sup.25 is independently selected from a group consisting of
halogen, --CN, --OH, --OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7,
--NO.sub.2, --N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6).sub.2, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0081] each R.sup.6 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, --C.sub.3-C.sub.8cycloalkyl-phenyl, and
C.sub.2-9heterocycle, wherein C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, --C.sub.3-C.sub.8cycloalkyl-phenyl, and
C.sub.2-9heterocycle are optionally substituted with one, two, or
three substituents selected from the group consisting of halo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; or two R.sup.6 on the same
heteroatom are taken together with that heteroatom to which they
are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl, wherein C.sub.2-9heterocycle or
C.sub.2-9heteroaryl are optionally substituted with one, two, or
three substituents selected from the group consisting of halo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; [0082] each R.sup.7 is
independently selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
C.sub.2-9heterocycle, wherein C.sub.3-C.sub.8cycloalkyl and
C.sub.2-9heterocycle are optionally substituted with one, two, or
three substituents selected from the group consisting of halo, oxo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; [0083] each R.sup.8 is
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0084] each R.sup.9 is independently selected
from the group consisting of hydrogen, halogen, and
C.sub.1-C.sub.6alkyl; [0085] each R.sup.13 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; [0086] each R.sup.14 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0087] n is 0, 1, 2, 3, or 4; [0088] p
is 0, 1, 2, or 3; and [0089] q is 0, 1, or 2.
[0090] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl, wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0091] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0092] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0093] In some embodiments, R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0094] In some embodiments, R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0095] In some embodiments, R.sup.25 is
##STR00023##
wherein each R.sup.11 is independently C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
[0096] In some embodiments, R.sup.25 is
##STR00024##
wherein each R.sup.12 is independently hydrogen, halo,
C.sub.1-C.sub.6alkyl, or C.sub.3-C.sub.6cycloalkyl; and m is 1 or
2.
[0097] In some embodiments, R.sup.25 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
[0098] In some embodiments, R.sup.25 is selected from a group
consisting of pyrimidine, pyrazine, and pyridazine; wherein
pyrimidine, pyrazine, and pyridazine are optionally substituted
with one or two substituents selected from the group consisting of
halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0099] In some embodiments, R.sup.25 is selected from a group
consisting of halogen, --OR.sup.6, --N(R.sup.6).sub.2,
C.sub.1-6alkyl, pyrazole, imidazole, thiazole, and pyridine;
wherein pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0100] In some embodiments, R.sup.25 is selected from a group
consisting of halogen, --OR.sup.6, --N(R.sup.6).sub.2,
C.sub.1-6alkyl, and unsubstituted pyridine.
[0101] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
[0102] In some embodiments, R.sup.25 is
##STR00025## ##STR00026##
[0103] In some embodiments, R.sup.25 is
##STR00027##
wherein R.sup.10 is a heteroaryl.
[0104] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle or a C.sub.2-9heteroaryl, wherein
C.sub.2-9heterocycle or C.sub.2-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, --C.sub.1-6alkyl, --O--C.sub.1-6alkyl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14.
[0105] In some embodiments, R.sup.25 is
##STR00028##
[0106] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle or a C.sub.2-9heteroaryl.
[0107] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 are taken together with that heteroatom to which
they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl.
[0108] In some embodiments, R.sup.25 is
##STR00029##
[0109] In some embodiments, R.sup.25 is --OR.sup.6 and R.sup.6 is
selected from the group consisting of C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, and
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle.
[0110] In some embodiments, R.sup.1 is
##STR00030##
[0111] In some embodiments, R.sup.1 is
##STR00031##
[0112] In some embodiments, R.sup.1 is
##STR00032##
[0113] In some embodiments, R.sup.1 is
##STR00033##
[0114] In some embodiments, R.sup.1 is
##STR00034##
[0115] In some embodiments,
##STR00035##
is
##STR00036##
In some embodiments, p is 0.
[0116] In some embodiments,
##STR00037##
is
##STR00038##
In some embodiments,
##STR00039##
is
##STR00040##
In some embodiments, q is 0.
[0117] In some embodiments, n is 0. In some embodiments, n is 1. In
some embodiments, n is 2. In some embodiments, Z is
C(R.sup.9).sub.2. In some embodiments, R.sup.9 is H.
[0118] In a further aspect described herein are pharmaceutical
compositions comprising a compound of Formula I, Formula II, or
Formula II, or a pharmaceutically acceptable salt or solvate
thereof, and at least one pharmaceutically acceptable
excipient.
[0119] In another aspect described herein are methods of treating
non-alcoholic steatohepatitis in a subject in need thereof,
comprising administering to the subject a therapeutically effective
amount of a compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt or solvate thereof. In another
aspect described herein are methods of treating non-alcoholic
steatohepatitis in a subject in need thereof, comprising
administering to the subject a therapeutically effective amount of
a pharmaceutical composition comprising a compound of Formula I,
Formula II, or Formula II, or a pharmaceutically acceptable salt or
solvate thereof, and at least one pharmaceutically acceptable
excipient.
[0120] Other objects, features and advantages of the compounds,
methods and compositions described herein will become apparent from
the following detailed description. It should be understood,
however, that the detailed description and the specific examples,
while indicating specific embodiments, are given by way of
illustration only, since various changes and modifications within
the spirit and scope of the instant disclosure will become apparent
to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWING
[0121] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawing of which:
[0122] FIG. 1 shows a graph comparing the inhibition of the hERG
potassium channel between compound 2 and compound 27 described
herein (cmpd. 2 and cmpd. 27, respectively), ASK1 inhibitor
GS-4997, and positive control Amitriptyline.
DETAILED DESCRIPTION OF THE INVENTION
[0123] ASK1 is a membrane-proximal MAP3K (MAP-kinase-kinase-kinase)
upstream of pathways which play important roles in the cellular
response to environmental stresses (e.g. the c-Jun and p38
pathways, which are known to be responsive to UV and oxidative
damage), is a promising therapeutic target for NASH. A positive
regulator of mitochondrial apoptosis, ASK1 is tightly regulated and
activated by cellular damage signals as diverse as receptor-acting
inflammatory cytokines (e.g. TNFa and LPS), calcium and
intracellular r sensors (e.g. the redox sensor thioredoxin, and the
ER-stress-responsive IRE).
[0124] Consistent with this role as an effector of stress signals,
ASK1 has been shown as an important mediator of pathological
stress-induced hepatic tissue remodeling. In a mouse model of
non-alcoholic liver injury, ASK1 null mice show resistance to
diet-induced steatohepatitis and subsequent fibrosis. Human data is
consistent with this role in directing responses to diet-induced
liver damage; ASK1 inhibitors (e.g. the small molecule
selonsertib/GS-4997 in clinical trial NCT02466516) have recently
shown utility in phase II trials against non-alcoholic
steatohepatitis (NASH) in affected patients, and NASH patients show
upregulation of ASK1 activity in separate molecular analyses.
[0125] In addition to its apparent role in NASH, recent studies
have produced evidence that ASK1 may be critical in diseases of
stress-induced tissue remodeling generally. Cardiac-targeted
deletion of ASK1 improves resistance to ischemia-, angiotensin II-,
and pressure-induced pathologic tissue remodeling. Further, the
ubiquitous expression of the molecule combined with its central
place upstream in stress-induced signaling cascades suggests
inhibitors of this molecule may be broadly useful for counteracting
diseases of dysfunctional tissue healing and fibrosis.
Certain Terminology
[0126] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a," "an"
and "the" include plural referents unless the context clearly
dictates otherwise. Unless otherwise indicated, conventional
methods of mass spectroscopy, NMR, HPLC, protein chemistry,
biochemistry, recombinant DNA techniques and pharmacology are
employed. In this application, the use of "or" or "and" means
"and/or" unless stated otherwise. Furthermore, use of the term
"including" as well as other forms, such as "include", "includes,"
and "included," is not limiting. The section headings used herein
are for organizational purposes only and are not to be construed as
limiting the subject matter described.
[0127] An "alkyl" group refers to an aliphatic hydrocarbon group.
The alkyl moiety may be branched or straight chain. The "alkyl"
group may have 1 to 15 carbon atoms (whenever it appears herein, a
numerical range such as "1 to 15" refers to each integer in the
given range; e.g., "1 to 15 carbon atoms" means that the alkyl
group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,
etc., up to and including 15 carbon atoms, although the present
definition also covers the occurrence of the term "alkyl" where no
numerical range is designated). In one aspect the alkyl is selected
from the group consisting of methyl, ethyl, propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups
include, but are in no way limited to, methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl,
neopentyl, hexyl, and the like.
[0128] The term "alkenyl" refers to a type of alkyl group in which
at least one carbon-carbon double bond is present. In one
embodiment, an alkenyl group has the formula --C(R).dbd.CR.sub.2,
wherein R refers to the remaining portions of the alkenyl group,
which may be the same or different. In some embodiments, R is H or
an alkyl. Non-limiting examples of an alkenyl group include
--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CHCH.sub.3,
--C(CH.sub.3).dbd.CHCH.sub.3, and --CH.sub.2CH.dbd.CH.sub.2.
[0129] The term "alkynyl" refers to a type of alkyl group in which
at least one carbon-carbon triple bond is present. In one
embodiment, an alkynyl group has the formula --C.ident.C--R,
wherein R refers to the remaining portions of the alkynyl group. In
some embodiments, R is H or an alkyl. Non-limiting examples of an
alkynyl group include --C.ident.CH,
--C.ident.CCH.sub.3--C.ident.CCH.sub.2CH.sub.3,
--CH.sub.2C.ident.CH.
[0130] The term "cycloalkyl" refers to a monocyclic or polycyclic
aliphatic, non-aromatic radical, wherein each of the atoms forming
the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be
saturated, or partially unsaturated. Cycloalkyls may be fused with
an aromatic ring, and the point of attachment is at a carbon that
is not an aromatic ring carbon atom. Cycloalkyl groups include
groups having from 3 to 10 ring atoms. In some embodiments,
cycloalkyl groups are selected from among cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,
and cyclooctyl. Cycloalkyl groups may be substituted or
unsubstituted. Depending on the structure, a cycloalkyl group can
be a monoradical or a diradical (i.e., an cycloalkylene group, such
as, but not limited to, cyclopropan-1,1-diyl, cyclobutan-1,1-diyl,
cyclopentan-1,1-diyl, cyclohexan-1,1-diyl, cyclohexan-1,4-diyl,
cycloheptan-1,1-diyl, and the like). In one aspect, a cycloalkyl is
a C.sub.3-C.sub.6cycloalkyl.
[0131] The term "aromatic" refers to a planar ring having a
delocalized .pi.-electron system containing 4n+2 .pi. electrons,
where n is an integer. Aromatics are optionally substituted. The
term "aromatic" includes both cycloalkyl aryl ("aryl", e.g.,
phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic")
groups (e.g., pyridine). The term includes monocyclic or fused-ring
polycyclic (i.e., rings which share adjacent pairs of carbon atoms)
groups. The term "aryl" refers to an aromatic ring wherein each of
the atoms forming the ring is a carbon atom. Aryl groups are
optionally substituted. Depending on the structure, an aryl group
can be a monoradical or a diradical (i.e., an arylene group).
[0132] The terms "heteroaryl" or, alternatively, "heteroaromatic"
refers to an aryl group that includes one or more ring heteroatoms
selected from nitrogen, oxygen and sulfur. Illustrative examples of
heteroaryl groups include the following moieties:
##STR00041##
and the like. Monocyclic heteroaryls include pyridinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
In some embodiments, a heteroaryl contains 0-3 N atoms in the ring.
In some embodiments, a heteroaryl contains 1-3 N atoms in the ring.
In some embodiments, a heteroaryl contains 0-3 N atoms, 0-1 O
atoms, and 0-1 S atoms in the ring. In some embodiments, a
heteroaryl is a monocyclic or bicyclic heteroaryl. In some
embodiments, heteroaryl is a C.sub.1-C.sub.9heteroaryl. In some
embodiments, monocyclic heteroaryl is a C.sub.1-C.sub.5heteroaryl.
In some embodiments, monocyclic heteroaryl is a 5-membered or
6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is
a C.sub.6-C.sub.9heteroaryl. Depending on the structure, a
heteroaryl group can be a monoradical or a diradical (i.e., a
heteroarylene group).
[0133] A "heterocycle" or "heterocycloalkyl" group refers to a
cycloalkyl group wherein at least one of the carbon atoms of the
cycloalkyl is replaced with nitrogen (unsubstituted or substituted,
e.g. --NH--, --N(alkyl)-), oxygen (--O--), or sulfur (e.g. --S--,
--S(.dbd.O)-- or --S(.dbd.O).sub.2--). The radicals may be fused
with an aryl or heteroaryl. In some embodiments, the
heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, and indolinyl. The term heteroalicyclic also includes
all ring forms of the carbohydrates, including but not limited to
the monosaccharides, the disaccharides and the oligosaccharides. In
one aspect, a heterocycloalkyl is a
C.sub.2-C.sub.10heterocycloalkyl. In another aspect, a
heterocycloalkyl is a C.sub.4-C.sub.10heterocycloalkyl. In some
embodiments, a heterocycloalkyl contains 0-3 N atoms in the ring.
In some embodiments, a heterocycloalkyl contains 0-3 N atoms, 0-3 O
atoms and 0-1 S atoms in the ring.
[0134] The term "halo" or, alternatively, "halogen" or "halide"
means fluoro (F), chloro (Cl), bromo (Br) or iodo (I). The term
"bond" or "single bond" refers to a chemical bond between two
atoms, or two moieties when the atoms joined by the bond are
considered to be part of larger substructure. In one aspect, when a
group described herein is a bond, the referenced group is absent
thereby allowing a bond to be formed between the remaining
identified groups.
[0135] The term "moiety" refers to a specific segment or functional
group of a molecule. Chemical moieties are often recognized
chemical entities embedded in or appended to a molecule.
[0136] The term "optionally substituted" or "substituted" means
that the referenced group may be substituted with one or more
additional group(s) individually and independently selected from
alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,
alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide,
arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, nitro,
haloalkyl, fluoroalkyl, fluoroalkoxy, and amino, including mono-
and di-substituted amino groups, and the protected derivatives
thereof. In some embodiments, optional substituents are
independently selected from halogen, --CN, --NH.sub.2,
--NH(CH.sub.3), --N(CH.sub.3).sub.2, --OH, --CO.sub.2H,
--CO.sub.2alkyl, --C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(alkyl),
--C(.dbd.O)N(alkyl).sub.2, --S(.dbd.O).sub.2NH.sub.2,
--S(.dbd.O).sub.2NH(alkyl), --S(.dbd.O).sub.2N(alkyl).sub.2, alkyl,
cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy,
heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio,
alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In
some embodiments, optional substituents are independently selected
from halogen, --CN, --NH.sub.2, --OH, --NH(CH.sub.3),
--N(CH.sub.3).sub.2, --CH.sub.3, --CH.sub.2CH.sub.3, --CF.sub.3,
--OCH.sub.3, and --OCF.sub.3. In some embodiments, substituted
groups are substituted with one or two of the preceding groups. In
some embodiments, an optional substituent on an aliphatic carbon
atom (acyclic or cyclic, saturated or unsaturated carbon atoms,
excluding aromatic carbon atoms) includes oxo (.dbd.O).
[0137] In certain embodiments, the compounds presented herein
possess one or more stereocenters and each center independently
exists in either the R or S configuration. The compounds presented
herein include all diastereomeric, enantiomeric, and epimeric forms
as well as the appropriate mixtures thereof. Stereoisomers are
obtained, if desired, by methods such as, stereoselective synthesis
and/or the separation of stereoisomers by chiral chromatographic
columns. In some embodiments, halogen is F or Cl. In some
embodiments, halogen is F.
[0138] The methods and formulations described herein include the
use of N-oxides (if appropriate), crystalline forms (also known as
polymorphs), or pharmaceutically acceptable salts of compounds
having the structure of Formula I, Formula II, or Formula III, as
well as active metabolites of these compounds having the same type
of activity. In some situations, compounds may exist as tautomers.
All tautomers are included within the scope of the compounds
presented herein. In specific embodiments, the compounds described
herein exist in solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In other
embodiments, the compounds described herein exist in unsolvated
form.
[0139] The term "acceptable" with respect to a formulation,
composition or ingredient, as used herein, means having no
persistent detrimental effect on the general health of the subject
being treated.
[0140] The term "pharmaceutical combination" as used herein, means
a product that results from the mixing or combining of more than
one active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. a compound of
Formula I, Formula II, or Formula II, or a pharmaceutically
acceptable salt thereof, and a co-agent, are both administered to a
patient simultaneously in the form of a single entity or dosage.
The term "non-fixed combination" means that the active ingredients,
e.g. a compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt thereof, and a co-agent, are
administered to a patient as separate entities either
simultaneously, concurrently or sequentially with no specific
intervening time limits, wherein such administration provides
effective levels of the two compounds in the body of the patient.
The latter also applies to cocktail therapy, e.g. the
administration of three or more active ingredients.
[0141] The term "subject" or "patient" encompasses mammals.
Examples of mammals include, but are not limited to, any member of
the Mammalian class: humans, non-human primates such as
chimpanzees, and other apes and monkey species; farm animals such
as cattle, horses, sheep, goats, swine; domestic animals such as
rabbits, dogs, and cats; laboratory animals including rodents, such
as rats, mice and guinea pigs, and the like. In one aspect, the
mammal is a human.
[0142] The terms "treat," "treating" or "treatment," as used
herein, include alleviating, abating or ameliorating at least one
symptom of a disease or condition, preventing additional symptoms,
inhibiting the disease or condition, e.g., arresting the
development of the disease or condition, relieving the disease or
condition, causing regression of the disease or condition,
relieving a condition caused by the disease or condition, or
stopping the symptoms of the disease or condition either
prophylactically and/or therapeutically.
Compounds
[0143] In one aspect, presented herein are compounds of the
structure of Formula I, or a pharmaceutically acceptable salt or
solvate thereof:
##STR00042##
wherein
##STR00043##
is
##STR00044## [0144] Z is O, S, C(.dbd.O), N(R.sup.8), or
C(R.sup.9).sub.2; [0145] R.sup.1 and R.sup.3 are each independently
selected from a group consisting of hydrogen, halogen, --CN, --OH,
--OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7, --NO.sub.2,
--N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--WC(.dbd.O)N(R.sup.6).sub.2, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6 alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0146] R.sup.2 is selected
from a group consisting of hydrogen, halogen, --CN, --OH,
--SR.sup.6, --S(.dbd.O)R.sup.7, --NO.sub.2, --N(R.sup.6).sub.2,
--S(.dbd.O).sub.2R.sup.7, --NHS(.dbd.O).sub.2R.sup.7,
--S(.dbd.O).sub.2N(R.sup.6).sub.2, --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6).sub.2, --WC(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; wherein R.sup.2 and R.sup.3
are not both hydrogen; [0147] each R.sup.4 and each R.sup.5 are
each independently selected from a group consisting of halogen,
--CN, and C.sub.1-6alkyl; [0148] R.sup.5a is selected from the
group consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0149] each
R.sup.6 is independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle; or two R.sup.6
on the same heteroatom are taken together with that heteroatom to
which they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl; [0150] each R.sup.7 is independently selected
from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0151] R.sup.8 is selected from the
group consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0152] each
R.sup.9 is independently selected from the group consisting of
hydrogen, halogen, and C.sub.1-C.sub.6alkyl; [0153] each R.sup.13
is independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; [0154] each R.sup.14 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0155] n is 0, 1, or 2; [0156] p is 0,
1, 2, or 3; and [0157] q is 0, 1, or 2.
[0158] In some embodiments, R.sup.2 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0159] In some embodiments, R.sup.2 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0160] In some embodiments, R.sup.2 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0161] In some embodiments, R.sup.2 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0162] In some embodiments, R.sup.2 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0163] In some embodiments, R.sup.2 is
##STR00045##
each R.sup.11 is C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.6cycloalkyl;
R.sup.11a is --CN, --OH, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.6cycloalkyl; and u is 0, 1 or 2.
[0164] In some embodiments, R.sup.2 is
##STR00046##
wherein R.sup.11 is C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
[0165] In some embodiments, R.sup.2 is
##STR00047## ##STR00048## ##STR00049## ##STR00050##
[0166] In some embodiments, R.sup.2 is
##STR00051##
wherein each R.sup.12 is independently halo, C.sub.1-C.sub.6alkyl,
or C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
[0167] In some embodiments, R.sup.2 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
[0168] In some embodiments, R.sup.2 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
[0169] In some embodiments, R.sup.2 is
##STR00052## ##STR00053##
[0170] In some embodiments, R.sup.2 is
##STR00054##
wherein R.sup.10 is a heteroaryl.
[0171] In some embodiments, R.sup.3 is hydrogen. In some
embodiments, R.sup.3 is C.sub.1-C.sub.6alkyl.
[0172] In some embodiments, R.sup.3 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0173] In some embodiments, R.sup.3 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0174] In some embodiments, R.sup.3 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0175] In some embodiments, R.sup.3 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0176] In some embodiments, R.sup.3 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0177] In some embodiments, R.sup.3 is
##STR00055##
each R.sup.11 is C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.6cycloalkyl;
R.sup.11a is --CN, --OH, C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl; and u is 0, 1 or 2.
[0178] In some embodiments, R.sup.3 is
##STR00056##
wherein R.sup.11 is C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
[0179] In some embodiments, R.sup.3 is
##STR00057## ##STR00058## ##STR00059## ##STR00060##
[0180] In some embodiments, R.sup.3 is
##STR00061##
wherein each R.sup.12 is independently halo, C.sub.1-C.sub.6alkyl,
or C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
[0181] In some embodiments, R.sup.3 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
[0182] In some embodiments, R.sup.3 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
[0183] In some embodiments, R.sup.3 is
##STR00062##
[0184] In some embodiments, R.sup.3 is
##STR00063##
wherein R.sup.10 is a heteroaryl.
[0185] In some embodiments, R.sup.3 is --OR.sup.6 and R.sup.6 is
selected from the group consisting of C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, and
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle. In some embodiments,
R.sup.2 is hydrogen. In some embodiments, R.sup.2 is
C.sub.1-C.sub.6alkyl.
[0186] In some embodiments, R.sup.1 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl, C.sub.2-6
alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O)--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0187] In some embodiments, R.sup.1 is selected from a group
consisting of a C.sub.1-9heteroaryl and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein the C.sub.1-9heteroaryl and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0188] In some embodiments, R.sup.1 is selected from a group
consisting of a C.sub.1-9heteroaryl and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein the C.sub.1-9heteroaryl and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one or two substituents selected from the group consisting of
halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0189] In some embodiments, R.sup.1 is selected from a group
consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole,
and tetrazole; wherein triazole, imidazole, oxazole, isoxazole,
oxadiazole, and tetrazole are optionally substituted with one or
two substituents selected from the group consisting of halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0190] In some embodiments, R.sup.1 is selected from a group
consisting of triazole, imidazole, oxazole, isoxazole, oxadiazole,
and tetrazole; wherein triazole, imidazole, oxazole, isoxazole,
oxadiazole, and tetrazole are optionally substituted with one or
two substituents selected from the group consisting of halo,
C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0191] In some embodiments, R.sup.1 is
##STR00064##
wherein R.sup.15 is C.sub.1-6alkyl or C.sub.3-8cycloalkyl; and
R.sup.16 is hydrogen, halo, --CN, C.sub.1-6alkyl or
C.sub.3-8cycloalkyl.
[0192] In some embodiments, R.sup.1 is
##STR00065##
wherein R.sup.15 is C.sub.1-6alkyl or C.sub.3-8cycloalkyl; and
R.sup.16 is halo, --CN, C.sub.1-6alkyl or C.sub.3-8cycloalkyl.
[0193] In some embodiments, R.sup.1 is
##STR00066## ##STR00067## ##STR00068## ##STR00069##
[0194] In some embodiments, R.sup.1 is
##STR00070##
[0195] In some embodiments, R.sup.1 is
##STR00071##
wherein each R.sup.17 is independently hydrogen, halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; each R.sup.18 is
independently hydrogen, halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(O)R.sup.14, and
--N(R.sup.13)S(.dbd.O)R.sup.13; v is 0, 1, 2, 3, 4, 5, or 6; and w
is 0, 1, 2, 3, or 4. In some embodiments, each R.sup.17 is
independently hydrogen, halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, or C.sub.3-8cycloalkyl;
each R.sup.18 is independently hydrogen, halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, or
C.sub.3-8cycloalkyl. In some embodiments, each R.sup.17 is
independently hydrogen, halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, or C.sub.1-6haloalkyl; each R.sup.18 is
independently hydrogen, halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, or C.sub.1-6haloalkyl. In some embodiments,
each R.sup.17 is independently hydrogen, halo, --CN, or
C.sub.1-6alkyl; each R.sup.18 is independently is hydrogen, halo,
--CN, or C.sub.1-6alkyl.
[0196] In some embodiments, R.sup.1 is
##STR00072##
[0197] In another aspect described herein are compounds of Formula
II, or a pharmaceutically acceptable salt or solvate thereof:
##STR00073##
wherein
##STR00074##
is
##STR00075## [0198] R.sup.1 is
[0198] ##STR00076## [0199] Z is O, S, C(.dbd.O), N(R.sup.8), or
C(R.sup.9).sub.2; [0200] X is O or S; [0201] R.sup.2 is
C.sub.3-6cycloalkyl; [0202] R.sup.3 is selected from a group
consisting of hydrogen, C.sub.1-6alkyl, and C.sub.3-6cycloalkyl;
each R.sup.4 is independently selected from a group consisting of
hydrogen, halo, C.sub.1-6alkyl, and C.sub.3-6 cycloalkyl; [0203] or
one R.sup.4 and another R.sup.2, R.sup.3, or R.sup.4, together with
the atoms to which they are attached, form a 5- or 6-membered ring
that is optionally containing one or two heteroatoms selected from
O, N, and S; wherein the 5- or 6-membered ring is saturated,
unsaturated, or aromatic; and wherein the 5- or 6-membered ring is
optionally substituted with one, two, or three substituents
selected from the group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0204] each R.sup.5 is
independently selected from a group consisting of halogen and
C.sub.1-6alkyl; [0205] R.sup.5a is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0206] R.sup.25 is
selected from a group consisting of halogen, --CN, --OH,
--OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7, --NO.sub.2,
--N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6), --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.7, C.sub.1-6 alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0207] each R.sup.6 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle; or two R.sup.6
on the same heteroatom are taken together with that heteroatom to
which they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl; [0208] each R.sup.7 is independently selected
from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0209] R.sup.8 is selected from the
group consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0210] each
R.sup.9 is independently selected from the group consisting of
hydrogen, halogen, and C.sub.1-C.sub.6alkyl; [0211] each R.sup.13
is independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; [0212] each R.sup.14 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0213] n is 0, 1, 2, 3 or 4; [0214] p is
0, 1, 2, or 3; and [0215] q is 0, 1, or 2.
[0216] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl, wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0217] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0218] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0219] In some embodiments, R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0220] In some embodiments, R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0221] In some embodiments, R.sup.25 is
##STR00077##
each R.sup.11 is C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.6cycloalkyl;
R.sup.11a is --CN, --OH, C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl; and u is 0, 1 or 2.
[0222] In some embodiments, R.sup.25 is
##STR00078##
wherein R.sup.11 is C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
[0223] In some embodiments, R.sup.25 is
##STR00079## ##STR00080## ##STR00081## ##STR00082##
[0224] In some embodiments, R.sup.25 is
##STR00083##
wherein R.sup.12 is halo, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
[0225] In some embodiments, R.sup.25 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
[0226] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
[0227] In some embodiments, R.sup.25 is
##STR00084## ##STR00085##
[0228] In some embodiments, R.sup.25 is
##STR00086##
wherein R.sup.10 is a heteroaryl.
[0229] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 are taken together with that heteroatom to which
they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl.
[0230] In some embodiments, R.sup.25 is
##STR00087##
[0231] In some embodiments, R.sup.25 is --OR.sup.6 and R.sup.6 is
selected from the group consisting of C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, and
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle.
[0232] In some embodiments,
##STR00088##
is
##STR00089##
In some embodiments, p is 0.
[0233] In some embodiments,
##STR00090##
is
##STR00091##
In some embodiments,
##STR00092##
is
##STR00093##
In some embodiments, q is 0.
[0234] In some embodiments, n is 0. In some embodiments, n is 1. In
some embodiments, Z is C(R.sup.9).sub.2. In some embodiments,
R.sup.9 is H.
[0235] In some embodiments, R.sup.1 is
##STR00094##
wherein R.sup.2 is C.sub.3-6cycloalkyl; R.sup.3 is selected from a
group consisting of hydrogen C.sub.1-6alkyl and C.sub.3-6
cycloalkyl; each R.sup.4 is independently selected from a group
consisting of hydrogen, halogen, C.sub.1-6alkyl, and
C.sub.3-6cycloalkyl; or one R.sup.4 and another R.sup.2, R.sup.3,
or R.sup.4, together with the atoms to which they are attached,
form a 5- or 6-membered ring that is optionally containing one or
two heteroatoms selected from O, N, and S; wherein the 5- or
6-membered ring is saturated, unsaturated or aromatic; and wherein
the 5- or 6-membered ring is optionally substituted with one, two,
or three substituents selected from the group consisting of halo,
--CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0236] In some embodiments, R.sup.1 is
##STR00095##
wherein R.sup.3 is selected from a group consisting of
C.sub.1-6alkyl and C.sub.3-6cycloalkyl; and each R.sup.4 is
independently selected from a group consisting of hydrogen,
halogen, C.sub.1-6alkyl, and C.sub.3-6 cycloalkyl.
[0237] In some embodiments, R.sup.1 is
##STR00096##
[0238] In some embodiments, R.sup.1 is
##STR00097##
[0239] In some embodiments, R.sup.1 is
##STR00098##
[0240] In some embodiments, R.sup.1 is
##STR00099##
wherein R.sup.2 and R.sup.4, together with the atoms to which they
are attached, form a 5- or 6-membered ring that is optionally
containing one or two heteroatoms selected from O, N, and S;
wherein the 5- or 6-membered ring is saturated, unsaturated or
aromatic; and wherein the 5- or 6-membered ring is optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0241] In some embodiments, R.sup.1 is
##STR00100##
wherein X is O, N or S; each R.sup.19 is independently halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O)R.sup.13; and y is 0, 1, 2, 3 or 4.
[0242] In some embodiments, R.sup.1 is
##STR00101##
wherein X is O, N or S.
[0243] In some embodiments, R.sup.1 is
##STR00102##
wherein X is N.
[0244] In some embodiments, R.sup.1 is
##STR00103##
wherein X is O or S; and one R.sup.4 and another R.sup.2, R.sup.3,
or R.sup.4, together with the atoms to which they are attached,
form a 5- or 6-membered ring that is optionally containing one or
two heteroatoms selected from O, N, and S; wherein the 5- or
6-membered ring is saturated, unsaturated or aromatic; and wherein
the 5- or 6-membered ring is optionally substituted with one, two,
or three substituents selected from the group consisting of halo,
--CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0245] In some embodiments, R.sup.1 is
##STR00104##
[0246] In some embodiments, R.sup.1 is
##STR00105##
[0247] In another aspect described herein are compounds of Formula
III, or a pharmaceutically acceptable salt or solvate thereof:
##STR00106##
wherein
##STR00107##
is
##STR00108## [0248] R.sup.1 is
[0248] ##STR00109## [0249] Z is O, S, C(.dbd.O), N(R.sup.8), or
C(R.sup.9).sub.2; [0250] X is O or S; [0251] R.sup.2 is
C.sub.3-6cycloalkyl; [0252] R.sup.3 is selected from a group
consisting of hydrogen, C.sub.1-6alkyl, and C.sub.3-6cycloalkyl;
[0253] each R.sup.4 is independently selected from a group
consisting of hydrogen, halo, C.sub.1-6alkyl, and C.sub.3-6
cycloalkyl; [0254] or one R.sup.4 and another R.sup.2, R.sup.3, or
R.sup.4, together with the atoms to which they are attached, form a
5- or 6-membered ring that is optionally containing one or two
heteroatoms selected from O, N, and S; wherein the 5- or 6-membered
ring is saturated, unsaturated, or aromatic; and wherein the 5- or
6-membered ring is optionally substituted with one, two, or three
substituents selected from the group consisting of halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0255] each R.sup.5 is
independently selected from a group consisting of halogen and
C.sub.1-6alkyl; [0256] R.sup.5a is selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl; [0257] each
R.sup.25 is independently selected from a group consisting of
halogen, --CN, --OH, --OR.sup.6, --SR.sup.6, --S(.dbd.O)R.sup.7,
--NO.sub.2, --N(R.sup.6).sub.2, --S(.dbd.O).sub.2R.sup.7,
--NHS(.dbd.O).sub.2R.sup.7, --S(.dbd.O).sub.2N(R.sup.6).sub.2,
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.6, --OC(.dbd.O)R.sup.7,
--C(.dbd.O)N(R.sup.6).sub.2, --OC(.dbd.O)N(R.sup.6).sub.2,
--NR.sup.6C(.dbd.O)N(R.sup.6).sub.2, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)OR.sup.6, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13; [0258] each R.sup.6 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, --C.sub.3-C.sub.8cycloalkyl-phenyl, and
C.sub.2-9heterocycle, wherein C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, --C.sub.3-C.sub.8cycloalkyl-phenyl, and
C.sub.2-9heterocycle are optionally substituted with one, two, or
three substituents selected from the group consisting of halo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; or two R.sup.6 on the same
heteroatom are taken together with that heteroatom to which they
are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl, wherein C.sub.2-9heterocycle or
C.sub.2-9heteroaryl are optionally substituted with one, two, or
three substituents selected from the group consisting of halo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; [0259] each R.sup.7 is
independently selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalkyl, and
C.sub.2-9heterocycle, wherein C.sub.3-C.sub.8cycloalkyl and
C.sub.2-9heterocycle are optionally substituted with one, two, or
three substituents selected from the group consisting of halo, oxo,
--OR.sup.8, --SR.sup.8, --N(R.sup.8).sub.2, --C.sub.1-6alkyl,
--O--C.sub.1-6alkyl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14; [0260] each R.sup.8 is
independently selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl; [0261] each R.sup.9 is independently selected
from the group consisting of hydrogen, halogen, and
C.sub.1-C.sub.6alkyl; [0262] each R.sup.13 is independently
selected from the group consisting of hydrogen,
C.sub.1-C.sub.6alkyl, and C.sub.3-C.sub.8cycloalkyl; or two
R.sup.13 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle; [0263] each R.sup.14 is independently
selected from the group consisting of C.sub.1-C.sub.6alkyl and
C.sub.3-C.sub.8cycloalkyl; [0264] n is 0, 1, 2, 3, or 4; [0265] p
is 0, 1, 2, or 3; and [0266] q is 0, 1, or 2.
[0267] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, and a fused
C.sub.5-9heteroaryl-cycloalkyl; wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl, wherein C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl, and
fused C.sub.5-9heteroaryl-cycloalkyl are optionally substituted
with one, two, or three substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0268] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0269] In some embodiments, R.sup.25 is selected from a group
consisting of C.sub.2-9heterocycle and C.sub.1-9heteroaryl; wherein
C.sub.2-9heterocycle and C.sub.1-9heteroaryl are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6 haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0270] In some embodiments, R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, --CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-9heterocycle,
C.sub.6-10aryl, C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14,
--C(.dbd.O)OR.sup.13, --C(.dbd.O)N(R.sup.13).sub.2,
--S(.dbd.O)R.sup.14, --S(.dbd.O).sub.2R.sup.13,
--S(.dbd.O).sub.2--N(R.sup.13).sub.2, --N(R.sup.13).sub.2,
--N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0271] In some embodiments, R.sup.25 is selected from a group
consisting of pyrazole, imidazole, thiazole, and pyridine; wherein
pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0272] In some embodiments, R.sup.25 is
##STR00110##
each R.sup.11 is C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.6cycloalkyl;
R.sup.11a is --CN, --OH, C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl; and u is 0, 1 or 2.
[0273] In some embodiments, R.sup.25 is
##STR00111##
wherein R.sup.11 is C.sub.1-C.sub.6alkyl or
C.sub.3-C.sub.6cycloalkyl.
[0274] In some embodiments, R.sup.25 is
##STR00112## ##STR00113## ##STR00114## ##STR00115##
[0275] In some embodiments, R.sup.25 is
##STR00116##
wherein R.sup.12 is halo, C.sub.1-C.sub.6alkyl, or
C.sub.3-C.sub.6cycloalkyl; and m is 1 or 2.
[0276] In some embodiments, R.sup.25 is selected from a group
consisting of unsubstituted pyrazole, unsubstituted imidazole,
unsubstituted thiazole, and unsubstituted pyridine.
[0277] In some embodiments, R.sup.25 is selected from a group
consisting of pyrimidine, pyrazine, and pyridazine; wherein
pyrimidine, pyrazine, and pyridazine are optionally substituted
with one or two substituents selected from the group consisting of
halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0278] In some embodiments, R.sup.25 is selected from a group
consisting of halogen, --OR.sup.6, --N(R.sup.6).sub.2,
C.sub.1-6alkyl, pyrazole, imidazole, thiazole, and pyridine;
wherein pyrazole, imidazole, thiazole, and pyridine are optionally
substituted with one or two substituents selected from the group
consisting of halo, C.sub.1-6alkyl, and C.sub.3-8cycloalkyl.
[0279] In some embodiments, R.sup.25 is selected from a group
consisting of halogen, --OR.sup.6, --N(R.sup.6).sub.2,
C.sub.1-6alkyl, and unsubstituted pyridine.
[0280] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and each R.sup.6 is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle,
--C.sub.1-C.sub.6alkyl-C.sub.2-9heteroaryl,
C.sub.3-C.sub.8cycloalkyl, and C.sub.2-9heterocycle.
[0281] In some embodiments, R.sup.25 is
##STR00117## ##STR00118##
[0282] In some embodiments, R.sup.25 is
##STR00119##
wherein R.sup.10 is a heteroaryl.
[0283] In some embodiments, R.sup.25 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 on the same heteroatom are taken together with that
heteroatom to which they are attached to form a
C.sub.2-9heterocycle or a C.sub.2-9heteroaryl, wherein
C.sub.2-9heterocycle or C.sub.2-9heteroaryl are optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --OR.sup.8, --SR.sup.8,
--N(R.sup.8).sub.2, --C.sub.1-6alkyl, --O--C.sub.1-6alkyl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13, and
--N(R.sup.13)C(.dbd.O)R.sup.14.
[0284] In some embodiments, R.sup.25 is
##STR00120##
[0285] In some embodiments, R.sup.2 is --C(.dbd.O)N(R.sup.6).sub.2
and two R.sup.6 are taken together with that heteroatom to which
they are attached to form a C.sub.2-9heterocycle or a
C.sub.2-9heteroaryl.
[0286] In some embodiments, R.sup.25 is
##STR00121##
[0287] In some embodiments, R.sup.25 is --OR.sup.6 and R.sup.6 is
selected from the group consisting of C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl-O--C.sub.1-C.sub.6alkyl, and
--C.sub.1-C.sub.6alkyl-C.sub.2-9heterocycle.
[0288] In some embodiments, n is 0. In some embodiments, n is 1. In
some embodiments, n is 2.
[0289] In some embodiments, Z is C(R.sup.9). In some embodiments, Z
is C(R.sup.9).sub.2 and each R.sup.9 is H.
[0290] In some embodiments, Z is N(R.sup.8). In some embodiments, Z
is N(R.sup.8) and each R.sup.8 is H. In some embodiments, Z is
N(R.sup.8) and each R.sup.8 is C.sub.1-C.sub.6alkyl.
[0291] In some embodiments,
##STR00122##
is
##STR00123##
In some embodiments, p is 0.
[0292] In some embodiments,
##STR00124##
is
##STR00125##
In some embodiments,
##STR00126##
is
##STR00127##
In some embodiments, q is 0.
[0293] In some embodiments, R.sup.1 is
##STR00128##
wherein R.sup.2 is C.sub.3-6cycloalkyl; R.sup.3 is selected from a
group consisting of hydrogen C.sub.1-6alkyl and C.sub.3-6
cycloalkyl; each R.sup.4 is independently selected from a group
consisting of hydrogen, halogen, C.sub.1-6alkyl, and
C.sub.3-6cycloalkyl; or one R.sup.4 and another R.sup.2, R.sup.3,
or R.sup.4, together with the atoms to which they are attached,
form a 5- or 6-membered ring that is optionally containing one or
two heteroatoms selected from O, N, and S; wherein the 5- or
6-membered ring is saturated, unsaturated or aromatic; and wherein
the 5- or 6-membered ring is optionally substituted with one, two,
or three substituents selected from the group consisting of halo,
--CN, C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6 haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0294] In some embodiments, R.sup.1 is
##STR00129##
wherein R.sup.3 is selected from a group consisting of
C.sub.1-6alkyl and C.sub.3-6cycloalkyl; and each R.sup.4 is
independently selected from a group consisting of hydrogen,
halogen, C.sub.1-6alkyl, and C.sub.3-6 cycloalkyl.
[0295] In some embodiments, R.sup.1 is
##STR00130##
[0296] In some embodiments, R.sup.1 is
##STR00131##
[0297] In some embodiments, R.sup.1 is
##STR00132##
[0298] In some embodiments, R.sup.1 is
##STR00133##
[0299] In some embodiments, R.sup.1 is
##STR00134##
[0300] In some embodiments, R.sup.1 is
##STR00135##
[0301] In some embodiments, R.sup.1 is
##STR00136##
[0302] In some embodiments, R.sup.1 is
##STR00137##
[0303] In some embodiments, R.sup.1 is
##STR00138##
wherein R.sup.2 and R.sup.4, together with the atoms to which they
are attached, form a 5- or 6-membered ring that is optionally
containing one or two heteroatoms selected from O, N, and S;
wherein the 5- or 6-membered ring is saturated, unsaturated or
aromatic; and wherein the 5- or 6-membered ring is optionally
substituted with one, two, or three substituents selected from the
group consisting of halo, --CN, C.sub.1-6alkyl,
--C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-9heterocycle, C.sub.6-10aryl, C.sub.1-9heteroaryl,
--C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0304] In some embodiments, R.sup.1 is
##STR00139##
wherein X is O, N or S; each R.sup.19 is independently halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O)R.sup.13; and y is 0, 1, 2, 3 or 4.
[0305] In some embodiments, R.sup.1 is
##STR00140##
wherein X is O, N or S.
[0306] In some embodiments, R.sup.1 is
##STR00141##
wherein X is N.
[0307] In some embodiments, R.sup.1 is
##STR00142##
X is O or S; and
[0308] one R.sup.4 and another R.sup.2, R.sup.3, or R.sup.4,
together with the atoms to which they are attached, form a 5- or
6-membered ring that is optionally containing one or two
heteroatoms selected from O, N, and S; wherein the 5- or 6-membered
ring is saturated, unsaturated or aromatic; and wherein the 5- or
6-membered ring is optionally substituted with one, two, or three
substituents selected from the group consisting of halo, --CN,
C.sub.1-6alkyl, --C.sub.1-6alkyl-OH, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-9heterocycle, C.sub.6-10aryl,
C.sub.1-9heteroaryl, --C(.dbd.O)R.sup.14, --C(.dbd.O)OR.sup.13,
--C(.dbd.O)N(R.sup.13).sub.2, --S(.dbd.O)R.sup.14,
--S(.dbd.O).sub.2R.sup.13, --S(.dbd.O).sub.2--N(R.sup.13).sub.2,
--N(R.sup.13).sub.2, --N(R.sup.13)C(.dbd.O)R.sup.14, and
--N(R.sup.13)S(.dbd.O).sub.2R.sup.13.
[0309] In some embodiments, R.sup.1 is
##STR00143##
[0310] In some embodiments, R.sup.1 is
##STR00144##
[0311] In one aspect, presented herein are pharmaceutical
compositions comprising a compound of Formula I, Formula II, or
Formula III, or a pharmaceutically acceptable salt or solvate
thereof, and at least one pharmaceutically acceptable
excipient.
[0312] In one aspect, presented herein are methods of treating
non-alcoholic steatohepatitis in a subject in need thereof,
comprising administering to the subject a therapeutically effective
amount of a compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt or solvate thereof. In some
embodiments is a method of treating non-alcoholic steatohepatitis
in a subject in need thereof, comprising administering to the
subject a therapeutically effective amount of a compound of Formula
I, or a pharmaceutically acceptable salt or solvate thereof. In
some embodiments is a method of treating non-alcoholic
steatohepatitis in a subject in need thereof, comprising
administering to the subject a therapeutically effective amount of
a compound of Formula II, or a pharmaceutically acceptable salt or
solvate thereof. In some embodiments is a method of treating
non-alcoholic steatohepatitis in a subject in need thereof,
comprising administering to the subject a therapeutically effective
amount of a compound of Formula III, or a pharmaceutically
acceptable salt or solvate thereof.
[0313] In some embodiments, the compound disclosed herein is a
compound of any one of Compounds 1-89, or a pharmaceutically
acceptable salt or solvate thereof.
[0314] In one aspect, the structures of the compounds described
herein are selected from Table 1.
TABLE-US-00001 TABLE 1 ##STR00145## ##STR00146## ##STR00147##
##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152##
##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157##
##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162##
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172##
##STR00173##
Synthesis of Compounds
[0315] Compounds described herein are synthesized using standard
synthetic techniques or using methods known in the art in
combination with methods described herein. In addition, solvents,
temperatures and other reaction conditions presented herein may
vary.
[0316] The starting material used for the synthesis of the
compounds described herein are either synthesized or obtained from
commercial sources, such as, but not limited to, Sigma-Aldrich,
Fluka, Acros Organics, Alfa Aesar, and the like. The compounds
described herein, and other related compounds having different
substituents are synthesized using techniques and materials
described herein or otherwise known, including those found in
March, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley 1992); Carey
and Sundberg, ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., Vols. A and
B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN
ORGANIC SYNTHESIS 3.sup.rd Ed., (Wiley 1999). General methods for
the preparation of compounds can be modified by the use of
appropriate reagents and conditions for the introduction of the
various moieties found in the formulae as provided herein. A
detailed description of techniques applicable to the creation of
protecting groups and their removal are described in Greene and
Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley
& Sons, New York, N.Y., 1999, and Kocienski, Protective Groups,
Thieme Verlag, New York, N.Y., 1994, which are incorporated herein
by reference for such disclosure.
[0317] In some embodiments, a compound, such as compound 1, is
prepared according to the route as shown in Scheme 1.
##STR00174##
[0318] In some embodiments, a phenolic compound, such as 1A, is
hydrazinated with a suitable hydrazination reagent, to provide a
hydrazide phenolic compound, such as 1B. In some embodiments, the
suitable hydrazination reagent is hydrazine hydrate. In some
embodiments, the hydrazide phenolic compound, such as 1B, is
coupled with an appropriate formamide compound to provide a coupled
hydrazide phenolic compound, such as 1C. In some embodiments, the
appropriate formamide compound is dimethylformamide dimethylacetal.
In some embodiments, the coupled hydrazide phenolic compound, such
as 1C, is subjected under suitable reaction conditions to provide a
polycyclic compound, such as 1D. In some embodiments, the suitable
reaction conditions include treatment with acetic acid. In some
embodiments, the polycyclic compound is subjected to suitable
reaction conditions to provide a compound, such as compounds 1.
[0319] In one aspect, compounds described herein are synthesized as
outlined in the Examples. Throughout the specification, groups and
substituents thereof are chosen by one skilled in the field to
provide stable moieties and compounds.
Further Forms of Compounds
[0320] In one aspect, compounds described herein possess one or
more stereocenters and each stereocenter exists independently in
either the R or S configuration. The compounds presented herein
include all diastereomeric, enantiomeric, and epimeric forms as
well as the appropriate mixtures thereof. The compounds and methods
provided herein include all cis-, trans-, syn-, anti-, entgegen
(E), and zusammen (Z) isomers as well as the appropriate mixtures
thereof. In certain embodiments, compounds described herein are
prepared as their individual stereoisomers by reacting a racemic
mixture of the compound with an optically active resolving agent to
form a pair of diastereoisomeric compounds/salts, separating the
diastereomers and recovering the optically pure enantiomers. In
some embodiments, resolution of enantiomers is carried out using
covalent diastereomeric derivatives of the compounds described
herein. In another embodiment, diastereomers are separated by
separation/resolution techniques based upon differences in
solubility. In other embodiments, separation of stereoisomers is
performed by chromatography or by the forming diastereomeric salts
and separation by recrystallization, or chromatography, or any
combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen,
"Enantiomers, Racemates and Resolutions", John Wiley And Sons,
Inc., 1981. In some embodiments, stereoisomers are obtained by
stereoselective synthesis.
[0321] "Pharmaceutically acceptable," as used herein, refers to a
material, such as a carrier or diluent, which does not abrogate the
biological activity or properties of the compound, and is
relatively nontoxic, i.e., the material may be administered to an
individual without causing undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained.
[0322] The term "pharmaceutically acceptable salt" refers to a
formulation of a compound that does not cause significant
irritation to an organism to which it is administered and does not
abrogate the biological activity and properties of the compound. In
some embodiments, pharmaceutically acceptable salts are obtained by
reacting a compound described herein with acids. Pharmaceutically
acceptable salts are also obtained by reacting a compound described
herein with a base to form a salt.
[0323] Compounds described herein may be formed as, and/or used as,
pharmaceutically acceptable salts. The type of pharmaceutical
acceptable salts, include, but are not limited to: (1) acid
addition salts, formed by reacting the free base form of the
compound with a pharmaceutically acceptable: inorganic acid to form
a salt such as, for example, a hydrochloric acid salt, a
hydrobromic acid salt, a sulfuric acid salt, a phosphoric acid
salt, a metaphosphoric acid salt, and the like; or with an organic
acid to form a salt such as, for example, an acetic acid salt, a
propionic acid salt, a hexanoic acid salt, a cyclopentanepropionic
acid salt, a glycolic acid salt, a pyruvic acid salt, a lactic acid
salt, a malonic acid salt, a succinic acid salt, a malic acid salt,
a maleic acid salt, a fumaric acid salt, a trifluoroacetic acid
salt, a tartaric acid salt, a citric acid salt, a benzoic acid
salt, a 3-(4-hydroxybenzoyl)benzoic acid salt, a cinnamic acid
salt, a mandelic acid salt, a methanesulfonic acid salt, an
ethanesulfonic acid salt, a 1,2-ethanedisulfonic acid salt, a
2-hydroxyethanesulfonic acid salt, a benzenesulfonic acid salt, a
toluenesulfonic acid salt, a 2-naphthalenesulfonic acid salt, a
4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid salt, a
glucoheptonic acid salt, a
4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid) salt, a
3-phenylpropionic acid salt, a trimethylacetic acid salt, a
tertiary butylacetic acid salt, a lauryl sulfuric acid salt, a
gluconic acid salt, a glutamic acid salt, a hydroxynaphthoic acid
salt, a salicylic acid salt, a stearic acid salt, a muconic acid
salt, a butyric acid salt, a phenylacetic acid salt, a
phenylbutyric acid salt, a valproic acid salt, and the like; (2)
salts formed when an acidic proton present in the parent compound
is replaced by a metal ion, e.g., an alkali metal ion (e.g. a
lithium salt, a sodium salt, or a potassium salt), an alkaline
earth ion (e.g. a magnesium salt, or a calcium salt), or an
aluminum ion (e.g. an aluminum salt). In some cases, compounds
described herein may coordinate with an organic base to form a
salt, such as, but not limited to, an ethanolamine salt, a
diethanolamine salt, a triethanolamine salt, a tromethamine salt, a
N-methylglucamine salt, a dicyclohexylamine salt, or a
tris(hydroxymethyl)methylamine salt. In other cases, compounds
described herein may form salts with amino acids such as, but not
limited to, an arginine salt, a lysine salt, and the like.
Acceptable inorganic bases used to form salts with compounds that
include an acidic proton, include, but are not limited to, aluminum
hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate, sodium hydroxide, and the like.
[0324] It should be understood that a reference to a
pharmaceutically acceptable salt includes the solvent addition
forms. Solvates contain either stoichiometric or non-stoichiometric
amounts of a solvent, and may be formed during the process of
crystallization with pharmaceutically acceptable solvents such as
water, ethanol, and the like. Hydrates are formed when the solvent
is water, or alcoholates are formed when the solvent is alcohol.
Solvates of compounds described herein can be conveniently prepared
or formed during the processes described herein. In addition, the
compounds provided herein can exist in unsolvated as well as
solvated forms.
Routes of Administration
[0325] Suitable routes of administration include, but are not
limited to, oral, intravenous, rectal, aerosol, parenteral,
ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic,
nasal, and topical administration. In addition, by way of example
only, parenteral delivery includes intramuscular, subcutaneous,
intravenous, intramedullary injections, as well as intrathecal,
direct intraventricular, intraperitoneal, intralymphatic, and
intranasal injections.
[0326] In certain embodiments, a compound as described herein is
administered in a local rather than systemic manner, for example,
via injection of the compound directly into an organ, often in a
depot preparation or sustained release formulation. In specific
embodiments, long acting formulations are administered by
implantation (for example subcutaneously or intramuscularly) or by
intramuscular injection. Furthermore, in other embodiments, the
drug is delivered in a targeted drug delivery system, for example,
in a liposome coated with organ-specific antibody. In such
embodiments, the liposomes are targeted to and taken up selectively
by the organ. In yet other embodiments, the compound as described
herein is provided in the form of a rapid release formulation, in
the form of an extended release formulation, or in the form of an
intermediate release formulation. In yet other embodiments, the
compound described herein is administered topically.
Pharmaceutical Compositions/Formulations
[0327] In some embodiments, the compounds described herein are
formulated into pharmaceutical compositions. Pharmaceutical
compositions are formulated in a conventional manner using one or
more pharmaceutically acceptable inactive ingredients that
facilitate processing of the active compounds into preparations
that can be used pharmaceutically. Proper formulation is dependent
upon the route of administration chosen. A summary of
pharmaceutical compositions described herein can be found, for
example, in Remington: The Science and Practice of Pharmacy,
Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover,
John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,
Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds.,
Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;
and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh
Ed. (Lippincott Williams & Wilkins 1999), herein incorporated
by reference for such disclosure.
[0328] Provided herein are pharmaceutical compositions that include
a compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable inactive ingredient. In some
embodiments is a pharmaceutical composition that includes a
compound of Formula I, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient. In
some embodiments is a pharmaceutical composition that includes a
compound of Formula II, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient. In
some embodiments is a pharmaceutical composition that includes a
compound of Formula III, or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient. In
some embodiments, the compounds described herein are administered
as pharmaceutical compositions in which a compound of Formula I,
Formula II, or Formula III, or a pharmaceutically acceptable salt
thereof, is mixed with other active ingredients, as in combination
therapy. In other embodiments, the pharmaceutical compositions
include other medicinal or pharmaceutical agents, carriers,
adjuvants, preserving, stabilizing, wetting or emulsifying agents,
solution promoters, salts for regulating the osmotic pressure,
and/or buffers. In yet other embodiments, the pharmaceutical
compositions include other therapeutically valuable substances.
[0329] A pharmaceutical composition, as used herein, refers to a
mixture of a compound of Formula I, Formula II, or Formula III, or
a pharmaceutically acceptable salt thereof, with other chemical
components (i.e. pharmaceutically acceptable inactive ingredients),
such as carriers, excipients, binders, filling agents, suspending
agents, flavoring agents, sweetening agents, disintegrating agents,
dispersing agents, surfactants, lubricants, colorants, diluents,
solubilizers, moistening agents, plasticizers, stabilizers,
penetration enhancers, wetting agents, anti-foaming agents,
antioxidants, preservatives, or one or more combination thereof.
The pharmaceutical composition facilitates administration of the
compound to a mammal.
[0330] A therapeutically effective amount can vary widely depending
on the severity of the disease, the age and relative health of the
subject, the potency of the compound used and other factors. The
compounds can be used singly or in combination with one or more
therapeutic agents as components of mixtures.
[0331] The pharmaceutical formulations described herein are
administered to a subject by appropriate administration routes,
including but not limited to, oral, parenteral (e.g., intravenous,
subcutaneous, intramuscular), intranasal, buccal, topical, rectal,
or transdermal administration routes. The pharmaceutical
formulations described herein include, but are not limited to,
aqueous liquid dispersions, self-emulsifying dispersions, solid
solutions, liposomal dispersions, aerosols, solid dosage forms,
powders, immediate release formulations, controlled release
formulations, fast melt formulations, tablets, capsules, pills,
delayed release formulations, extended release formulations,
pulsatile release formulations, multiparticulate formulations, and
mixed immediate and controlled release formulations.
[0332] Pharmaceutical compositions including a compound of Formula
I, Formula II, or Formula III, or a pharmaceutically acceptable
salt thereof, are manufactured in a conventional manner, such as,
by way of example only, by means of conventional mixing,
dissolving, granulating, dragee-making, levigating, emulsifying,
encapsulating, entrapping or compression processes.
[0333] The pharmaceutical compositions will include at least one
compound of Formula I, Formula II, or Formula III, as an active
ingredient in free-acid or free-base form, or in a pharmaceutically
acceptable salt form. In addition, the methods and pharmaceutical
compositions described herein include the use of N-oxides (if
appropriate), crystalline forms, amorphous phases, as well as
active metabolites of these compounds having the same type of
activity. In some embodiments, compounds described herein exist in
unsolvated form or in solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. The
solvated forms of the compounds presented herein are also
considered to be disclosed herein.
[0334] The pharmaceutical compositions described herein, which
include a compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt thereof, are formulated into any
suitable dosage form, including but not limited to, aqueous oral
dispersions, liquids, gels, syrups, elixirs, slurries, suspensions,
solid oral dosage forms, controlled release formulations, fast melt
formulations, effervescent formulations, lyophilized formulations,
tablets, powders, pills, dragees, capsules, delayed release
formulations, extended release formulations, pulsatile release
formulations, multiparticulate formulations, and mixed immediate
release and controlled release formulations.
[0335] Pharmaceutical preparations that are administered orally
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. The push-fit capsules contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In some embodiments, the push-fit capsules
do not include any other ingredient besides the capsule shell and
the active ingredient. In soft capsules, the active compounds are
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In some
embodiments, stabilizers are added.
[0336] All formulations for oral administration are in dosages
suitable for such administration.
[0337] In one aspect, solid oral dosage forms are prepared by
mixing a compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt thereof, with one or more of the
following: antioxidants, flavoring agents, and carrier materials
such as binders, suspending agents, disintegration agents, filling
agents, surfactants, solubilizers, stabilizers, lubricants, wetting
agents, and diluents.
[0338] In some embodiments, the solid dosage forms disclosed herein
are in the form of a tablet, (including a suspension tablet, a
fast-melt tablet, a bite-disintegration tablet, a
rapid-disintegration tablet, an effervescent tablet, or a caplet),
a pill, a powder, a capsule, solid dispersion, solid solution,
bioerodible dosage form, controlled release formulations, pulsatile
release dosage forms, multiparticulate dosage forms, beads,
pellets, granules. In other embodiments, the pharmaceutical
formulation is in the form of a powder. In still other embodiments,
the pharmaceutical formulation is in the form of a tablet. In other
embodiments, pharmaceutical formulation is in the form of a
capsule.
[0339] In some embodiments, solid dosage forms, e.g., tablets,
effervescent tablets, and capsules, are prepared by mixing
particles of a compound of Formula I, Formula II, or Formula III,
or a pharmaceutically acceptable salt thereof, with one or more
pharmaceutical excipients to form a bulk blend composition. The
bulk blend is readily subdivided into equally effective unit dosage
forms, such as tablets, pills, and capsules. In some embodiments,
the individual unit dosages include film coatings. These
formulations are manufactured by conventional formulation
techniques.
[0340] Conventional formulation techniques include, e.g., one or a
combination of methods: (1) dry mixing, (2) direct compression, (3)
milling, (4) dry or non-aqueous granulation, (5) wet granulation,
or (6) fusion. Other methods include, e.g., spray drying, pan
coating, melt granulation, granulation, fluidized bed spray drying
or coating (e.g., wurster coating), tangential coating, top
spraying, tableting, extruding and the like.
[0341] In some embodiments, tablets will include a film surrounding
the final compressed tablet. In some embodiments, the film coating
can provide a delayed release of the compound of Formula I, Formula
II, or Formula III, or a pharmaceutically acceptable salt thereof,
from the formulation. In other embodiments, the film coating aids
in patient compliance (e.g., Opadry.RTM. coatings or sugar
coating). Film coatings including Opadry.RTM. typically range from
about 1% to about 3% of the tablet weight.
[0342] A capsule may be prepared, for example, by placing the bulk
blend of the formulation of the compound described above, inside of
a capsule. In some embodiments, the formulations (non-aqueous
suspensions and solutions) are placed in a soft gelatin capsule. In
other embodiments, the formulations are placed in standard gelatin
capsules or non-gelatin capsules such as capsules comprising HPMC.
In other embodiments, the formulation is placed in a sprinkle
capsule, wherein the capsule is swallowed whole or the capsule is
opened and the contents sprinkled on food prior to eating.
[0343] In various embodiments, the particles of the compound of
Formula I, Formula II, or Formula III, or a pharmaceutically
acceptable salt thereof, and one or more excipients are dry blended
and compressed into a mass, such as a tablet, having a hardness
sufficient to provide a pharmaceutical composition that
substantially disintegrates within less than about 30 minutes, less
than about 35 minutes, less than about 40 minutes, less than about
45 minutes, less than about 50 minutes, less than about 55 minutes,
or less than about 60 minutes, after oral administration, thereby
releasing the formulation into the gastrointestinal fluid.
[0344] In still other embodiments, effervescent powders are also
prepared. Effervescent salts have been used to disperse medicines
in water for oral administration.
[0345] In some embodiments, the pharmaceutical solid oral dosage
forms are formulated to provide a controlled release of the active
compound. Controlled release refers to the release of the active
compound from a dosage form in which it is incorporated according
to a desired profile over an extended period of time. Controlled
release profiles include, for example, sustained release, prolonged
release, pulsatile release, and delayed release profiles. In
contrast to immediate release compositions, controlled release
compositions allow delivery of an agent to a subject over an
extended period of time according to a predetermined profile. Such
release rates can provide therapeutically effective levels of agent
for an extended period of time and thereby provide a longer period
of pharmacologic response while minimizing side effects as compared
to conventional rapid release dosage forms. Such longer periods of
response provide for many inherent benefits that are not achieved
with the corresponding short acting, immediate release
preparations.
[0346] In some embodiments, the solid dosage forms described herein
are formulated as enteric coated delayed release oral dosage forms,
i.e., as an oral dosage form of a pharmaceutical composition as
described herein which utilizes an enteric coating to affect
release in the small intestine or large intestine. In one aspect,
the enteric coated dosage form is a compressed or molded or
extruded tablet/mold (coated or uncoated) containing granules,
powder, pellets, beads or particles of the active ingredient and/or
other composition components, which are themselves coated or
uncoated. In one aspect, the enteric coated oral dosage form is in
the form of a capsule containing pellets, beads or granules.
[0347] Conventional coating techniques such as spray or pan coating
are employed to apply coatings. The coating thickness must be
sufficient to ensure that the oral dosage form remains intact until
the desired site of topical delivery in the intestinal tract is
reached.
[0348] In other embodiments, the formulations described herein are
delivered using a pulsatile dosage form. A pulsatile dosage form is
capable of providing one or more immediate release pulses at
predetermined time points after a controlled lag time or at
specific sites. In one embodiment, the pulsatile dosage form
includes at least two groups of particles, (i.e. multiparticulate)
each containing the formulation described herein. The first group
of particles provides a substantially immediate dose of the active
compound upon ingestion by a mammal. The first group of particles
can be either uncoated or include a coating and/or sealant. In one
aspect, the second group of particles comprises coated particles.
The coating on the second group of particles provides a delay of
from about 2 hours to about 7 hours following ingestion before
release of the second dose. Suitable coatings for pharmaceutical
compositions are described herein or in the art.
[0349] In some embodiments, pharmaceutical formulations are
provided that include particles of a compound of Formula I, Formula
II, or Formula III, or a pharmaceutically acceptable salt thereof,
and at least one dispersing agent or suspending agent for oral
administration to a subject. The formulations may be a powder
and/or granules for suspension, and upon admixture with water, a
substantially uniform suspension is obtained.
[0350] In one aspect, liquid formulation dosage forms for oral
administration are in the form of aqueous suspensions selected from
the group including, but not limited to, pharmaceutically
acceptable aqueous oral dispersions, emulsions, solutions, elixirs,
gels, and syrups. See, e.g., Singh et al., Encyclopedia of
Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002). In addition
to the particles of the compound of Formula I, Formula II, or
Formula III, the liquid dosage forms include additives, such as:
(a) disintegrating agents; (b) dispersing agents; (c) wetting
agents; (d) at least one preservative, (e) viscosity enhancing
agents, (f) at least one sweetening agent, and (g) at least one
flavoring agent. In some embodiments, the aqueous dispersions can
further include a crystalline inhibitor.
[0351] Buccal formulations that include a compound of Formula I,
Formula II, or Formula III, or a pharmaceutically acceptable salt
thereof, are administered using a variety of formulations known in
the art. For example, such formulations include, but are not
limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and
5,739,136. In addition, the buccal dosage forms described herein
can further include a bioerodible (hydrolysable) polymeric carrier
that also serves to adhere the dosage form to the buccal mucosa.
For buccal or sublingual administration, the compositions may take
the form of tablets, lozenges, or gels formulated in a conventional
manner.
[0352] In some embodiments, compounds of Formula I, Formula II, or
Formula III, or a pharmaceutically acceptable salt thereof, are
prepared as transdermal dosage forms. In one embodiment, the
transdermal formulations described herein include at least three
components: (1) a formulation of a compound of Formula I, Formula
II, or Formula II, or a pharmaceutically acceptable salt thereof,
(2) a penetration enhancer; and (3) an aqueous adjuvant. In some
embodiments the transdermal formulations include additional
components such as, but not limited to, gelling agents, creams and
ointment bases, and the like. In some embodiments, the transdermal
formulation further includes a woven or non-woven backing material
to enhance absorption and prevent the removal of the transdermal
formulation from the skin. In other embodiments, the transdermal
formulations described herein can maintain a saturated or
supersaturated state to promote diffusion into the skin.
[0353] In one aspect, formulations suitable for transdermal
administration of compounds described herein employ transdermal
delivery devices and transdermal delivery patches and can be
lipophilic emulsions or buffered, aqueous solutions, dissolved
and/or dispersed in a polymer or an adhesive. In one aspect, such
patches are constructed for continuous, pulsatile, or on demand
delivery of pharmaceutical agents. Still further, transdermal
delivery of the compounds described herein can be accomplished by
means of iontophoretic patches and the like. In one aspect,
transdermal patches provide controlled delivery of the active
compound. In one aspect, transdermal devices are in the form of a
bandage comprising a backing member, a reservoir containing the
compound optionally with carriers, optionally a rate controlling
barrier to deliver the compound to the skin of the host at a
controlled and predetermined rate over a prolonged period of time,
and means to secure the device to the skin.
[0354] In one aspect, a compound of Formula I, Formula II, or
Formula III, or a pharmaceutically acceptable salt thereof, is
formulated into a pharmaceutical composition suitable for
intramuscular, subcutaneous, or intravenous injection. In one
aspect, formulations suitable for intramuscular, subcutaneous, or
intravenous injection include physiologically acceptable sterile
aqueous or non-aqueous solutions, dispersions, suspensions or
emulsions, and sterile powders for reconstitution into sterile
injectable solutions or dispersions. Examples of suitable aqueous
and non-aqueous carriers, diluents, solvents, or vehicles include
water, ethanol, polyols (propyleneglycol, polyethylene-glycol,
glycerol, cremophor and the like), vegetable oils and organic
esters, such as ethyl oleate. In some embodiments, formulations
suitable for subcutaneous injection contain additives such as
preserving, wetting, emulsifying, and dispensing agents. Prolonged
absorption of the injectable pharmaceutical form can be brought
about by the use of agents delaying absorption, such as aluminum
monostearate and gelatin.
[0355] For intravenous injections, compounds described herein are
formulated in aqueous solutions, preferably in physiologically
compatible buffers such as Hank's solution, Ringer's solution, or
physiological saline buffer.
[0356] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art. For other parenteral
injections, appropriate formulations include aqueous or nonaqueous
solutions, preferably with physiologically compatible buffers or
excipients. Such excipients are known.
[0357] Parenteral injections may involve bolus injection or
continuous infusion. Formulations for injection may be presented in
unit dosage form, e.g., in ampoules or in multi-dose containers,
with an added preservative. The pharmaceutical composition
described herein may be in a form suitable for parenteral injection
as a sterile suspensions, solutions or emulsions in oily or aqueous
vehicles, and may contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. In one aspect, the active
ingredient is in powder form for constitution with a suitable
vehicle, e.g., sterile pyrogen-free water, before use.
[0358] In certain embodiments, delivery systems for pharmaceutical
compounds may be employed, such as, for example, liposomes and
emulsions. In certain embodiments, compositions provided herein can
also include an mucoadhesive polymer, selected from among, for
example, carboxymethylcellulose, carbomer (acrylic acid polymer),
poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic
acid/butyl acrylate copolymer, sodium alginate and dextran.
[0359] In some embodiments, the compounds described herein may be
administered topically and can be formulated into a variety of
topically administrable compositions, such as solutions,
suspensions, lotions, gels, pastes, medicated sticks, balms, creams
or ointments. Such pharmaceutical compounds can contain
solubilizers, stabilizers, tonicity enhancing agents, buffers and
preservatives.
Combination Treatments
[0360] In certain instances, it is appropriate to administer at
least one compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt thereof, in combination with one
or more other therapeutic agents.
[0361] In one embodiment, the therapeutic effectiveness of one of
the compounds described herein is enhanced by administration of an
adjuvant (i.e., by itself the adjuvant may have minimal therapeutic
benefit, but in combination with another therapeutic agent, the
overall therapeutic benefit to the patient is enhanced). Or, in
some embodiments, the benefit experienced by a patient is increased
by administering one of the compounds described herein with another
therapeutic agent (which also includes a therapeutic regimen) that
also has therapeutic benefit.
[0362] In one specific embodiment, a compound of Formula I, Formula
II, or Formula III, or a pharmaceutically acceptable salt thereof,
is co-administered with a second therapeutic agent, wherein the
compound of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt thereof, and the second
therapeutic agent modulate different aspects of the disease,
disorder or condition being treated, thereby providing a greater
overall benefit than administration of either therapeutic agent
alone.
[0363] In any case, regardless of the disease, disorder or
condition being treated, the overall benefit experienced by the
patient may simply be additive of the two therapeutic agents or the
patient may experience a synergistic benefit.
[0364] In certain embodiments, different therapeutically-effective
dosages of the compounds disclosed herein will be utilized in
formulating pharmaceutical composition and/or in treatment regimens
when the compounds disclosed herein are administered in combination
with one or more additional agent, such as an additional
therapeutically effective drug, an adjuvant or the like.
Therapeutically-effective dosages of drugs and other agents for use
in combination treatment regimens can be determined by means
similar to those set forth hereinabove for the actives themselves.
Furthermore, the methods of prevention/treatment described herein
encompasses the use of metronomic dosing, i.e., providing more
frequent, lower doses in order to minimize toxic side effects. In
some embodiments, a combination treatment regimen encompasses
treatment regimens in which administration of a compound of Formula
I, Formula II, or Formula III, or a pharmaceutically acceptable
salt thereof, is initiated prior to, during, or after treatment
with a second agent, and continues until any time during treatment
with the second agent or after termination of treatment with the
second agent. It also includes treatments in which a compound of
Formula I, Formula II, or Formula III, or a pharmaceutically
acceptable salt thereof, and the second agent being used in
combination are administered simultaneously or at different times
and/or at decreasing or increasing intervals during the treatment
period. Combination treatment further includes periodic treatments
that start and stop at various times to assist with the clinical
management of the patient.
[0365] It is understood that the dosage regimen to treat, prevent,
or ameliorate the condition(s) for which relief is sought, is
modified in accordance with a variety of factors (e.g. the disease,
disorder or condition from which the subject suffers; the age,
weight, sex, diet, and medical condition of the subject). Thus, in
some instances, the dosage regimen actually employed varies and, in
some embodiments, deviates from the dosage regimens set forth
herein.
[0366] For combination therapies described herein, dosages of the
co-administered compounds vary depending on the type of co-drug
employed, on the specific drug employed, on the disease or
condition being treated and so forth. In additional embodiments,
when co-administered with one or more other therapeutic agents, the
compound provided herein is administered either simultaneously with
the one or more other therapeutic agents, or sequentially.
[0367] In combination therapies, the multiple therapeutic agents
(one of which is one of the compounds described herein) are
administered in any order or even simultaneously. If administration
is simultaneous, the multiple therapeutic agents are, by way of
example only, provided in a single, unified form, or in multiple
forms (e.g., as a single pill or as two separate pills).
[0368] The compounds of Formula I, Formula II, or Formula III, or a
pharmaceutically acceptable salt thereof, as well as combination
therapies, are administered before, during or after the occurrence
of a disease or condition, and the timing of administering the
composition containing a compound varies. Thus, in one embodiment,
the compounds described herein are used as a prophylactic and are
administered continuously to subjects with a propensity to develop
conditions or diseases in order to prevent the occurrence of the
disease or condition. In another embodiment, the compounds and
compositions are administered to a subject during or as soon as
possible after the onset of the symptoms. In specific embodiments,
a compound described herein is administered as soon as is
practicable after the onset of a disease or condition is detected
or suspected, and for a length of time necessary for the treatment
of the disease. In some embodiments, the length required for
treatment varies, and the treatment length is adjusted to suit the
specific needs of each subject. For example, in specific
embodiments, a compound described herein or a formulation
containing the compound is administered for at least 2 weeks, about
1 month to about 5 years.
EXAMPLES
[0369] Compounds disclosed herein are made by the methods depicted
in the reaction schemes shown below. Procedures are provided herein
that, in combination with the knowledge of the synthetic organic
chemist of ordinary skill in the art, are in some embodiments used
to prepare the full range of compounds as disclosed and claimed
herein.
[0370] The starting materials and reagents used in preparing these
compounds are either available from commercial suppliers such as
Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.),
or Sigma (St. Louis, Mo.) or are prepared by methods known to those
skilled in the art following procedures set forth in references
such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes
1-17 (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, 4th Edition) and Larock's Comprehensive Organic
Transformations (VCH Publishers Inc., 1989). These schemes are
merely illustrative of some methods by which the compounds
disclosed herein are in some embodiments synthesized, and various
modifications to these schemes can be made and will be suggested to
one skilled in the art having referred to this disclosure. The
starting materials and the intermediates, and the final products of
the reaction may be isolated and purified if desired using
conventional techniques, including but not limited to filtration,
distillation, crystallization, chromatography and the like. Such
materials may be characterized using conventional means, including
physical constants and spectral data. Proton nuclear magnetic
resonance spectra were obtained on a Bruker 400 MHz spectrometer.
Spectra are given in ppm and coupling constants, J values, are
reported in hertz (Hz). Mass spectra analyses were performed on
Agilent 6120 Mass Spectrometer in ESI or APCI mode when
appropriate.
Some abbreviations used herein are as follows:
[0371] DCM: dichloromethane
[0372] DMAP: 4-dimethylaminopyridine
[0373] DMF: dimethyl formamide
[0374] DMF-DMA: N,N-dimethylformamide dimethyl acetal
[0375] EDCI: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
[0376] EtOAc: ethyl acetate
[0377] EtOH: ethanol
[0378] MeOH: methanol
[0379] PE: petroleum ether.
Example 1: Preparation of
2-(6-(4-Cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-1-one
(Compound 1)
##STR00175##
[0381] Hydrazine hydrate (1.16 mg, 23.1 mmol, 10 eq) was added to a
solution of methy 6-bromopicolinate (500 mg, 2.31 mmol, 1.0 eq) in
MeOH (15 mL) at room temperature, then the reaction was stirred for
1 hour. The reaction mixture was concentrated under reduced
pressure to give the desired hydrazide product 1A which was used
without further purification: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.84 (s, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.71 (t, J=7.7 Hz,
1H), 7.62 (d, J=7.9 Hz, 1H), 4.10 (br s, 2H).
##STR00176##
[0382] A solution of 1B (500 mg, 2.31 mmol, 1.0 eq) and DMF-DMA
(1.38 g, 11.6 mmol, 5.0 eq) in DCM (10 mL) was refluxed for 6
hours. After cooling, the reaction mixture was concentrated under
reduced pressure to give the desired product 1C which was used in
the subsequent step without any further purification.
##STR00177##
[0383] Cyclopropylamine (396 mg, 6.93 mmol, 3.0 eq) was added to a
stirred solution of 1C (630 mg, 2.31 mmol, 1.0 equiv) in glacial
acetic acid (15 ml) at room temperature. After stirring at
90.degree. C. for 3 hours, the reaction mixture was allowed to cool
to room temperature. The solvent was removed under reduced pressure
and the residue was purified by column chromatography (30%-100%
EtOAc in PE) to give 500 mg of 1D (>85% purity). The partially
purified material was then used directly in the next step. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.29 (s, 1H), 8.24 (d, J=7.7 Hz,
1H), 7.70 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 3.91-3.83 (m,
1H), 1.20 (q, J=6.9 Hz, 2H), 0.93 (q, J=6.6 Hz, 2H).
##STR00178##
[0384] A mixture of isoindolin-1-one (150 mg, 1.13 mmol), 1D (300
mg, 1.13 mmol), Pd.sub.2(dba).sub.3 (31 mg, 0.034 mmol), Xantphos
(20 mg, 0.034 mmol) and Cs.sub.2CO.sub.3 (443 mg, 1.36 mmol) in
dioxane (25 mL) was heated to 100.degree. C. for 16 hours under a
nitrogen atmosphere. The reaction mixture was allowed to cool to
room temperature, filtered and the resulting filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (1-5% MeOH in DCM) to afford compound 1
(270 mg, 75% yield) as an off-white solid: .sup.1H NMR (400 MHz
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.07
(t, J=8 Hz, 1H), 7.88-7.83 (m, 2H), 7.72 (d, J=8.4 Hz, 2H),
7.59-7.53 (m, 1H), 5.18 (s, 2H), 4.12-4.07 (m, 1H), 1.14-1.09 (m,
2H), 1.0-0.95 (m, 2H); ESI m/z 318.1 [M+1].sup.+.
Example 2: Preparation of
2-(6-(4-Cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-N,N-dimethyl-1-ox-
oisoindoline-5-carboxamide (Compound 2)
##STR00179##
[0386] A stirred mixture of 1-oxoisoindoline-5-carboxylic acid (200
mg, 1.13 mmol, 1.0 eq), dimethylamine hydrochloride (138 mg, 1.69
mmol, 1.5 eq), EDCI (324 mg, 1.69 mmol, 1.5 eq), DMAP (276 mg, 2.26
mmol, 2.0 eq) in DMF (20 mL) and DCM (20 mL) was stirred at room
temperature overnight under a nitrogen atmosphere. The reaction
mixture was concentrated under reduced pressure and purified by
silica gel chromatography (30/6-100% EtOAc in PE) to give 2A (140
mg, 61% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.91 (d,
J=7.8 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 6.68 (s, 1H),
4.49 (s, 2H), 3.06 (d, J=65.0 Hz, 6H).
##STR00180##
[0387] Compound was synthesized according to the procedure for
compound 1 substituting intermediate 2A in place of
isoindolin-1-one to give the product in 43% yield: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.76 (d, J=8.1 Hz, 1H), 8.37 (s, 1H),
8.03-7.89 (m, 3H), 7.63 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 5.11 (s,
2H), 4.02-3.91 (m, 1H), 3.07 (d, J=59.0 Hz, 6H), 0.14 (d, J=6.7 Hz,
2H), 0.98 (d, J==2.8 Hz, 2H); ESI m/z 389.2[M+1].sup.+.
[0388] Compounds 3-25 in Table 2synthesized according to the
procedure for compound 2 substituting the appropriate amine in
place of dimethylamine.
TABLE-US-00002 TABLE 2 Compound Name Structure Characterization 3
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-N-
methyl-1- oxoisoindoline-5- carboxamide ##STR00181## .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.68 (d, J = 4.8 Hz,
1H), 8.64 (d, J = 8 Hz, 1H), 8.17 (s, 1H), 8.08 (t, J = 8 Hz, 1H),
7.99 (d, J = 8 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H),
4.14-4.09 (m, 1H), 2.83 (d, J = 4.4 Hz, 2H), 1.16-1.11 (m, 2H),
1.02-0.96 (m, 2H); ESI m/z 375.1 [M + 1].sup.+ 4
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-N-
(2-methoxyethyl)-1- oxoisoindoline-5- carboxamide ##STR00182##
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.77 (s, 2H), 8.65 (d,
J = 8 Hz, 1H), 8.19 (s, 1H), 8.11-8.07 (m, 1H), 8.01 (d, J = 7.6
Hz, 1H), 7.91 (d, J = 7.6 Hz, 2H), 5.23 (s, 2H), 4.12 (br, 1H),
3.48 (s, 4H), 3.28 (s, 3H), 1.14 (d, J = 6 Hz, 2H), 1.0 (s, 2H);
ESI m/z 418.9 [M + 1].sup.+ 5 N-(2-(1H-imidazol-
1-yl)ethyl)-2-(6-(4- cyclopropyl-4H- 1,2,4-triazol-3-
yl)pyridin-2-yl)-1- oxoisoindoline-5- carboxamide ##STR00183##
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.16 (s, 1H), 8.95-8.92
(m, 1H), 8.78 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.13-8.08 (m, 2H),
7.96-7.91 (m, 3H), 7.79 (s, 1H), 7.67 (s, 1H), 5.22 (s, 2H), 4.41
(s, 2H), 4.12-4.10 (m, 2H), 3.77-3.76 (m, 2H), 1.13-1.12 (m, 2H),
1.10 (s, 2H); ESI m/z 454.9 [M + 1].sup.+ 6 2-(6-(4-cyclopropyl-
4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5- (1H-pyrazole-1-
carbonyl)isoindolin- 1-one ##STR00184## .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.67-8.65 (m, 2H), 8.34 (s,
1H), 8.5 (d, J = 8 Hz, 1H), 8.10 (t, J = 8 Hz, 1H), 8.01 (t, J = 8
Hz, 2H), 7.92 (d, J = 7.6 Hz, 1H), 6.77-6.76 (m, 1H), 5.23 (s, 2H),
4.15-4.10 (m, 1H), 1.16-1.11 (m, 2H), 1.0- 0.96 (m, 2H); ESI m/z
412.1 [M + 1].sup.+ 7 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-5- (morpholine-4- carbonyl)isoindolin- 1-one
##STR00185## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.64 (d, J = 8 Hz, 1H), 8.08 (t, J = 7.6 Hz, 1H), 7.89 (dd, J
= 8 Hz, 2.4 Hz, 2H), 7.76 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 5.21
(s, 2H), 4.12-4.06 (m, 1H), 3.66-3.58 (m, 8H), 1.14-1.09 (m, 2H),
1.0-0.96 (m, 2H); ESI m/z 431.1 [M + 1].sup.+ 8 N-cyclopropyl-2-(6-
(4-cyclopropyl-4H- 1,2,4-triazol-3- yl)pyridin-2-yl)-1-
oxoisoindoline-5- carboxamide ##STR00186## .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.68 (d, J = 4.4 Hz, 1H), 8.63
(d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.08 (t, J = 8 Hz, 1H), 7.97 (d,
J = 8 Hz, 1H), 7.91-7.88 (m, 2H), 5.21 (s, 2H), 4.13-4.08 (m, 1H),
2.93-2.87 (m, 1H), 1.15-1.10 (m, 2H), 1.01-0.97 (m, 2H), 0.75-0.70
(m, 2H), 0.62-0.58 (m, 2H); ESI m/z 400.2 [M + 1].sup.+ 9
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-1-
oxo-N-(tetrahydro- 2H-pyran-4- yl)isoindoline-5- carboxamide
##STR00187## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.65 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.18 (s,
1H), 8.09 (t, J = 8 Hz, 1H), 8.01 (d, J = 8 Hz, 1H), 7.91 (d, J = 8
Hz, 2H), 5.23 (s, 2H), 4.13-4.03 (m, 2H), 3.90 (d, J = 9.6 Hz, 2H),
3.43-3.38 (m, 2H), 1.80-1.77 (m, 2H), 1.66-1.59 (m, 2H), 1.16-1.12
(m, 2H), 1.02-0.98 (m, 2H); ESI m/z 445.2 [M + 1].sup.+ 10
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(4-methylpiperazine- 1-carbonyl)isoindolin- 1-one ##STR00188##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.75 (d, J = 8.4 Hz, 1H),
8.24 (s, 1H), 8.00-7.92 (m, 3H), 7.62 (s, 1H), 7.53 (d, J = 8 Hz,
1H), 5.11 (s, 2H), 3.95-3.91 (m, 1H), 3.83 (br, 2H), 3.48-3.44 (m,
2H), 2.52 (br, 2H), 2.37 (d, J = 0.8 Hz, 2H), 2.34 (s, 1H), 1.15-
1.10 (m, 2H), 0.98-0.94 (m, 2H); ESI m/z 444.1 [M + 1].sup.+ 11
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(piperidine-1- carbonyl)isoindolin- 1-one ##STR00189## .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.76 (dd, J = 0.8 Hz, 1H), 8.25 (s,
1H), 8.01-7.92 (m, 3H), 7.60 (s, 1H), 7.52-7.50 (m, 1H), 5.11 (s,
2H), 3.96-3.91 (m, 1H), 3.75 (br, 2H), 3.36 (br, 2H), 1.71 (s, 4H),
1.31 (s, 2H), 1.16-1.10 (m, 2H), 0.98-0.94 (m, 2H); ESI m/z 429.1
[M + 1].sup.+ 12 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-5- (4-hydroxypiperidine- 1-carbonyl)isoindolin-
1-one ##STR00190## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71
(s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.09 (t, J = 8 Hz, 1H), 7.89 (d,
J = 8 Hz, 2H), 7.73 (s, 1H), 7.53 (s, 1H), 5.21 (s, 2H), 4.82 (d, J
= 4 Hz, 1H), 4.15- 3.98 (m, 2H), 3.81-3.73 (m, 1H), 3.51-3.41 (m,
1H), 3.29- 3.20 (m, 1H), 3.19-3.06 (m, 1H), 1.88-1.68 (m, 2H),
1.47- 1.29 (m, 2H), 1.16-1.07 (m, 2H), 1.01-0.94 (m, 2H); ESI m/z
445.1 [M + 1].sup.+ 13 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-5- (4-hydroxy-4- methylpiperidine-1-
carbonyl)isoindolin- 1-one ##STR00191## .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.09
(t, J = 8 Hz, 1H), 7.90 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.88 (d, J =
2 Hz, 1H), 7.72 (s, 1H), 7.54 (d, J = 8 Hz, 1H), 5.21 (s, 2H), 4.46
(s, 1H), 4.13-4.06 (m, 2H), 1.60-1.39 (m, 5H), 1.17 (s, 3H),
1.13-1.09 (m, 2H), 1.0-0.96 (m, 2H); ESI m/z 459.1 [M + 1].sup.+ 14
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5- (4-
methoxypyridine-1- carbonyl)isoindolin- 1-one ##STR00192## .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.64 (d, J = 8.4
Hz, 1H), 8.87 (m, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.74 (s, 1H), 7.55
(d, J = 8 Hz, 1H), 5.21 (s, 2H), 4.12-4.07 (m, 1H), 3.96 (br, 1H),
3.48-3.44 (m, 2H), 3.39-3.36 (m, 1H), 3.27 (s, 3H), 3.17 (br, 1H),
1.91 (s, 1H), 1.80 (s, 1H), 1.49 (s, 1H), 1.43 (s, 1H), 1.15-1.10
(m, 2H), 1.0- 0.96 (m, 2H); ESI m/z 459.1 [M + 1].sup.+ 15
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5- (4-
(dimethylamino) piperidine-1- carbonyl)isoindolin- 1-one
##STR00193## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.64 (d, J = 8.4 Hz, 1H), 8.09 (t, J = 8 Hz, 1H), 7.89 (d, J =
8 Hz, 2H) 7.73 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 5.21 (s, 2H),
4.46 (br, 1H), 4.12-4.06 (m, 1H), 3.60-3.51 (m, 1H), 3.09-3.03 (m,
1H), 2.88-2.83 (m, 1H), 2.39-2.33 (m, 1H), 2.18 (s, 6H), 1.86-1.83
(m, 1H), 1.71-1.68 (m, 1H), 1.39-1.32 (m, 2H), 1.14-1.09 (m, 2H),
1.0-0.95 (m, 2H); ESI m/z 472.2 [M + 1].sup.+ 16 5-(4-
acetylpiperazine-1- carbonyl)-2-(6-(4- cyclopropyl-4H-
1,2,4-triazol-3- yl)pyridin-2- yl)isoindolin-1-one ##STR00194##
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.64 (d,
J = 8.4 Hz, 1H), 8.09 (t, J = 8 Hz, 1H), 7.90 (t, J = 6.8 Hz, 2H),
7.77 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.12-4.06 (m,
1H), 3.69-3.37 (m, 8H), 2.04 (br, 3H), 1.14-1.09 (m, 2H), 1.00-
0.96 (m, 2H); ESI m/z 472.1 [M + 1].sup.+ 17 N-(1-(2-(6-(4-
cyclopropyl-4H- 1,2,4-triazol-3- yl)pyridin-2-yl)-1-
oxoisoindoline-5- carbonyl)piperidin- 4-yl)acetamide ##STR00195##
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.64 (d,
J = 8.4 Hz, 1H), 8.08 (t, J = 7.6 Hz, 1H), 7.91-7.86 (m, 3H), 7.72
(s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 5.22 (s, 2H), 4.33 (br, 1H),
4.12-4.07 (m, 1H), 3.87-3.78 (m, 1H), 3.645-3.52 (m, 1H), 3.16-3.00
(m, 2H), 1.80 (s, 3H), 1.29-1.24 (m, 4H), 1.14-1.09 (m, 2H),
1.00-0.96 (m, 2H); ESI m/z 486.1 [M + 1].sup.+ 18
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(pyrrolidine-1- carbonyl)isoindolin- 1-one ##STR00196## .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.72 (s, 1H), 8.64 (d, J = 8.4 Hz,
1H), 8.09 (t, J = 8 Hz, 1H), 7.90-7.87 (m, 2H), 7.85 (s, 1H), 7.67
(d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 4.11-4.07 (m, 1H), 3.50 (t, 6.4
Hz, 2H), 3.40-3.37 (m, 2H), 1.91-1.81 (m, 4H), 1.12- 1.07 (m 4H),
1.0-0.96 (m, 2H); ESI m/z 415.1 [M + 1].sup.+ 19 5-(azetidine-1-
carbonyl)-2-(6-(4- cyclopropyl-4H- 1,2,4-triazol-3- yl)pyridin-2-
yl)isoindolin-1-one ##STR00197## .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.74 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.0-7.91 (m, 3H),
7.87 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 5.11 (s, 2H), 4.30 (tt, J =
7.6 Hz, 4H), 3.97-3.91 (m, 1H), 2.41 (m, 2H), 1.16-1.11 (m, 2H),
0.98-0.94 (m, 2H); ESI m/z 401.1 [M + 1].sup.+ 20
2-(6-(4-cyclopropyl-1- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(3-oxopiperazine-1- carbonyl)isoindolin- 1-one ##STR00198## .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.64 (d, J = 8.4
Hz, 1H), 8.14-8.07 (m, 2H), 7.90 (t, J = 8 Hz, 2H), 7.80 (s, 1H),
7.61 (d, J = 8 Hz, 1H), 5.22 (s, 2H), 4.14-4.06 (m, 2H), 3.86 (m,
2H), 3.50 (s, 1H), 3.25 (s, 2H), 1.13-1.09 (m, 2H), 1.00-0.96 (m,
2H); ESI m/z 444.0 [M + 1].sup.+ 21 5-((1R,5S)-8-oxa-3-
azabicyclo[3.2.1] octane-3-carbonyl)-2- (6-(4-cyclopropyl-
4H-1,2,4-triazol-3- yl)pyridine-2- yl)isoindolin-1-one ##STR00199##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.75 (d, J = 8 Hz, 1H),
8.26 (s, 1H), 8.0-7.92 (m, 3H), 7.61 (s, 1H), 7.50 (d, J = 7.6 Hz,
1H), 5.11 (s, 1H), 4.48-4.41 (m, 2H), 4.26 (s, 1H), 3.96-3.91 (m,
1H), 3.52-3.48 (m, 1H), 3.30 (d, J = 12.4 Hz, 1H), 3.18 (d, J =
12.8 Hz, 1H), 1.98 (s, 3H), 1.68 (s, 1H), 1.13 (d, J = 7.2 Hz, 1H),
0.97 (s, 2H); ESI m/z 457.1 [M + 1].sup.+ 22 (R)-2-(6-(4-
cyclopropyl-4H- 1,2,4-triazol-3- yl)pyridin-2-yl)-5- (3-methoxy-
pyrrolidine-1- carbonyl)isoindolin- 1-one ##STR00200## .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.64 (d, J = 8.4 Hz,
1H), 8.11-8.07 (m, 1H), 7.90-7.87 (m, 3H), 7.67 (d, J = 8 Hz, 1H),
5.22 (s, 2H), 4.12- 3.95 (m, 2H), 3.59 (s, 2H), 3.36 (s, 3H), 3.28
(s, 2H), 3.17 (s, 1H), 2.02-1.92 (m, 2H), 1.13 (d, J = 6.4 Hz, 2H),
0.99 (s, 2H); ESI m/z 445.1 [M + 1].sup.+ 23 methyl 1-(2-(6-(4-
cyclopropyl-4H- 1,2,4-triazol-3- yl)pyridin-2-yl)-1-
oxoisoindoline-5- carbonyl)piperidine- 4-carboxylate ##STR00201##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.78 (d, J = 8 Hz, 1H),
8.43 (s, 1H), 8.02-7.93 (m, 3H), 7.61 (s, 1H), 7.52 (d, J = 8 Hz,
1H), 5.12 (s, 2H), 4.55 (s, 1H), 4.01- 3.92 (m, 1H), 3.72 (s, 2H),
3.11-2.82 (s, 3H), 2.67-2.60 (m, 1H), 2.11-1.73 (m, 4H), 1.22- 1.16
(m, 2H), 1.01 (s, 2H); ESI m/z 487.1 [M + 1].sup.+ 24
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(thiomorpholine-4- carbonyl)isoindolin- 1-one ##STR00202## .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.70 (s, 1H), 8.64 (d, J = 8.4
Hz, 1H), 8.09 (t, J = 8 Hz, 1H), 7.91-7.89 (m, 2H), 7.75 (s, 1H),
7.57 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.13-4.06 (m, 1H),
3.97-3.85 (m, 2H), 3.61-3.50 (m, 2H), 2.70-2.62 (m, 4H), 1.14-1.09
(m, 2H), 1.00-0.96 (m, 2H); ESI m/z 447.0 [M + 1].sup.+ 25
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(4-(methylthio) piperidine-1- carbonyl)isoindolin- 1-one
##STR00203## .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (d, J =
8 Hz, 1H), 8.25 (s, 1H), 8.01-7.94 (m, 3H), 7.60 (s, 1H), 7.51 (d,
J = 7.6 Hz, 1H), 5.11 (s, 2H), 4.48 (br, 1H), 3.94 (t, 6.8 Hz, 1H),
3.67 (br, 1H), 3.17 (t, J = 10.8 Hz, 2H), 2.88- 2.83 (m, 1H),
2.13-1.95 (m, 5H), 1.68-1.54 (m, 2H), 1.16- 1.12 (m, 2H), 0.99-0.95
(m, 2H); ESI m/z 475.0 [M + 1].sup.+
Example 3: Preparation of
6-chloro-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morph-
oline-4-carbonyl)isoindolin-1-one (Compound 26)
##STR00204##
[0390] Bromine (7.43 mL, 0.14 mol) was added dropwise to a
-12.degree. C. suspension of dimethyl 2-aminoterephthalate (25.0 g,
0.12 mol) and pyridine (19 mL, 0.24 mol) in dichloromethane (500
mL) over 1 hour. After the addition, the reaction mixture was
allowed to warm to ambient temperature and stirred overnight. The
mixture was concentrated and the residue was recrystallized from
95% ethanol to give compound 3A (20 g, 58% yield) as a yellow
solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09 (s, 1H), 7.05
(s, 1H), 3.90 (d, J=10.8 Hz, 6H), 1.59 (s, 2H); ESI m/z 289.2,
291.2 [M+1].sup.+.
[0391] A mixture of 3A (20.0 g, 69.4 mmol), zinc (II) cyanide (9.37
g, 83.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.0 g,
3.47 mmol) was suspended in DMF (200 mL) and the reaction mixture
was degassed and purged with argon. The reaction mixture was heated
at 120.degree. C. for 1 hour and then concentrated under vacuum.
The residue was triturated with hot water (200 mL) and the product
was collected by filtration to give intermediate 3B (11.2 g, 70%
yield) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.11 (s, 1H), 7.63 (s, 2H), 7.52 (s, 1H), 3.88 (s, 3H), 3.84 (s,
3H); ESI m/z 235.2 [M+1].sup.+.
[0392] Raney Ni (1 g) was added to a mixture of 3B (4 g 17.1 mmol)
in MeOH (150 mL), TEA (20 mL) and dioxane (100 mL). The reaction
mixture was stirred under 0.5 MPa of H.sub.2 at 80.degree. C. for
20 hours. The reaction mixture was filtered and the filtrate was
concentrated under vacuum. The product was purified by flash
chromatography on silica gel (1-2% MeOH in DCM) to give 3C (2.9 g,
82% yield) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.61 (s, 1H), 7.87 (s, 1H), 7.07 (s, 1H), 6.78 (s, 2H),
4.21 (s, 2H), 3.82 (s, 3H); ESI m/z 207.3 [M+H].sup.+.
[0393] A solution of sodium nitrite (1.94 g, 28.1 mmol) in water
(40 mL) was added to a suspension of 3C (2.9 g, 14.06 mmol) in
conc. HCl (100 mL) at 0.degree. C. After stirring at 0.degree. C.
for 10 minutes, copper(I) chloride (2.88 g, 28.1 mmol) in conc. HCl
(100 mL) was added and the reaction mixture was stirred at
65.degree. C. for 1 hour. The reaction mixture was cooled to room
temperature, diluted with water (100 mL) and the mixture was
extracted with ethyl acetate (3.times.200 mL). The combined organic
fractions were washed with brine (20 mL), dried with sodium sulfate
and concentrated under vacuum. The residue was purified by
chromatography on silica gel (3% MeOH in DCM) to give 3D (723 mg,
23% yield) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.94 (s, 1H), 7.89 (s, 1H), 4.48 (s, 2H), 3.98 (s, 3H); ESI
m/z 226.0, 228.0 [M+H].sup.+.
[0394] A mixture of 3D (400 mg, 1.77 mmol), intermediate 1D (470
mg, 1.77 mmol), cesium carbonate (1.15 g, 3.54 mmol), Xantphos
(1.02 g, 0.09 mmol) and Pd.sub.2(dba).sub.3 (49 mg, 0.05 mmol) in
dioxane (40 mL) was stirred at 100.degree. C. overnight under a
nitrogen atmosphere. The mixture was concentrated under reduced
pressure and purified by chromatography on silica gel (0.5%-1.5%
MeOH in DCM) to give 3E (354 mg, 49% yield) as a white solid: ESI
m/z 410.1, 412.1 [M+H].sup.+.
[0395] A suspension of 3E (150 mg, 0.37 mmol) in HCl (6M, 10 mL)
and dioxane (10 mL) was stirred at 85.degree. C. overnight. The
reaction mixture was concentrated under reduced pressure to give
carboxylate 3F (120 mg, 83% yield) as a yellow solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.72 (dd, J=7.6 Hz, 1.2 Hz), 8.25
(s, 1H), 8.03-8.01 (m, 2H), 7.97 (s, 1H), 5.10 (s, 2H), 3.94-3.88
(m, 1H), 1.12 (q, J=6.4 Hz, 2H), 0.99-0.95 (m, 2H); ESI m/z 396.0,
397.0 [M+H].sup.+.
[0396] A mixture of 3F (60 mg, 0.15 mmol), morpholine (26 mg, 0.30
mmol), HATU (86 mg, 0.23 mmol) and DIEA (1 mL) in ACN (6 mL) was
stirred at room temperature overnight. The reaction mixture was
concentrated under vacuum and purified by chromatography on silica
gel (1-2% MeOH in DCM) to give compound 25 (45 mg, 64% yield) as a
white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.61 (d, J=8 Hz, 1H), 8.10 (t, J=8 Hz, 1H), 7.96 (s, 1H), 7.91
(d, J=6.8 Hz, 1H), 7.78 (s, 1H), 5.25-5.15 (m, 2H), 4.10-4.05 (m,
1H), 3.68 (s, 4H), 3.57-3.54 (m, 2H), 3.19-3.16 (m, 2H), 1.12-1.11
(m, 2H), 0.99-0.98 (m, 2H); ESI m/z 465.0, 466.0 [M+H].sup.+.
Example 4: Preparation of
6-chloro-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(morph-
oline-4-carbonyl)isoindolin-1-one (Compound 27)
##STR00205##
[0398] A mixture of compound 5-bromoisoindolin-1-one (200 mg, 0.94
mmol, 1.0 eq),
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyra-
zole (215 mg, 1.04 mmol, 1.1 eq), cesium carbonate (922 mg, 2.83
mmol, 1.2 eq), and Pd(dppf)Cl.sub.2 (21 mg, 0.03 mmol) in
1,4-dioxane (15 mL) and water (2 mL) was stirred at 100.degree. C.
for 16 hours under a nitrogen atmosphere. After cooling to room
temperature, the reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (30-100/EtOAc in PE) to give 4A (120 mg,
60% yield): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (s, 1H),
7.89 (d, J=0.8 Hz, 2H), 7.43 (d, J=2.2 Hz, 1H), 6.62 (d, J=2.3 Hz,
1H), 6.36 (s, 1H), 4.48 (s, 2H), 3.99 (s, 3H).
##STR00206##
[0399] A mixture of compound 4A (81 mg, 0.38 mmol, 1.0 eq),
compound 1D (78 mg, 0.38 mmol, 1.0 eq), cesium carbonate (148 mg,
0.46 mmol, 1.2 eq), Pd.sub.2(dba).sub.3 (10 mg, 0.01 mmol), X-Phos
(5 mg, 0.01 mmol) in 1,4-dioxane (10 mL) was stirred at 100.degree.
C. for 16 hours under a nitrogen atmosphere. The reaction mixture
was allowed to cool to room temperature, filtered and the resulting
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (1%-5% MeOH in DCM) and the
residue was stirred in diethyl ether (20 mL) for 1 hour. The solid
was filtered off to give 27 (58 mg, 39% yield): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.77 (d, J=8.3 Hz, 1H), 8.31 (s, 1H),
8.05-7.86 (m, 5H), 7.43 (d, J=2.1 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H),
5.09 (s, 2H), 3.99 (s, 4H), 1.16 (d, J=6.8 Hz, 2H), 1.00 (d, J=3.7
Hz, 2H); ESI m/z 398.1[M+1].sup.+.
[0400] Compounds 28-30 in Table 3 were synthesized according to the
procedure for compound 27 substituting the appropriate boronate in
place of
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
TABLE-US-00003 TABLE 3 Compound Name Structure Characterization 28
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(1H-pyrazol-3- yl)isoindolin-1-one ##STR00207## .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 13.12 (s, 1H), 8.71 (s, 1H), 8.66 (d, J
= 5.2 Hz, 1H), 8.18- 7.87 (m, 6H), 6.88 (s, 1H), 5.22 (s, 2H), 4.13
(s, 1H), 1.14 (d, J = 6 Hz, 4H); ESI m/z 384.1 [M + 1].sup.+ 29
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(1-methyl-1H- pyrazol-5- yl)isoindolin-1-one ##STR00208## .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.77 (dd, J = 8.4 Hz, 0.4 Hz,
1H), 8.24 (s, 1H), 8.04 (d, J = 8 Hz, 1H), 7.98 (m, 1H), 7.95 (d, J
= 8 Hz, 1H), 7.60-7.58 (m, 2H), 7.56 (d, J = 2 Hz, 1H), 6.40 (d, J
= 2 Hz, 1H), 5.14 (s, 2H), 3.95 (s, 4H), 1.16-1.11 (m, 2H),
0.99-0.95 (m, 2H); ESI m/z 398.2 [M + 1].sup.+ 30
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-5-
(1-methyl-1H- imidazol-4-yl) isoindolin-1-one ##STR00209## .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.81 (s, 1H),
8.62 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 8.08-8.05 (m, 2H),
7.94-7.88 (m, 3H), 5.19 (s, 2H), 5.23 (s, 2H), 4.10-4.09 (m, 4H),
1.14-1.12 (m, 2H), 1.03 (br, 2H); ESI m/z 397.9 [M + 1].sup.+
Example 5: Preparation of
5-amino-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)isoindolin-
-1-one (Compound 31)
##STR00210##
[0402] A mixture of 5-bromoisoindolin-1-one (636 mg, 3.0 mmol), 1D
(800 mg, 3.0 mmol), Pd.sub.2(dba).sub.3 (82 mg, 0.09 mmol),
Xantphos (52 mg, 0.09 mmol) and Cs.sub.2CO.sub.3 (1.17 g, 3.6 mmol)
in dioxane (60 mL) was heated to 100.degree. C. for 4 h. After that
time, the mixture was allowed to cool to room temperature and
filtered. The filtrate was concentrated under vacuum and purified
by column chromatography on silica gel (1%-10% EtOAc in pet. ether)
to afford 5A (400 mg, 34%) as a yellow solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.07
(t, J=8.41 Hz, 1H), 8.0 (d, J=7.6 Hz, 1H), 7.89 (d, J=8 Hz, 1H),
7.76 (d, J=3.2 Hz, 2H), 5.17 (s, 2H), 4.11-4.04 (m, 1H), 1.14-1.11
(m, 2H), 1.0-0.95 (m, 2H); ESI m/z 396.1, 398.1 [M+1].sup.+.
[0403] A mixture of 5A (400 mg, 1.01 mmol), diphenylmethanimine
(550 mg, 3.03 mmol), Pd.sub.2(dba).sub.3 (28 mg, 0.03 mmol),
Xantphos (29 mg, 0.05 mmol) and Cs.sub.2CO.sub.3 (987 mg, 3.03
mmol) in dioxane (40 mL) was heated to 100.degree. C. for 16 h.
After cooling to room temperature, HCl (1.0 M, 50 mL) was added and
the mixture was stirred at room temperature for 4 h, After that
time, the mixture was extracted with ethyl acetate. The aqueous
phase was neutralized with a saturated solution of sodium
bicarbonate and extracted with ethyl acetate. The organic layer was
dried with sodium sulfate, concentrated under vacuum and purified
by column chromatography on silica gel (2%-50% EtOAc in pet. ether)
to give compound 31 (30 mg, 9% yield) as a white solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.61 (d, J=8.4 Hz,
1H), 7.99 (t, J=8 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.48 (d, J=8.4
Hz, 1H), 6.71-6.67 (m, 2H), 4.97 (s, 2H), 4.12-4.07 (m, 1H),
1.12-1.07 (m, 2H), 0.98-0.94 (m, 2H); ESI m/z 333.2
[M+1].sup.+.
Example 6: Preparation of
N-(2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxoisoindoli-
n-5-yl)acetamide (Compound 32)
##STR00211##
[0405] A mixture of 5A (100 mg, 0.25 mmol), acetamide (45 mg, 0.76
mmol), Pd.sub.2(dba).sub.3 (7 mg, 0.0076 mmol), Xantphos (8 mg,
0.013 mmol) and Cs.sub.2CO.sub.3 (100 mg, 0.31 mmol) in dioxane (5
mL) was heated to 130.degree. C. for 1 h in the microwave. After
cooling, the reaction mixture was concentrated under reduced
pressure and purified by column chromatography on silica gel (1%-5%
MeOH in DCM) to afford compound 32 (5 mg, 5%) as a white solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.37 (s, 1H), 8.71 (s,
1H), 8.63 (d, J=8 Hz, 1H), 8.72 (s, 1H), 8.07-8.03 (m, 1H), 7.85
(d, J=6.8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 5.14
(s, 2H), 4.13 (br, 1H), 2.12 (s, 3H), 1.12-1.11 (m, 2H), 0.95 (s,
2H); ESI m/z 375.2 [M+1].sup.+.
##STR00212##
[0406]
N-(2-(6-(4-Cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxoiso-
indolin-5-yl)-1-phenylcyclopropane-1-carboxamide (compound 33) was
prepared according to the procedure for compound 32 substituting
1-phenylcyclopropane-1-carboxamide in place of acetamide. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.49 (s, 1H), 8.70 (s, 1H),
8.61 (d, J=8.4 Hz, 1H), 8.08-8.02 (m, 2H), 7.86 (d, J=7.6 Hz, 1H),
7.73 (d, J=8.4 Hz, 1H), 7.62 (dd, J=7.6 Hz, 6.8 Hz, 1H), 7.43-7.36
(m, 4H), 7.32-7.28 (m, 1H), 5.11 (s, 2H), 4.14-4.09 (m, 1H),
1.50-1.48 (m, 2H), 1.19-1.16 (m, 2H), 1.14-1.09 (m, 2H), 1.0-0.95
(m, 2H); ESI m/z 477.1 [M+1].sup.+.
Example 7: Preparation of
N-(2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-oxoisoindoli-
n-5-yl)acetamide (Compound 34)
##STR00213##
[0408] A stirred mixture of 7A (250 mg, 1.42 mmol), 1D (376 mg,
1.42 mmol), Pd.sub.2(dba).sub.3 (91 mg, 0.099 mmol),
Cs.sub.2CO.sub.3 (1.39 g, 4.26 mmol) and Xantphos (82 mg, 0.142
mmol) in 1,4-dioxane (30 mL) was heated to 100.degree. C.
overnight. The reaction mixture was allowed to cool to room
temperature and filtered. The resulting filtrate was concentrated
under reduced pressure and the residue was purified by silica
column chromatography (1%-5% MeOH in DCM) to give compound 34 (60
mg, 12% yield) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.69 (s, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.0 (t, J=7.6 Hz,
1H), 7.80 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 6.88 (s, 1H),
6.84 (dd, J=8.4 Hz, 2.0 Hz, 1H), 5.02 (s, 2H), 4.11-4.07 (m, 1H),
3.05 (s, 6H), 1.14-1.09 (m, 2H), 1.0-0.97 (m, 2H); ESI m/z 361.0
[M+1].sup.+.
Example 8: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(ethylamino)iso-
indolin-1-one (Compound 35)
##STR00214##
[0410] A mixture of 5A (400 mg, 1.0 mmol), ethylamine in THF (2.0M,
8 mL), Pd.sub.2(dba).sub.3 (27 mg, 0.03 mmol), Xantphos (29 mg,
0.05 mmol) and Cs.sub.2CO.sub.3 (391 mg, 1.2 mmol) in dioxane (4
mL) was heated to 130.degree. C. for 30 min in the microwave. After
cooling, the reaction mixture was concentrated under reduced
pressure and purified by column chromatography on silica gel (1-10%
MeOH in DCM) to afford compound 35 (50 mg, 14%) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.66 (dd, J=7.6 Hz, 1.2
Hz, 1H), 8.15 (s, 1H), 7.84-7.71 (m, 2H), 7.63 (d, J=8.4 Hz, 1H),
7.19 (s, 1H), 6.58 (dd, J=8.4 Hz, 2 Hz, 1H), 6.52 (s, 1H), 4.86 (s,
2H), 3.91-3.86 (m, 1H), 3.21-3.15 (m, 2H), 1.24 (t, J=7.2 Hz, 3H),
1.08-1.03 (m, 2H), 0.90-0.86 (m, 2H); ESI m/z 361.1
[M+1].sup.+.
Example 9: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(1-methyl-1H-im-
idazol-5-yl)isoindolin-1-one (Compound 36)
##STR00215##
[0412] A mixture of 6-bromoisoindolin-1-one (287 mg, 1.35 mmol),
1-methyl-5-(tributylstannyl)-1H-imidazole (500 mg, 1.35 mmol),
Pd(dppf)Cl.sub.2 (33 mg, 0.041 mmol) and Cs.sub.2CO.sub.3 (1.32 g,
4.05 mmol) in dioxane (50 mL) and water (8 mL) was heated to
100.degree. C. overnight. After cooling, the mixture was
concentrated under vacuum and purified by column chromatography on
silica gel ((1%-3% MeOH in DCM) to afford 9A (220 mg, 76% yield) as
a brown solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.66 (s,
1H), 7.76-7.15 (m, 4H), 7.15 (s, 1H), 4.43 (s, 2H), 3.72 (s, 3H);
ESI m/z 214.1 [M+1].sup.+.
[0413] A stirred mixture of 9A (220 mg, 1.03 mmol), 1D (273 mg,
1.03 mmol), Pd.sub.2(dba).sub.3 (28 mg, 0.03 mmol),
Cs.sub.2CO.sub.3 (404 mg, 1.24 mmol) and Xantphos (18 mg, 0.03
mmol) in dioxane (50 mL) was heated to 100.degree. C. overnight.
The reaction mixture was allowed to cool to room temperature and
filtered. The resulting filtrate was concentrated under reduced
pressure and the residue was purified by silica column
chromatography (1%-3% MeOH in DCM) to give compound 36 (100 mg, 24%
yield) as a light yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.73 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.08 (t, J=8 Hz, 1H),
7.90-7.80 (m, 5H), 7.24 (s, 1H), 5.23 (s, 2H), 4.14-4.08 (m, 1H),
3.76 (s, 3H), 1.16-1.11 (m, 2H), 1.0-0.97 (m, 2H); ESI m/z 398.2
[M+1].sup.+.
Example 10: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(1H-imidazol-1--
yl)isoindolin-1-one (Compound 37)
##STR00216##
[0415] A mixture of 6-bromoisoindolin-1-one (1.0 g, 4.72 mmol),
1H-imidazole (1.28 g, 18.87 mmol), CuI (179 mg, 0.94 mmol),
L-proline (108 mg, 0.94 mmol) and K.sub.2CO.sub.3 (1.30 g, 9.44
mmol) in NMP (6 mL) was heated to 200.degree. C. for 1 h in the
microwave. The mixture was poured into water and extracted with
EtOAc (3.times.100 mL). The organic layer was washed with water and
dried with sodium sulfate and concentrated. The residue was
purified by silica gel column (2%-7% MeOH in DCM) to give 10A (150
mg, 16% yield) as a yellow solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.75 (br, 1H), 8.38 (s, 1H), 7.92-7.88 (m,
3H), 7.71 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 4.42 (s, 2H); ESI m/z
200.1 [M+1].sup.+.
[0416] Compound 37 was synthesized according to the procedure for
compound 36 substituting intermediate 10A for 9A. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.76 (s, 1H), 8.76 (s, 1H), 8.64 (d, J=8
Hz, 1H), 8.40 (s, 1H), 8.29 (d, J=2 Hz, 1H), 8.15-8.07 (m, 2H),
8.97 (d, J=8 Hz, 1H), 7.90 (d, J=7.2 Hz, 2H), 5.27 (s, 2H),
4.13-4.08 (m, 1H), 1.16-1.11 (m, 2H), 1.01-0.97 (m, 2H); ESI m/z
384.2 [M+1].sup.+.
##STR00217##
[0417]
6-(1H-Benzo[d]imidazol-1-yl)-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-
-yl)pyridin-2-yl)isoindolin-1-one (compound 38) was prepared
according to the procedure for compound 37 substituting
1H-benzimidazole in place of 1H-imidazole. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.72-8.66 (m, 3H), 8.13-8.05 (m, 3H), 7.98
(d, J=8 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H),
7.66 (d, J=7.6 Hz, 1H), 7.40-7.33 (m, 2H), 5.30 (s, 2H), 4.16-4.10
(m, 1H), 1.17-1.12 (m, 2H), 1.02-0.98 (m, 2H); ESI m/z 434.0
[M+H].sup.+.
Example 11: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(1-methyl-1H-py-
razol-3-yl)isoindolin-1-one (Compound 39)
##STR00218##
[0419] A mixture of 6-bromoisoindolin-1-one (509 mg, 2.4 mmol),
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(500 mg, 2.4 mmol), Pd(dppf)Cl.sub.2 (59 mg, 0.072 mmol) and
Cs.sub.2CO.sub.3 (2.3 g, 7.2 mmol) in dioxane (50 mL) and water (8
mL) was heated to 100.degree. C. overnight. After that time, the
mixture was cooled to room temperature and filtered. The filtrate
was concentrated under reduced pressure and purified by column
chromatography on silica gel (1%-3% MeOH in DCM) to give 11A (390
mg, 76% yield) as a yellow solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.57 (s, 1H), 8.03-8.01 (m, 2H), 7.75 (d,
J=2.4 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H), 4.38
(s, 2H), 3.90 (s, 3H); ESI m/z 214.1 [M+H].sup.+.
[0420] Compound 39 was synthesized according to the procedure for
compound 36 substituting intermediate 11A for 9A. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.65 (d, J=7.6 Hz, 1H),
8.17 (s, 1H), 8.14 (d, J=8 Hz, 1H), 8.07 (t, J=8 Hz, 1H), 7.88 (d,
J=7.2 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 6.85
(d, J=2 Hz, 1H), 5.17 (s, 2H), 4.13-4.08 (m, 1H), 3.91 (s, 3H),
1.16-1.11 (m, 2H), 1.02-0.96 (m, 2H); ESI m/z 398.2
[M+1].sup.+.
[0421] Compounds 40-55 in Table 4 were synthesized according to the
procedure for compound 39 substituting the appropriate boronate in
place of
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
TABLE-US-00004 TABLE 4 Compound Name Structure Characterization 40
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6-
(pyridin-3- yl)isoindolin-1-one ##STR00219## .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.0 (s, 1H), 8.72 (s, 1H), 8.68 (d, J = 8.4
Hz, 1H), 8.63 (d, J = 4 Hz, 1H), 8.22 (d, J = 8 Hz, 1H), 8.15 (s,
1H), 8.12-8.08 (m, 2H), 7.91-7.85 (m, 2H), 7.55- 7.53 (m, 1H), 5.25
(s, 2H), 4.15-4.09 (m, 1H), 1.16-1.11 (m, 2H), 1.01-0.96 (m, 2H);
ESI m/z 395.2 [M + 1].sup.+ 41 2-(6-(4-cyclopropyl-
4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6- (4-methylpyridin-3-
yl)isoindolin-1-one ##STR00220## .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.48
(d, J = 5.2 Hz, 1H), 8.43 (s, 1H), 8.10-8.06 (m, 1H), 7.89 (d, J =
7.6 Hz, 1H), 7.84-7.81 (m, 2H), 7.75 (dd, J = 7.6 Hz, 0.8 Hz, 1H),
7.37 (d, J = 5.2 Hz, 1H), 5.25 (s, 2H), 4.14-4.09 (m, 1H), 2.29 (s,
3H), 1.16-1.11 (m, 2H), 1.00-0.96 (m, 2H); ESI m/z 409.2 [M +
1].sup.+ 42 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (6-methylpyridin-3- yl)isoindolin-1-one
##STR00221## .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.18 (s,
1H), 8.81 (dd, J = 6.4 Hz, 2.8 Hz, 1H), 8.42-8.39 (m, 2H), 8.18 (s,
1H), 8.00-7.92 (m, 3H), 7.75-7.68 (m, 2H), 5.18 (s, 2H), 4.01-3.96
(m, 1H), 2.89 (s, 3H), 1.23-1.18 (m, 2H), 1.04- 1.0 (m, 2H); ESI
m/z 409.1 [M + 1].sup.+ 43 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (pyrimidin-5- yl)isoindolin-1-one ##STR00222##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.27 (s, 1H), 9.03 (s,
1H), 8.78 (dd, J = 8 Hz, 1.2 Hz, 1H), 7.72 (d, J = 8 Hz, 1H), 5.17
(s, 2H), 3.98-3.93 (m, 1H), 1.18-1.13 (m, 2H), 1.0-0.96 (m, 2H);
ESI m/z 396.1 [M + 1].sup.+ 44 2-(6-(4-cyclopropyl-
4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6- (2-methylpyrimidin-
5-yl)isoindolin-1- one ##STR00223## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.93 (s, 2H), 8.78 (d, J = 8 Hz, 1H), 8.25 (s,
1H), 8.16 (s, 1H), 8.01-7.93 (m, 2H), 7.84 (dd, J = 7.6 Hz, 1.2 Hz,
1H), 7.70 (d, J = 7.6 Hz, 1H), 5.16 (s, 2H), 3.98-3.93 (m, 1H),
2.82 (s, 3H), 1.18-1.13 (m, 2H), 1.0-0.96 (m, 2H); ESI m/z 410.1 [M
+ 1].sup.+ 45 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (6-methoxypyridin- 3-yl)isoindolin-1- one
##STR00224## .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.78 (d, J =
8 Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 8.0-7.87 (m,
2H), 7.86 (d, J = 8 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.62 (d, J =
7.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.12 (s, 2H), 4.0 (s, 3H),
4.0-3.92 (m, 1H), 1.16-1.14 (m, 2H), 1.0-0.96 (m, 2H); ESI m/z
425.0 [M + 1].sup.+ 46 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (6-cyclopropylpyridin- 3-yl)isoindolin-1-one
##STR00225## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.78 (d, J
= 1.2 Hz, 1H), 8.71 (s, 1H), 8.65 (d, J = 7.6, 1H), 8.08 (t, J = 8
Hz, 2H), 8.04- 8.01 (m, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.81 (d, J =
8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 5.20 (s, 2H), 4.11 (m, 1H),
2.19-2.13 (m, 1H), 1.16-1.11 (m, 2H), 1.0-0.96 (m, 6H); ESI m/z
435.1 [M + 1].sup.+ 47 6-(1-cyclopropyl- 1H-pyrazol-4-yl)-2-
(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-
yl)isoindolin-1-one ##STR00226## .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.76 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 8.0-7.98 (m, 2H),
7.91 (t, 8.4 Hz, 1H), 7.81 (d, J = 6 Hz, 2H), 7.73 (dd, J = 8 Hz,
1.6 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 5.06 (s, 2H), 3.97-3.94 (m,
1H), 3.68-3.63 (m, 1H), 1.21-1.05 (m, 6H), 0.98-0.94 (m, 2H); ESI
m/z 424.1 [M + 1].sup.+ 48 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (4-fluoropyridin-3- yl)isoindolin-1-one
##STR00227## .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (t, J =
8 Hz, 2H), 8.63- 8.60 (m, 1H), 8.25 (s, 1H), 8.14 (s, 1H),
8.00-7.92 (m, 2H), 7.82 (d, J = 8 Hz, 1H), 7.68 (d, J = 8 Hz, 1H),
7.20-7.16 (m, 1H), 5.51 (s, 2H), 3.99-3.93 (m, 1H), 1.17-1.12 (m,
2H), 1.00-0.95 (m, 2H); ESI m/z 413.0 [M + 1].sup.+ 49
6-(4-chloropyridin- 3-yl)-2-(6-(4- cyclopropyl-4H- 1,2,4-triazol-3-
yl)pyridin-2- yl)isoindolin-1-one ##STR00228## .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.77 (d, J = 8.4 Hz, 1H), 8.60 (s, 1 H),
8.54 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 8.0-7.94 (m,
2H), 7.74-7.66 (m, 2H), 7.48 (d, J = 5.2 Hz, 1H), 5.16 (s, 2H),
3.98-3.95 (m, 1H), 1.18-1.11 (m, 2H), 1.01-0.93 (m, 2H); ESI m/z
429.0 [M + 1].sup.+ 50 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (pyridin-4- yl)isoindolin-1-one ##STR00229##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.79 (dd, J = 8 Hz, 0.8
Hz, 1H), 8.73-8.72 (m, 2H), 8.25 (s, 1H), 8.24 (d, J = 0.6 Hz, 1H),
8.01- 7.91 (m, 3H), 7.68 (d, J = 8 Hz, 2H), 7.59-7.58 (m, 2H), 5.16
(s, 2H), 3.99-3.93 (m, 1H), 1.18- 1.23 (m, 2H), 1.0-0.98 (m, 2H);
ESI m/z 395.0 [M + 1].sup.+ 51 2-(6-(4-cyclopropyl-
4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6- (2-methylthiazol-5-
yl)isoindolin-1-one ##STR00230## .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.76 (d, J = 8.4 Hz, 1H), 8.25 (s, 1H), 8.07 (s, 1H),
8.00-7.90 (m, 3H), 7.79 (dd, J = 8 Hz, 1.2 Hz, 1H), 7.57 (d, J = 8
Hz, 1H), 5.10 (s, 2H), 3.98-3.92 (m, 1H), 2.76 (s, 3H), 1.14 (q, J
= 6.8 Hz, 2H), 0.99-0.95 (m, 2H); ESI m/z 415.0 [M + 1].sup.+ 52
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6-
(2-methylpyridin-3- yl)isoindolin-1-one ##STR00231## .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 8.65 (d, J = 8.4 Hz,
1H), 8.50 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 8.09 (t, J = 8 Hz, 1H),
7.89 (d, J = 7.2 Hz, 1H), 7.83-7.80 (m, 2H), 7.75 (dd, J = 8 Hz,
1.6 Hz, 1H), 7.69 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.34 (dd, J = 7.6
Hz, 4.8 Hz, 1H), 5.25 (s, 2H), 4.14-4.08 (m, 1H), 2.45 (s, 3H),
1.13 (q, J = 5.6 Hz, 2H), 0.98-0.96 (m, 2H); ESI m/z 409.1 [M +
1].sup.+ 53 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (2-fluoropyridin-3- yl)isoindolin-1-one
##STR00232## .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.65 (d, J = 8.4 Hz, 1H), 8.50 (dd, J = 4.8 Hz, 1.2 Hz, 1H),
8.09 (t, J = 8 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.83-7.80 (m,
2H), 7.75 (dd, J = 8 Hz, 1.6 Hz 1H), 7.69 (dd, J = 7.6 Hz, 1.2 Hz,
1H), 7.34 (dd, J = 7.6 Hz, 4.8 Hz, 1H), 5.25 (s, 2H), 4.14-4.08 (m,
1H), 2.45 (s, 3H), 1.13 (dd, J = 12.8 Hz, 7.2 Hz, 2H), 0.98-0.96
(m, 2H); ESI m/z 413.0 [M + 1].sup.+ 54 2-(6-(4-cyclopropyl-
4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6- (5-methylpyridin-3-
yl)isoindolin-1-one ##STR00233## .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.78 (d, J = 8 Hz, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.48 (s,
1H), 8.25 (s, 1H), 8.15 (s, 1H), 8.00- 7.91 (m, 2H), 7.86 (dd, J =
8 Hz, 1.6 Hz, 1H), 7.76 (s, 1H), 7.65 (d, J = 8 Hz, 1H), 5.14 (s,
2H), 4.00-3.94 (m, 1H), 2.44 (s, 3H), 1.15 (q, J = 6.4 Hz, 1H),
1.00-0.95 (m, 2H); ESI m/z 409.1 [M + 1].sup.+ 55
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6-
(5-fluoropyridin-3- yl)isoindolin-1-one ##STR00234## .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.79 (m, 1H), 8.53 (d, J = 2.4 Hz,
1H), 8.25 (s, 1H), 8.17 (d, J = 0.8 Hz, 1H), 8.01-7.93 (m, 2H),
7.86 (dd, J = 8 Hz, 1.6 Hz 1H), 7.70-7.66 (m, 2H), 5.16 (s, 2H),
3.99-3.93 (m, 1H), 7.15 (q, J = 6.8 Hz, 2H), 1.00-0.96 (m, 2H); ESI
m/z 413.0 [M + 1].sup.+
Example 12: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(2-cyclopropylp-
yrimidin-5-yl)isoindolin-1-one (Compound 56)
##STR00235##
[0423] 5-Bromo-2-iodo-pyrimidine (5.0 g, 17.6 mmol) and
Pd(PPh.sub.3).sub.4 (1.02 g, 0.88 mmol) were suspended in THF (80
mL), and cyclopropylmagnesium bromide (1.0 M in THF, 35 ml, 35
mmol) was added dropwise under a nitrogen atmosphere. After
stirring at 70.degree. C. for 2 h, the reaction was diluted with
water (20 ml). The mixture was extracted with ethyl acetate (100
mL.times.3) and the combined organic fractions were dried over
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography (1:50
ethyl acetate/pet. ether) to obtain 12A (0.8 g, 23% yield): .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.53 (s, 2H), 2.18-2.13 (m, 1H),
1.06-1.04 (m, 4H); ESI m/z 199.1, 201.1 [M+1].sup.+.
[0424] A mixture of 12A (0.8 g, 4.02 mmol), Pd(dppf)Cl.sub.2 (147
mg, 0.20 mmol), KOAc (592 mg, 6.03 mmol) and bis(pinacolato)diboron
(1.16 g, 4.82 mmol) in dioxane (20 mL) was heated to 90.degree. C.
overnight. After cooling, the reaction mixture was concentrated and
the residue was purified by silica gel column chromatography (1/50
to 1/10 ethyl acetate/pet. ether) to give 12B (0.38 g, 39% yield)
as a yellow solid: ESI m/z 247.1 [M+H].sup.+.
[0425] Compound 56 was synthesized according to the procedure for
compound 39 substituting intermediate 12B in place of
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.83 (s, 2H), 8.77 (d,
J=8 Hz, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 8.0-7.92 (m, 1H), 7.80
(dd, J=8 Hz, 1.6 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 5.14 (s, 2H),
3.98-3.93 (m, 1H), 1.23-1.19 (m, 2H), 1.17-1.13 (m, 4H), 0.99-0.95
(m, 2H); ESI m/z 436.1 [M+1].sup.+.
Example 13: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(1-methyl-1H-im-
idazol-2-yl)isoindolin-1-one (Compound 57)
##STR00236##
[0427] A mixture of 6-bromoisoindolin-1-one (2.0 g, 9.44 mmol),
bis(pinacolato)diboron (2.41 g, 9.7 mmol), KOAc (1.86 g, 18.66
mmol) and Pd(dppf).sub.2Cl.sub.2 (0.39 g, 0.49 mmol) in dioxane (50
mL) was stirred at 100.degree. C. overnight under a nitrogen
atmosphere. The mixture was poured into water and extracted with
EtOAc (100 mL.times.3). The combined organic fractions were washed
with brine, dried over sodium sulfate and concentrated under
vacuum. The residue was purified by chromatography on silica gel
(1/10 to 1/5 EtOAc in pet. ether) to give compound 13A (600 mg, 25%
yield) as a white solid. ESI m/z 260.0 [M+1].sup.+.
[0428] A mixture of 13A (321 mg, 1.98 mmol),
2-bromo-1-methyl-1H-imidazole (626 mg, 2.41 mmol), K.sub.2CO.sub.3
(1.10 g, 7.92 mmol) and Pd(PPh.sub.3).sub.4 (114 mg, 0.098 mmol) in
dioxane (20 mL), ethanol (10 mL) and water (10 mL) was stirred at
100.degree. C. overnight under a nitrogen atmosphere. The mixture
was poured into water and extracted with EtOAc (100 mL.times.3).
The combined organic fractions were washed with brine, dried over
sodium sulfate and concentrated under vacuum. The residue was
purified by chromatography on silica gel (1%-2% MeOH in DCM) to
give compound 13B (200 mg, 47% yield) as a yellow solid. ESI m/z
214.0 [M+1].sup.+.
[0429] A mixture of 13B (200 mg, 0.82 mmol), intermediate 1D (212
mg, 0.82 mmol), Cs.sub.2CO.sub.3 (834 mg, 2.56 mmol), Xantphos (30
mg, 0.041 mmol) and Pd(dba).sub.3 (30 mg, 0.024 mmol) in dioxane
(20 mL) was stirred at 100.degree. C. overnight under a nitrogen
atmosphere. The reaction mixture was concentrated under vacuum and
purified by chromatography on silica gel (1%-3% MeOH in DCM) to
give compound 57 (60 mg, 19% yield) as a white solid: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.77 (d, J=8.4 Hz, 1H), 8.25 (s, 1H),
8.12 (s, 1H), 8.08 (d, J=8 Hz, 1H), 8.01-7.92 (m, 2H), 7.66 (d, J=8
Hz, 1H), 7.17 (s, 1H), 7.03 (s, 1H), 5.14 (s, 2H), 3.99-3.93 (m,
1H), 3.84 (s, 3H), 1.15 (q, J=6.8 Hz, 2H), 0.99-0.95 (m, 2H); ESI
m/z 7398.1[M+1].sup.+.
[0430] Compounds 58-60 in Table 5were synthesized according to the
procedure for compound 57 substituting the appropriate heteroaryl
halide in place of 2-bromo-1-methyl-1H-imidazole.
TABLE-US-00005 TABLE 5 Compound Name Structure Characterization 58
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6-
(pyridin-2- yl)isoindolin-1-one ##STR00237## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.78 (d, J = 8 Hz, 1H), 8.72 (d, J = 5.2 Hz,
1H), 8.49 (s, 1H), 8.41 (dd, J = 8 Hz, 2.4 Hz, 1H), 8.24 (s, 1H),
7.99 (d, J = 6.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.85-7.81 (m, 2H),
7.65 (d, J = 8 Hz, 1H), 7.31-7.28 (m, 1H), 5.13 (s, 2H), 4.0-3.94
(m, 1H), 1.18-1.13 (m, 2H), 1.0-1.95 (m, 2H); ESI m/z 395.0 [M +
1].sup.+ 59 2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3-
yl)pyridin-2-yl)-6- (pyridazin-3- yl)isoindolin-1-one ##STR00238##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.23 (dd, J = 4.8 Hz, 1.2
Hz, 1H), 8.80 (d, J = 8.8 Hz, 1H), 8.63 (dd, J = 8 Hz, 1.6 Hz, 1H),
8.50 (s, 1H), 8.26 (s, 1H), 8.02- 7.93 (m, 3H), 7.74 (d, J = 8 Hz,
1H), 7.63 (m, 1H), 5.18 (s, 2H), 4.01-3.94 (m, 1H), 1.17-1.12 (m,
2H), 1.01-0.95 (m, 2H); ESI m/z 396.0 [M + 1].sup.+ 60
2-(6-(4-cyclopropyl- 4H-1,2,4-triazol-3- yl)pyridin-2-yl)-6-
(5-cyclopropylpyrazin- 2-yl)isoindolin-1-one ##STR00239## .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.90 (s, 1H), 8.76 (d, J = 8 Hz,
1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.30 (d, J = 8 Hz, 1H), 8.24 (s,
1H), 7.99-7.90 (m, 2H), 7.65 (d, J = 8 Hz, 1H), 5.12 (s, 2H),
3.99-3.93 (m, 1H), 2.14-2.11 (m 1H), 1.17-1.08 (m, 6H), 0.99-0.95
(m, 2H); ESI m/z 436.1 [M + 1].sup.+
Example 14: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(6-cyclopropylp-
yridazin-3-yl)isoindolin-1-one (Compound 61)
##STR00240##
[0432] A mixture of 13A (2.2 g, 8.4 mmol), 3,6-dibromopyridazine (2
g, 8.4 mmol), Pd(dppf).sub.2Cl.sub.2 (307 mg, 0.4 mmol) and
K.sub.2CO.sub.3 (3.5 g, 25 mmol) in dioxane (100 mL) and water (10
mL) was heated to 100.degree. C. for 5 h under a nitrogen
atmosphere. After cooling, the mixture was poured into water and
extracted with EtOAc (150 mL.times.3). The combined organic layers
were washed with water and brine and dried with sodium sulfate. The
solvent was evaporated and the residue was purified by column
chromatography on silica gel (1%-2% MeOH in DCM) to afford compound
14A (660 mg, 28% yield) as an off-white solid. ESI m/z 291.9, 289.9
[M+1].sup.+.
[0433] A mixture of 14A (370 mg, 1.3 mmol) cyclopropylboronic acid
(329 mg, 3.8 mmol), palladium diacetate (29 mg, 0.10 mmol),
K2CO.sub.3 (1.1 g, 7.7 mmol) and tricyclohexylphosphine (72 mg, 0.3
mmol) in dioxane (17 mL) and water (2 mL) was heated to 100.degree.
C. for 8 hours under nitrogen. The reaction mixture was
concentrated under vacuum and the residue was purified by column
chromatography on silica gel (1%-2% MeOH in DCM) to give 14B (125
mg, 39% yield) as a white solid. ESI m/z 252.1 [M+1].sup.+.
[0434] A mixture of 14B (125 mg, 0.5 mmol), 1D (158 mg, 0.6 mmol),
Pd.sub.2(dba).sub.3 (23 mg, 0.02 mmol), Xantphos (20 mg, 0.03 mmol)
and Cs.sub.2CO.sub.3 (486 mg, 1.5 mmol) in dioxane (25 mL) was
heated to 100.degree. C. overnight under nitrogen. The reaction
mixture was concentrated under vacuum and the residue was purified
by column chromatography on silica gel (1%-2% MeOH in DCM) to
afford compound 61 (12 mg, 5% yield) as a yellow solid: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.59 (dd, J=7.6 Hz, 1.6 Hz 1H), 8.44
(s, 1H), 8.25 (s, 1H), 8.01-7.92 (m, 2H), 7.84 (d, J=8.8 Hz, 1H),
7.69 (d, J=8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 5.15 (s, 2H),
4.00-3.94 (m, 1H), 2.25-2.18 (m, 1H), 1.31-1.29 (m, 2H), 1.21-1.15
(m, 4H), 1.00-0.95 (m, 2H); ESI m/z 436.1 [M+1].sup.+.
Example 15: Preparation of
6-(4-cyclopropyl-H-1,2,3-triazol-1-yl)-2-(6-(4-cyclopropyl-4H-1,2,4-triaz-
ol-3-yl)pyridin-2-yl)isoindolin-1-one (Compound 62)
##STR00241##
[0436] A mixture of 6-bromoisoindolin-1-one (5 g, 23.6 mmol),
sodium azide (3.07 g, 47.2 mmol), sodium ascorbate (234 mg, 1.18
mmol), CuI (450 mg, 2.36 mmol) and
trans-N,N-dimethyl-1,2-diaminocyclohexane (504 mg, 3.54 mmol) in
ethanol (35 mL) and water (15 mL) was stirred at reflux for 5.5 h
under nitrogen. The reaction mixture was allowed to cool to room
temperature and extracted with EtOAc (100 mL.times.3). The combined
organic fractions were washed with brine and dried with anhydrous
sodium sulfate. The solvent was evaporated under reduced pressure
and the residue was purified by chromatography on silica gel
(10-50% EtOAc in pet. ether) to give 15A (1.2 g, 29% yield) as an
off-white solid. ESI m/z 175.0 [M+1].sup.+.
[0437] A mixture of 15A (100 mg, 0.57 mmol), sodium ascorbate (12
mg, 0.06 mmol), ethynylcyclopropane (46 mg, 0.69 mmol),
CuSO.sub.4.5H.sub.2O (11 mg, 0.06 mmol) in 3 mL of a 1:1 solution
of t-BuOH/H.sub.2O was stirred at room temperature overnight. The
mixture was concentrated under vacuum and the residue was purified
by silica gel column chromatography (1%-50% EtOAc in pet. ether) to
afford 15B (30 mg, 22% yield) as an off-white solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.77 (br, 1H), 8.68 (s, 1H),
8.13-8.08 (m, 2H), 7.77 (d, J=8.4 Hz, 1H), 4.45 (s, 2H), 2.06-2.0
(m, 1H), 1.0-0.95 (m, 2H), 0.83-0.80 (m, 2H); ESI m/z 241.0
[M+1].sup.+.
[0438] A mixture of 15B (240 mg, 1.0 mmol), 1D (265 mg, 1.0 mmol),
Pd.sub.2(dba).sub.3 (28 mg, 0.03 mmol), Xantphos (29 mg, 0.05 mmol)
and K.sub.2CO.sub.3 (276 mg, 2.0 mmol) in dioxane (45 mL) was
heated to 100.degree. C. overnight under a nitrogen atmosphere. The
mixture was allowed to cool to room temperature and filtered. The
filtrate was concentrated under reduced pressure and the residue
was purified by column chromatography on silica gel (1%-5% MeOH in
DCM) to give compound 62 (100 mg, 23% yield) as a white solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.76 (s, 1H), 8.72 (s,
1H), 8.66 (d, J=8.4 Hz, 1H), 8.26-8.25 (m, 2H), 8.11 (t, J=8 Hz,
1H), 7.93-7.90 (m, 2H), 5.26 (s, 2H), 4.14-4.08 (m, 1H), 2.08-2.01
(m, 1H), 1.18-1.13 (m, 2H), 1.0-0.98 (m, 4H), 0.85-0.82 (m, 2H);
ESI m/z 425.1 [M+1]+.
Example 16: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-fluoro-6-(pyrid-
in-3-yl)isoindolin-1-one (Compound 63)
##STR00242##
[0440] Fuming nitric acid (8 mL) was added dropwise to a mixture of
2-bromo-4-fluorobenzoic acid (20 g, 91.2 mmol) in concentrated
sulfuric acid (68 mL) at 0.degree. C. After stirring at room
temperature for 3h, the mixture was poured into ice water and
stirred rapidly for 1 hour. The solid was collected by filtration,
washed with water and dried to give compound 16A (17.59 g, 73%
yield) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.81 (d, J=8 Hz, 1H), 7.73 (d, J=10 Hz, 1H).
[0441] A mixture of 16A (11.5 g, 43.7 mmol) in methanol (230 mL)
and H.sub.2SO.sub.4 (1.7 mL) was heated to 75.degree. C. overnight.
The reaction mixture was taken up in ethyl acetate and washed with
saturated sodium bicarbonate. The organic fraction was dried over
anhydrous sodium sulfate, concentrated and purified by column
chromatography (1/30 to 1/5 EtOAc in pet. ether) to give the
compound 16B (3.5 g, 29% yield) as a white solid: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.63 (d, J=7.6 Hz, 1H), 7.67 (d, J=10 Hz,
1H), 3.98 (s, 3H).
[0442] A mixture of 16B (10 g, 36.1 mmol) and Fe (10.1 g, 180.5
mmol) in acetic acid (10 mL), EtOH (240 mL) and water (60 mL) was
heated to 110.degree. C. for 5 h. After cooling to room
temperature, the reaction mixture was filtered. The filtrate was
poured into water and extracted with EtOAc (3.times.300 mL). The
combined organic fractions were washed with water and brine and
dried with sodium sulfate. The solvent was removed under vacuum and
the residue was purified by silica column chromatography (1/10 to
1/2 EtOAc in pet. ether) to afford 16C (7.5 g, 84% yield) as an
off-white solid: ESI m/z 248.0, 250.0 [M+H].sup.+.
[0443] A mixture of 16C (8.5 g, 34.4 mmol), and CuCN (4.6 g, 51.6
mmol) in DMF (120 mL) was heated to 160.degree. C. for 1 h under
nitrogen. After cooling to room temperature, the mixture was
partitioned between EtOAc and water. The organic layer was washed
with water and brine and dried with sodium acetate. The solvent was
evaporated and the residue was purified by column chromatography on
silica gel (1/100 to 1/1 EtOAc in pet. ether) to give 16D (4.0 g,
60% yield) as a brown solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.66 (d, J=11.6, 1H), 7.45 (d, J=8 Hz, 1H), 6.53 (s, 2H),
3.86 (s, 3H); ESI m/z 195.0 [M+H].sup.+.
[0444] A mixture of 16D (2.0 g, 10.2 mmol) and Raney Nickel (1.0 g)
in water (15 mL) and methanol (70 mL) was heated to 50.degree. C.
under 1 atm of H.sub.2 for 8 h. The reaction mixture was filtered
and the filtrate was poured into water and extracted with EtOAc (50
mL.times.3). The combined organic fractions were washed with brine
and dried with sodium sulfate. The solvent was evaporated and the
residue was purified by column chromatography (1/4 to 1/1 EtOAc in
pet. ether) to afford compound 16E (1.1 g, 65% yield) as a white
solid: ESI m/z 167.1 [M+H].sup.+.
[0445] A solution of NaNO.sub.2 (126 mg, 1.8 mmol) in water (2 mL)
was added dropwise to a mixture of 16E (200 mg, 1.2 mmol) in water
(8 mL) and H.sub.2SO.sub.4 (3 mL) at 0.degree. C. After the
addition, the mixture was stirred at 0.degree. C. for 1 hour. Then
CuBr (516 mg, 3.6 mmol) in HBr (25 mL) was added dropwise to the
reaction mixture. The reaction was then heated to 60.degree. C. for
5 h. The resulting mixture was poured into water and extracted with
EtOAc (3.times.50 mL). The combined organic fractions were washed
with water and brine and dried over sodium sulfate. The solvent was
concentrated under reduced pressure and the residue was purified by
column chromatography (1%-2.5% MeOH in DCM) to give 16F (130 mg,
47% yield) as a white powder: ESI m/z 231.9, 229.9 [M+H].sup.+.
[0446] A mixture of 16F (260 mg, 1.1 mmol), pyridin-3-ylboronic
acid (139 mg, 1.1 mmol), Pd(dppf).sub.2Cl (25 mg, 0.03 mmol) and
K.sub.2CO.sub.3 (469 mg, 3.4 mmol) in dioxane (25 mL) and water
(2.5 mL) was heated to 100.degree. C. overnight under nitrogen. The
resulting mixture was concentrated under reduced pressure and
purified by column chromatography on silica gel (1%-2% MeOH in DCM)
to afford compound 16G (110 mg, 43% yield) as a white solid: ESI
m/z 229.0 [M+H].sup.+.
[0447] A mixture of 16G (110 mg, 0.48 mmol), 1D (153 mg, 0.6 mmol),
Pd.sub.2(dba).sub.3 (22 mg, 0.02 mmol), Xantphos (20 mg, 0.03 mmol)
and Cs.sub.2CO.sub.3 (471 mg, 1.4 mmol) in dioxane (20 mL) was
heated to 100.degree. C. overnight under nitrogen. The reaction
mixture was concentrated and purified by column chromatography on
silica gel (1%-2% MeOH in DCM) to afford compound 63 (35 mg, 18%
yield) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.85 (s, 1H), 8.75 (dd, J=8.4 Hz, 1.2 Hz, 1H), 8.68 (s, 1H), 8.25
(s, 1H), 8.05 (d, J=7.2 Hz, 1H), 8.01-7.90 (m, 3H), 7.45-7.38 (m,
2H), 5.13 (s, 2H), 3.97-3.91 (s, 1H), 1.17-1.12 (m, 2H); ESI m/z
413.1 [M+H].sup.+.
Example 17: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methyl-6-(pyrid-
in-3-yl)isoindolin-1-one (Compound 6)
##STR00243##
[0449] Bromine (23 g, 144 mmol) was added dropwise to a suspension
of 3-methoxy-4-methylbenzoic acid (20 g, 120 mmol) in acetic acid
(153 mL) and water (153 mL) at room temperature. The reaction
mixture was heated to 60.degree. C. for 2h. After cooling to room
temperature, the reaction mixture was filtered and rinsed with cold
water (400 mL) to afford product 17A (28 g, 95% yield) as a white
solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.26 (br, 1H),
7.48 (s, 1H), 7.28 (s, 1H), 3.82 (s, 3H), 2.16 (s, 3H); ESI m/z
268.9, 266.9 [M+Na].sup.+.
[0450] A mixture of 17A (30 g, 122.4 mmol) in methanol (600 mL) and
H.sub.2S4 (3 mL) was heated to 75.degree. C. overnight. The
reaction mixture was taken up in ethyl acetate and washed with
saturated sodium bicarbonate. The organic fraction was dried over
anhydrous sodium sulfate and concentrated under reduced pressure to
give 17B (20 g, 59% yield) as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.52 (d, 0.8 Hz, 1H), 7.29 (s, 1H), 3.84 (s,
3H), 3.82 (s, 3H), 2.17 (s, 3H); ESI m/z 282.9, 280.9
[M+Na].sup.+.
[0451] A mixture of 17B (9.6 g, 37.1 mmol) and CuCN (5 g, 55.8
mmol) in DMF (120 mL) was heated to 155.degree. C. for 2 hours
under nitrogen. After cooling to room temperature, the mixture was
partitioned between EtOAc and water. The organic layer was washed
with water and brine and dried with sodium acetate. The solvent was
evaporated and the residue was purified by column chromatography on
silica gel (1/100 to 1/1 EtOAc in pet. ether) to give 17C (6 g, 67%
yield) as an off-white solid: ESI m/z 206.0 [M+H].sup.+.
[0452] A mixture of 17C (4.5 g, 21.9 mmol), Raney Nickel (1 g) in
Et.sub.3N (25 mL), THF (45 mL) and methanol (100 mL) was shaken
under a hydrogen atmosphere of 55 psi at room temperature
overnight. The reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (1/10 to 1/1 EtOAc in pet.
ether) to afford compound 17D (2.9 g, 74% yield) as an off-white
solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.39 (s, 1H),
7.32 (s, 1H), 7.13 (s, 1H), 4.24 (s, 2H), 3.84 (s, 3H), 2.23 (s,
3H); ESI m/z 178.0 [M+H].sup.+
[0453] A mixture of 17D (1.85 g, 10.4 mmol) and AlCl.sub.3 (4.2 g,
31.3 mmol) in DCM (80 mL) was stirred at room temperature for 5 min
under nitrogen. Ethanethiol (1.9 g, 31.3 mmol) was added and the
reaction mixture was stirred for 3h at room temperature. A
precipitate formed as the mixture was poured into water. The solid
was collected by filtration, washed with water and dried under
vacuum. The product was further purified by column chromatography
(2%-10% MeOH in DCM) to give 17E (1.35 g, 80%) as a white solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.70 (s, 1H), 8.31 (s,
1H), 7.23 (s, 1H), 7.04 (s, 1H), 4.19 (s, 2H), 2.19 (s, 3H); ESI
m/z 164.0 [M+H].
[0454] Trifluoromethanesulfonyl chloride (1.2 g, 7.4 mmol) was
added dropwise to a mixture of 17E (600 mg, 3.7 mmol),
triethylamine (2.2 g, 22.1 mmol) and DMAP (449 mg, 3.7 mmol) in DMF
(20 mL) at 0.degree. C. over a period of 10 min. The reaction
mixture was warmed to room temperature and stirred for 3 hours
under a nitrogen atmosphere. The resulting mixture was poured into
water and extracted with EtOAc (100 mL.times.3). The organic
fractions were washed with water and brine and dried over sodium
sulfate. The solvent was removed under vacuum and the residue was
purified by column chromatography on silica gel (1%-2% MeOH in DCM)
to afford 17F (600 mg, 55%) as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.79 (s, 1H), 7.70 (s, 1H), 7.56 (s, 1H),
4.40 (s, 2H), 2.43 (s, 3H); ESI m/z 295.9 [M+H].sup.+.
[0455] A mixture of 17F (400 mg, 1.4 mmol), pyridin-3-ylboronic
acid (217 mg, 1.8 mmol), Pd(dppf).sub.2Cl.sub.2 (50 mg, 0.06 mmol)
and K.sub.2CO.sub.3 (562 mg, 4.1 mmol) in dioxane (35 mL) and water
(5 mL) was heated to 100.degree. C. overnight under nitrogen. The
resulting mixture was concentrated under reduced pressure and
purified by column chromatography on silica gel (1%-3% MeOH in DCM)
to afford compound 17G (210 mg, 70%) as a white solid: ESI m/z
225.0 [M+H].sup.+.
[0456] A mixture of 17G (210 mg, 0.9 mmol), 1D (248 mg, 0.9 mmol),
Pd(dba).sub.3 (43 mg, 0.05 mmol), Xantphos (38 mg, 0.07 mmol) and
Cs.sub.2CO.sub.3 (915 mg, 2.8 mmol) in dioxane (25 mL) was heated
to 100.degree. C. overnight under nitrogen. The reaction mixture
was concentrated and purified by column chromatography on silica
gel (1%-3% MeOH in DCM) to give compound 64 (95 mg, 25% yield) as a
white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (s,
1H), 8.64-8.62 (m, 3H), 8.07 (t, J=7.6 Hz, 1H), 7.89-7.86 (m, 2H),
7.70 (s, 1H), 7.64 (s, 1H), 7.52 (dd, 7.6 Hz, 4.8 Hz, 1H), 5.20 (s,
2H), 4.14-4.08 (m, 1H), 2.35 (s, 3H), 1.15-1.10 (m, 2H), 1.01-0.97
(m, 2H); ESI m/z 409.0 [M+H]0.4
Example 18: Preparation of
5-chloro-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(pyrid-
in-3-yl)isoindolin-1-one (Compound 65)
##STR00244##
[0458] To a mixture of methyl 4-amino-2-methylbenzoate (15.0 g,
85.86 mmol) in DMF (80 mL) was added sodium periodate (7.36 g,
34.42 mmol) and iodine (17.6. g, 68.84 mmol). The reaction mixture
was stirred at 50.degree. C. for 3 hours. The mixture was poured
into a solution of NaHSO.sub.3 (2.6 g) in water (200 mL). After
stirring for 3h, the mixture was extracted with DCM (300
mL.times.3). The organic layer was dried over sodium sulfate,
concentrated under reduced pressure and purified by chromatography
on silica gel (2%-30% EtOAc in pet. ether) to give 18A (16.15 g,
65% yield) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.20 (s, 1H), 6.47 (s, 1H), 3.75 (s, 3H), 2.42 (s, 3H); ESI
m/z 292.0 [M+H].sup.+.
[0459] A solution of NaNO.sub.2 (5.33 g, 77.25 mmol) in water (150
mL) was added dropwise to a solution of 18A (15.0 g, 51.53 mmol) in
conc. HCl (150 mL) at -5.degree. C. over a period of 20 min. The
reaction mixture was stirred at -5.degree. C. for 1 hour, then a
solution of CuCl (7.72 g, 0.078 mmol) in conc. HCl (150 mL) was
added. The reaction mixture was stirred at 60.degree. C. for 4
hours. After cooling, the resulting mixture was extracted with
EtOAc (400 mL.times.3). The combined organic fractions were washed
with water and brine and dried over sodium sulfate. The solvent was
concentrated under reduced pressure and the residue was purified by
chromatography on silica gel (4% EtOAc in pet. ether) to provide
18B (9.69 g, 60% yield) as yellow oil: ESI m/z 311, 313.0
[M+H].sup.+.
[0460] A mixture of 18B (5.0 g, 16.10 mmol) AIBN (530 mg, 3.23
mmol) and NBS (5.73 g, 32.19 mmol) in ACN (80 mL) was stirred at
90.degree. C. overnight. The reaction mixture was concentrated and
the residue was purified by chromatography on silica gel (1% EtOAc
in pet. ether) to give 18C (4.43 g, 71% yield) as yellow oil: ESI
m/z 391.2 [M+H].sup.+.
[0461] A solution of 18C (5 g, 12.84 mmol) in NH.sub.3/MeOH (7.0 M,
100 mL) was stirred in a sealed tube at 100.degree. C. for 2 h. The
mixture was concentrated under reduced pressure and purified by
chromatography on silica gel (2/6-50% EtOAc in pet. ether) to
afford 18D (3 g, 80% yield) as an off-white solid: ESI m/z 293.8,
295.8 [M+H].sup.+.
[0462] A mixture of 18D (3.0 g, 10.22 mmol), pyridin-3-ylboronic
acid (1.5 g, 12.27 mmol), K.sub.2CO.sub.3 (4.24 g, 30.66 mmol) and
Pd(dppf).sub.2Cl.sub.2 (0.37 g, 0.51 mmol) in dioxane (160 mL) and
H.sub.2O (40 mL) was stirred at 90.degree. C. for 10 hours under
nitrogen. The mixture was poured into water and extracted with
EtOAc (100 mL.times.3). The combined organic fractions were washed
with water and brine and dried over sodium sulfate. The solvent was
removed under reduced pressure and the residue was purified by
chromatography on silica gel (1%-2% MeOH in DCM) to provide
compound 18E (1.0 g, 41% yield) as a yellow solid: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.71 (d, J=1.6 Hz, 1H), 8.67 (dd, J=7.6
Hz, 1.2 Hz, 1H), 7.85 (s, 1H), 7.79 (tt, J=1.6 Hz, 1H), 7.65 (s,
1H), 7.42-7.39 (m, 1H), 6.96 (s, 1H), 4.52 (s, 2H); ESI m/z 245.0,
247.0 [M+H].sup.+.
[0463] A mixture of 18E (200 mg, 0.82 mmol), 1D (217 mg, 0.82
mmol), Cs.sub.2CO.sub.3 (533 mg, 1.64 mmol), Xantphos (24 mg, 0.041
mmol) and Pd(dba).sub.3 (22 mg, 0.025 mmol) in dioxane (40 mL) was
stirred at 90.degree. C. overnight under a nitrogen atmosphere. The
reaction mixture was concentrated under reduced pressure and
purified by chromatography on silica gel (1%-2% MeOH in DCM) to
give compound 65 (70 mg, 20% yield) as a white solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.72-8.62 (m, 4H), 8.10 (t, J=8.4
Hz, 1H), 8.03 (s, 1H), 7.97-7.90 (m, 2H), 7.87 (s, 1H), 7.57-7.54
(m, 1H), 5.24 (s, 2H), 4.12-4.07 (m, 1H), 1.16-1.11 (m, 2H),
1.02-0.98 (m, 2H); ESI m/z 429.0, 431.0 [M+H].sup.+.
Example 19: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methoxy-6-(pyri-
din-3-yl)isoindolin-1-one (Compound 66)
##STR00245##
[0465] Bromine (14.3 g, 90.3 mmol) was added dropwise at 5.degree.
C. to a mixture of 4-methoxy-2-methylbenzoic acid (15 g, 90.3
mmol), Fe (3.51 g, 62.8 mmol) in chloroform (90 mL). The reaction
mixture was warmed to room temperature and stirred overnight. The
reaction mixture was diluted with chloroform (600 mL) and washed
with 10% sodium hydrogen sulfate (200 mL.times.2) and brine. The
organic fraction was dried with sodium sulfate and solvent was
removed under reduced pressure. The residue was purified by
chromatography on silica gel (1%-10% EtOAc in pet. ether) to afford
19A (4 g, 18% yield) as a yellow solid: ESI m/z 266.9,
268.9[M+Na].sup.+.
[0466] Thionyl chloride (11.4 mL) was slowly added to a solution of
19A (4 g, 16.3 mmol) in methanol (30 mL). The mixture was refluxed
for 3 h then cooled to room temperature. After the bulk of solvent
was evaporated, the residue was diluted with water and extracted
with EtOAc (100 mL.times.3). The combined organic fractions were
dried over sulfate and concentrated under vacuum. The residue was
purified by silica gel column chromatography (1%-5% EtOAc in pet.
ether) to afford 19B (3.0 g, 71% yield) as a white solid: ESI m/z
258.9, 260.9[M+H].sup.+.
[0467] A mixture of 19B (2.8 g, 10.8 mmol), NBS (2.02 g, 11.3 mmol)
and AIBN (177 mg, 1.08 mmol) in CCl.sub.4 (50 mL) was heated to
90.degree. C. for 4 h. After that time, the mixture was cooled to
room temperature and concentrated under reduced pressure. The
residue was purified by column chromatography (1%-5% EtOAc in pet.
ether) to give the 19C (3.1 g, 86% yield) as a white solid: ESI m/z
338.8, 340.8 [M+H].sup.+.
[0468] A mixture of 19C (2.8 g, 8.28 mmol) in NH.sub.3/MeOH (7.0 M,
30 mL) was heated to 120.degree. C. for 2 h in a sealed tube. After
that time, the mixture was cooled to room temperature and
concentrated under reduced pressure. The residue was purified by
column chromatography (1%-50% EtOAc in pet. ether) to provide 19D
(1.4 g, 65% yield) as a yellow solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.47 (s, 1H), 7.77 (s, 1H), 7.33 (s, 1H),
4.31 (s, 2H), 3.92 (s, 3H); ESI m/z 241.9, 243.9 [M+H].sup.+.
[0469] A mixture of 19D (700 mg, 2.9 mmol), Pd(dppf)Cl.sub.2 (110
mg, 0.15 mmol), K.sub.2CO.sub.3 (1.2 g, 8.7 mmol) and
3-pyridylboronic acid (355 mg, 2.9 mmol) in dioxane (40 mL) and
water (5 mL) was heated to 100.degree. C. overnight. The mixture
was poured into water and extracted with EtOAc (50 mL.times.3). The
combined organic fractions were washed with brine and dried over
sodium sulfate. The solvent was removed under vacuum and the
residue was purified by column chromatography on silica gel (1%-2%
MeOH in DCM) to give 19E (270 mg, 38% yield) as a brown solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.69 (s, 1H), 8.55 (d,
J=4 Hz, 1H), 8.41 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.55 (s, 1H),
7.47-7.44 (m, 1H), 7.35 (s, 1H), 4.39 (s, 2H), 3.86 (s, 3H); ESI
m/z 241.0 [M+H].sup.+.
[0470] A mixture of 19E (258 mg, 1.08 mmol), 1D (285 mg, 1.08
mmol), Pd.sub.2(dba).sub.3 (31 mg, 0.03 mmol), Xantphos (32 mg,
0.05 mmol) and Cs.sub.2CO.sub.3 (420 mg, 1.29 mmol) in dioxane (45
mL) was heated to 100.degree. C. overnight under a nitrogen
atmosphere. After that time, the mixture was cooled to room
temperature and filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by column
chromatography on silica gel (1%-5% MeOH in DCM) to afford compound
66 (260 mg, 57% yield) as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.72 (br, 1H), 8.71 (s, 1H), 8.63 (d, J=8.4
Hz, 1H), 8.57 (d, J=4 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.95 (tt,
J=1.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.73 (s, 1H), 7.50-7.46 (m,
2H), 5.19 (s, 2H), 4.14-4.09 (m, 1H), 3.92 (s, 3H), 1.17-1.12 (m,
2H), 1.03-0.99 (m, 2H); ESI m/z 425.1 [M+H].sup.+.
Example 20: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(dimethylamino)-
-6-(pyridin-3-yl)isoindolin-1-one (Compound 67)
##STR00246##
[0472] A mixture of 7A (425 mg, 2.41 mmol) and NBS (429 mg, 2.41
mmol) in DMF (15 mL) was stirred at RT overnight. The mixture was
poured into water and extracted with EtOAc (3.times.80 mL). The
combined organic fractions were washed with water and brine and
dried over sodium sulfate. The solvent was concentrated under
vacuum and the residue was purified by column chromatography on
silica gel (1%-2% MeOH in DCM) to give 20A (200 mg, 33% yield) as a
yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.54 (s,
1H), 7.60 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.24 (s, 2H),
2.81 (s, 6H); ESI m/z 254.9, 256.9 [M+H].sup.+.
[0473] A mixture of 20A (250 mg, 1.0 mmol) pyridin-3-ylboronic acid
(181 mg, 1.5 mmol), Pd(dppf).sub.2Cl (36 mg, 0.05 mmol) and
K.sub.2CO.sub.3 (406 mg, 3.0 mmol) in dioxane (20 mL), methanol (1
mL) and water (1 mL) was heated to 100.degree. C. overnight under a
nitrogen atmosphere. The reaction mixture was concentrated under
vacuum and the residue was purified by column chromatography (1%-2%
MeOH in DCM) to afford 20B (160 mg, 64% yield) as a brown solid:
ESI m/z 254.0 [M+H].sup.+.
[0474] A mixture of 20B (160 mg, 0.6 mmol), 1D (167 mg, 0.6 mmol),
Pd.sub.2(dba).sub.3 (29 mg, 0.03 mmol), Xantphos (26 mg, 0.04 mmol)
and Cs.sub.2CO.sub.3 (617 mg, 1.9 mmol) in dioxane (20 mL) was
heated to 100.degree. C. overnight. The reaction mixture was
concentrated under vacuum and the residue was purified by column
chromatography (1%-2% MeOH in DCM) to provide compound 67 (110 mg,
40% yield) as a yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.67 (d, J=2.8 Hz, 1H), 8.63-8.60 (m, 2H), 8.56 (d, J=8.4
Hz, 1H), 8.01 (t, J=8 Hz, 1H), 7.95-7.92 (m, 1H), 7.87 (d, J=7.6
Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.52 (dd, J=7.6 Hz, 2.4 Hz, 1H),
7.22 (d, J=8.4 Hz, 1H), 4.86 (s, 2H), 3.88-3.82 (m, 1H), 2.62 (s,
6H), 0.96-0.95 (m, 2H), 0.77 (q, J=6 Hz, 2H); ESI m/z 438.0
[M+H].sup.+.
Example 21: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-isopropoxy-6-(p-
yridin-3-yl)isoindolin-1-one (Compound 68)
##STR00247##
[0476] A mixture of compound 66 (250 mg, 0.59 mmol) and pyridine
hydrochloride was heated at 185.degree. C. for 4h. After cooling to
room temperature, the mixture was dissolved into water and
extracted with EtOAc (50 mL.times.3). The combined organic
fractions were washed with brine and dried with sodium sulfate. The
solvent was concentrated under vacuum and the residue was purified
by silica gel column chromatography (1%-5% MeOH in DCM) to afford
21A (130 mg, 54% yield) as a yellow solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.73 (s, 1H), 9.19 (s, 1H), 9.15 (s, 1H),
8.94 (d, J=5.2 Hz, 1H), 8.89 (d, J=5.2 Hz, 1H), 8.85 (d, J=8.4 Hz,
1H), 8.68 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.88 (d, J=7.6 Hz, 1H),
7.32 (s, 1H), 7.20 (s, 1H), 5.17 (s, 2H), 4.21-4.14 (n, 1H),
1.18-1.34 (m, 2H), 1.05-1.01 (m, 2H); ESI m/z 411.0
[M+H].sup.+.
[0477] A mixture of 21A (100 mg, 0.24 mmol), 2-bromopropane (90 mg,
0.73 mmol) and Cs.sub.2CO.sub.3 (238 mg, 0.73 mmol) in DMF (8 mL)
was heated at 55.degree. C. for 14 h. The mixture was poured into
water and extracted with EtOAc (50 mL.times.3 The combined organic
fractions were washed with brine and dried with sodium sulfate. The
solvent was concentrated under vacuum and the residues was purified
by silica gel column chromatography (1%-5% MeOH in DCM) to provide
compound 68 (25 mg, 23% yield) as a yellow solid: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.82 (s, 1H), 8.75 (d, J=7.6 Hz, 1H), 8.59
(d, J=3.6 Hz, 1H), 8.25 (s, 1H), 7.96-7.87 (m, 4H), 7.40-7.376 (m,
1H), 7.10 (s, 1H), 5.08 (s, 2H), 4.74-4.68 (m, 1H), 3.96-3.94 (m,
1H), 1.36 (d, J=5.6 Hz, 6H), 1.17-1.12 (m, 2H), 1.0-0.95 (m, 2H);
ESI m/z 453.1 [M+H].sup.+.
##STR00248##
[0478]
5-(Cyclopentyloxy)-2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridi-
n-2-yl)-6-(pyridin-3-yl)isoindolin-1-one (compound 69) was prepared
according to the procedure for compound 68 substituting
bromocyclopentane in place of 2-bromopropane. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.79 (s, 1H), 8.75 (d, J=8 Hz, 1H), 8.59 (d,
J=1.6 Hz, 1H), 8.25 (s, 1H), 7.95-7.15 (m, 4H), 7.40-7.36 (m, 1H),
7.09 (s, 1H), 5.07 (s, 2H), 4.91 (br, 1H), 3.97-3.94 (m, 1H),
1.95-1.89 (m, 4H), 1.73-1.64 (m, 4H), 1.17-1.14 (m, 2H), 0.97-0.95
(m, 2H); ESI m/z 479.1 [M+H].sup.+.
Example 22: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-isopropoxy-6-(p-
yridin-3-yl)isoindolin-1-one (Compound 70)
##STR00249##
[0480] A solution of NaNO.sub.2 (953 mg, 11 mmol) in water (15 mL)
was added dropwise to a mixture of 3C (1.5 g, 7.3 mmol) in water
(55 mL) and H.sub.2SO.sub.4 (20 mL) at 0.degree. C. over a period
of 10 min. After stirring at 0.degree. C. for 1 hour, CuBr (3.1 g,
22 mmol) in HBr (150 mL) was added dropwise to the reaction mixture
for 10 min, then the reaction was heated to 60.degree. C. for 5 h.
After cooling, the reaction mixture was poured into water,
neutralized with NaHCO.sub.3, and extracted with EtOAc (3.times.300
mL). The combined organic fractions were washed with brine and
dried with sodium sulfate. The solvent was evaporated and the
residue was purified by column chromatography on silica gel (1%
MeOH in DCM) to give bromide 22A (400 mg, 18% yield) as a yellow
powder: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98 (s, 1H),
7.91 (s, 1H), 4.48 (s, 2H), 3.98 (s, 3H); ESI m/z 271.9, 269.9
[M+H].sup.+.
[0481] A mixture of 22A (300 mg, 1.1 mmol), pyridin-3-ylboronic
acid (273 mg, 2.2 mmol), Pd(dppf).sub.2Cl (41 mg, 0.06 mmol) and
K.sub.2CO.sub.3 (461 mg, 3.3 mmol) in dioxane (20 mL), methanol (1
mL) and water (1 mL) was heated to 100.degree. C. overnight. The
resulting mixture was concentrated and purified by column
chromatography on silica gel (1%-2% MeOH in DCM) to afford 22B (200
mg, 67% yield) as a pink solid: ESI m/z 269.0 [M+H].sup.+.
[0482] A mixture of 22B (200 mg, 0.75 mmol), 1D (198 mg, 0.75
mmol), Pd.sub.2(dba).sub.3 (34 mg, 0.04 mmol), Xantphos (30 mg,
0.05 mmol) and Cs.sub.2CO.sub.3 (729 mg, 2.2 mmol) in dioxane (20
mL) was heated to 100.degree. C. overnight. The mixture was
concentrated and purified by column chromatography on silica gel
(1%-2% MeOH in DCM) to provide compound 70 (90 mg, 27% yield) as a
yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.73 (s,
1H), 8.65-8.58 (m, 3H), 8.24 (s, 1H), 8.10 (t, J=7.6 Hz, 1H), 7.93
(d, J=7.6 Hz, 1H), 7.86-7.83 (m, 2H), 7.51 (dd, J=7.6 Hz, 2.4 Hz,
1H), 5.29 (s, 2H), 4.15-4.09 (m, 2H), 3.68 (s, 3H), 1.15 (q, J=6
Hz, 2H), 1.01-0.97 (m, 2H); ESI m/z 453.0 [M+H].sup.+.
Example 23: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(pyridin-3-yl)--
5-(pyrrolidine-1-carbonyl)isoindolin-1-one (Compound 71)
##STR00250##
[0484] A mixture of compound 70 (100 mg, 0.2 mmol) in 6M HCl (8 mL)
and dioxane (7 mL) was heated to 95.degree. C. overnight. The
reaction mixture was concentrated under reduced pressure to give
23A (90 mg, 93% yield) as a yellow solid: ESI m/z 439.0
[M+H].sup.+.
[0485] A mixture of 23A (90 mg, 0.2 mmol), pyrrolidine (44 mg, 0.6
mmol), HATU (156 mg, 0.4 mmol) and DIEA (159 mg, 1.2 mmol) in ACN
(10 mL) was stirred at room temperature overnight. The reaction
mixture was concentrated under reduced pressure and purified by
column chromatography (1%-2% MeOH in DCM) to afford compound 71 (88
mg, 87% yield) as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.72 (s, 1H), 8.68-8.62 (m, 3H), 8.10 (t, J=8
Hz, 1H), 7.93-7.89 (m, 3H), 7.81 (s, 1H), 7.50 (dd, J=7.6 Hz, 4.8
Hz, 1H), 5.27 (s, 2H), 4.13-4.08 (m, 1H), 3.30-3.27 (m, 2H), 2.87
(s, 2H), 1.68-1.62 (m, 2H), 1.55-1.52 (m, 2H), 1.16-1.11 (m, 2H),
1.02-0.98 (m, 2H); ESI m/z 492.1 [M+H].sup.+.
Example 24: Preparation of methyl
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxoisoindoline--
5-carboxylate (Compound 72)
##STR00251##
[0487] A mixture of 6-bromoisoindolin-1-one (5.0 g, 23.58 mmol),
Pd(AcO).sub.2 (528 mg, 2.30 mmol), Xantphos (1.36 g, 2.36 mmol) and
TEA (1.19 g, 117.9 mmol) in methanol (100 mL) was heated to
70.degree. C. under 1 atm of CO (gas) overnight. The reaction
mixture was filtered and the filtrate was concentrated under
vacuum. The residue was purified by silica column chromatography
(1%-2% MeOH in DCM) to give 72A (500 mg, 11% yield) as a white
solid: ESI m/z 192.1 [M+H].sup.+.
[0488] A stirred mixture of 72A (66 mg, 0.35 mmol), 1D (80 mg, 0.30
mmol), Pd.sub.2(dba).sub.3 (28 mg, 0.03 mmol), Cs.sub.2CO.sub.3
(196 mg, 0.60 mmol) and Xantphos (20 mg, 0.03 mmol) in 1,4-dioxane
(5 mL) was heated to 100.degree. C. overnight under a nitrogen
atmosphere. The reaction mixture was allowed to cool to room
temperature and filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by silica column
chromatography (1%-2% MeOH in DCM) to provide compound 72 (50 mg,
44% yield) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.76 (d, J=8.4 Hz, 1H), 8.62 (s, 1H), 8.34 (d, J=7.6 Hz,
1H), 8.26 (br, 1H), 8.01-7.92 (m, 2H), 7.64 (d, J=8 Hz, 1H), 5.14
(s, 2H), 3.98 (s, 3H), 3.96-3.90 (m, 3H), 1.15-1.13 (m, 2H),
1.0-0.95 (m, 2H); ESI m/z 376.1 [M+H].sup.+.
Example 25: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-3-oxoisoindoline--
5-carboxylic acid (Compound 73)
##STR00252##
[0490] A suspension of compound 72 (100 mg, 0.26 mmol) in dioxane
(5 mL) and HCl (6M, 5 mL) was heated to 90.degree. C. overnight.
The solvent was concentrated and the addition of water (5 mL)
caused a precipitate to form. The solid was collected by filtration
and dried to give compound 73 (70 mg, 73% yield) as a white solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.01 (s, 1H), 8.67 (d,
J=8.4 Hz, 1H), 8.28-8.25 (m, 2H), 8.10 (t, J=8 Hz, 1H), 7.91 (d,
J=7.2 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 5.25 (s, 2H), 4.16-4.10 (m,
1H), 1.17-1.12 (m, 2H), 1.01-1.0 (m, 2H); ESI m/z 362.1
[M+H].sup.+.
Example 26: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-N,N-dimethyl-3-ox-
oisoindoline-5-carboxamide (Compound 74)
##STR00253##
[0492] A mixture of compound 73 (80 mg, 0.22 mmol), dimethylamine
hydrochloride (36 mg, 0.44 mmol), HATU (167 mg, 0.44 mg) and
triethylamine (111 mg, 1.10 mmol) in MeCN (6 mL) was stirred at
room temperature for 2 h. The solid was collected by filtration,
washed with water and dried to provide compound 74 (30 mg, 35%
yield) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.71 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 8.09 (t, J=8 Hz, 1H),
7.89 (d, J=7.6 Hz, 1H), 7.82 (s, 1H), 7.77 (q, J=7.6 Hz, 2H), 5.22
(s, 2H), 3.0 (d, J=7.2 Hz, 1H), 1.14-1.09 (m, 2H), 0.99-0.95 (m,
2H); ESI m/z 389.2 [M+H].sup.+.
Example 27: Preparation of
N-(2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-fluoro-3-oxo-
isoindolin-5-yl)cyclopropanecarboxamide (Compound 75)
##STR00254##
[0494] To a mixture of 16E (200 mg, 1.2 mmol) and NaHCO.sub.3 (1.0
g, 12.0 mmol) in DCM (15 mL) and THF (15 mL) was added
cyclopropanecarbonyl chloride (377 mg, 3.6 mmol) in three portions
at 0.degree. C. After stirring at room temperature for 4 h, the
mixture was poured into water and extracted with EtOAc (50
mL.times.3). The combined organic fractions were washed with water
and brine and dried over sodium sulfate. The solvent was removed
under vacuum and the residue was purified by column chromatography
on silica gel (1%-2% MeOH in DCM) to afford 75A (70 mg, 25% yield)
as an off-white solid: ESI m/z 235.0 [M+H].sup.+.
[0495] A mixture of 75A (70 mg, 0.3 mmol), 1D (79 mg, 0.3 mmol),
Pd.sub.2(dba).sub.3 (14 mg, 0.015 mmol), Xantphos (12 mg, 0.02
mmol), and Cs.sub.2CO.sub.3 (195 mg, 0.6 mmol) in dioxane (15 mL)
was heated to 100.degree. C. overnight. The reaction mixture was
allowed to cool to room temperature and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified by
silica column chromatography (1%-2% MeOH in DCM) to provide
compound 75 (20 mg, 20% yield) as a yellow powder: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.76 (dd, J=0.8 Hz, 1H), 8.25 (s, 1H),
8.01-7.92 (m, 3H), 7.60 (s, 1H), 7.52-7.50 (m, 1H), 5.11 (s, 2H),
3.96-3.91 (m, 1H), 3.75 (br, 2H), 3.36 (br, 2H), 1.71 (s, 4H), 1.31
(s, 2H), 1.16-1.10 (m, 2H), 0.98-0.94 (m, 2H); ESI m/z 429.1
[M+H].sup.+.
Example 28: Preparation of
2-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-yl)isoin-
dolin-1-one (Compound 76)
##STR00255##
[0497] A mixture of 1B (2.1 g, 10 mmol),
5-methoxy-3,4-dihydro-2H-pyrrole (1.49 g, 15 mmol) and acetic acid
(5 drops) in methanol (12 mL) was heated by microwave at
100.degree. C. for 2 hours. The mixture was concentrated and the
residue was purified by column chromatography on silica gel
(EtOAc/Pet. Ether, 1/4 to 4/1, v/v) to give 76A (2 g, 76% yield) as
a white solid: ESI m/z 266.9, 264.9 [M+H].sup.+.
[0498] A mixture of 76A (500 mg, 1.89 mmol), isoindolin-1-one (504
mg, 3.79 mmol), Pd.sub.2(dba).sub.3 (52 mg, 0.06 mmol), Xantphos
(55 mg, 0.10 mmol) and Cs.sub.2CO.sub.3 (2.47 g, 7.57 mmol) in
dioxane (20 mL) was heated to 100.degree. C. overnight. The
reaction mixture was concentrated under vacuum and the residue was
purified by column chromatography on silica gel (1%-5% MeOH in DCM)
to afford compound 76 (50 mg, 8% yield) as a white solid: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.67 (d, J=8.4 Hz, 1H), 8.05 (d,
J=7.6 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.85 (t, J=8 Hz, 1H),
7.66-7.51 (m, 3H), 5.08 (s, 2H), 4.51 (t, J=7.2 Hz, 2H), 3.05 (t,
J=8 Hz, 2H), 2.92-2.85 (m, 2H); ESI m/z 318.0 [M+H].sup.+.
[0499]
2-(6-(5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)pyridin-
-2-yl)isoindolin-1-one (compound 77) was prepared according to the
procedure for compound 76 substituting
6-methoxy-2,3,4,5-tetrahydropyridine in place of
5-methoxy-3,4-dihydro-2H-pyrrole. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.55 (d, J=8 Hz, 1H), 8.00 (t, J=8 Hz, 1H),
7.90 (d, J=7.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.73-7.70 (m, 2H),
7.58-7.54 (m, 1H), 5.15 (s, 2H), 4.53 (t, J=6 Hz, 2H), 2.96-2.93
(m, 2H), 2.02-1.99 (m, 2H), 1.92-1.89 (m, 2H); ESI m/z 332.1
[M+H].sup.+.
Example 29: Preparation of
2-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyridin-2-
-yl)isoindolin-1-one (Compound 78)
##STR00256##
[0501] A mixture of 5-methylpyrrolidin-2-one (3.0 g, 30.3 mmol) and
dimethyl sulfate (5.2 g, 31.8 mmol) was heated at 60.degree. C. for
16 h. The reaction mixture was then cooled and added to a saturated
aqueous solution of potassium carbonate (30 mL). The mixture was
extracted with ether and the organic layer was dried over sodium
sulfate. The solvent was evaporated to afford the 78A (860 mg, 25%
yield) as a brown oil.
[0502] A mixture of 78A (100 mg, 0.57 mmol) and 1B (1.09 mg, 5.1
mmol) in methanol (10 mL) and acetic acid (8 drops) was heated at
120.degree. C. by microwave for 2 h. The mixture was then cooled
and concentrated under vacuum. The residue was purified by silica
gel column chromatography (1%-50% EtOAc in pet. ether) to give 78B
(125 mg, 9% yield) as a yellow oil: ESI m/z 279.0, 280.9
[M+H].sup.+.
[0503] A mixture of 78B (125 mg, 0.45 mmol), isoindolin-1-one (60
mg, 0.45 mmol), Pd.sub.2(dba).sub.3 (13 mg, 0.014 mmol), Xantphos
(14 mg, 0.023 mmol) and Cs.sub.2CO.sub.3 (176 mg, 0.54 mmol) in
dioxane (45 mL) was heated to 100.degree. C. overnight. After that
time, the mixture was cooled to room temperature and filtered. The
filtrate was concentrated under reduced pressure and purified by
column chromatography on silica gel (1%-50% EtOAc in pet. ether) to
provide compound 78 (50 mg, 34% yield) as alight yellow solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.59 (d, J=7.2 Hz, 1H),
8.02 (d, J=7.2 Hz, 1H), 7.94 (d, J=4.2 Hz, 1H), 7.85 (d, J=5.6 Hz,
1H), 7.75 (d, J=11.2 Hz, 2H), 7.58 (s, 1H), 5.29-5.08 (m, 3H), 3.04
(br, 2H), 2.91 (d, J=4 Hz, 1H), 2.40 (s, 1H), 1.49 (s, 3H); ESI m/z
332.1 [M+H]+.
Example 30: Preparation of
(R)-2-(6-(5-(hydroymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3--
yl)pyridin-2-yl)isoindolin-1-one (Compound 79)
##STR00257##
[0505] tert-Butylchlorodiphenylsilane (25.8 g, 93.83 mmol) was
added to a solution of (R)-5-(hydroxymethyl)pyrrolidin-2-one (9 g,
78.19 mmol) and 1H-imidazole (6.4 g, 93.83 mmol) in DMF (180 mL).
After stirring at room temperature overnight, the reaction mixture
was poured into water and extracted with EtOAc. The organic
fraction was washed with water and brine and dried over sodium
sulfate. The solvent was concentrated under vacuum and the residue
was purified by chromatography on silica gel (1%-2% MeOH in DCM) to
afford silyl ether 79A (22 g, 80% yield) as a colorless oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.65-7.62 (m, 4H),
7.46-7.37 (m, 6H), 5.86 (br, 1H), 3.84-3.77 (m, 1H), 3.64-3.61 (m,
1H), 3.53-3.49 (m, 1H), 2.35-2.31 (m, 2H), 2.18-2.11 (m, 1H),
1.76-1.61 (m, 2H), 1.05 (s, 9H); ESI m/z 354.1 [M+H].sup.+.
[0506] A mixture of 79A (22.0 g, 62.27 mmol) and dimethyl sulfate
(7.85 g, 7.93 mmol) in benzene (73 mL) was heated to 60.degree. C.
for 18 h. The mixture was cooled to room temperature and the
reaction mixture was stirred with hexane (73 mL). The upper layer
was removed and then the reaction mixture was stirred with ether
(140 mL). After removing the ether layer, the residual oil was
diluted with DCM (100 mL) and washed with aqueous NaOH (1 M,
2.times.50 mL) and brine. The organic layer was dried over sodium
sulfate and concentrated under reduced pressure to give 79B (15 g,
62% yield) as yellow oil: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.64-7.60 (m, 5H), 7.50-7.44 (m, 5H), 4.18 (s, 2H), 3.76
(t, J=4.4 Hz, 2H), 3.59 (s, 1H), 3.04 (t, J=8.4 Hz, 2H), 1.03 (s,
3H), 1.00 (s, 9H); ESI m/z 368.1 [M+H].sup.+.
[0507] A mixture of 79B (12.3 g, 33.3 mmol), 1B (6.0 g, 27.8 mmol)
and triethylamine (10 mL) in methanol (300 mL) was stirred at
80.degree. C. overnight. The mixture was concentrated under vacuum
and purified by chromatography on silica gel (1%-3% MeOH in DCM) to
afford 79C as yellow solid (12 g, 81% yield): ESI m/z 551.0, 553.0
[M+H].sup.+.
[0508] A solution of 79C (9.0 g, 16.3 mmol) in AcOH (300 mL) was
stirred at 120.degree. C. overnight. The mixture was concentrated
under vacuum and purified by chromatography on silica gel (1%-2%
MeOH in DCM) to provide triazole 79D (6.8 g, 60% yield) as yellow
oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.14 (d, J=8 Hz,
1H), 7.56-7.52 (m, 2H), 7.46 (d, J=6.4 Hz, 2H), 7.33-7.25 (m, 3H),
7.20 (d, J=7.2 Hz, 2H), 7.14 (t, J=7.2 Hz, 1H), 7.03 (t, J=8 Hz,
2H), 4.15 (dd, J=2.8 Hz, 1H), 3.84 (dd, J=2.6 Hz, 1H), 2.96-2.86
(m, 2H); ESI m/z 533.0, 535.0 [M+H].sup.+.
[0509] A stirred mixture of 79D (4.6 g, 8.64 mmol),
isoindolin-1-one (1.15 g, 8.64 mmol), Pd.sub.2(dba).sub.3 (791 mg,
0.864 mmol), Cs.sub.2CO.sub.3 (8.44 g, 25.92 mmol) and Xantphos
(700 mg, 1.21 mmol) in 1,4-dioxane (150 mL) was heated to
100.degree. C. overnight. The reaction mixture was allowed to cool
to room temperature and filtered. The filtrate was concentrated
under reduced pressure and the residue was purified by silica
column chromatography (1%-5% MeOH in DCM) to give 79E (2.6 g, 56%
yield) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.54 (d, J=8 Hz, 1H), 8.05 (t, J=7.6 Hz, 1H), 7.99 (d,
J=6.8 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H),
7.57-7.48 (m, 3H), 7.22 (t, J=7.6 Hz, 1H), 7.13-7.04 (m, 4H), 5.19
(d, J=7.2 Hz, 1H), 5.03 (d, J=17.6 Hz, 1H), 4.56 (d, J=17.6 Hz,
1H), 4.11 (dd, J=10.4 Hz, 3 Hz, 1H), 3.95 (d, J=9.2 Hz, 1H),
3.12-2.93 (m, 3H), 2.81-2.75 (m, 1H), 0.80 (s, 9H); ESI m/z 586.1
[M+H].sup.+.
[0510] TBAF (1.0 M in THF, 3 mL, 3.0 mmol) was added dropwise to a
solution of 79E (600 mg, 1.02 mmol) in THF (15 mL) at room
temperature. After stirring at room temperature overnight, the
mixture was concentrated and purified by silica gel chromatography
(1%-5% MeOH in DCM) to provide compound 79 (260 mg, 73% yield) as a
white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.58 (d,
J=8.4 Hz, 1H), 8.03 (t, J=8 Hz, 1H), 7.94 (d, J=7.2 Hz, 1H), 7.85
(d, J=8.4 Hz, 1H), 7.74 (d, J=4 Hz, 2H), 7.59-7.55 (m, 1H), 5.21
(d, J=17.6 Hz, 1H), 5.07-5.02 (m, 3H), 3.82-3.80 (m, 2H), 3.82-2.80
(m, 3H), 2.74-2.67 (m, 1H); ESI m/z 348.0 [M+H].sup.+.
Example 31: Preparation of
(S)-2-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)pyrid-
in-2-yl)isoindolin-1-one (Compound 80)
##STR00258##
[0512] Sodium t-butoxide (415 mg, 4.32 mmol) was added in portions
to a solution of compound 79 (600 mg, 1.73 mmol) in DMF (20 mL) at
room temperature. After 30 min, 4-toluenesulfonyl chloride (660 mg,
3.46 mmol) was added and the reaction mixture was stirred at room
temperature overnight. The mixture was poured into water and
extracted with EtOAc (3.times.100 mL). The combined organic
fractions were washed with water and brine and dried over sodium
sulfate. The solvent was removed under vacuum and the residue was
purified by silica gel chromatography (3% MeOH in DCM) to give 80A
(260 mg, 30% yield) as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.55 (d, J=8.4 Hz, 1H), 8.01 (t, J=8.4 Hz,
1H), 7.86 (d, J=7.6 Hz, 1H), 7.80-7.71 (m, 3H), 7.59 (t, J=7.2 Hz,
1H), 7.42 (d, J=8.4 Hz, 2H), 7.13 (d, J=8 Hz, 2H), 5.27 (d, J=8 Hz,
1H), 5.11 (d, J=17.6 Hz, 1H), 4.79 (d, J=17.6 Hz, 1H), 4.61-4.52
(m, 2H), 3.10-2.99 (m, 1H), 2.92-2.89 (m, 2H), 2.62-2.68 (m, 1H),
2.27 (s, 3H); ESI m/z 502.0 [M+H].sup.+.
[0513] A mixture of 80A (200 mg, 0.40 mmol) and LiBr (695 mg, 0.80
mmol) in acetone (50 mL) was heated to 80.degree. C. overnight.
After cooling, the reaction mixture was concentrated and purified
by silica gel chromatography (1% MeOH in DCM) to afford bromide 80B
(140 mg, 85% yield) as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.62 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.6 Hz,
1H), 7.97 (d. J=7.6 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.77-7.71 (m,
2H), 7.58 (t, J=7.2 Hz, 1H), 5.41 (s, 1H), 5.29-5.13 (m, 2H),
4.14-4.04 (m, 2H), 3.16-3.04 (m, 2H), 2.95-2.87 (m, 1H), 2.71-2.64
(m, 1H); ESI m/z 409.9, 411.9 [M+H].sup.+.
[0514] A mixture of 80B (100 mg, 0.24 mmol) and Pd/C (wet, 10%, 100
mg) in triethylamine (10 mL) and methanol (30 mL) was stirred at
30.degree. C. under 0.5 Mpa of H.sub.2 overnight. The mixture was
filtered and the filtrate was concentrated under vacuum. The
residue was purified by silica gel chromatography (3% MeOH in DCM)
to provide compound 80 (40 mg, 50% yield) as a white solid: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.70 (d, J=8.4 Hz, 1H), 8.11 (d,
J=7.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.89 (t, 8 Hz, 1H), 7.66 (t,
7.2 Hz, 7.2 Hz, 1H), 7.59-7.52 (m, 2H), 5.15-5.04 (m, 3H),
3.11-3.03 (m, 3H), 2.51-2.44 (m, 1H), 1.55 (d, J=6.8 Hz, 3H); ESI
m/z 332.0 [M+H].sup.+.
##STR00259##
[0515]
(S)-2-(6-(5-(Hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tri-
azol-3-yl)pyridin-2-yl)isoindolin-1-one (compound 81) was prepared
according to the procedure for compound 79 substituting
(S)-5-(hydroxymethyl)pyrrolidin-2-one in place of
(R)-5-(hydroxymethyl)pyrrolidin-2-one. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.59 (d, J=8 Hz, 1H), 8.03 (t, J=8 Hz, 1H),
7.94 (d, J=7.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.74 (d, J=4 Hz,
2H), 7.59-7.55 (m, 1H), 5.21 (d, J=18 Hz, 1H), 5.07-5.03 (m, 3H),
3.83-3.82 (m, 2H), 2.98-2.82 (m, 3H), 2.73-2.67 (m, 1H); ESI m/z
348.0 [M+H].sup.+.
##STR00260##
[0516]
(R)-2-(6-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl-
)pyridin-2-yl)isoindolin-1-one (compound 82) was prepared according
to the procedure for compound 80 substituting compound 81 in place
of compound 79. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.60
(d, J=8.4 Hz, 1H), 8.04 (t, J=8 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H),
7.79-7.72 (m, 2H), 7.58 (t, J=7.2 Hz, 1H), 5.28 (d, J=17.6 Hz, 1H),
5.12 (t, J=6.8 Hz, 1H), 5.11 (d, J=17.6 Hz, 1H), 3.09-2.87 (m, 3H),
2.42-2.37 (m, 1H), 1.48 (d, J=6.4 Hz, 3H); ESI m/z 332.0
[M+H].sup.+.
Example 32: Preparation of
2-(6-(5-cyclopropyl-1H-1,2,3-triazol-1-yl)pyridin-2-yl)isoindolin-1-one
(Compound 83)
##STR00261##
[0518] A mixture of 2-bromo-6-hydrazinylpyridine (10 g, 53.2 mmol),
NaNO.sub.2 (4.1 g, 58.5 mmol) in conc. HCl (20 mL), H.sub.2O (70
mL) and ether (32 mL) was stirred at room temperature overnight.
The reaction mixture was extracted with ether and the organic
fractions were washed with brine and dried over sodium sulfate. The
solvent was evaporated and the residue was purified by column
chromatography on silica gel (1%-5% EtOAc in pet. ether) to afford
83A (4.2 g, 40% yield) as a yellow solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.76 (t, J=8 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H),
7.01 (d, J=8 Hz, 1H); ESI m/z 199.9, 201.9 [M+H].sup.+.
[0519] A mixture of 83A (500 mg, 2.51 mmol), ZnEt.sub.2 in THF (1.0
M, 3.8 mL), ethynylcyclopropane (200 mg, 3.02 mmol) and
1-methyl-1H-imidazole (21 mg, 0.25 mmol) was stirred at room
temperature overnight under nitrogen. The mixture was poured into
water and extracted with EtOAc (100 mL.times.3). The combined
organic fractions were washed with water and brine and dried over
sodium sulfate. The solvent was removed under vacuum and the
residue was purified by column chromatography on silica gel (1%-10%
EtOAc in pet. ether) to give the 83B (200 mg, 30% yield) as a
yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.09 (t,
J=8 Hz, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.86 (d, J=8 Hz, 1H), 7.64 (s,
1H), 2.40-2.33 (m, 1H), 1.07-1.02 (m, 2H), 0.81-0.77 (m, 2H); ESI
m/z 265.0, 267.0 [M+H].sup.+.
[0520] A mixture of 83B (200 mg, 0.8 mmol), isoindolin-1-one (107
mg, 0.8 mmol), Pd.sub.2(dba).sub.3 (22 mg, 0.024 mmol), Xantphos
(23 mg, 0.04 mmol) and Cs.sub.2CO.sub.3 (313 mg, 0.96 mmol) in
dioxane (50 mL) was heated to 100.degree. C. for 4 h. After cooling
to room temperature, the reaction mixture was filtered. The
filtrate was concentrated and the residue was purified by column
chromatography on silica gel (1%-5% EtOAc in pet. ether) to provide
compound 83 (180 mg, 31% yield) as an off-white solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.66 (d, J=8.4 Hz, 1H), 8.19 (t,
J=8 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.73-7.69 (m, 3H), 7.63 (s,
1H), 7.59-7.55 (m, 1H), 5.14 (s, 2H), 2.62-2.56 (m, 1H), 1.13-1.09
(m, 2H), 0.83-0.79 (m, 2H); ESI m/z 318.0 [M+H].sup.+.
Example 33: Preparation of
2-(6-(H-1,2,3-triazol-1-yl)pyridin-2-yl)isoindolin-1-one (Compound
84)
##STR00262##
[0522] A mixture of 83A (600 mg, 3.02 mmol) and
ethynyltrimethylsilane (890 mg, 9.06 mmol) in toluene (20 mL) was
heated to 110.degree. C. overnight in a sealed tube. After cooling,
the mixture was concentrated under vacuum and the residue was
purified by column chromatography on silica gel (1%-5% EtOAc in
pet. ether) to give 84A (600 mg, 58% yield) as a white solid: ESI
m/z 298.9, 296.9 [M+H].sup.+.
[0523] TBAF (1.0 M in THF, 3.1 mL, 3.03 mmol) was added to a
solution of 84A (300 mg, 1.01 mmol) in THF (2 mL). After stirring
at room temperature overnight the reaction mixture was diluted with
water and extracted with EtOAc. The combined organic fractions were
washed with brine, dried over sodium sulfate and evaporated. The
residue was purified by flash chromatography (10%-30% EtOAc in pet.
ether) to afford 84B as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.83 (s, 1H), 8.15 (d, J=8 Hz, 1H), 8.08-8.04
(m, 1H), 8.01 (s, 1H), 7.81 (d, J=8 Hz, 1H); ESI m/z 224.9, 226.9
[M+H].sup.+.
[0524] A mixture of 84B (225 mg, 1.0 mmol), isoindolin-1-one (133.1
mg, 1.0 mmol), Pd.sub.2(dba).sub.3 (28 mg, 0.03 mmol), Xantphos (29
mg, 0.05 mmol) and Cs.sub.2CO.sub.3 (391 mg, 1.2 mmol) in dioxane
(45 mL) was heated to 100.degree. C. overnight. After cooling to
room temperature, the reaction mixture was filtered. The filtrate
was concentrated under vacuum and the residue was purified by
column chromatography on silica gel (1%-30% EtOAc in pet. ether) to
provide compound 84 (170 mg, 61% yield) as a white solid: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.72 (dd, J=7.6 Hz, 6.4 Hz, 1H),
8.57 (d, J=1.2 Hz, 1H), 8.01-7.94 (m, 3H), 7.86 (d, J=0.8 Hz, 1H),
7.69-7.65 (m, 1H), 7.59-7.52 (m, 2H), 5.14 (s, 2H); ESI m/z 278.0
[M+H].sup.+.
Example 34: Preparation of
2-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-6-(pyridin-3-yl)iso-
indolin-1-one (Compound 85)
##STR00263##
[0526] A mixture of 1C (2.1 g, 7.75 mmol), propan-2-amine
hydrochloride (3.71 g, 38.8 mmol) and DIPEA (5.0 g, 38.8 mmol) in
acetonitrile (32 mL) and acetic acid (8 mL) was heated to
90.degree. C. overnight. After cooling, the reaction mixture was
concentrated under vacuum and purified by column chromatography on
silica gel (1%-50% EtOAc in pet. ether) to give triazole 85A (1.7
g, 82% yield) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.92 (s, 1), 8.15 (d, J=8 Hz, 1H), 7.96-7.92 (m, 1H), 7.77
(d, J=8 Hz, 1H), 5.34-5.24 (m, 1H), 1.48 (d, J=6.8 Hz, 6H); ESI m/z
266.9, 268.9 [M+H].sup.+.
[0527] A mixture of 6-bromoisoindolin-1-one (1.0 g, 4.72 mmol),
Pd(dppf)Cl.sub.2 (104 mg, 0.14 mmol), K.sub.2CO.sub.3 (1.96 g, 14.2
mmol) and 3-pyridylboronic acid (580 mg, 4.72 mmol) in dioxane (45
mL) and water (5 mL) was heated to 100.degree. C. overnight. After
cooling, the mixture was poured into water and extracted with EtOAc
(3.times.100 mL). The combined organic fractions were washed with
brine and dried over sodium sulfate. The solvent was evaporated and
the residue was purified by column chromatography on silica gel
(1%-50% EtOAc in pet. ether) to afford 85B (500 mg, 50% yield) as
an off-white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.94 (d, J=2 Hz, 1H), 8.67 (s, 1H), 8.60 (dd, J=4.8 Hz, 1.2 Hz,
1H), 8.16-8.13 (m, 1H), 7.96-7.94 (m, 2H), 7.71 (d, J=8.8 Hz, 1H),
7.52-7.49 (m, 1H), 4.44 (s, 2H); ESI m/z 211.0 [M+H].sup.+.
[0528] A mixture of 85B (210 mg, 1.0 mmol), 85A (267 mg, 1.0 mmol),
Pd.sub.2(dba).sub.3 (28 mg, 0.03 mmol), Xantphos (29 mg, 0.05 mmol)
and Cs.sub.2CO.sub.3 (391 mg, 1.2 mmol) in dioxane (45 mL) was
heated to 100.degree. C. overnight. After cooling to room
temperature, the reaction was filtered. The filtrate was
concentrated under reduced pressure and purified by column
chromatography on silica gel (1%-5% MeOH in EtOAc) to provide
compound 85 (220 mg, 55% yield) as a white solid: .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.0 (s, 1H), 8.93 (s, 1H), 8.66-8.61 (m,
2H), 8.19 (d, J=8 Hz, 1H), 8.13 (s, 1H), 8.10-8.06 (m, 2H), 7.92
(d, J=7.6 Hz, 1H), 7.87 (d, J=8 Hz, 1H), 7.54-7.51 (m, 1H),
5.57-5.51 (m, 1H), 5.21 (s, 2H), 1.59 (d, J=6.8 Hz, 6H); ESI m/z
397.0 [M+H].sup.+.
Example 35: Preparation of
2-(4-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyrimidin-2-yl)isoindolin-1-one
(Compound 86)
##STR00264##
[0530] A mixture of methyl 2-chloropyrimidine-4-carboxylate (2.8 g,
16.2 mmol) and hydrazine hydrate (0.80 g, 16.2 mmol) in methanol
(50 mL) was stirred at 0.degree. C. for 1 hour. The solid was
collected by filtration and washed with hexane to give 86A (1.71 g,
61% yield) as a yellow solid: ESI m/z 173.0 [M+H].sup.+.
[0531] A mixture of 86A (1.5 g, 8.70 mmol) and DMF-DMA (5.1 g, 43.4
mmol) in DCM (100 mL) was heated to reflux for 4 hours. The mixture
was concentrated under vacuum and triturated with pet. ether to
afford 86B (1.9 g, 96% yield) as a yellow solid: ESI m/z 228.1
[M+H].sup.+.
[0532] Cyclopropylamine (1.44 g, 25.2 mmol) was added to a solution
of 86B (1.9 g, 8.40 mmol) in acetic acid (60 mL). The reaction
mixture was stirred at 90.degree. C. for 3 hours. The mixture was
concentrated under reduced pressure and purified by chromatography
on silica gel (1%-3% MeOH in DCM) to give 86C (1.2 g, 65% yield) as
a yellow solid: ESI m/z 222.1 [M+H].sup.+.
[0533] A mixture of 86C (150 mg, 0.68 mmol), isoindolin-1-one (90
mg, 0.68 mmol), Cs.sub.2CO.sub.3 (265 mg, 0.82 mmol), Xantphos (19
mg, 0.034 mmol) and Pd(dba).sub.3 (18 mg, 0.02 mmol) in dioxane (8
mL) was stirred at 100.degree. C. overnight under a nitrogen
atmosphere. The mixture was poured into water and extracted with
EtOAc (100 mL.times.3). The combined organic fractions were dried
over sodium sulfate, concentrated under reduced pressure and
purified by chromatography on silica gel (1%-3% MeOH in DCM) to
provide compound 86 (15 mg, 7% yield) as a white solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.94 (d, J=5.2 Hz, 1H), 8.80 (s,
1H), 7.91 (d, J=4.8 Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.74-7.72 (m,
2H), 7.58-7.54 (m, 1H), 5.18 (s, 2H), 4.65-4.62 (m, 1H), 1.14-1.11
(m, 2H), 1.08-1.06 (m, 2H); ESI m/z 319.1 [M+H].sup.+.
Example 36: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1,2-dihydro-3H-in-
dazol-3-one (Compound 87)
##STR00265##
[0535] A mixture of 3,4-dihydro-2H-pyran (2.1 g, 24.6 mmol),
1H-indazol-3 (2H)-one (3 g, 22.4 mmol), toluene-4-sulfonic acid
(775 mg, 4.5 mmol) in THF (25 mL) was stirred at RT overnight. The
mixture was concentrated under vacuum and purified by silica gel
column chromatography (1%-5% EtOAc in pet. ether) to afford 87A (2
g, 41% yield) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.79 (s, 1H), 7.62 (d, J=8 Hz, 1H), 7.52 (d, J=8.4 Hz,
1H), 7.36 (t, J=7.6 Hz, 1H), 7.07-7.03 (m, 1H), 5.58 (dd, J=10 Hz,
1 Hz, 1H), 3.87-3.84 (m, 1H), 3.69-3.62 (m, 1H), 2.34-2.24 (m, 1H),
2.01-1.98 (m, 1H), 1.91-1.87 (m, 1H), 1.76-1.65 (m, 1H), 1.55-1.48
(m, 2H); ESI m/z 219.1 [M+H].sup.+.
[0536] A mixture of 87A (550 mg, 2.52 mmol), 1D (668 mg, 2.52 mmol)
Pd.sub.2(dba).sub.3 (74 mg, 0.08 mmol), Xantphos (75 mg, 0.13 mmol)
and Cs.sub.2CO.sub.3 (985 mg, 3.0 mmol) in dioxane (50 mL) was
heated to 100.degree. C. overnight. After cooling to room
temperature, the reaction mixture was filtered. The filtrate was
concentrated under reduced pressure and purified by column
chromatography (1%-50% EtOAc in pet. ether) to give 87B (600 mg,
60% yield) as a yellow solid: ESI m/z 403.1 [M+H].sup.+.
[0537] A mixture of 87B (600 mg, 1.49 mmol) and HCl (1.0 M, 20 mL)
in THF (10 mL) was stirred at room temperature overnight. The
mixture was poured into water and extracted with EtOAc (100
mL.times.3). The combined organic fractions were washed with water
and brine and dried over sodium sulfate. The solvent was removed
under vacuum and the residue was purified by column chromatography
on silica gel (1%-5% MeOH in DCM) to provide compound 87 (230 mg,
48% yield) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.69 (s, 1H), 8.42 (s, 1H), 8.13-8.09 (m, 1H), 7.91 (d,
J=7.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.44-7.36 (m, 3H), 7.06 (t,
J=7.2 Hz, 1H), 2.85-2.79 (m, 1H), 0.65-0.60 (m, 2H), 0.15-0.10 (m,
2H); ESI m/z 319.0 [M+H].sup.+.
Example 37: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1-methyl-1,2-dihy-
dro-3H-indazol-3-one (Compound 88)
##STR00266##
[0539] To a mixture of compound 87 (100 mg, 0.31 mmol) and
Cs.sub.2CO.sub.3 (206 mg, 0.63 mmol) in DMF (10 mL) was added
iodomethane (67 mg, 0.47 mmol). After stirring at room temperature
for 2 h, the mixture was poured into water and extracted with EtOAc
(50 mL.times.3), the organic layer was washed with water and brine,
dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by
silica gel column chromatography (MeOH/DCM=1/100 to 1/30, v/v) and
Prep-TLC (MeOH/DCM=1/15, v/v) to afford the product (13 mg, 13%
yield) as a white solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.43 (s, 1H), 8.11 (t, J=8 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H),
7.64 (d, J=8.8 Hz, 1H), 7.45-7.38 (m, 3H), 7.11-7.07 (m, 1H), 3.97
(s, 3H), 2.87-2.81 (m, 1H), 0.66-0.62 (m, 2H), 0.17-0.12 (m, 2H);
ESI m/z 333.0 [M+H].sup.+.
Example 38: Preparation of
2-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)benzo[d]isothiazol-
-3 (2H)-one (Compound 89)
##STR00267##
[0541] A stirred mixture of benzo[d]isothiazol-3 (2H)-one (113 mg,
0.75 mmol), 1D (200 mg, 0.75 mmol), Pd.sub.2(dba).sub.3 (34 mg,
0.0375 mmol), Cs.sub.2CO.sub.3 (733 mg, 2.25 mmol) and Xantphos (30
mg, 0.0525 mmol) in 1,4-dioxane (20 mL) was heated to 100.degree.
C. overnight. The reaction mixture was allowed to cool to room
temperature and filtered. The filtrate was concentrated under
reduced pressure and the residue was purified by silica column
chromatography (1%-5% MeOH in DCM) to afford compound 89 (20 mg, 8%
yield) as a yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.86 (d, J=8.4 Hz, 1H), 8.27 (s, 1H), 8.10 (dd, J=7.6 Hz, 3.2 Hz,
1H), 7.97 (t, J=8 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.57 (d, J=8 Hz,
1H), 7.44 (t, J=7.6 Hz, 1H), 4.16-4.11 (m, 1H), 1.28-1.23 (m, 2H),
0.96-0.92 (m, 2H); ESI m/z 336.0 [M+H].sup.+.
Example 39: ASK1 Kinase Assay
[0542] The ASK1 enzymatic assay was run following Promega ASK1
Kinase Enzyme System (Cat #V3881). The kit provides the protocol,
enzymes and all reagents necessary to run an assay.
[0543] Firstly, the compounds, enzyme, substrate and ATP were
diluted in provided assay buffer. The final concentration of the
enzyme was 50 nM, substrate (Myelin basic protein) 1 .mu.g/ml and
ATP 10 .mu.M. The compound and the enzyme were pre-incubated in a
384 well white solid bottom plate (Greiner, Cat #784075) for 10
minutes. After incubation, the substrate and ATP were added and
incubated for further 60 minutes. After 60 minutes, ADP-Glo.TM. was
added and plate was incubated for another 40 minutes. After 40
minutes, Kinase Detection Reagent was added and the plate was
incubated for 45 minutes. After 45 minutes, plate was read on
Perkin Elmer EnVision using luminescence read (0.5 seconds/well).
IC50 data for compounds are shown in Table 6.
Example 40: Inhibition of LPS-Induced TNFalpha in Human PBMCs
[0544] Cryopreserved human PBMCs were obtained from AllCells (cat
#PB003F). After thawing/dilution protocols using RPMI medium
supplemented with 5% FBS (heat inactivated), 100 ul/well of
1.times.10.sup.6 cells/ml were plated into 96 well tissue culture
plates (Corning). Cells were then pre-incubated for 1 hr at
37.degree. C. in humidified 5% CO2 and 95% air with test compounds
diluted in DMSO (final DMSO concentration 0.3%). Each compound was
tested at 10 concentrations in duplicate wells. After the
pre-incubation, 100 ng/ml LPS (E. Coli; Sigma) in RPMI media with
5% FBS was added for a 6 hr incubation at 37.degree. C. in
humidified 5% CO2 and 95% air. Controls on each plate included
cells and LPS only, cells and media only (no LPS), and media only.
After the 6 hr incubation, plates were centrifuged and the
supernatants transferred to a new plate and frozen for subsequent
TNFalpha analysis. Human TNFalpha was analyzed by ELISA according
to the manufacturer's instructions (BD Sciences, BD OptEIAm Cat
#550610) and analyzed on a SpectraMax M series (Molecular Devices)
microplate reader at OD 450 nm. IC50s were calculated using XLFit4
curve fitting software (IDBS) and a 4-parameter one-site sigmoid
dose response fit. IC50 data for compounds are shown in Table
6.
Example 41: MYLK/MLCK Assay
[0545] MYLK dissociation constants (Kd) for compounds were
determined using the DiscoverX KdELECT platform. The MYLK kinase
(accession number NP_444254.3) was labeled with a DNA tag for
subsequent qPCR readout while a known active site binding ligand
(staurosporine) was immobilized on a solid support (beads). Test
compounds were prepared as 111.times. stocks in 100% DMSO and Kds
were determined using an 11-point 3-fold compound dilution series
with three DMSO control points. The compounds were then diluted
directly into the assays such that the final concentration of DMSO
was 0.9%. The assay plates were incubated at room temperature with
shaking for 1 hour to equilibrate. The affinity beads were washed
(lx PBS, 0.05% Tween 20) to remove unbound kinase and quantify MYLK
captured on solid support by qPCR. The Kd was determined by
measuring the amount of MYLK captured on the solid support as a
function of the test compound concentration. The Kd values were
calculated by fitting dose-response curves to the Hill binding
equation using the Levenberg-Marquardt algorithm. The Kd data for
compounds are shown in Table 6.
[0546] For the myosin light chain kinase (MLCK) IC50
determinations, the Reaction Biology Corporation radioactive kinase
platform (CAT #: MLCK) was utilized. The MLCK peptide substrate
(KKLNRTLSFAEPG, 20 uM) was freshly prepared in base reaction buffer
(20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02
mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) with 1 uM calmodulin
and 30 uM ATP (Km). Test compounds were tested in 10-dose IC50 mode
with a 3-fold serial dilution starting at 60 uM. The control
compound, staurosporine, was tested in 10-dose IC50 mode with
4-fold serial dilution starting at 20 uM. Compounds were incubated
for 20 minutes with the peptide substrate and the MLCK kinase
enzyme (UniProtKB Q15746 (MYLK_HUMAN)) prior to the addition of
.sup.33P-ATP (specific activity 10 .mu.Ci/.mu.l), to initiate the
reaction, resulting in .sup.33P-Substrate+ADP. After 2 hr
incubation at room temperature the reactions are spotted onto P81
ion exchange paper and the kinase activity detected by a
filter-binding method. IC50 values and curve fits were obtained
using Prism GraphPad Software. IC50 data for compounds are shown in
Table 6.
Example 42: hERG QPatchHTX Assay
[0547] The hERG QPatchHTX assay was conducted at room temperature.
The whole-cell protocols, voltage protocols and application
protocols were established with QPatch Assay Software 5.2 (Sophion
Bioscience). Chinese hamster ovary (CHO) cells stably expressing
hERG potassium channels (Aviva Bioscience) were cultured at more
than 75% confluent. Cells were harvested using TrypLE and
resuspended in the extracellular solution at the room
temperature.
[0548] Test compounds described herein, commercial compound GS-4997
and positive control Amitriptyline were dissolved in 100% DMSO to
obtain stock solutions and were further diluted into extracellular
solution to achieve final concentrations for testing. Visual check
for precipitation was conducted before testing. Final DMSO
concentration in extracellular solution was not more than 0.30% for
the test compounds and Amitriptyline (positive) control. Three
additions of 5 .mu.l of the vehicle were applied, followed by
30runs of voltage protocol for a baseline period. Then the
ascending doses of each compound were added with three repetitions
(5 .mu.l*3). The exposure of test compound at each concentration
was no less than 5 minutes. The recording for the whole process had
to pass the quality control or the well was abandoned and the
compound was retested, all automatically set by QPatch Assay
Software. Two concentrations (10 M and 30 PM) were tested for each
compound. Minimum 2 replicates per concentration were obtained.
[0549] Voltage command protocol: From this holding potential of -80
mV, the voltage was first stepped to -50 mV for 80 ms for leak
subtraction, and then stepped to +20 mV for 4800 ms to open hERG
channels. After that, the voltage was stepped back down to -50 mV
for 5000ins, causing a "rebound" or tail current, which was
measured and collected for data analysis. Finally, the voltage was
stepped back to the holding potential (-80 mV, 3100ins). This
voltage command protocol was repeated every 15000 msec. This
command protocol was performed continuously during the test
(vehicle control and test compounds described herein).
[0550] Compound 2and Compound 27 did not have a significant effect
on hERG current up to 30 .mu.M (FIG. 1). In contrast, the
ASK1inhibitor GS-4997 and the positive control compound both had
significant effect on hERG current. Activity data for compounds are
shown in Table 6.
TABLE-US-00006 TABLE 6 TNFa MYLK/MLCK hERG ASK1 Kinase Inhibition
Kinase IC.sub.50 Inhibition Compound Avg IC.sub.50 IC.sub.50 or
K.sub.d at 10 .mu.M 1 +++ +++ 2 +++ ++ + + 3 +++ 4 +++ 5 +++ 6 +++
7 +++ + + ++ 8 +++ ++ 9 +++ ++ 10 +++ ++ + 11 +++ ++ + 12 +++ + 13
+++ + 14 +++ ++ + 15 +++ ++ + 16 +++ + + 17 +++ + 18 +++ 19 +++ 20
+++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ ++ 28 +++ ++
29 +++ 30 +++ ++ ++ 31 +++ 32 ++ ++ 33 ++ 34 +++ 35 +++ 36 +++ 37
+++ 38 +++ 39 +++ 40 +++ +++ +++ +++ 41 +++ +++ +++ +++ 42 +++ 43
+++ ++ ++ 44 +++ ++ + 45 +++ 46 +++ +++ +++ +++ 47 +++ 48 +++ 49
+++ 50 +++ 51 +++ + 52 +++ 53 +++ 54 +++ 55 ++ 56 +++ 57 +++ 58 +++
59 +++ 60 +++ + +++ 61 +++ 62 +++ 63 +++ + 64 +++ +++ ++ 65 +++ +
66 +++ +++ +++ 67 +++ 68 +++ +++ ++ 69 +++ +++ ++ 70 +++ 71 +++ ++
++ 72 +++ 73 +++ 74 ++ 75 ++ 76 ++ 77 + 78 +++ +++ 79 +++ 80 ++ 81
+ 82 +++ 83 +++ 84 ++ 85 +++ 86 + 87 + 88 + 89 + For ASK1 Kinase
Assay: +++ = IC.sub.50 < 200 nM; ++ = IC.sub.50 200 nM-<1
.mu.M; + = IC.sub.50 1-10 .mu.M. For TNFa Inhibition Assay: +++ =
IC.sub.50 < 2 .mu.M; ++ = IC.sub.50 2-10 .mu.M; + = IC.sub.50
> 10 .mu.M. For MYLK/MLCK Kinase Assay: +++ = Kd or IC.sub.50
< 1 .mu.M; ++ = Kd or IC.sub.50 1-10 .mu.M; + = Kd or IC.sub.50
> 10 .mu.M. For hERG Inhibition Assay: +++ >20% inhibition;
++ = 10-20% inhibition; + = <%10 inhibition.
Example 43: Clinical Trial of ASK1 Inhibitors in Human NASH Patient
Selection/Management
[0551] Patient inclusion criteria are: age 18-75, greater than 60
UL serum alanine transaminase (ALT), ultrasound-documented fatty
liver, biopsy-consistent NASH without cirrhosis, platelet count
.gtoreq.75,000/mm.sup.3, absolute neutrophil count
.gtoreq.1500/mm.sup.3, hemoglobin .gtoreq.11.0 g/dL, and creatinine
clearance .gtoreq.70 mL/min as calculated with the Cockcroft-Gault
equation.
[0552] Histological criteria used for NASH in biopsy analysis are:
steatosis (>5% of hepatocytes containing liver fat), hepatocyte
ballooning, and lobular inflammation, regardless of the amount of
fibrosis.
[0553] Patients are required to have a stable weight (within 4%)
before screening, and to maintain their existing diets and physical
activity levels over the course of the study.
[0554] Patient exclusion criteria are: any other cause of liver
disease (e.g., viral hepatitis, autoimmune hepatitis,
hemochromatosis, and others), hepatocellular carcinoma (HCC), daily
alcohol consumption higher than 30 g in males and 20 g in females,
or drug-induced/secondary NASH.
Cohort Design/Drug Administration
[0555] The study is randomized, double-blind, parallel-group, and
placebo-controlled. Patients successfully meeting selection
criteria are stratified by comorbid conditions that may exacerbate
liver injury (e.g. type-2 diabetes). After stratification, subjects
are randomly assigned to one of five parallel treatment groups:
placebo or 4 escalating doses of any of the ASK-1 inhibitors of
Formula I, Formula II, or Formula III described herein. The
inhibitor is administered orally once daily for 4 weeks. On
completion of treatment, subjects are followed for 4 weeks.
Measures of Drug Efficacy
[0556] Serum ALT and AST (liver function markers) are measured from
weekly blood samples collected during the treatment and follow-up
periods. Normal levels are defined as 43 U/L ALT and 36 U/L AST for
males, and 34 U/L ALT and 34 U/L AST for females.
[0557] Cytokeratin-18 fragments (resulting from caspase-3 cleavage
and apoptotic activity, liver damage markers) are measured using
ELISA from blood samples collected at week 2 and week 4 of the
treatment period.
[0558] Concentrations of ASK-1 inhibitors are determined in plasma
by using a validated bioanalytical assay to assess drug
concentration. Steady state analysis of pharmacokinetic parameters
(e.g. (C.sub.max), time of C.sub.max (T.sub.max), half-life
(T.sub.1/2), and area under the plasma concentration versus time
curve over the dosing interval (AUC.sub.tau)) occurs between weeks
2 and 4.
Safety Analysis
[0559] Safety monitoring includes clinical laboratory tests,
physical examinations, vital signs measurements, 12-lead
electrocardiograms, and documentation of adverse events (AEs).
Efficacy Endpoints
[0560] Absolute and percent change from baseline in ALT levels, AST
levels, and CK-18 fragment levels at week 4 are assessed by an
analysis of covariance (ANCOVA) model with adjustment for baseline
values.
[0561] Plasma concentration-time data for each subject are analyzed
using standard noncompartmental methods to compute pharmacokinetic
parameters. Exposure/response relationships for ASK-1 inhibitors
are determined by fitting C.sub.max or AUC.sub.tau to time-weighted
absolute changes in CK-18 fragment, AST, or ALT levels.
[0562] The examples and embodiments described herein are for
illustrative purposes only and various modifications or changes
suggested to persons skilled in the art to be included within the
spirit and purview of this application and scope of the appended
claims.
* * * * *