U.S. patent application number 17/581740 was filed with the patent office on 2022-05-12 for nonpeptide somatostatin type 5 receptor agonists and uses thereof.
The applicant listed for this patent is Crinetics Pharmaceuticals, Inc.. Invention is credited to Mi CHEN, Joseph PONTILLO, Shimiao WANG, Jian ZHAO, Yunfei ZHU.
Application Number | 20220144802 17/581740 |
Document ID | / |
Family ID | 1000006098134 |
Filed Date | 2022-05-12 |
United States Patent
Application |
20220144802 |
Kind Code |
A1 |
ZHAO; Jian ; et al. |
May 12, 2022 |
NONPEPTIDE SOMATOSTATIN TYPE 5 RECEPTOR AGONISTS AND USES
THEREOF
Abstract
Described herein are compounds that are somatostatin modulators,
methods of making such compounds, pharmaceutical compositions and
medicaments comprising such compounds, and methods of using such
compounds in the treatment of conditions, diseases, or disorders
that would benefit from modulation of somatostatin activity.
Inventors: |
ZHAO; Jian; (San Diego,
CA) ; ZHU; Yunfei; (San Diego, CA) ; WANG;
Shimiao; (San Diego, CA) ; CHEN; Mi; (San
Diego, CA) ; PONTILLO; Joseph; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Crinetics Pharmaceuticals, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000006098134 |
Appl. No.: |
17/581740 |
Filed: |
January 21, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16989193 |
Aug 10, 2020 |
|
|
|
17581740 |
|
|
|
|
62886764 |
Aug 14, 2019 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/14 20130101;
A61P 3/10 20180101; C07D 401/04 20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; A61P 3/10 20060101 A61P003/10; C07D 401/14 20060101
C07D401/14 |
Goverment Interests
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
[0002] This invention was made with government support under grant
number DK115290 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A compound of Formula (VI), or a pharmaceutically acceptable
salt, or solvate thereof: ##STR00795## wherein: R.sup.c is
hydrogen, halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f,
--CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, substituted or unsubstituted
monocyclic C.sub.3-C.sub.6cycloalkyl, or substituted or
unsubstituted monocyclic C.sub.2-C.sub.5heterocycloalkyl; R.sup.f
is -L.sup.1-R.sup.g; L.sup.1 is absent or C.sub.1-C.sub.6alkylene;
R.sup.9 is hydrogen, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted phenyl,
--CO.sub.2R.sup.9, or --C(.dbd.O)N(R.sup.9).sub.2, or substituted
or unsubstituted monocyclic C.sub.2-C.sub.5heterocycloalkyl;
R.sup.3 is hydrogen or --CH.sub.3; R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, C.sub.1-C.sub.4alkylene, or --CHR.sup.6b--; R.sup.6a is
substituted or unsubstituted cyclopropyl, substituted or
unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl,
substituted or unsubstituted aziridinyl, substituted or
unsubstituted oxetanyl, or substituted or unsubstituted theitanyl;
R.sup.6b is hydrogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4fluoroalkyl, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.4cycloalkyl; R.sup.7 is hydrogen or
C.sub.1-C.sub.6alkyl; R.sup.8 is hydrogen or halogen; R.sup.11 and
R.sup.12 are each independently hydrogen, halogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, or --OR.sup.9; each R.sup.9 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; or two R.sup.9 on the same N atom are
taken together with the N atom to which they are attached to form a
substituted or unsubstituted N-containing heterocycle.
2. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein: R.sup.c is hydrogen, --F, --Cl, --CN,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--C(CH.sub.3).sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCF.sub.3,
--OCH.sub.2CHF.sub.2, --OCH.sub.2CF.sub.3, --O-(cyclopropyl),
--O--CH.sub.2-(cyclopropyl), --O--CH.sub.2-(phenyl),
--OCH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --CONHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,
pyrrolidinyl, piperidinyl, or morpholinyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound has the structure of
Formula (VIa), or a pharmaceutically acceptable salt, or solvate
thereof: ##STR00796## wherein: R.sup.c is hydrogen, halogen, --CN,
--N(R.sup.9).sub.2, --OR.sup.f, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or C.sub.1-C.sub.6fluoroalkoxy; R.sup.f
is -L.sup.1-R.sup.g; L.sup.1 is absent or C.sub.1-C.sub.6alkylene;
and R.sup.g is hydrogen, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted phenyl, or
--CO.sub.2R.sup.9.
4. The compound of claim 3, or a pharmaceutically acceptable salt,
or solvate thereof, wherein: R.sup.8 is hydrogen, --F, or --Cl; and
R.sup.11 and R.sup.12 are each independently hydrogen, --F, --Cl,
--CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3, or
--OCHF.sub.2.
5. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound has the structure of
Formula (VIa-1), or a pharmaceutically acceptable salt, or solvate
thereof: ##STR00797## wherein: R.sup.c is hydrogen, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3,
--CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2; and R.sup.11 and R.sup.12 are each
independently --F or --Cl.
6. The compound of claim 5, or a pharmaceutically acceptable salt,
or solvate thereof, wherein: R.sup.6 is C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6fluoroalkyl; and R.sup.7 is hydrogen or
--CH.sub.3.
7. The compound of claim 6, or a pharmaceutically acceptable salt,
or solvate thereof, wherein: R.sup.6 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3),
--C(CH.sub.3)(CHCH.sub.3).sub.2, --C(CH.sub.3).sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH(CF.sub.3)(CH.sub.3), --CH(CF.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CF.sub.2CH.sub.3, or
--CH(CH.sub.3)(CH.sub.2CF.sub.3).
8. The compound of claim 5, or a pharmaceutically acceptable salt,
or solvate thereof, wherein: L.sup.2 is absent, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted azetidine, or substituted or unsubstituted
oxetanyl; R.sup.6b is hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CHF.sub.2,
--CH.sub.2F, --CF.sub.3, cyclopropyl, or cyclobutyl; and R.sup.7 is
hydrogen or --CH.sub.3.
9. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound has the structure of
Formula (VIb), or a pharmaceutically acceptable salt, or solvate
thereof: ##STR00798## wherein: R.sup.c is hydrogen, halogen, --CN,
--N(R.sup.9).sub.2, --OR.sup.f, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or C.sub.1-C.sub.6fluoroalkoxy; R.sup.f
is -L.sup.1-R.sup.g; L.sup.1 is absent or C.sub.1-C.sub.6alkylene;
R.sup.9 is hydrogen, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted phenyl, or
--CO.sub.2R.sup.9; R.sup.8 is hydrogen, --F, or --Cl; and R.sup.11
and R.sup.12 are each independently hydrogen, --F, --Cl, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3, or
--OCHF.sub.2.
10. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound has the structure of
Formula (VIb-1), or a pharmaceutically acceptable salt, or solvate
thereof: ##STR00799## wherein: R.sup.c is hydrogen, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3,
--CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2; R.sup.6 is C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6fluoroalkyl; R.sup.7 is hydrogen or --CH.sub.3; and
R.sup.11 and R.sup.12 are each independently --F or --Cl.
11. The compound of claim 10, or a pharmaceutically acceptable
salt, or solvate thereof, wherein: R.sup.6 is --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3),
--C(CH.sub.3)(CHCH.sub.3).sub.2, --C(CH.sub.3).sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH(CF.sub.3)(CH.sub.3), --CH(CF.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CF.sub.2CH.sub.3, or
--CH(CH.sub.3)(CH.sub.2CF.sub.3).
12. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound has the structure of
Formula (VIb-1), or a pharmaceutically acceptable salt, or solvate
thereof: ##STR00800## wherein: R.sup.c is hydrogen, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3,
--CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2; L.sup.2 is absent, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted azetidine, or substituted or unsubstituted
oxetanyl; R.sup.6b is hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CHF.sub.2,
--CH.sub.2F, --CF.sub.3, cyclopropyl, or cyclobutyl; R.sup.7 is
hydrogen or --CH.sub.3; and R.sup.11 and R.sup.12 are each
independently --F or --Cl.
13. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound is: 1-8:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)-N-(1-methylcyclobutyl)p-
yridine-3-carboxamide; 1-19:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-ethylcyclobutyl)-5-(3-fluor-
o-5-methylphenyl)pyridine-3-carboxamide; 1-22:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(3,3-di-
methylcyclobutyl)pyridine-3-carboxamide; 1-23:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopropyl-5-(3,5-difluorophe-
nyl)pyridine-3-carboxamide; 1-24:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclopropylethyl)-5-(3-fluo-
ro-5-methylphenyl)pyridine-3-carboxamide; 1-25:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-5-(3-flu-
oro-5-methylphenyl)pyridine-3-carboxamide; 1-26:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclopropylmethyl)-5-(3-fluor-
o-5-methylphenyl)pyridine-3-carboxamide; 1-28:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,2,2--
trifluoroethyl)pyridine-3-carboxamide; 1-29:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-tert-butyl-5-(3,5-difluorophen-
yl)pyridine-3-carboxamide; 1-30:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide; 1-31:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(pentan-
-3-yl)pyridine-3-carboxamide; 1-32:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1-met-
hylcyclopropyl)methyl]pyridine-3-carboxamide; 1-33:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclobutylmethyl)-5-(3,5-difl-
uorophenyl)pyridine-3-carboxamide; 1-34:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(1-meth-
ylcyclobutyl)pyridine-3-carboxamide; 1-35:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(3-
,3-difluorocyclobutyl)pyridine-3-carboxamide; 1-38:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(3-meth-
ylbutan-2-yl)pyridine-3-carboxamide; 1-39:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,4-di-
methylpentan-3-yl)pyridine-3-carboxamide; 1-40:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2-cyclopropylpropan-2-yl)-5-(-
3,5-difluorophenyl)pyridine-3-carboxamide; 1-41:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)pyridine-3-carboxamide; 1-42:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(2,2-difluorocyclopropyl)meth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-43:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2,2-d-
imethylcyclopropyl)methyl]pyridine-3-carboxamide; 1-44:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1R)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)pyridine-3-carboxamide; 1-45:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(1,1,1--
trifluoro-3-methylbutan-2-yl)pyridine-3-carboxamide; 1-46:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-meth-
ylpropyl)pyridine-3-carboxamide; 1-47:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1-flu-
orocyclobutyl)methyl]pyridine-3-carboxamide; 1-50:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(3,3-difluorocyclobutyl)methy-
l]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-51:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-5-(3,5-d-
ifluorophenyl)pyridine-3-carboxamide; 1-53:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2R)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-54:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-55:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(trans-
-3-fluorocyclobutyl]pyridine-3-carboxamide; 1-56:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclobutyl-2,2,2-trifluoroe-
thyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-57:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-meth-
ylbutyl)pyridine-3-carboxamide; 1-58:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-ethy-
lbutyl)pyridine-3-carboxamide; 1-59:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[cis-3--
fluorocyclobutyl]pyridine-3-carboxamide; 1-60:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(4,4,4--
trifluorobutan-2-yl)pyridine-3-carboxamide; 1-61:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(dicyclopro-
pylmethyl)pyridine-3-carboxamide; 1-62:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,2-di-
fluoropropyl)pyridine-3-carboxamide; 1-68:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(3,3-difluorocyclobutyl)-5-(3,5-
-difluorophenyl)pyridine-3-carboxamide; 1-69:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide; 1-70:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(dicyclopropylmethyl)-5-(3,5-di-
fluorophenyl)pyridine-3-carboxamide; 1-71:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,-
1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-72:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(pentan--
3-yl)pyridine-3-carboxamide; 1-76:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(pentan-3-yl)pyridine-3-carboxamide; 1-77:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-79:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(3,3-difluorocyclobuty-
l)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-85:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(2-methylpropyl)pyridine-3-carboxamide; 1-86:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(cyclopropylmethyl)-5--
(3,5-difluorophenyl)pyridine-3-carboxamide; 1-87:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-cyclobutyl-5-(3,5-difl-
uorophenyl)pyridine-3-carboxamide; 1-91:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(propan-2-yl)pyridine-3-carboxamide; 1-92:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; 1-96:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(-
1S)-1-cyclopropylethyl]pyridine-3-carboxamide; 1-116:
4-[(3R)-3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclo-
propylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-118:
4-[(3S)-3-amino-3-(2,2-difluoroethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-c-
yclopropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
1-120:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-[3-(difluoromethoxy)phenyl]pyridine-3-carboxamide; 1-122:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-methylpyridine-3-carboxamide; 1-123:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-fluorophenyl)-N-[(1-
S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-124:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
-fluorophenyl)-6-methylpyridine-3-carboxamide; 1-125:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-127:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide; 1-135:
4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyl-
ethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-137:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-138:
4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-
-cyano-N-[(1S)-1-cyclopropylethyl]pyridine-3-carboxamide; 1-140:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-
-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-141:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-143:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-
-(difluoromethoxy)-5-fluorophenyl]pyridine-3-carboxamide; 1-146:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)-6-methylpyridine-3-carboxamide; 1-147:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methyl--
N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-149:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-
-(difluoromethoxy)phenyl]pyridine-3-carboxamide; 1-151:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-N-[(2S)--
1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-152:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluo-
rophenyl)-6-methoxypyridine-3-carboxamide; 1-153:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-fluorophenyl)-N-[(1-
S)-1-cyclopropylethyl]-6-methoxypyridine-3-carboxamide; 1-154:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-me-
thoxy-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide; 1-164:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-
-fluoro-5-(trifluoromethyl)phenyl]-6-methoxypyridine-3-carboxamide;
1-165:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-
-(difluoromethoxy)phenyl]-6-methoxypyridine-3-carboxamide; 1-168:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-[3-(difluoromethoxy)ph-
enyl]-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-171:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorop-
henyl]-6-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-172:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl-
)-5-[3-(difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide;
1-173:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide;
1-176:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-(3,5-difluorophenyl)-6-ethoxypyridine-3-carboxamide; 1-177:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-(2-
,2-difluoroethoxy)-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
1-178:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-(c-
yclopropylmethoxy)-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
1-179:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(2-methoxyethoxy)pyridine-3-carboxamide;
1-180:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-[3-(difluoromethoxy)-5-
-fluorophenyl]-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-188:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5--
fluorophenyl]-6-methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carb-
oxamide; 1-189:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide;
1-190:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide;
1-191:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropoxy-N-[(1S)-1-cyclopr-
opylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-192:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-194:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5--
(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-195:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide;
1-197:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(-
i S)-1-cyclopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide;
1-198:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1-cyc-
lopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide; 1-199:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluo-
rophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; 1-209:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,4-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide;
1-212:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-(trifluoromethyl-
)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-215:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-dichlo-
rophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; 1-218:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(cyclopropylmethyl)-5--
(3,5-difluorophenyl)-N-methylpyridine-3-carboxamide; 1-219:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)-N-methylpyridine-3-carboxamide; 1-222:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2R)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-225:
4-(3-aminopyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N-(1,1,1-triflu-
oropropan-2-yl)pyridine-3-carboxamide; 1-226:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(1,1,1-t-
rifluoropropan-2-yl)pyridine-3-carboxamide; 1-227:
4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2R)-1,-
1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-228:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-me-
thoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-229:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methoxypyridine-3-carboxamide; 1-230:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methyl-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-231:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6--
methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-232:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-[3-(difluoromethoxy)phenyl]-6-methyl-N--
[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-247:
2-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropylethyl]-
carbamoyl}-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)acetic acid;
1-259:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,4-difluorophenyl)-6-methoxy-
-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-260:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-3-fluorophenyl)-6-me-
thoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-261:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-6-me-
thoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-262:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,4-difluorophenyl)-6-methoxypyridine-3-carboxamide; 1-263:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-3-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methoxypyridine-3-carboxamide; 1-264:
3-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropylethyl]-
carbamoyl}-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)propanoic acid;
1-265:
4-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropylethyl]-
carbamoyl}-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)butanoic acid;
1-266:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-[(oxetan-3-yl)methoxy]pyridine-3-carboxamide;
1-267:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-(benzyloxy)-N-[(1S)-1-cyclopro-
pylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; 1-269:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-(3-
,3-difluorocyclobutyl)-6-methylpyridine-3-carboxamide; 1-272:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1-cyc-
lopropylethyl]-6-methylpyridine-3-carboxamide; 1-275:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-6-me-
thyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-276:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methyl-N-[(-
2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-279:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,4-difluorophenyl)-6-methyl--
N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-280:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; 1-282:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1-cyc-
lopropylethyl]-6-methoxypyridine-3-carboxamide; 1-283:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methoxy-N-[-
(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; 1-285:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(3,3-difluo-
rocyclobutyl)-6-methoxypyridine-3-carboxamide; 1-287:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-6-me-
thyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
1-288:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,4-difluorophenyl)-6-methylpyridine-3-carboxamide; 1-289:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; or 1-290:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-5-(3,5-difluorophe-
nyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; or
a pharmaceutically acceptable salt, or solvate thereof.
14. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound is: 1-30:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide, or a pharmaceutically
acceptable salt, or solvate thereof.
15. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound is: 1-54:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
16. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound is: 1-71:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,-
1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
17. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound is: 1-77:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
18. The compound of claim 1, or a pharmaceutically acceptable salt,
or solvate thereof, wherein the compound is: 1-192:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
19. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt, or solvate thereof, and at
least one pharmaceutically acceptable excipient.
20. The pharmaceutical composition of claim 19, wherein the
compound, or a pharmaceutically acceptable salt, or solvate
thereof, is: 1-30:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide, or a pharmaceutically
acceptable salt, or solvate thereof.
21. The pharmaceutical composition of claim 19, wherein the
compound, or a pharmaceutically acceptable salt, or solvate
thereof, is: 1-54:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
22. The pharmaceutical composition of claim 19, wherein the
compound, or a pharmaceutically acceptable salt, or solvate
thereof, is: 1-71:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,-
1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
23. The pharmaceutical composition of claim 19, wherein the
compound, or a pharmaceutically acceptable salt, or solvate
thereof, is: 1-77:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
24. The pharmaceutical composition of claim 19, wherein the
compound, or a pharmaceutically acceptable salt, or solvate
thereof, is: 1-192:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
25. A method of treating hyperinsulinism in a mammal comprising
administering a compound of claim 1, or a pharmaceutically
acceptable salt, or solvate thereof, to the mammal in need
thereof.
26. The method of claim 25, wherein the compound, or a
pharmaceutically acceptable salt, or solvate thereof, is: 1-30:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide, or a pharmaceutically
acceptable salt, or solvate thereof.
27. The method of claim 25, wherein the compound, or a
pharmaceutically acceptable salt, or solvate thereof, is: 1-54:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
28. The method of claim 25, wherein the compound, or a
pharmaceutically acceptable salt, or solvate thereof, is: 1-71:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,-
1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
29. The method of claim 25, wherein the compound, or a
pharmaceutically acceptable salt, or solvate thereof, is: 1-77:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
30. The method of claim 25, wherein the compound, or a
pharmaceutically acceptable salt, or solvate thereof, is: 1-192:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide, or a
pharmaceutically acceptable salt, or solvate thereof.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/989,193, filed on Aug. 10, 2020, which
claims the benefit of U.S. Provisional Patent Application No.
62/886,764, filed on Aug. 14, 2019, each of which is incorporated
herein by reference in its entirety.
FIELD OF THE INVENTION
[0003] Described herein are compounds that are somatostatin
modulators, methods of making such compounds, pharmaceutical
compositions and medicaments comprising such compounds, and methods
of using such compounds in the treatment of conditions, diseases,
or disorders that would benefit from modulating somatostatin
activity.
BACKGROUND OF THE INVENTION
[0004] Somatostatin is a peptide hormone that regulates the
endocrine system and affects neurotransmission and cell
proliferation via interaction with G-protein-coupled somatostatin
receptors and inhibition of the release of numerous secondary
hormones. Six subtype somatostatin receptor proteins have been
identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are
encoded by five different somatostatin receptor genes. Modulation
of a particular subtype somatostatin receptor or combination
thereof, is attractive for the treatment of conditions, diseases,
or disorders that would benefit from modulating somatostatin
activity.
SUMMARY OF THE INVENTION
[0005] Compounds described herein are somatostatin modulator
compounds. In some embodiments, compounds described herein modulate
one or more of the subtype somatostatin receptor proteins. In some
embodiments, compounds described herein modulate one subtype
somatostatin receptor. In some embodiments, compounds described
herein modulate SST5 receptor. Somatostatin peptide analogs, such
as octreotide, lanreotide and pasireotide, formulated as depot
injections, are routinely used to normalize hormone levels for the
treatment of Growth Hormone (GH) secreting adenomas, pancreatic
neuroendocrine tumors, and carcinoid tumors. Octreotide is also
reported to be used as a treatment for congenital hyperinsulinism
(CHI, sometimes referred to as congenital hyperinsulinism of
infancy, or persistent hyperinsulinemic hypoglycemia of infancy), a
condition that causes individuals to have abnormally high levels of
insulin, which in turn to lead to frequent episodes of low blood
sugar (hypoglycemia). The depot preparations of these peptide drugs
are extremely expensive and require frequent doctor's office visits
for painful injections that can lead to injection site reactions.
Compounds described herein are molecules that are structurally
different from peptide analogs. The compounds described herein are
somatostatin modulators that selectively activate somatostatin
receptor subtype 5 (SSTR5) that in turn inhibits insulin secretion
and promotes glucose release and also inhibits GH secretion.
[0006] In one aspect, described herein is a compound of Formula
(I), or a pharmaceutically acceptable salt, or pharmaceutically
acceptable solvate thereof:
##STR00001## [0007] wherein: [0008] Ring A is carbocycle or
heterocycle; [0009] X is N or C--R.sup.a; Y is N or C--R.sup.b; Z
is N or C--R.sup.c; [0010] R.sup.a, R.sup.b, and R.sup.c are each
independently hydrogen, halogen, --CN, --N(R.sup.9).sub.2,
--OR.sup.f, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkoxy, substituted or
unsubstituted C.sub.1-C.sub.6heteroalkyl, substituted or
unsubstituted monocyclic carbocycle, or substituted or
unsubstituted monocyclic heterocycle; [0011] R.sup.f is
-L.sup.1-R.sup.g; [0012] L.sup.1 is absent,
C.sub.1-C.sub.6alkylene, C.sub.1-C.sub.6fluoroalkylene, or
C.sub.1-C.sub.6heteroalkylene; [0013] R.sup.g is hydrogen,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted phenyl, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, or substituted or unsubstituted
monocyclic heterocycle; [0014] R.sup.1 and R.sup.2 are
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, or substituted or unsubstituted
C.sub.3-C.sub.5heterocycloalkyl; [0015] R.sup.3 is hydrogen, --CN,
--CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; [0016] R.sup.4 and R.sup.5 are each
independently hydrogen, halogen, --OR.sup.9, --N(R.sup.9).sub.2,
--CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; [0017] R.sup.6 is substituted or
unsubstituted C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl, or -L.sup.2-R.sup.6a. [0018] L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.8alkylene, or
--CHR.sup.6b--; [0019] R.sup.6a is substituted or unsubstituted
C.sub.3-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted
C.sub.2-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; [0020] R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl; [0021] R.sup.7 is
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.10cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10aryl, substituted or
unsubstituted C.sub.2-C.sub.10heterocycloalkyl, or substituted or
unsubstituted C.sub.1-C.sub.9 heteroaryl; [0022] or R.sup.6 and
R.sup.7 are taken together with the nitrogen to which they are
attached to form a substituted or unsubstituted N-containing
heterocycle; [0023] each R.sup.8, R.sup.11, and R.sup.12 is
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted monocyclic
carbocycle, substituted or unsubstituted monocyclic heterocycle,
--CN, --OR.sup.9, --C(.dbd.O)R.sup.10, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2,
--NR.sup.9C(.dbd.O)R.sup.10, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9C(.dbd.O)N(R.sup.9).sub.2, --C(R.sup.9).dbd.N--OR.sup.9,
--SR.sup.9, --S(.dbd.O)R.sup.9, --SO.sub.2R.sup.9, or
--SO.sub.2N(R.sup.9).sub.2; [0024] or R.sup.11 is taken together
with an adjacent R.sup.8 and the atoms connecting the R.sup.11 and
the adjacent R.sup.8 to form a fused substituted or unsubstituted
carbocycle, or a fused substituted or unsubstituted heterocycle;
[0025] each R.sup.9 is independently hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, substituted or unsubstituted monocyclic
3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl, and substituted or unsubstituted monocyclic heteroaryl;
[0026] or two R.sup.9 on the same N atom are taken together with
the N atom to which they are attached to form a substituted or
unsubstituted N-containing heterocycle; [0027] each R.sup.10 is
independently substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.7cycloalkyl, substituted
or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl,
substituted or unsubstituted phenyl, and substituted or
unsubstituted monocyclic heteroaryl; and [0028] n is 0-3.
[0029] Any combination of the groups described above for the
various variables is contemplated herein. Throughout the
specification, groups and substituents thereof are chosen by one
skilled in the field to provide stable moieties and compounds.
[0030] Also described herein is a pharmaceutical composition
comprising a compound described herein, or a pharmaceutically
acceptable salt, or solvate thereof, and at least one
pharmaceutically acceptable excipient. In some embodiments, the
pharmaceutical composition is formulated for administration to a
mammal by intravenous administration, subcutaneous administration,
oral administration, inhalation, nasal administration, dermal
administration, or ophthalmic administration. In some embodiments,
the pharmaceutical composition is formulated for administration to
a mammal by oral administration. In some embodiments, the
pharmaceutical composition is in the form of a tablet, a pill, a
capsule, a liquid, a suspension, a gel, a dispersion, a solution,
an emulsion, an ointment, or a lotion. In some embodiments, the
pharmaceutical composition is in the form of a tablet, a pill, or a
capsule.
[0031] Also described herein is a method of treating a disease or
condition in a mammal that would benefit from the modulation of
somatostatin receptor activity comprising administering a compound
described herein, or pharmaceutically acceptable salt, or solvate
thereof, to the mammal in need thereof. In some embodiments, the
compound described herein, or pharmaceutically acceptable salt, or
solvate thereof, is orally administered. In some embodiments, the
disease or condition is persistent or recurring hyperinsulinemia,
hypoglycemia, acromegaly, a neuroendocrine tumor, an insulinoma,
Cushing's disease, an ophthalmic disease or condition, cancer,
pain, a neurodegenerative disease or condition, an inflammatory
disease or condition, a psychiatric disease or condition, or
combinations thereof. In some embodiments, the disease or condition
is hyperinsulinemic hypoglycemia. In some embodiments, the disease
or condition is hypoglycemia due to endogenous insulin, drug
induced hyperinsulinism, or hypoglycemia due to exogenous
insulin.
[0032] In any of the aforementioned aspects are further embodiments
in which the effective amount of the compound of Formula (I), or a
pharmaceutically acceptable salt, or solvate thereof, is: (a)
systemically administered to the mammal; and/or (b) administered
orally to the mammal; and/or (c) intravenously administered to the
mammal; and/or (d) administered by inhalation; and/or (e)
administered by nasal administration; or and/or (f) administered by
injection to the mammal; and/or (g) administered topically to the
mammal; and/or (h) administered by ophthalmic administration;
and/or (i) administered rectally to the mammal; and/or j)
administered non-systemically or locally to the mammal.
[0033] In any of the aforementioned aspects are further embodiments
comprising single administrations of the effective amount of the
compound, including further embodiments in which the compound is
administered once a day to the mammal or the compound is
administered to the mammal multiple times over the span of one day.
In some embodiments, the compound is administered on a continuous
dosing schedule. In some embodiments, the compound is administered
on a continuous daily dosing schedule.
[0034] In any of the embodiments disclosed herein, the mammal is a
human.
[0035] In some embodiments, compounds provided herein are orally
administered to a human.
[0036] Articles of manufacture, which include packaging material, a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, within the packaging material, and a label that indicates
that the compound or composition, or pharmaceutically acceptable
salt, tautomers, pharmaceutically acceptable N-oxide,
pharmaceutically active metabolite, pharmaceutically acceptable
prodrug, or pharmaceutically acceptable solvate thereof, is used
for modulating one or more subtype somatostatin receptor proteins,
or for the treatment, prevention or amelioration of one or more
symptoms of a disease or condition that would benefit from
modulating one or more subtype somatostatin receptor proteins, are
provided.
[0037] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0038] Somatostatin (SST), also known as somatotropin release
inhibiting factor (SRIF) was initially isolated as a 14-amino acid
peptide from ovine hypothalami (Brazeau et al., Science 179, 77-79,
1973). An N-terminal extended 28-amino acid peptide with similar
biological activity to 14-amino acid somatostatin was subsequently
isolated (Pradayrol et, al., FEBS Letters, 109, 55-58, 1980; Esch
et al., Proc. Natl. Acad. Sci. USA, 77, 6827-6831, 1980). SST is a
regulatory peptide produced by several cell types in response to
other neuropeptides, neurotransmitters, hormones, cytokines, and
growth factors. SST acts through both endocrine and paracrine
pathways to affect its target cells. Many of these effects are
related to the inhibition of secretion of other hormones, most
notably growth hormone (GH). They are produced by a wide variety of
cell types in the central nervous system (CNS) and gut and have
multiple functions including modulation of secretion of growth
hormone (GH), insulin, glucagon, as well as many other hormones
that are anti-proliferative.
[0039] These pleotropic actions of somatostatins are mediated by
six somatostatin receptor proteins (SSTR1, SSTR2a, SSTR2b, SSTR3,
SSTR4, SSTR5). The six somatostatin receptor proteins are encoded
by five different somatostatin receptor genes (Reisine and Bell,
Endocr Rev. 16, 427-442, 1995; Patel and Srikant, Trends Endocrinol
Metab 8, 398-405, 1997). All the receptors are members of the
class-A subgroup of the GPCR superfamily.
[0040] It is possible to selectively modulate any one of the
somatostatin receptor subtypes, or combination thereof. In some
embodiments, selectively modulating any one of the somatostatin
receptor subtypes relative to the other somatostatin receptor
subtypes reduces unwanted side effects in a variety of clinical
applications.
[0041] In one aspect, compounds described herein are modulators of
SSTR5. In some embodiments, compounds described herein selectively
modulate the activity of SSTR5 relative to the other somatostatin
receptors. In some embodiments, compounds described herein
selectively modulate the activity of SSTR5 relative to SSTR2.
[0042] In some embodiments, compounds described here are amenable
to oral administration to a mammal in need of treatment with a
somatostatin modulator.
[0043] In some embodiments, somatostatin receptor modulators
described herein have utility over a wide range of therapeutic
applications. In some embodiments, somatostatin receptor modulators
described herein are used in the treatment of a variety of diseases
or conditions such as, but not limited to, acromegaly,
neuroendocrine tumors and hyperinsulinism. In some embodiments,
somatostatin receptor modulators described herein are used in the
treatment of hyperinsulinism in a mammal.
[0044] In some embodiments, somatostatin receptor modulators
described herein inhibit the secretion of various hormones and
trophic factors in mammals. In some embodiments, the compounds are
used to suppress certain endocrine secretions, such as, but not
limited to GH, IGF-1 and insulin. The suppression of certain
endocrine secretions is useful in the treatment of disorders such
as acromegaly, hyperinsulinism, endocrine tumors such as
carcinoids, VIPomas, insulinomas and glucagonomas. In some
embodiments, somatostatin receptor modulators described herein are
used to suppress exocrine secretions in the pancreas, stomach and
intestines, for the treatment of disorders such as pancreatitis,
fistulas, bleeding ulcers and diarrhea associated with such
diseases as AIDS or cholera. Disorders involving autocrine or
paracrine secretions of trophic factors such as IGF-1 (as well as
some endocrine factors) which may be treated by administration of
the compounds described herein include cancers of the breast,
prostate, and lung (both small cell and non-small cell
epidermoids), as well as hepatomas, neuroblastomas, insulinomas,
colon and pancreatic adenocarcinomas (ductal type),
chondrosarcomas, and melanomas, and atherosclerosis associated with
vascular grafts and restenosis following angioplasty.
[0045] In some embodiments, somatostatin receptor modulators
described herein are used to suppress the mediators of neurogenic
inflammation (e.g. substance P or the tachykinins), and may be used
in the treatment of rheumatoid arthritis; psoriasis; topical
inflammation such as is associated with sunburn, eczema, or other
sources of itching; inflammatory bowel disease; irritable bowel
syndrome; allergies, including asthma and other respiratory
diseases In some other embodiments, the somatostatin receptor
modulators described herein function as neuromodulators in the
central nervous system and are useful in the treatment of
Alzheimer's disease and other forms of dementia, pain, and
headaches. In some embodiments, somatostatin receptor modulators
described herein provide cytoprotection in disorders involving the
splanchnic blood flow, including cirrhosis and oesophagal
varices.
[0046] In some embodiments, somatostatin receptor modulators
described herein are used to treat hyperinsulinemia in a mammal.
Hyperinsulinemia leads to several conditions, such as but not
limited to, hypoglycemia or low blood sugar, diabetes or
uncontrolled blood sugar that fluctuates between a low and high
level, increased risk of Polycystic Ovarian Syndrome (PCOS),
increased production of very low-density lipoproteins (VLDLs)
(referred to as hypertriglyceridemia), increased risk of
cardiovascular or heart disease, coronary artery disease (the high
insulin level damages the endothelial cells that line the coronary
arteries), hypertension or high blood pressure, underactive thyroid
gland, weight gain and lethargy.
[0047] Hyperinsulinism refers to an above normal level of insulin
in the blood of a person or animal. Normal insulin secretion and
blood levels are closely related to the level of glucose in the
blood, so that a given level of insulin can be normal for one blood
glucose level but low or high for another. Hyperinsulinism can be
associated with several types of medical problems, which can be
roughly divided into two broad and largely non-overlapping
categories: those tending toward reduced sensitivity to insulin and
high blood glucose levels (hyperglycemia), and those tending toward
excessive insulin secretion and low glucose levels
(hypoglycemia).
[0048] Hyperinsulinemic hypoglycemia (HH) is one of the most
frequent causes of persistent hypoglycemia in infants. It is a
heterogeneous condition caused by increased insulin secretion from
pancreatic .beta.-cells. HH can result in apneas, seizures,
developmental delays, learning disabilities, epilepsy, and even
death. The most severe form of HH is inherited and referred to as
congenital hyperinsulinism (CHI). As with many rare diseases, there
are no current drugs specifically tailored for patients with CHI,
though some drugs have been adapted for use, including but not
limited to diazoxide and octreotide.
[0049] The pancreas is a principal site of somatostatin action, and
there it inhibits the synthesis and secretion of the two major
hormones that control glucose homeostasis: glucagon and insulin.
Different somatostatin receptor subtypes control these vital
processes: sst2 receptors suppress glucagon, while both sst2 and
sst5 are responsible for the suppression of insulin.
[0050] Hypoglycemia due to excessive endogenous insulin can be
congenital or acquired, apparent in the newborn period, or many
years later. The hypoglycemia can be severe and life-threatening or
a minor, occasional nuisance. By far the most common type of severe
but transient hyperinsulinemic hypoglycemia occurs accidentally in
persons with type 1 diabetes who take insulin.
[0051] Hypoglycemia due to endogenous insulin includes, but is not
limited to, congenital hyperinsulinism, transient neonatal
hyperinsulinism, focal hyperinsulinism (KATP channel disorders),
diffuse hyperinsulinism, acquired forms of hyperinsulinism,
insulinomas (insulin-secreting tumors), adult nesidioblastosis,
autoimmune insulin syndrome, noninsulinoma pancreatogenous
hypoglycemia, reactive hypoglycemia, a side effect of gastric
bypass surgery or gastric dumping syndrome.
[0052] Drug induced hyperinsulinism results from exposure to
certain drugs such as, but not limited to, sulfonylureas, aspirin,
pentamidine, quinine, disopyramide, Bordetella pertussis vaccine or
infection, D-chiro-inositol and myo-inositol.
[0053] Hypoglycemia due to exogenous (injected) insulin includes
but is not limited to, insulin self-injected for treatment of
diabetes (i.e., diabetic hypoglycemia), insulin self-injected
surreptitiously (e.g., Munchausen syndrome), insulin self-injected
in a suicide attempt or successful suicide, insulin potentiation
therapy, and insulin-induced coma for depression treatment.
Compounds
[0054] Compounds of Formula (I), including pharmaceutically
acceptable salts, prodrugs, active metabolites, and
pharmaceutically acceptable solvates thereof, are somatostatin
receptor modulators. In some embodiments, the compounds of Formula
(I), including pharmaceutically acceptable salts, prodrugs, active
metabolites, and pharmaceutically acceptable solvates thereof, are
SST5 receptor modulators.
[0055] In some embodiments, compounds described herein are SST5
selective modulators. In some embodiments, compounds described
herein are at least 10 times, at least 15 times, at least 20 times,
at least 30 times, at least 40 times, at least 50 times, at least
100 times, at least 200 times, at least 300 times, at least 400
times, or greater than 500 times more selective at modulating SST5
receptor activity than SST1, SST2, SST3, and/or SST4 receptor
activity. In some embodiments, compounds described herein are at
least 10 times, at least 15 times, at least 20 times, at least 30
times, at least 40 times, at least 50 times, at least 100 times, at
least 200 times, at least 300 times, at least 400 times, or greater
than 500 times more selective at modulating SST5 receptor activity
than SST2 receptor activity.
[0056] In one aspect, provided herein is a compound of Formula (I),
or a pharmaceutically acceptable salt, or pharmaceutically
acceptable solvate thereof:
##STR00002## [0057] wherein: [0058] Ring A is carbocycle or
heterocycle; [0059] X is N or C--R.sup.a; Y is N or C--R.sup.b; Z
is N or C--R.sup.c; [0060] R.sup.a, R.sup.b, and R.sup.c are each
independently hydrogen, halogen, --CN, --N(R.sup.9).sub.2,
--OR.sup.f, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkoxy, substituted or
unsubstituted C.sub.1-C.sub.6heteroalkyl, substituted or
unsubstituted monocyclic carbocycle, or substituted or
unsubstituted monocyclic heterocycle; [0061] R.sup.f is
-L.sup.1-R.sup.g; [0062] L.sup.1 is absent,
C.sub.1-C.sub.6alkylene, C.sub.1-C.sub.6fluoroalkylene, or
C.sub.1-C.sub.6heteroalkylene; [0063] R.sup.g is hydrogen,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted phenyl, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, or substituted or unsubstituted
monocyclic heterocycle; [0064] R.sup.1 and R.sup.2 are
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, or substituted or unsubstituted
C.sub.3-C.sub.5heterocycloalkyl; [0065] R.sup.3 is hydrogen, --CN,
--CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; [0066] R.sup.4 and R.sup.5 are each
independently hydrogen, halogen, --OR.sup.9, --N(R.sup.9).sub.2,
--CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; [0067] R.sup.6 is substituted or
unsubstituted C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl, or -L.sup.2-R.sup.6a. [0068] L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.8alkylene, or
--CHR.sup.6b--; [0069] R.sup.6a is substituted or unsubstituted
C.sub.3-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted
C.sub.2-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; [0070] R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl; [0071] R.sup.7 is
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.10 cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10 aryl, substituted or
unsubstituted C.sub.2-C.sub.10 heterocycloalkyl, or substituted or
unsubstituted C.sub.1-C.sub.9 heteroaryl; [0072] or R.sup.6 and
R.sup.7 are taken together with the nitrogen to which they are
attached to form a substituted or unsubstituted N-containing
heterocycle; [0073] each R.sup.8, R.sup.11, and R.sup.12 is
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted monocyclic
carbocycle, substituted or unsubstituted monocyclic heterocycle,
--CN, --OR.sup.9, --C(.dbd.O)R.sup.10, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2,
--NR.sup.9C(.dbd.O)R.sup.10, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9C(.dbd.O)N(R.sup.9).sub.2, --C(R.sup.9).dbd.N--OR.sup.9,
--SR.sup.9, --S(.dbd.O)R.sup.9, --SO.sub.2R.sup.9, or
--SO.sub.2N(R.sup.9).sub.2; [0074] or R.sup.11 is taken together
with an adjacent R.sup.8 and the atoms connecting the R.sup.11 and
the adjacent R.sup.8 to form a fused substituted or unsubstituted
carbocycle, or a fused substituted or unsubstituted heterocycle;
[0075] each R.sup.9 is independently hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, substituted or unsubstituted monocyclic
3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl, and substituted or unsubstituted monocyclic heteroaryl;
[0076] or two R.sup.9 on the same N atom are taken together with
the N atom to which they are attached to form a substituted or
unsubstituted N-containing heterocycle; [0077] each R.sup.10 is
independently substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.7cycloalkyl, substituted
or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl,
substituted or unsubstituted phenyl, and substituted or
unsubstituted monocyclic heteroaryl; and [0078] n is 0-3.
[0079] For any and all of the embodiments, substituents are
selected from among a subset of the listed alternatives. For
example, in some embodiments, R.sup.1 and R.sup.2 are independently
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl. In some
embodiments, R.sup.1 and R.sup.2 are independently hydrogen or
substituted or unsubstituted C.sub.1-C.sub.6alkyl. In some
embodiments, R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.1 is hydrogen and
R.sup.2 is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, or substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl. In some embodiments, R.sup.1 is hydrogen
and R.sup.2 is hydrogen or substituted or unsubstituted
C.sub.1-C.sub.6alkyl. R.sup.1 is hydrogen and R.sup.2 is hydrogen
or C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.1 and R.sup.2
are each hydrogen.
[0080] In some embodiments, R.sup.3 is hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl. In some embodiments, R.sup.3 is
hydrogen, --CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
substituted or unsubstituted C.sub.1-C.sub.4alkyl, substituted or
unsubstituted C.sub.1-C.sub.4fluoroalkyl or substituted or
unsubstituted C.sub.1-C.sub.4heteroalkyl. In some embodiments,
R.sup.3 is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.4alkyl, substituted or unsubstituted
C.sub.1-C.sub.4fluoroalkyl or substituted or unsubstituted
C.sub.1-C.sub.4heteroalkyl. In some embodiments, R.sup.3 is
hydrogen, --CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, or substituted
or unsubstituted C.sub.1-C.sub.6fluoroalkyl. In some embodiments,
R.sup.3 is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, R.sup.3 is
hydrogen, --CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, or
substituted or unsubstituted C.sub.1-C.sub.6alkyl. In some
embodiments, R.sup.3 is hydrogen or substituted or unsubstituted
C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.3 is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6fluoroalkoxy, or
C.sub.1-C.sub.6heteroalkyl. In some embodiments, R.sup.3 is
hydrogen, --CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl or
C.sub.1-C.sub.4heteroalkyl. In some embodiments, R.sup.3 is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl or
C.sub.1-C.sub.4heteroalkyl. In some embodiments, R.sup.3 is
hydrogen, --CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6fluoroalkyl. In some
embodiments, R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, R.sup.3 is
hydrogen or C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.3 is
hydrogen, --CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, or
C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.3 is hydrogen,
--CN, --CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --CH.sub.3, --CH.sub.2OH,
--CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2F, --CH.sub.2CHF.sub.2, or
--CH.sub.2CF.sub.3. In some embodiments, R.sup.3 is hydrogen, --CN,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NHCH.sub.3,
--C(.dbd.O)N(CH.sub.3).sub.2, --CH.sub.3, --CH.sub.2OH,
--CH.sub.2OCH.sub.3, or --CH.sub.2CHF.sub.2. In some embodiments,
R.sup.3 is hydrogen, --CH.sub.3, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2CH.sub.2F, --CH.sub.2CHF.sub.2, or --CH.sub.2CF.sub.3. In
some embodiments, R.sup.3 is hydrogen, --CH.sub.3, --CH.sub.2OH,
--CH.sub.2OCH.sub.3, or --CH.sub.2CHF.sub.2. In some embodiments,
R.sup.3 is hydrogen or --CH.sub.3. In some embodiments, R.sup.3 is
hydrogen. In some embodiments, R.sup.3 is --CH.sub.3.
[0081] In some embodiments, R.sup.4 and R.sup.5 are each
independently hydrogen, halogen, --OR.sup.9, --N(R.sup.9).sub.2,
--CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, or substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl. In some embodiments,
R.sup.4 and R.sup.5 are each independently hydrogen, halogen,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, or substituted
or unsubstituted C.sub.1-C.sub.6fluoroalkyl. In some embodiments,
R.sup.4 and R.sup.5 are each independently hydrogen, halogen,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6fluoroalkyl. In some
embodiments, R.sup.4 and R.sup.5 are each independently hydrogen or
halogen. In some embodiments, R.sup.4 and R.sup.5 are each
independently hydrogen or --F.
[0082] In some embodiments, R.sup.1 is hydrogen; R.sup.2 is
hydrogen or C.sub.1-C.sub.6alkyl; R.sup.3 is hydrogen,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6fluoroalkyl; and R.sup.4
and R.sup.5 are each independently hydrogen, halogen,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6fluoroalkyl. In some
embodiments, R.sup.1 and R.sup.2 are each hydrogen; R.sup.3 is
hydrogen or --CH.sub.3; and R.sup.4 and R.sup.5 are each hydrogen.
In some embodiments, R.sup.1 is hydrogen; R.sup.2 is hydrogen or
C.sub.1-C.sub.6alkyl; R.sup.3 is hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl; R.sup.4 is hydrogen, halogen,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6fluoroalkyl; and R.sup.5 is
hydrogen, halogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, R.sup.1 is
hydrogen; R.sup.2 is hydrogen; R.sup.3 is hydrogen, --CH.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CHF.sub.2, or --CH.sub.2CF.sub.3; R.sup.4 is hydrogen or
F; and R.sup.5 is hydrogen or F. In some embodiments, R.sup.1 is
hydrogen; R.sup.2 is hydrogen or C.sub.1-C.sub.6alkyl; R.sup.3 is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl or
C.sub.1-C.sub.4heteroalkyl; R.sup.4 is hydrogen, halogen,
C.sub.1-C.sub.4alkyl, or C.sub.1-C.sub.4fluoroalkyl; and R.sup.5 is
hydrogen, halogen, C.sub.1-C.sub.4alkyl, or
C.sub.1-C.sub.4fluoroalkyl.
[0083] In some embodiments, the compound has the structure of
Formula (Ia) or (Ib), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00003##
[0084] In some embodiments, the compound has the structure of
Formula (Ia), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00004##
[0085] In some embodiments, the compound has the structure of
Formula (Ib), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00005##
[0086] In some embodiments, X is C--R.sup.a; Y is N; and Z is
C--R.sup.c; or X is CH; Y is N; and Z is C--R.sup.c; or X is
C--R.sup.a; Y is N; and Z is CH; or X is N; Y is C--R.sup.b; and Z
is C--R.sup.c; or X is C--R.sup.a; Y is C--R.sup.b; and Z is N; or
X is N; Y is N; and Z is C--R.sup.c; or X is C--R.sup.a; Y is N;
and Z is N. In some embodiments, X is C--R.sup.a; Y is N; and Z is
C--R.sup.c. In some embodiments, X is CH; Y is N; and Z is
C--R.sup.c. In some embodiments, X is C--R.sup.a; Y is N; and Z is
CH. In some embodiments, X is N; Y is C--R.sup.b; and Z is
C--R.sup.c. In some embodiments, X is C--R.sup.a; Y is C--R.sup.b;
and Z is N. In some embodiments, X is N; Y is N; and Z is
C--R.sup.c. In some embodiments, X is C--R.sup.a; Y is N; and Z is
N.
[0087] In some embodiments, X is N or CH; Y is N or CH; and Z is N
or C--R.sup.c;
[0088] In some embodiments, R.sup.a, R.sup.b, and R.sup.c are each
independently hydrogen, halogen, --CN, --N(R.sup.9).sub.2,
--OR.sup.f, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkoxy, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted monocyclic carbocycle, or substituted
or unsubstituted monocyclic heterocycle. In some embodiments,
R.sup.a, R.sup.b, and R.sup.c are each independently hydrogen,
halogen, --CN, --OR.sup.f, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
monocyclic carbocycle. In some embodiments, R.sup.a, R.sup.b, and
R.sup.c are each independently hydrogen, halogen, --CN, --OR.sup.f,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, or monocyclic carbocycle. In some
embodiments, R.sup.a, R.sup.b, and R.sup.c are each independently
hydrogen, halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl. In some embodiments, R.sup.a, R.sup.b,
and R.sup.c are each independently hydrogen, halogen, --CN,
--N(R.sup.9).sub.2, --OR.sup.f, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy,
substituted or unsubstituted monocyclic C.sub.3-C.sub.6cycloalkyl,
or substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl.
[0089] In some embodiments, R.sup.a, R.sup.b, and R.sup.c are each
independently hydrogen, halogen, --CN, --N(R.sup.9).sub.2,
--OR.sup.f, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted monocyclic
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; R.sup.f is -L.sup.1-R.sup.g;
L.sup.1 is absent, or C.sub.1-C.sub.6alkylene; and R.sup.9 is
hydrogen, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl,
substituted or unsubstituted phenyl, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl. In some embodiments,
R.sup.a, R.sup.b, and R.sup.c are each independently hydrogen,
halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; R.sup.f is --Li--R.sup.g; L.sup.1 is
absent or C.sub.1-C.sub.6alkylene; and R.sup.9 is hydrogen,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted phenyl, or --CO.sub.2R.sup.9.
[0090] In some embodiments, R.sup.a, R.sup.b, and R.sup.c are each
independently hydrogen, --F, --Cl, --CN, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--C(CH.sub.3).sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCF.sub.3,
--OCH.sub.2CHF.sub.2, --OCH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2OCH.sub.3, --O-(cyclopropyl),
--O--CH.sub.2-(cyclopropyl), --O--CH.sub.2-(phenyl),
--OCH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --CONHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2,
cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,
pyrrolidinyl, piperidinyl, or morpholinyl. In some embodiments,
R.sup.a, R.sup.b, and R.sup.c are each independently hydrogen, --F,
--Cl, --CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH.sub.2CHF.sub.2, --OCH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2OCH.sub.3, --O-(cyclopropyl),
--O--CH.sub.2-(cyclopropyl), --O--CH.sub.2-(phenyl),
--OCH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3, or
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3. In some
embodiments, R.sup.a, R.sup.b, and R.sup.c are each independently
hydrogen, --CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3,
--CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2. In some embodiments, R.sup.a,
R.sup.b, and R.sup.c are each independently hydrogen, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3,
--CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2, or cyclopropyl. In some embodiments,
R.sup.a, R.sup.b, and R.sup.c are each independently hydrogen or
--CN.
[0091] In some embodiments, the compound has the structure of
Formula (II), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00006##
[0092] In some embodiments, the compound has the structure of
Formula (IIa) or (IIb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00007##
[0093] In some embodiments, the compound has the structure of
Formula (IIa), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00008##
[0094] In some embodiments, the compound has the structure of
Formula (IIb), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00009##
[0095] In some embodiments, the compound has the structure of
Formula (IX), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00010##
[0096] In some embodiments, the compound has the structure of
Formula (IIa) or (IIb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00011##
[0097] In some embodiments, the compound has the structure of
Formula (X), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00012##
[0098] In some embodiments, the compound has the structure of
Formula (Xa) or (Xb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00013##
[0099] In some embodiments, Ring A is phenyl, monocyclic heteroaryl
or bicyclic heteroaryl.
[0100] In some embodiments, Ring A is phenyl.
[0101] In some embodiments, Ring A is monocyclic heteroaryl; and n
is 0, 1, or 2. In some embodiments, Ring A is pyrrolyl, furanyl,
thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl,
isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl. In some
embodiments, Ring A is pyrazolyl, thiazolyl, isoxazolyl, pyridinyl,
or pyrimidinyl. In some embodiments, Ring A is pyridinyl.
[0102] In some embodiments, Ring A is phenyl or monocyclic
heteroaryl. In some embodiments, Ring A is phenyl; or Ring A is
pyridinyl; or Ring A is Ring A is pyrazolyl, thiazolyl, isoxazolyl,
or pyrimidinyl. In some embodiments, Ring A is phenyl or
pyridinyl.
[0103] In some embodiments, the compound has the structure of
Formula (III), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00014##
[0104] In some embodiments, the compound has the structure of
Formula (IIIa) or (IIIb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00015##
[0105] In some embodiments, the compound has the structure of
Formula (IV), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00016##
[0106] wherein:
[0107] A.sup.1 and A.sup.2 are each independently C--R.sup.8 or N;
and
[0108] A.sup.3 is C--R.sup.12 or N.
[0109] In some embodiments, the compound has the structure of
Formula (IVa) or (IVb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00017##
[0110] In some embodiments, A.sup.1 is C--R.sup.8; A.sup.2 is
C--R.sup.8, and A.sup.3 is C--R.sup.12; or A.sup.1 is N; A.sup.2 is
C--R.sup.8, and A.sup.3 is C--R.sup.12; or A.sup.1 is C--R.sup.8;
A.sup.2 is N, and A.sup.3 is C--R.sup.12; or A.sup.1 is C--R.sup.8;
A.sup.2 is C--R.sup.8, and A.sup.3 is N. In some embodiments,
A.sup.1 is C--R.sup.8; A.sup.2 is C--R.sup.8, and A.sup.3 is
C--R.sup.12. In some embodiments, A.sup.1 is N; A.sup.2 is
C--R.sup.8, and A.sup.3 is C--R.sup.12. In some embodiments,
A.sup.1 is C--R.sup.8; A.sup.2 is N, and A.sup.3 is C--R.sup.12. In
some embodiments, A.sup.1 is C--R.sup.8; A.sup.2 is C--R.sup.8, and
A.sup.3 is N.
[0111] In some embodiments, the compound has the structure of
Formula (IVa-1) or (IVb-1), or a pharmaceutically acceptable salt,
or solvate thereof:
##STR00018##
[0112] wherein:
[0113] A.sup.1 is C--R.sup.8; and A.sup.2 is C--R.sup.8; or
[0114] A.sup.1 is N; and A.sup.2 is C--R.sup.8; or
[0115] A.sup.1 is C--R.sup.8; and A.sup.2 is N.
[0116] In some embodiments, the compound has the structure of
Formula (IVa-2), (IVb-2), (IVa-3), (IVb-3), (IVa-4), (IVb-4),
(IVa-5), or (IVb-5), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00019##
[0117] In some embodiments, the compound has the structure of
Formula (V), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00020##
[0118] wherein:
[0119] A.sup.2 is C--R.sup.8 or N.
[0120] In some embodiments, the compound has the structure of
Formula (Va) or (Vb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00021##
[0121] In some embodiments, the compound has the structure of
Formula (Va-1), (Vb-1), (Va-2), or (Vb-2), or a pharmaceutically
acceptable salt, or solvate thereof:
##STR00022##
[0122] In some embodiments, each R.sup.8 is independently hydrogen,
halogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted monocyclic carbocycle, --CN,
--OR.sup.9, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
--N(R.sup.9).sub.2, --NR.sup.9C(.dbd.O)R.sup.10, --SO.sub.2R.sup.9,
or --SO.sub.2N(R.sup.9).sub.2. In some embodiments, each R.sup.8 is
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10. In some embodiments, each R.sup.8 is
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, each R.sup.8 is
independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, each R.sup.8 is
independently hydrogen or halogen. In some embodiments, each
R.sup.8 is independently hydrogen, --F, or --Cl.
[0123] In some embodiments, the compound has the structure of
Formula (Va-3) or (Vb-3), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00023##
[0124] In some embodiments, R.sup.11 and R.sup.12 are each
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted monocyclic
carbocycle, substituted or unsubstituted monocyclic heterocycle,
--CN, --OR.sup.9, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
--N(R.sup.9).sub.2, --NR.sup.9C(.dbd.O)R.sup.10,
--NR.sup.9C(.dbd.O)OR.sup.10, --NR.sup.9C(.dbd.O)N(R.sup.9).sub.2,
--C(R.sup.9).dbd.N--OR.sup.9, --SR.sup.9, --S(.dbd.O)R.sup.9,
--SO.sub.2R.sup.9, or --SO.sub.2N(R.sup.9).sub.2. In some
embodiments, R.sup.11 and R.sup.12 are each independently hydrogen,
halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, --CN,
--OR.sup.9, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
--N(R.sup.9).sub.2, or --NR.sup.9C(.dbd.O)R.sup.10, substituted or
unsubstituted monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, or substituted or unsubstituted
monocyclic C.sub.1-C.sub.5heteroaryl. In some embodiments, R.sup.11
and R.sup.12 are each independently hydrogen, halogen, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic carbocycle. In some embodiments, R.sup.11 and R.sup.12
are each independently hydrogen, halogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.8cycloalkyl. In some embodiments, R.sup.11
and R.sup.12 are each independently hydrogen, halogen, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, or substituted or
unsubstituted monocyclic cycloalkyl. In some embodiments, R.sup.11
and R.sup.12 are each independently hydrogen, halogen, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.8cycloalkyl. In some
embodiments, R.sup.11 and R.sup.12 are each independently hydrogen,
halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, --CN,
--OR.sup.9, or substituted or unsubstituted monocyclic
C.sub.3-C.sub.8cycloalkyl. In some embodiments, R.sup.11 and
R.sup.12 are each independently hydrogen, halogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9. In some embodiments,
R.sup.11 and R.sup.12 are each independently hydrogen, halogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, --CN, or
--OR.sup.9. In some embodiments, R.sup.11 and R.sup.12 are each
independently hydrogen, --F, --Cl, --CN, --CH.sub.3, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, or --OCHF.sub.2. In some embodiments,
R.sup.11 and R.sup.2 are each independently halogen. In some
embodiments, R.sup.11 and R.sup.12 are each independently --F or
--Cl. In some embodiments, R.sup.11 and R.sup.12 are each --F.
[0125] In some embodiments, R.sup.11 is taken together with an
adjacent R.sup.8 and the atoms connecting the R.sup.11 and the
adjacent R.sup.8 to form a fused substituted or unsubstituted
carbocycle, or a fused substituted or unsubstituted heterocycle. In
some embodiments, R.sup.11 is taken together with an adjacent
R.sup.8 and the atoms connecting the R.sup.11 and the adjacent
R.sup.8 to form a fused substituted or unsubstituted
C.sub.3-C.sub.8cycloalkyl, or a fused substituted or unsubstituted
C.sub.2-C.sub.5heterocycloalkyl. In some embodiments, R.sup.11 is
taken together with an adjacent R.sup.8 and the atoms connecting
the R.sup.11 and the adjacent R.sup.8 to form a fused substituted
or unsubstituted C.sub.2-C.sub.5heterocycloalkyl. In some
embodiments, R.sup.11 is taken together with an adjacent R.sup.8
and the atoms connecting the R.sup.11 and the adjacent R.sup.8 to
form a fused substituted or unsubstituted dioxolane or a fused
substituted or unsubstituted dioxane.
[0126] In some embodiments, each R.sup.8 is independently hydrogen,
halogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl, --CN,
--OR.sup.9, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
--N(R.sup.9).sub.2, or --NR.sup.9C(.dbd.O)R.sup.10; and R.sup.11
and R.sup.12 are each independently hydrogen, halogen, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted monocyclic
carbocycle, substituted or unsubstituted monocyclic heterocycle,
--CN, --OR.sup.9, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
--N(R.sup.9).sub.2, --NR.sup.9C(.dbd.O)R.sup.10,
--NR.sup.9C(.dbd.O)OR.sup.10, --NR.sup.9C(.dbd.O)N(R.sup.9).sub.2,
--C(R.sup.9).dbd.N--OR.sup.9, --SR.sup.9, --S(.dbd.O)R.sup.9,
--SO.sub.2R.sup.9, or --SO.sub.2N(R.sup.9).sub.2. In some
embodiments, each R.sup.8 is independently hydrogen, halogen,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, or substituted
or unsubstituted C.sub.1-C.sub.6fluoroalkyl; and R.sup.11 and
R.sup.12 are each independently hydrogen, halogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic carbocycle. In some embodiments, each R.sup.8 is
independently hydrogen or halogen; and R.sup.11 and R.sup.12 are
each independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, or substituted or
unsubstituted monocyclic cycloalkyl. In some embodiments, each
R.sup.8 is independently hydrogen or halogen; and R.sup.11 and
R.sup.12 are each independently hydrogen, halogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, or substituted or
unsubstituted monocyclic cycloalkyl. In some embodiments, each
R.sup.8 is independently hydrogen, --F, or --Cl; and R.sup.11 and
R.sup.12 are each independently hydrogen, --F, --Cl, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3, or
--OCHF.sub.2.
[0127] In some embodiments, the compound has the structure of
Formula (VI), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00024##
[0128] In some embodiments, R.sup.3 is hydrogen or --CH.sub.3;
R.sup.8 is hydrogen or halogen; R.sup.11 and R.sup.12 are each
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9; R.sup.c is hydrogen,
halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted monocyclic C.sub.3-C.sub.6cycloalkyl,
or substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; R.sup.f is -L.sup.1-R.sup.g;
L.sup.1 is absent or C.sub.1-C.sub.6alkylene; and R.sup.g is
hydrogen, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl,
substituted or unsubstituted phenyl, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl.
[0129] In some embodiments, the compound has the structure of
Formula (VIa) or (VIb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00025##
[0130] In some embodiments, R.sup.3 is hydrogen or --CH.sub.3;
R.sup.8 is hydrogen or halogen; R.sup.11 and R.sup.12 are each
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9; R.sup.c is hydrogen,
halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted monocyclic C.sub.3-C.sub.6cycloalkyl,
or substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; R.sup.f is -L.sup.1-R.sup.g;
L.sup.1 is absent or C.sub.1-C.sub.6alkylene; and R.sup.9 is
hydrogen, substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl,
substituted or unsubstituted phenyl, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl. In some embodiments,
R.sup.c is hydrogen, halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; R.sup.f is -L.sup.1-R.sup.g; L.sup.1 is
absent or C.sub.1-C.sub.6alkylene; and R.sup.9 is hydrogen,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted phenyl, or --CO.sub.2R.sup.9.
[0131] In some embodiments, R.sup.8 is hydrogen, --F, or --Cl;
R.sup.11 and R.sup.12 are each independently hydrogen, --F, --Cl,
--CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3, or
--OCHF.sub.2; and R.sup.c is hydrogen, --F, --Cl, --CN, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--C(CH.sub.3).sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCF.sub.3,
--OCH.sub.2CHF.sub.2, --OCH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2OCH.sub.3, --O-(cyclopropyl),
--O--CH.sub.2-(cyclopropyl), --O--CH.sub.2-(phenyl),
--OCH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --CONHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,
pyrrolidinyl, piperidinyl, or morpholinyl. In some embodiments,
R.sup.c is hydrogen, --F, --Cl, --CN, --CH.sub.3, --CF.sub.3,
--OCH.sub.3, --OCH.sub.2CH.sub.3, --OCH.sub.2CHF.sub.2,
--OCH.sub.2CF.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--O-(cyclopropyl), --O--CH.sub.2-(cyclopropyl),
--O--CH.sub.2-(phenyl), --OCH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CO.sub.2CH.sub.3, --OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3, or
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3. In some
embodiments, R.sup.10 is hydrogen, --CN, --CH.sub.3, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, --CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2,
--CONHCH.sub.3, or --C(.dbd.O)N(CH.sub.3).sub.2, or cyclopropyl. In
some embodiments, R.sup.10 is hydrogen, --CN, --CH.sub.3,
--CF.sub.3, --OCH.sub.3, --OCF.sub.3, --CO.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2.
[0132] In some embodiments, the compound has the structure of
Formula (VIa-1) or (VIb-1), or a pharmaceutically acceptable salt,
or solvate thereof:
##STR00026##
[0133] In some embodiments, R.sup.3 is hydrogen or --CH.sub.3; and
R.sup.10 is hydrogen, --CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3,
--OCF.sub.3, --CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2,
--CONHCH.sub.3, or --C(.dbd.O)N(CH.sub.3).sub.2. In some
embodiments, R.sup.11 and R.sup.12 are each independently hydrogen,
halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, --CN, or
--OR.sup.9. In some embodiments, R.sup.11 and R.sup.12 are each
independently hydrogen, --F, --Cl, --CN, --CH.sub.3, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, or --OCHF.sub.2. In some embodiments,
R.sup.11 and R.sup.12 are each independently halogen. In some
embodiments, R.sup.11 and R.sup.12 are each independently --F or
--Cl. In some embodiments, R.sup.11 and R.sup.12 are each --F.
[0134] In some embodiments, Ring A is bicyclic heteroaryl. In some
embodiments, Ring A is 9- or 10-membered bicyclic heteroaryl. In
some embodiments, Ring A is indolyl, isoindolyl, indazolyl,
benzimidazolyl, azaindolyl, benzisoxazolyl, benzoxazolyl,
benzoisoxazolyl, benzothiazolyl, benzoxadiazolyl,
benzothiadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or
quinazolinyl. In some embodiments, Ring A is benzimidazolyl,
indazolyl, or benzoxadiazolyl. In some embodiments, Ring A is
benzimidazolyl.
[0135] In some embodiments, the compound has the structure of
Formula (VII), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00027## [0136] wherein: [0137] R.sup.8 is hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl.
[0138] In some embodiments, the compound has the structure of
Formula (VIIa) or (VIIb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00028##
[0139] In some embodiments, R.sup.c is hydrogen, halogen, --CN,
--N(R.sup.9).sub.2, --OR.sup.f, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl; R is
-L.sup.1-R.sup.g; L.sup.1 is absent or C.sub.1-C.sub.6alkylene; and
R.sup.9 is hydrogen, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted phenyl, or
--CO.sub.2R.sup.9. In some embodiments, R.sup.8 is hydrogen,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3), or
--C(CH.sub.3).sub.3; and R.sup.c is hydrogen, --F, --Cl, --CN,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--C(CH.sub.3).sub.3, --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3, --OCF.sub.3,
--OCH.sub.2CHF.sub.2, --OCH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2OCH.sub.3, --O-(cyclopropyl),
--O--CH.sub.2-(cyclopropyl), --O--CH.sub.2-(phenyl),
--OCH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --CONHCH.sub.3, --C(.dbd.O)N(CH.sub.3).sub.2,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,
pyrrolidinyl, piperidinyl, or morpholinyl. In some embodiments,
R.sup.8 is hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3; and R.sup.c is
hydrogen, --F, --Cl, --CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH.sub.2CHF.sub.2, --OCH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2OCH.sub.3, --O-(cyclopropyl),
--O--CH.sub.2-(cyclopropyl), --O--CH.sub.2-(phenyl),
--OCH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3, or
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3. In some
embodiments, R.sup.c is hydrogen, --CN, --CH.sub.3, --CF.sub.3,
--OCH.sub.3, --OCF.sub.3, --CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2,
--CONHCH.sub.3, or --C(.dbd.O)N(CH.sub.3).sub.2, or cyclopropyl. In
some embodiments, R.sup.c is hydrogen, --CN, --CH.sub.3,
--CF.sub.3, --OCH.sub.3, --OCF.sub.3, --CO.sub.2CH.sub.3,
--C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2.
[0140] In some embodiments, n is 0, 1, 2, or 3. In some
embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3.
In some embodiments, n is 2 or 3. In some embodiments, n is 0. In
some embodiments, n is 1. In some embodiments, n is 2. In some
embodiments, n is 3.
[0141] In some embodiments,
##STR00029##
wherein A.sup.1 and A.sup.2 are each independently C--R.sup.8 or N;
and A.sup.3 is C--R.sup.12 or N. In some embodiments,
##STR00030##
wherein A.sup.2 is C--R.sup.8 or N. In some embodiments,
##STR00031##
In some embodiments,
##STR00032##
In some embodiments,
##STR00033##
In some embodiments,
##STR00034##
In some embodiments,
##STR00035##
In some embodiments,
##STR00036##
wherein R.sup.8 is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl.
[0142] In some embodiments, R.sup.7 is hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.3-C.sub.4 cycloalkyl, or substituted or unsubstituted
C.sub.2-C.sub.3 heterocycloalkyl. In some embodiments, R.sup.7 is
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.3-C.sub.4 cycloalkyl, or
substituted or unsubstituted 3- or 4-membered heterocycloalkyl. In
some embodiments, R.sup.7 is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, R.sup.7 is
hydrogen or C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.7 is
hydrogen or --CH.sub.3. In some embodiments, R.sup.7 is hydrogen.
In some embodiments, R.sup.7 is --CH.sub.3.
[0143] In some embodiments, R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.8alkylene, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
C.sub.3-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted
C.sub.2-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl.
[0144] In some embodiments, R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, or substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl. In some embodiments, R.sup.6 is
C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8fluoroalkyl, or substituted or
unsubstituted C.sub.1-C.sub.8heteroalkyl. In some embodiments,
R.sup.6 is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl. In some
embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or C.sub.1-C.sub.6heteroalkyl. In some
embodiments, R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.8alkyl, or substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl. In some embodiments, R.sup.6 is
substituted or unsubstituted C.sub.1-C.sub.6alkyl, or substituted
or unsubstituted C.sub.1-C.sub.6fluoroalkyl. In some embodiments,
R.sup.6 is C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6fluoroalkyl. In
some embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl. In some
embodiments, R.sup.6 is C.sub.1-C.sub.6fluoroalkyl. In some
embodiments, R.sup.6 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3),
--C(CH.sub.3)(CHCH.sub.3).sub.2, --C(CH.sub.3).sub.3, --CH.sub.2F,
--CHF.sub.2, --CF.sub.3, --CH.sub.2CF.sub.3,
--CH(CF.sub.3)(CH.sub.3), --CH(CF.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CF.sub.2CH.sub.3, or --CH(CH.sub.3)(CH.sub.2CF.sub.3). In
some embodiments, R.sup.6 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.3), --CH.sub.2CF.sub.3,
--CH(CF.sub.3)(CH.sub.3), or --CH(CF.sub.3)(CH.sub.2CH.sub.3).
[0145] In some embodiments, R.sup.6 is -L.sup.2-R.sup.6a.
[0146] In some embodiments, L.sup.2 is absent, substituted or
unsubstituted C.sub.1-C.sub.8alkylene, or --CHR.sup.6b--. In some
embodiments, L.sup.2 is absent, substituted or unsubstituted
C.sub.1-C.sub.6alkylene, or --CHR.sup.6b--. In some embodiments,
L.sup.2 is absent, C.sub.1-C.sub.6alkylene, or --CHR.sup.6b--. In
some embodiments, L.sup.2 is absent, C.sub.1-C.sub.4alkylene, or
--CHR.sup.6b--. In some embodiments, L.sup.2 is absent,
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
or --CHR.sup.6b--. In some embodiments, L.sup.2 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CHR.sup.6b--. In some embodiments, L.sup.2 is --CH.sub.2-- or
--CHR.sup.6b--. In some embodiments, L.sup.2 is --CH.sub.2--,
--CH(CH.sub.3)-- or --CH(CF.sub.3)--.
[0147] In some embodiments, R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl. In some embodiments,
R.sup.6b is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or substituted or unsubstituted
C.sub.3-C.sub.4cycloalkyl. In some embodiments, R.sup.6b is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
C.sub.3-C.sub.4cycloalkyl. In some embodiments, R.sup.6b is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or
C.sub.3-C.sub.4cycloalkyl. In some embodiments, R.sup.6b is
hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CHF.sub.2,
--CH.sub.2F, --CF.sub.3, cyclopropyl, or cyclobutyl. In some
embodiments, R.sup.6b is hydrogen, --CH.sub.3, --CHF.sub.2,
--CF.sub.3, cyclopropyl, or cyclobutyl. In some embodiments,
R.sup.6b is hydrogen, --CH.sub.3, --CF.sub.3, or cyclopropyl. In
some embodiments, R.sup.6b is hydrogen, --CH.sub.3, or
--CF.sub.3.
[0148] In some embodiments, R.sup.6a is substituted or
unsubstituted monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or
unsubstituted polycyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted indanyl,
substituted or unsubstituted tetrahydronaphthyl, substituted or
unsubstituted naphthyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, substituted or unsubstituted
polycyclic C.sub.5-C.sub.10heterocycloalkyl, substituted or
unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl or substituted
or unsubstituted bicyclic C.sub.6-C.sub.9heteroaryl. In some
embodiments, R.sup.6a is substituted or unsubstituted monocyclic
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted bridged
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted
spirocyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted adamantyl, substituted or unsubstituted phenyl,
substituted or unsubstituted indanyl, substituted or unsubstituted
tetrahydronaphthyl, or substituted or unsubstituted naphthyl. In
some embodiments, R.sup.6a is substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl, substituted or
unsubstituted bridged C.sub.5-C.sub.10heterocycloalkyl, substituted
or unsubstituted spirocyclic C.sub.5-C.sub.10heterocycloalkyl,
substituted or unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl
or substituted or unsubstituted bicyclic
C.sub.6-C.sub.9heteroaryl.
[0149] In some embodiments, R.sup.6a is substituted or
unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl, substituted or
unsubstituted monocyclic or bicyclic C.sub.5-C.sub.10cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10aryl, substituted or
unsubstituted monocyclic C.sub.2-C.sub.3heterocycloalkyl,
substituted or unsubstituted monocyclic or bicyclic
C.sub.4-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl. In some embodiments, R.sup.6a is
substituted or unsubstituted monocyclic 3- or 4-membered monocyclic
cycloalkyl, 3- or 4-membered monocyclic heterocycloalkyl,
substituted or unsubstituted monocyclic or bicyclic
C.sub.5-C.sub.10cycloalkyl, or substituted or unsubstituted 5- to
10-membered heteroaryl.
[0150] In some embodiments, R.sup.6a is substituted or
unsubstituted C.sub.3-C.sub.4cycloalkyl, or substituted or
unsubstituted 3- or 4-membered C.sub.2-C.sub.3heterocycloalkyl. In
some embodiments, R.sup.6a is substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted azetidinyl, or substituted or unsubstituted
oxetanyl. In some embodiments, R.sup.6a is substituted or
unsubstituted C.sub.3-C.sub.4cycloalkyl. In some embodiments,
R.sup.6a is substituted or unsubstituted cyclopropyl or substituted
or unsubstituted cyclobutyl. In some embodiments, R.sup.6a is
substituted or unsubstituted cyclopropyl. In some embodiments,
R.sup.6a is substituted or unsubstituted cyclobutyl.
[0151] In some embodiments, L.sup.2 is absent, substituted or
unsubstituted C.sub.1-C.sub.8alkylene, or --CHR.sup.6b--; R.sup.6a
is substituted or unsubstituted C.sub.3-C.sub.10cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10aryl, substituted or
unsubstituted C.sub.2-C.sub.10heterocycloalkyl, or substituted or
unsubstituted C.sub.1-C.sub.9heteroaryl; and R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl. In some embodiments,
L.sup.2 is absent, C.sub.1-C.sub.6alkylene, or --CHR.sup.6b--;
R.sup.6a is substituted or unsubstituted monocyclic
C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted polycyclic
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted phenyl,
substituted or unsubstituted indanyl, substituted or unsubstituted
tetrahydronaphthyl, substituted or unsubstituted naphthyl,
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, substituted or unsubstituted
polycyclic C.sub.5-C.sub.10heterocycloalkyl, substituted or
unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl or substituted
or unsubstituted bicyclic C.sub.6-C.sub.9heteroaryl; and R.sup.6b
is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl.
[0152] In some embodiments, L.sup.2 is absent,
C.sub.1-C.sub.4alkylene, or --CHR.sup.6b--; and R.sup.6b is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl. In some
embodiments, R.sup.6a is substituted or unsubstituted monocyclic
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted bridged
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted
spirocyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted adamantyl, substituted or unsubstituted phenyl,
substituted or unsubstituted indanyl, substituted or unsubstituted
tetrahydronaphthyl, or substituted or unsubstituted naphthyl. In
some embodiments, R.sup.6a is substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl, substituted or
unsubstituted bridged C.sub.5-C.sub.10heterocycloalkyl, substituted
or unsubstituted spirocyclic C.sub.5-C.sub.10heterocycloalkyl,
substituted or unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl
or substituted or unsubstituted bicyclic
C.sub.6-C.sub.9heteroaryl.
[0153] In some embodiments, R.sup.6a is substituted or
unsubstituted C.sub.3-C.sub.4cycloalkyl, or substituted or
unsubstituted 3- or 4-membered C.sub.2-C.sub.3heterocycloalkyl; and
R.sup.6b is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or substituted or unsubstituted
C.sub.3-C.sub.4cycloalkyl. In some embodiments, L.sup.2 is absent,
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
or --CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted azetidinyl, or substituted or unsubstituted
oxetanyl; and R.sup.6b is hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CHF.sub.2,
--CH.sub.2F, --CF.sub.3, cyclopropyl, or cyclobutyl.
[0154] In some embodiments, R.sup.6 and R.sup.7 are taken together
with the nitrogen to which they are attached to form a substituted
or unsubstituted N-containing heterocycle. In some embodiments,
R.sup.6 and R.sup.7 are taken together with the nitrogen to which
they are attached to form a substituted or unsubstituted
N-containing heterocycle that is monocyclic, bicyclic, or
polycyclic. In some embodiments, R.sup.6 and R.sup.7 are taken
together with the nitrogen to which they are attached to form a
substituted or unsubstituted N-containing heterocycloalkyl. In some
embodiments, R.sup.6 and R.sup.7 are taken together with the
nitrogen to which they are attached to form a substituted or
unsubstituted monocyclic N-containing heterocycloalkyl or a
substituted or unsubstituted polycyclic N-containing
heterocycloalkyl. In some embodiments, R.sup.6 and R.sup.7 are
taken together with the nitrogen to which they are attached to form
a substituted or unsubstituted monocyclic N-containing
heterocycloalkyl containing 1-2 N atoms, 0-2 O atoms and 0-1 S. In
some embodiments, R.sup.6 and R.sup.7 are taken together with the
nitrogen to which they are attached to form a substituted or
unsubstituted bicyclic N-containing
C.sub.5-C.sub.10heterocycloalkyl, wherein bicyclic N-containing
C.sub.5-C.sub.10heterocycloalkyl is a fused bicyclic
C.sub.5-C.sub.10heterocycloalkyl, bridged bicyclic
C.sub.5-C.sub.10heterocycloalkyl, or spiro bicyclic
C.sub.5-C.sub.10heterocycloalkyl.
[0155] In some embodiments, [0156] R.sup.7 is hydrogen, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, or substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl; and [0157] R.sup.6 is
substituted or unsubstituted C.sub.1-C.sub.8alkyl, substituted or
unsubstituted C.sub.1-C.sub.8fluoroalkyl, substituted or
unsubstituted C.sub.1-C.sub.8heteroalkyl, or -L.sup.2-R.sup.6a.
[0158] L.sup.2 is absent, substituted or unsubstituted
C.sub.1-C.sub.8alkylene, or --CHR.sup.6b--; [0159] R.sup.6a is
substituted or unsubstituted C.sub.3-C.sub.10cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10aryl, substituted or
unsubstituted C.sub.2-C.sub.10heterocycloalkyl, or substituted or
unsubstituted C.sub.1-C.sub.9heteroaryl; [0160] R.sup.6b is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl; [0161] or
R.sup.6 and R.sup.7 are taken together with the nitrogen to which
they are attached to form a substituted or unsubstituted
N-containing heterocycloalkyl.
[0162] In some embodiments, [0163] X is N or CH; [0164] Y is N or
CH; [0165] Z is N or C--R.sup.1; [0166] R.sup.c is hydrogen,
halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; [0167] R.sup.f is -L.sup.1-R.sup.g;
[0168] L.sup.1 is absent, C.sub.1-C.sub.6alkylene, or
C.sub.1-C.sub.6fluoroalkylene; [0169] R.sup.g is hydrogen,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted phenyl, --CO.sub.2R.sup.9, or
--C(.dbd.O)N(R.sup.9).sub.2; [0170] R.sup.1 is hydrogen; [0171]
R.sup.2 is hydrogen or C.sub.1-C.sub.6alkyl; [0172] R.sup.3 is
hydrogen, C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6fluoroalkyl;
[0173] R.sup.4 is hydrogen, halogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl; [0174] R.sup.5 is hydrogen, halogen,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6fluoroalkyl; [0175] R.sup.6
is C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8fluoroalkyl, or
-L.sup.2-R.sup.6a. [0176] L.sup.2 is absent,
C.sub.1-C.sub.6alkylene, or --CHR.sup.6b; [0177] R.sup.6a is
substituted or unsubstituted C.sub.3-C.sub.10cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10aryl, substituted or
unsubstituted C.sub.2-C.sub.10heterocycloalkyl, or substituted or
unsubstituted C.sub.1-C.sub.9heteroaryl; [0178] R.sup.6b is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl; [0179]
R.sup.7 is hydrogen or C.sub.1-C.sub.6alkyl; [0180] or R.sup.6 and
R.sup.7 are taken together with the nitrogen to which they are
attached to form a substituted or unsubstituted heterocycle.
[0181] In some embodiments, X is N or CH; [0182] Y is N or CH;
[0183] Z is N or C--R.sup.c; [0184] R.sup.c is hydrogen, --CN,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3,
--CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2; [0185] R.sup.1 is hydrogen; [0186]
R.sup.2 is hydrogen; [0187] R.sup.3 is hydrogen, --CH.sub.3,
--CH.sub.2OH, --CH.sub.2OCH.sub.3, --CH.sub.2CH.sub.2F,
--CH.sub.2CHF.sub.2, or --CH.sub.2CF.sub.3; [0188] R.sup.4 is
hydrogen or F; [0189] R.sup.5 is hydrogen or F; [0190] R.sup.6 is
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
-L.sup.2-R.sup.6a. [0191] L.sup.2 is absent,
C.sub.1-C.sub.6alkylene or --CHR.sup.6b--; [0192] R.sup.6a is
substituted or unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl,
substituted or unsubstituted monocyclic or bicyclic
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.3heterocycloalkyl, substituted or unsubstituted
monocyclic or bicyclic C.sub.4-C.sub.10heterocycloalkyl, or
substituted or unsubstituted C.sub.1-C.sub.9heteroaryl; [0193]
R.sup.6b is hydrogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4fluoroalkyl, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.4cycloalkyl; [0194] R.sup.7 is hydrogen or
C.sub.1-C.sub.6alkyl; [0195] or R.sup.6 and R.sup.7 are taken
together with the nitrogen to which they are attached to form a
substituted or unsubstituted heterocycle.
[0196] In some embodiments, the compound has the structure of
Formula (VIII), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00037## [0197] wherein: [0198] Ring A is phenyl or pyridinyl;
[0199] R.sup.a and R.sup.c are each independently hydrogen,
halogen, --CN, --N(R.sup.9).sub.2, --OR, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy,
substituted or unsubstituted monocyclic C.sub.3-C.sub.6cycloalkyl,
or substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0200] R.sup.f is
-L.sup.1-R.sup.g; [0201] L.sup.1 is absent, or
C.sub.1-C.sub.6alkylene; [0202] R.sup.9 is hydrogen, substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted phenyl, --CO.sub.2R.sup.9, or
--C(.dbd.O)N(R.sup.9).sub.2, or substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl; [0203] R.sup.1 is
hydrogen; [0204] R.sup.2 is hydrogen or C.sub.1-C.sub.6alkyl;
[0205] R.sup.3 is hydrogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4fluoroalkyl or C.sub.1-C.sub.4heteroalkyl; [0206]
R.sup.4 is hydrogen, halogen, C.sub.1-C.sub.4alkyl, or
C.sub.1-C.sub.4fluoroalkyl; [0207] R.sup.5 is hydrogen, halogen,
C.sub.1-C.sub.4alkyl, or C.sub.1-C.sub.4fluoroalkyl; [0208] R.sup.6
is C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
-L.sup.2-R.sup.6a. [0209] L.sup.2 is absent,
C.sub.1-C.sub.6alkylene or --CHR.sup.6b--; [0210] R.sup.6a is
substituted or unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl,
substituted or unsubstituted monocyclic or bicyclic
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.3heterocycloalkyl, substituted or unsubstituted
monocyclic or bicyclic C.sub.4-C.sub.10heterocycloalkyl, or
substituted or unsubstituted C.sub.1-C.sub.9heteroaryl; [0211]
R.sup.6b is hydrogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4fluoroalkyl, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.4cycloalkyl; [0212] R.sup.7 is hydrogen or
C.sub.1-C.sub.6alkyl; [0213] each R.sup.8 is independently
hydrogen, halogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl; [0214] R.sup.11 and R.sup.12 are each
independently hydrogen, halogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, or substituted or unsubstituted
monocyclic C.sub.1-C.sub.5heteroaryl; [0215] each R.sup.9 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; [0216] or two R.sup.9 on the same N
atom are taken together with the N atom to which they are attached
to form a substituted or unsubstituted N-containing heterocycle;
[0217] each R.sup.10 is independently substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; and [0218] n is 0-3.
[0219] In some embodiments, the compound has the structure of
Formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt,
or solvate thereof:
##STR00038##
[0220] In some embodiments, the compound has the structure of
Formula (VIIIa-1) or (VIIIb-1), or a pharmaceutically acceptable
salt, or solvate thereof:
##STR00039##
[0221] In some embodiments, R.sup.3 is hydrogen or --CH.sub.3;
R.sup.4 and R.sup.5 are each hydrogen; each R.sup.8 is
independently hydrogen or halogen; and R.sup.11 and R.sup.12 are
each independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9.
[0222] In some embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, C.sub.1-C.sub.6alkylene or --CHR.sup.6b--; R.sup.6a is
substituted or unsubstituted monocyclic 3-4 membered
C.sub.3-C.sub.4cycloalkyl, substituted or unsubstituted monocyclic
or bicyclic 5-10 membered C.sub.5-C.sub.10cycloalkyl, substituted
or unsubstituted 6-10 membered C.sub.6-C.sub.10aryl, substituted or
unsubstituted monocyclic 3-4 membered
C.sub.2-C.sub.3heterocycloalkyl, substituted or unsubstituted
monocyclic or bicyclic 5-10 membered
C.sub.4-C.sub.10heterocycloalkyl, or substituted or unsubstituted
5-10 membered C.sub.1-C.sub.9heteroaryl; R.sup.6b is hydrogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl; R.sup.7 is
hydrogen or C.sub.1-C.sub.6alkyl.
[0223] In some embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, C.sub.1-C.sub.4alkylene or --CHR.sup.6b--; R.sup.6a is
substituted or unsubstituted cyclopropyl, substituted or
unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl,
substituted or unsubstituted aziridinyl, substituted or
unsubstituted oxetanyl, or substituted or unsubstituted theitanyl;
R.sup.6b is hydrogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4fluoroalkyl, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.4cycloalkyl; R.sup.7 is hydrogen or
C.sub.1-C.sub.6alkyl.
[0224] In some embodiments, the compound has the structure of
Formula (IX), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00040## [0225] wherein: [0226] A.sup.1 is C--R.sup.8; and
A.sup.2 is C--R.sup.8; or [0227] A.sup.1 is N; and A.sup.2 is
C--R.sup.8; or [0228] A.sup.1 is C--R.sup.8; and A.sup.2 is N;
[0229] R.sup.a and R.sup.c are each independently hydrogen,
halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy,
substituted or unsubstituted monocyclic C.sub.3-C.sub.6cycloalkyl,
or substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0230] R.sup.f is
-L.sup.1-R.sup.g; [0231] L.sup.1 is absent, or
C.sub.1-C.sub.6alkylene; [0232] R.sup.g is hydrogen, substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted phenyl, --CO.sub.2R.sup.9, or
--C(.dbd.O)N(R.sup.9).sub.2, or substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl; [0233] R.sup.3 is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl or
C.sub.1-C.sub.4heteroalkyl; [0234] R.sup.4 is hydrogen, halogen,
C.sub.1-C.sub.4alkyl, or C.sub.1-C.sub.4fluoroalkyl; [0235] R.sup.5
is hydrogen, halogen, C.sub.1-C.sub.4alkyl, or
C.sub.1-C.sub.4fluoroalkyl; [0236] R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a. [0237] L.sup.2 is
absent, C.sub.1-C.sub.6alkylene or --CHR.sup.6b--; [0238] R.sup.6a
is substituted or unsubstituted monocyclic
C.sub.3-C.sub.4cycloalkyl, substituted or unsubstituted monocyclic
or bicyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted C.sub.6-C.sub.10aryl, substituted or unsubstituted
monocyclic C.sub.2-C.sub.3heterocycloalkyl, substituted or
unsubstituted monocyclic or bicyclic
C.sub.4-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; [0239] R.sup.6b is hydrogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl; [0240] R.sup.7
is hydrogen or C.sub.1-C.sub.6alkyl; [0241] each R.sup.8 is
independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl; [0242] R.sup.11 and R.sup.12 are each
independently hydrogen, halogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, or substituted or unsubstituted
monocyclic C.sub.1-C.sub.5heteroaryl; [0243] each R.sup.9 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; [0244] or two R.sup.9 on the same N
atom are taken together with the N atom to which they are attached
to form a substituted or unsubstituted N-containing heterocycle;
and [0245] each R.sup.10 is independently substituted or
unsubstituted C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl.
[0246] In some embodiments, the compound has the structure of
Formula (IXa) or (IXb), or a pharmaceutically acceptable salt, or
solvate thereof:
##STR00041##
[0247] In some embodiments, the compound has the structure of
Formula (VIIIa-1) or (VIIIb-1), or a pharmaceutically acceptable
salt, or solvate thereof:
##STR00042##
[0248] In some embodiments, R.sup.3 is hydrogen or --CH.sub.3;
R.sup.4 and R.sup.5 are each hydrogen; each R.sup.8 is
independently hydrogen or halogen; and R.sup.11 and R.sup.12 are
each independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9.
[0249] In some embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, C.sub.1-C.sub.6alkylene or --CHR.sup.6b--; R.sup.6a is
substituted or unsubstituted monocyclic 3-4 membered
C.sub.3-C.sub.4cycloalkyl, substituted or unsubstituted monocyclic
or bicyclic 5-10 membered C.sub.5-C.sub.10cycloalkyl, substituted
or unsubstituted 6-10 membered C.sub.6-C.sub.10aryl, substituted or
unsubstituted monocyclic 3-4 membered
C.sub.2-C.sub.3heterocycloalkyl, substituted or unsubstituted
monocyclic or bicyclic 5-10 membered
C.sub.4-C.sub.10heterocycloalkyl, or substituted or unsubstituted
5-10 membered C.sub.1-C.sub.9heteroaryl; R.sup.6b is hydrogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl; R.sup.7 is
hydrogen or C.sub.1-C.sub.6alkyl.
[0250] In some embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, C.sub.1-C.sub.4alkylene or --CHR.sup.6b--; R.sup.6a is
substituted or unsubstituted cyclopropyl, substituted or
unsubstituted cyclobutyl, substituted or unsubstituted azetidinyl,
substituted or unsubstituted aziridinyl, substituted or
unsubstituted oxetanyl, or substituted or unsubstituted theitanyl;
R.sup.6b is hydrogen, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4fluoroalkyl, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.4cycloalkyl; R.sup.7 is hydrogen or
C.sub.1-C.sub.6alkyl.
[0251] In some embodiments, each R.sup.9 is independently hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, or substituted or
unsubstituted monocyclic 3- to 8-membered heterocycloalkyl; or two
R.sup.9 on the same N atom are taken together with the N atom to
which they are attached to form a substituted or unsubstituted
N-containing heterocycle; and each R.sup.10 is independently
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, or substituted or
unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. In some
embodiments, each R.sup.9 is independently hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; or two R.sup.9 on the same N atom are
taken together with the N atom to which they are attached to form a
substituted or unsubstituted N-containing heterocycle; and each
R.sup.10 is independently substituted or unsubstituted
C.sub.1-C.sub.6alkyl or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, each R.sup.9 is
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl; or two R.sup.9 on the same N atom are
taken together with the N atom to which they are attached to form a
substituted or unsubstituted N-containing heterocycle; and each
R.sup.10 is independently C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6fluoroalkyl.
[0252] In one aspect, provided herein is a compound of Formula
(A1), or a pharmaceutically acceptable salt, or pharmaceutically
acceptable solvate thereof:
##STR00043## [0253] wherein: [0254] Ring A is carbocycle or
heterocycle; [0255] X is N or C--R.sup.a; Y is N or C--R.sup.b; Z
is N or C--R.sup.c; [0256] R.sup.L is hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; [0257] R.sup.a, R.sup.b, and R.sup.c
are each independently hydrogen, halogen, --CN, --N(R.sup.9).sub.2,
--OR.sup.f, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkoxy, substituted or
unsubstituted C.sub.1-C.sub.6heteroalkyl, substituted or
unsubstituted monocyclic carbocycle, or substituted or
unsubstituted monocyclic heterocycle; [0258] R.sup.f is
-L.sup.1-R.sup.g; [0259] L.sup.1 is absent,
C.sub.1-C.sub.6alkylene, C.sub.1-C.sub.6fluoroalkylene, or
C.sub.1-C.sub.6heteroalkylene; [0260] R.sup.g is hydrogen,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted phenyl, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, or substituted or unsubstituted
monocyclic heterocycle; [0261] R.sup.1 and R.sup.2 are
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, or substituted or unsubstituted
C.sub.3-C.sub.5heterocycloalkyl; [0262] R.sup.3 is hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; [0263] R.sup.4 and R.sup.5 are each
independently hydrogen, halogen, --OR.sup.9, --N(R.sup.9).sub.2,
--CN, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, substituted
or unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6alkoxy, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; [0264] R.sup.6 is substituted or
unsubstituted C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl, or -L2-R.sup.6a; [0265] L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.8alkylene, or
--CHR.sup.6b--; [0266] R.sup.6a is substituted or unsubstituted
C.sub.3-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted
C.sub.2-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; [0267] R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl; [0268] R.sup.7 is
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.10 cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10 aryl, substituted or
unsubstituted C.sub.2-C.sub.10 heterocycloalkyl, or substituted or
unsubstituted C.sub.1-C.sub.9 heteroaryl; [0269] or R.sup.6 and
R.sup.7 are taken together with the nitrogen to which they are
attached to form a substituted or unsubstituted N-containing
heterocycle; [0270] each R.sup.8, R.sup.11, and R.sup.12 is
independently hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted monocyclic
carbocycle, substituted or unsubstituted monocyclic heterocycle,
--CN, --OR.sup.9, --C(.dbd.O)R.sup.10, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2,
--NR.sup.9C(.dbd.O)R.sup.10, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9C(.dbd.O)N(R.sup.9).sub.2, --C(R.sup.9).dbd.N--OR.sup.9,
--SR.sup.9, --S(.dbd.O)R.sup.9, --SO.sub.2R.sup.9, or
--SO.sub.2N(R.sup.9).sub.2; [0271] or R.sup.11 is taken together
with an adjacent R.sup.8 and the atoms connecting the R.sup.11 and
the adjacent R.sup.8 to form a fused substituted or unsubstituted
carbocycle, or a fused substituted or unsubstituted heterocycle;
[0272] each R.sup.9 is independently hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted
C.sub.3-C.sub.7cycloalkyl, substituted or unsubstituted monocyclic
3- to 8-membered heterocycloalkyl, substituted or unsubstituted
phenyl, and substituted or unsubstituted monocyclic heteroaryl;
[0273] or two R.sup.9 on the same N atom are taken together with
the N atom to which they are attached to form a substituted or
unsubstituted N-containing heterocycle; [0274] each R.sup.10 is
independently substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl,
substituted or unsubstituted C.sub.3-C.sub.7cycloalkyl, substituted
or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl,
substituted or unsubstituted phenyl, and substituted or
unsubstituted monocyclic heteroaryl; and [0275] n is 0-3.
[0276] In some embodiments, R.sup.L is substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, R.sup.L is
C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6fluoroalkyl. In some
embodiments, R.sup.L is C.sub.1-C.sub.6alkyl. In some embodiments,
R.sup.L is --CH.sub.3.
[0277] In some embodiments, R.sup.1 and R.sup.2 are independently
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl. In some
embodiments, R.sup.1 and R.sup.2 are independently hydrogen or
substituted or unsubstituted C.sub.1-C.sub.6alkyl. In some
embodiments, R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.1 is hydrogen and
R.sup.2 is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, or substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl. In some embodiments, R.sup.1 is hydrogen
and R.sup.2 is hydrogen or substituted or unsubstituted
C.sub.1-C.sub.6alkyl. R.sup.1 is hydrogen and R.sup.2 is hydrogen
or C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.1 and R.sup.2
are each hydrogen.
[0278] In some embodiments, R.sup.1 is hydrogen; R.sup.2 is
hydrogen or substituted or unsubstituted C.sub.1-C.sub.6alkyl; and
R.sup.L is substituted or unsubstituted C.sub.1-C.sub.6alkyl. In
some embodiments, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and
R.sup.L is --CH.sub.3.
[0279] In some embodiments, X, Y, Z, R.sup.a, R.sup.b, R.sup.c are
as described for Formula (I).
[0280] In some embodiments, X is C--R.sup.a; Y is N; and Z is
C--R.sup.c; or X is CH; Y is N; and Z is C--R.sup.c; or X is
C--R.sup.a; Y is N; and Z is CH; or X is N; Y is C--R.sup.b; and Z
is C--R.sup.c; or X is C--R.sup.a; Y is C--R.sup.b; and Z is N; or
X is N; Y is N; and Z is C--R.sup.c; or X is C--R.sup.a; Y is N;
and Z is N. In some embodiments, X is N or CH; Y is N or CH; and Z
is N or C--R.sup.0.
[0281] In some embodiments, R.sup.a, R.sup.b, and R.sup.c are each
independently hydrogen, halogen, --CN, --N(R.sup.9).sub.2, --OR,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl,
C.sub.1-C.sub.6fluoroalkoxy, or substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl; R.sup.f is -L.sup.1-R.sup.g; L.sup.1 is
absent or C.sub.1-C.sub.6alkylene; and R.sup.g is hydrogen,
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted
or unsubstituted phenyl, or --CO.sub.2R.sup.9. In some embodiments,
R.sup.a, R.sup.b, and R.sup.c are each independently hydrogen,
--CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCF.sub.3,
--CO.sub.2CH.sub.3, --C(.dbd.O)NH.sub.2, --CONHCH.sub.3, or
--C(.dbd.O)N(CH.sub.3).sub.2, or cyclopropyl.
[0282] In some embodiments, Ring A, each R.sup.8, R.sup.11,
R.sup.12, and n are as described for Formula (I).
[0283] In some embodiments, Ring A is phenyl, monocyclic heteroaryl
or bicyclic heteroaryl. In some embodiments, Ring A is phenyl or
monocyclic heteroaryl. In some embodiments, Ring A is phenyl; or
Ring A is pyridinyl; or Ring A is Ring A is pyrazolyl, thiazolyl,
isoxazolyl, or pyrimidinyl. In some embodiments, Ring A is phenyl
or pyridinyl. In some embodiments, Ring A is bicyclic heteroaryl.
In some embodiments, Ring A is benzimidazolyl, indazolyl, or
benzoxadiazolyl.
[0284] In some embodiments, each R.sup.8 is independently hydrogen,
halogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl,
substituted or unsubstituted monocyclic carbocycle, --CN,
--OR.sup.9, --CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2,
--N(R.sup.9).sub.2, --NR.sup.9C(.dbd.O)R.sup.10, --SO.sub.2R.sup.9,
or --SO.sub.2N(R.sup.9).sub.2. In some embodiments, each R.sup.8 is
independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, each R.sup.8 is
independently hydrogen or halogen.
[0285] In some embodiments, R.sup.11 is halogen, substituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, substituted or unsubstituted monocyclic
carbocycle, substituted or unsubstituted monocyclic heterocycle,
--CN, --OR.sup.9, --C(.dbd.O)R.sup.10, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2,
--NR.sup.9C(.dbd.O)R.sup.10, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9C(.dbd.O)N(R.sup.9).sub.2, --C(R.sup.9).dbd.N--OR.sup.9,
--SR.sup.9, --S(.dbd.O)R.sup.9, --SO.sub.2R.sup.9, or
--SO.sub.2N(R.sup.9).sub.2. In some embodiments, R.sup.11 is
halogen, substituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.1-C.sub.6heteroalkyl, substituted or
unsubstituted monocyclic carbocycle, substituted or unsubstituted
monocyclic heterocycle, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2,
--NR.sup.9C(.dbd.O)R.sup.10, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9C(.dbd.O)N(R.sup.9).sub.2, --C(R.sup.9).dbd.N--OR.sup.9,
--SR.sup.9, --S(.dbd.O)R.sup.9, --SO.sub.2R.sup.9, or
--SO.sub.2N(R.sup.9).sub.2. In some embodiments, R.sup.11 is
halogen, substituted C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, substituted or unsubstituted
monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, or substituted or unsubstituted
monocyclic C.sub.1-C.sub.5heteroaryl. In some embodiments, R.sup.11
is halogen, substituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9,
--CO.sub.2R.sup.9, --C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2,
or --NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic carbocycle. In some embodiments, R.sup.11 is halogen,
substituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.8cycloalkyl. In some embodiments, R.sup.11
is halogen, substituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, or
substituted or unsubstituted monocyclic cycloalkyl. In some
embodiments, R.sup.11 is halogen, substituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl, --CN,
--OR.sup.9, or substituted or unsubstituted monocyclic
C.sub.3-C.sub.8cycloalkyl. In some embodiments, R.sup.11 is
halogen, substituted C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.8cycloalkyl. In some
embodiments, R.sup.11 is halogen, substituted C.sub.1-C.sub.6alkyl,
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl, --CN,
--OR.sup.9. In some embodiments, R.sup.11 is halogen,
C.sub.1-C.sub.6fluoroalkyl, --CN, or --OR.sup.9. In some
embodiments, R.sup.11 is --F, --Cl, --CN, --CF.sub.3, --OCH.sub.3,
--OCF.sub.3, or --OCHF.sub.2. In some embodiments, R.sup.11 is
halogen. In some embodiments, R.sup.11 is --F or --Cl. In some
embodiments, R.sup.11 is --F. In some embodiments, R.sup.11 is
--Cl.
[0286] In some embodiments, R.sup.11 is taken together with an
adjacent R.sup.8 and the atoms connecting the R.sup.11 and the
adjacent R.sup.8 to form a fused substituted or unsubstituted
carbocycle, or a fused substituted or unsubstituted heterocycle. In
some embodiments, R.sup.11 is taken together with an adjacent
R.sup.8 and the atoms connecting the R.sup.11 and the adjacent
R.sup.8 to form a fused substituted or unsubstituted
C.sub.3-C.sub.8cycloalkyl, or a fused substituted or unsubstituted
C.sub.2-C.sub.5heterocycloalkyl.
[0287] In some embodiments, R.sup.12 is hydrogen, halogen,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.1-C.sub.6heteroalkyl, substituted or
unsubstituted monocyclic carbocycle, substituted or unsubstituted
monocyclic heterocycle, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2,
--NR.sup.9C(.dbd.O)R.sup.10, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9C(.dbd.O)N(R.sup.9).sub.2, --C(R.sup.9).dbd.N--OR.sup.9,
--SR.sup.9, --S(.dbd.O)R.sup.9, --SO.sub.2R.sup.9, or
--SO.sub.2N(R.sup.9).sub.2. In some embodiments, R.sup.12 is
hydrogen, halogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, substituted or unsubstituted
monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, or substituted or unsubstituted
monocyclic C.sub.1-C.sub.5heteroaryl. In some embodiments, R.sup.12
is hydrogen, halogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.8cycloalkyl. In some
embodiments, R.sup.12 is hydrogen, halogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, --CN, or --OR.sup.9. In some
embodiments, R.sup.12 is hydrogen, --F, --Cl, --CN, --CH.sub.3,
--CF.sub.3, --OCH.sub.3, --OCF.sub.3, or --OCHF.sub.2. In some
embodiments, R.sup.12 is hydrogen or halogen. In some embodiments,
R.sup.12 is hydrogen, --F, or --Cl.
[0288] In some embodiments, n is 0, 1, 2, or 3. In some
embodiments, n is 0, 1, or 2. In some embodiments, n is 1, 2, or 3.
In some embodiments, n is 2 or 3. In some embodiments, n is 0. In
some embodiments, n is 1. In some embodiments, n is 2. In some
embodiments, n is 3.
[0289] In some embodiments,
##STR00044##
wherein A.sup.1 and A.sup.2 are each independently C--R.sup.8 or N;
and A.sup.3 is C--R.sup.12 or N. In some embodiments,
##STR00045##
wherein A.sup.2 is C--R.sup.8 or N. In some embodiments,
##STR00046##
In some embodiments,
##STR00047##
In some embodiments,
##STR00048##
In some embodiments,
##STR00049##
In some embodiments
##STR00050##
In some embodiments,
##STR00051##
wherein R.sup.8 is hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl.
[0290] In some embodiments, R.sup.6 and R.sup.7 are as described
for Formula (I).
[0291] In some embodiments, R.sup.7 is hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.3-C.sub.4 cycloalkyl, or substituted or unsubstituted 3- or
4-membered heterocycloalkyl. In some embodiments, R.sup.7 is
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6alkyl, or
substituted or unsubstituted C.sub.1-C.sub.6fluoroalkyl. In some
embodiments, R.sup.7 is hydrogen or C.sub.1-C.sub.6alkyl.
[0292] In some embodiments, R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.8alkylene, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
C.sub.3-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted
C.sub.2-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl.
[0293] In some embodiments, R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, or substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl. In some embodiments, R.sup.6 is
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.1-C.sub.6heteroalkyl. In some embodiments,
R.sup.6 is substituted or unsubstituted C.sub.1-C.sub.8alkyl or
substituted or unsubstituted C.sub.1-C.sub.8fluoroalkyl. In some
embodiments, R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, R.sup.6 is
C.sub.1-C.sub.6alkyl or C.sub.1-C.sub.6fluoroalkyl.
[0294] In some embodiments, R.sup.6 is -L.sup.2-R.sup.6a.
[0295] In some embodiments, L.sup.2 is absent, substituted or
unsubstituted C.sub.1-C.sub.8alkylene, or --CHR.sup.6b--. In some
embodiments, L.sup.2 is absent, substituted or unsubstituted
C.sub.1-C.sub.6alkylene, or --CHR.sup.6b--. In some embodiments,
L.sup.2 is absent, C.sub.1-C.sub.6alkylene, or --CHR.sup.6b--. In
some embodiments, L.sup.2 is absent, C.sub.1-C.sub.4alkylene, or
--CHR.sup.6b--. In some embodiments, L.sup.2 is absent,
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
or --CHR.sup.6b--. In some embodiments, L.sup.2 is --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CHR.sup.6b--. In some embodiments, L.sup.2 is --CH.sub.2-- or
--CHR.sup.6b--. In some embodiments, L.sup.2 is --CH.sub.2--,
--CH(CH.sub.3)-- or --CH(CF.sub.3)--.
[0296] In some embodiments, R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl. In some embodiments,
R.sup.6b is hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or substituted or unsubstituted
C.sub.3-C.sub.4cycloalkyl. In some embodiments, R.sup.6b is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
C.sub.3-C.sub.4cycloalkyl. In some embodiments, R.sup.6b is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or
C.sub.3-C.sub.4cycloalkyl. In some embodiments, R.sup.6b is
hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CHF.sub.2,
--CH.sub.2F, --CF.sub.3, cyclopropyl, or cyclobutyl. In some
embodiments, R.sup.6b is hydrogen, --CH.sub.3, --CHF.sub.2,
--CF.sub.3, cyclopropyl, or cyclobutyl. In some embodiments,
R.sup.6b is hydrogen, --CH.sub.3, --CF.sub.3, or cyclopropyl. In
some embodiments, R.sup.6b is hydrogen, --CH.sub.3, or
--CF.sub.3.
[0297] In some embodiments, R.sup.6a is substituted or
unsubstituted monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or
unsubstituted polycyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted phenyl, substituted or unsubstituted indanyl,
substituted or unsubstituted tetrahydronaphthyl, substituted or
unsubstituted naphthyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, substituted or unsubstituted
polycyclic C.sub.5-C.sub.10heterocycloalkyl, substituted or
unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl or substituted
or unsubstituted bicyclic C.sub.6-C.sub.9heteroaryl. In some
embodiments, R.sup.6a is substituted or unsubstituted monocyclic
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted bridged
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted
spirocyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted adamantyl, substituted or unsubstituted phenyl,
substituted or unsubstituted indanyl, substituted or unsubstituted
tetrahydronaphthyl, or substituted or unsubstituted naphthyl. In
some embodiments, R.sup.6a is substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl, substituted or
unsubstituted bridged C.sub.5-C.sub.10heterocycloalkyl, substituted
or unsubstituted spirocyclic C.sub.5-C.sub.10heterocycloalkyl,
substituted or unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl
or substituted or unsubstituted bicyclic
C.sub.6-C.sub.9heteroaryl.
[0298] In some embodiments, R.sup.6a is substituted or
unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl, substituted or
unsubstituted monocyclic or bicyclic C.sub.5-C.sub.10cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10aryl, substituted or
unsubstituted monocyclic C.sub.2-C.sub.3heterocycloalkyl,
substituted or unsubstituted monocyclic or bicyclic
C.sub.4-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl. In some embodiments, R.sup.6a is
substituted or unsubstituted monocyclic 3- or 4-membered monocyclic
cycloalkyl, 3- or 4-membered monocyclic heterocycloalkyl,
substituted or unsubstituted monocyclic or bicyclic
C.sub.5-C.sub.10cycloalkyl, or substituted or unsubstituted 5- to
10-membered heteroaryl.
[0299] In some embodiments, R.sup.6a is substituted or
unsubstituted C.sub.3-C.sub.4cycloalkyl, or substituted or
unsubstituted 3- or 4-membered C.sub.2-C.sub.3heterocycloalkyl. In
some embodiments, R.sup.6a is substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted azetidinyl, or substituted or unsubstituted
oxetanyl. In some embodiments, R.sup.6a is substituted or
unsubstituted C.sub.3-C.sub.4cycloalkyl. In some embodiments,
R.sup.6a is substituted or unsubstituted cyclopropyl or substituted
or unsubstituted cyclobutyl. In some embodiments, R.sup.6a is
substituted or unsubstituted cyclopropyl. In some embodiments,
R.sup.6a is substituted or unsubstituted cyclobutyl.
[0300] In some embodiments, R.sup.6 is substituted or unsubstituted
C.sub.1-C.sub.8alkyl, substituted or unsubstituted
C.sub.1-C.sub.8fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.8heteroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, substituted or unsubstituted C.sub.1-C.sub.8alkylene, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
C.sub.3-C.sub.10cycloalkyl, substituted or unsubstituted
C.sub.6-C.sub.10aryl, substituted or unsubstituted
C.sub.2-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; and R.sup.6b is hydrogen,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl. In some embodiments,
R.sup.6 is C.sub.1-C.sub.8alkyl, C.sub.1-C.sub.8fluoroalkyl,
substituted or unsubstituted C.sub.1-C.sub.8heteroalkyl, or
-L.sup.2-R.sup.6a; L.sup.2 is absent, C.sub.1-C.sub.6alkylene, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted monocyclic
C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted polycyclic
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted phenyl,
substituted or unsubstituted indanyl, substituted or unsubstituted
tetrahydronaphthyl, substituted or unsubstituted naphthyl,
substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, substituted or unsubstituted
polycyclic C.sub.5-C.sub.10heterocycloalkyl, substituted or
unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl or substituted
or unsubstituted bicyclic C.sub.6-C.sub.9heteroaryl; and R.sup.6b
is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl.
[0301] In some embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, substituted or unsubstituted
C.sub.1-C.sub.6heteroalkyl, or -L.sup.2-R.sup.6a; L.sup.2 is
absent, C.sub.1-C.sub.4alkylene, or --CHR.sup.6b--; and R.sup.6b is
hydrogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl. In some
embodiments, R.sup.6a is substituted or unsubstituted monocyclic
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted bridged
C.sub.5-C.sub.10cycloalkyl, substituted or unsubstituted
spirocyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted adamantyl, substituted or unsubstituted phenyl,
substituted or unsubstituted indanyl, substituted or unsubstituted
tetrahydronaphthyl, or substituted or unsubstituted naphthyl. In
some embodiments, R.sup.6a is substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl, substituted or
unsubstituted bridged C.sub.5-C.sub.10heterocycloalkyl, substituted
or unsubstituted spirocyclic C.sub.5-C.sub.10heterocycloalkyl,
substituted or unsubstituted monocyclic C.sub.1-C.sub.5heteroaryl
or substituted or unsubstituted bicyclic
C.sub.6-C.sub.9heteroaryl.
[0302] In some embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl, or
-L.sup.2-R.sup.6a. L.sup.2 is absent, C.sub.1-C.sub.4alkylene, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
C.sub.3-C.sub.4cycloalkyl, or substituted or unsubstituted 3- or
4-membered C.sub.2-C.sub.3heterocycloalkyl; and R.sup.6b is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.4cycloalkyl. In some
embodiments, R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl, or
-L.sup.2-R.sup.6a; L.sup.2 is absent, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, or
--CHR.sup.6b--; R.sup.6a is substituted or unsubstituted
cyclopropyl, substituted or unsubstituted cyclobutyl, substituted
or unsubstituted azetidinyl, or substituted or unsubstituted
oxetanyl; and R.sup.6b is hydrogen, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2, --CHF.sub.2,
--CH.sub.2F, --CF.sub.3, cyclopropyl, or cyclobutyl.
[0303] In some embodiments, R.sup.6 and R.sup.7 are taken together
with the nitrogen to which they are attached to form a substituted
or unsubstituted N-containing heterocycle. In some embodiments,
R.sup.6 and R.sup.7 are taken together with the nitrogen to which
they are attached to form a substituted or unsubstituted
N-containing heterocycloalkyl. In some embodiments, R.sup.6 and
R.sup.7 are taken together with the nitrogen to which they are
attached to form a substituted or unsubstituted monocyclic
N-containing heterocycloalkyl containing 1-2 N atoms, 0-2 O atoms
and 0-1 S.
[0304] In some embodiments, X is N or CH; [0305] Y is N or CH;
[0306] Z is N or C--R.sup.c; [0307] R.sup.c is hydrogen, halogen,
--CN, --N(R.sup.9).sub.2, --OR.sup.f, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy, or
substituted or unsubstituted C.sub.1-C.sub.6heteroalkyl; [0308]
R.sup.f is -L.sup.1-R.sup.g; [0309] L.sup.1 is absent,
C.sub.1-C.sub.6alkylene, or C.sub.1-C.sub.6fluoroalkylene; [0310]
R.sup.g is hydrogen, substituted or unsubstituted
C.sub.3-C.sub.6cycloalkyl, substituted or unsubstituted phenyl,
--CO.sub.2R.sup.9, or --C(.dbd.O)N(R.sup.9).sub.2; [0311] R.sup.1
is hydrogen; [0312] R.sup.2 is hydrogen or C.sub.1-C.sub.6alkyl;
[0313] R.sup.L is C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6fluoroalkyl; [0314] R.sup.6 is C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8fluoroalkyl, or -L.sup.2-R.sup.6a. [0315] L.sup.2 is
absent, C.sub.1-C.sub.6alkylene, or --CHR.sup.6b--; [0316] R.sup.6a
is substituted or unsubstituted C.sub.3-C.sub.10cycloalkyl,
substituted or unsubstituted C.sub.6-C.sub.10aryl, substituted or
unsubstituted C.sub.2-C.sub.10heterocycloalkyl, or substituted or
unsubstituted C.sub.1-C.sub.9heteroaryl; [0317] R.sup.6b is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, or
substituted or unsubstituted C.sub.3-C.sub.6cycloalkyl; [0318]
R.sup.7 is hydrogen or C.sub.1-C.sub.6alkyl; [0319] or R.sup.6 and
R.sup.7 are taken together with the nitrogen to which they are
attached to form a substituted or unsubstituted heterocycle.
[0320] In some embodiments, X is N or CH; [0321] Y is N or CH;
[0322] Z is N or C--R.sup.c. [0323] R.sup.c is hydrogen, --F, --Cl,
--CN, --CH.sub.3, --CF.sub.3, --OCH.sub.3, --OCH.sub.2CH.sub.3,
--OCH.sub.2CHF.sub.2, --OCH.sub.2CF.sub.3,
--OCH.sub.2CH.sub.2OCH.sub.3, --O-(cyclopropyl),
--O--CH.sub.2-(cyclopropyl), --O--CH.sub.2-(phenyl),
--OCH.sub.2CO.sub.2H, --OCH.sub.2CH.sub.2CO.sub.2H,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2H, --OCH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.3,
--OCH.sub.2CO.sub.2CH.sub.2CH.sub.3,
--OCH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3, or
--OCH.sub.2CH.sub.2CH.sub.2CO.sub.2CH.sub.2CH.sub.3; [0324] R.sup.1
is hydrogen; [0325] R.sup.2 is hydrogen; [0326] R.sup.L is
C.sub.1-C.sub.6alkyl; [0327] R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a. [0328] L.sup.2 is
absent, C.sub.1-C.sub.6alkylene or --CHR.sup.6b--; [0329] R.sup.6a
is substituted or unsubstituted monocyclic
C.sub.3-C.sub.4cycloalkyl, substituted or unsubstituted monocyclic
or bicyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted C.sub.6-C.sub.10aryl, substituted or unsubstituted
monocyclic C.sub.2-C.sub.3heterocycloalkyl, substituted or
unsubstituted monocyclic or bicyclic
C.sub.4-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; [0330] R.sup.6b is hydrogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl; [0331] R.sup.7
is hydrogen or C.sub.1-C.sub.6alkyl; [0332] or R.sup.6 and R.sup.7
are taken together with the nitrogen to which they are attached to
form a substituted or unsubstituted heterocycle.
[0333] In some embodiments, the compound has the structure of
Formula (A2), or a pharmaceutically acceptable salt, or solvate
thereof:
##STR00052## [0334] wherein: [0335] Ring A is phenyl or pyridinyl;
[0336] R.sup.a and R.sup.c are each independently hydrogen,
halogen, --CN, --N(R.sup.9).sub.2, --OR.sup.f, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy,
substituted or unsubstituted monocyclic C.sub.3-C.sub.6cycloalkyl,
or substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl; [0337] R.sup.f is
-L.sup.1-R.sup.g; [0338] L.sup.1 is absent, or
C.sub.1-C.sub.6alkylene; [0339] R.sup.g is hydrogen, substituted or
unsubstituted C.sub.3-C.sub.6cycloalkyl, substituted or
unsubstituted phenyl, --CO.sub.2R.sup.9, or
--C(.dbd.O)N(R.sup.9).sub.2, or substituted or unsubstituted
monocyclic C.sub.2-C.sub.5heterocycloalkyl; [0340] R.sup.1 is
hydrogen; [0341] R.sup.2 is hydrogen or C.sub.1-C.sub.6alkyl;
[0342] R.sup.L is C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6fluoroalkyl; [0343] R.sup.6 is C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, or -L.sup.2-R.sup.6a. [0344] L.sup.2 is
absent, C.sub.1-C.sub.6alkylene or --CHR.sup.6b--; [0345] R.sup.6a
is substituted or unsubstituted monocyclic
C.sub.3-C.sub.4cycloalkyl, substituted or unsubstituted monocyclic
or bicyclic C.sub.5-C.sub.10cycloalkyl, substituted or
unsubstituted C.sub.6-C.sub.10aryl, substituted or unsubstituted
monocyclic C.sub.2-C.sub.3heterocycloalkyl, substituted or
unsubstituted monocyclic or bicyclic
C.sub.4-C.sub.10heterocycloalkyl, or substituted or unsubstituted
C.sub.1-C.sub.9heteroaryl; [0346] R.sup.6b is hydrogen,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4fluoroalkyl, or substituted or
unsubstituted monocyclic C.sub.3-C.sub.4cycloalkyl; [0347] R.sup.7
is hydrogen or C.sub.1-C.sub.6alkyl; [0348] each R.sup.8 is
independently hydrogen, halogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl; [0349] R.sup.11 and R.sup.12 are each
independently hydrogen, halogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, --CN, --OR.sup.9, --CO.sub.2R.sup.9,
--C(.dbd.O)N(R.sup.9).sub.2, --N(R.sup.9).sub.2, or
--NR.sup.9C(.dbd.O)R.sup.10, or substituted or unsubstituted
monocyclic C.sub.3-C.sub.8cycloalkyl, substituted or unsubstituted
phenyl, substituted or unsubstituted monocyclic
C.sub.2-C.sub.5heterocycloalkyl, or substituted or unsubstituted
monocyclic C.sub.1-C.sub.5heteroaryl; [0350] each R.sup.9 is
independently hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; [0351] or two R.sup.9 on the same N
atom are taken together with the N atom to which they are attached
to form a substituted or unsubstituted N-containing heterocycle;
and [0352] each R.sup.10 is independently substituted or
unsubstituted C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. [0353] n is 0-3.
[0354] In some embodiments, each R.sup.9 is independently hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, or substituted or
unsubstituted monocyclic 3- to 8-membered heterocycloalkyl; or two
R.sup.9 on the same N atom are taken together with the N atom to
which they are attached to form a substituted or unsubstituted
N-containing heterocycle; and each R.sup.10 is independently
substituted or unsubstituted C.sub.1-C.sub.6alkyl, substituted or
unsubstituted C.sub.1-C.sub.6fluoroalkyl, substituted or
unsubstituted C.sub.3-C.sub.7cycloalkyl, or substituted or
unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. In some
embodiments, each R.sup.9 is independently hydrogen, substituted or
unsubstituted C.sub.1-C.sub.6alkyl, or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl; or two R.sup.9 on the same N atom are
taken together with the N atom to which they are attached to form a
substituted or unsubstituted N-containing heterocycle; and each
R.sup.10 is independently substituted or unsubstituted
C.sub.1-C.sub.6alkyl or substituted or unsubstituted
C.sub.1-C.sub.6fluoroalkyl. In some embodiments, each R.sup.9 is
independently hydrogen, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6fluoroalkyl; or two R.sup.9 on the same N atom are
taken together with the N atom to which they are attached to form a
substituted or unsubstituted N-containing heterocycle; and each
R.sup.10 is independently C.sub.1-C.sub.6alkyl or
C.sub.1-C.sub.6fluoroalkyl.
[0355] In some embodiments, compounds described herein have the
following structure:
##STR00053##
wherein,
##STR00054##
is as described in Table 1:
[0356] R.sup.3 is as described in Table 1;
[0357] R.sup.4 is as described in Table 1;
[0358] R.sup.4 is as described in Table 1; and
[0359] NR.sup.6R.sup.7 is as described in Table 1.
[0360] In some embodiments, compounds described herein have the
following structure:
##STR00055##
[0361] wherein,
##STR00056##
[0362] is as described in Table 2;
[0363] R.sup.c is as described in Table 2; and
[0364] NR.sup.6R.sup.7 is as described in Table 2.
[0365] In some embodiments, compounds described herein have the
following structure:
##STR00057##
[0366] wherein,
[0367] R.sup.11 is as described in Table 3;
[0368] R.sup.12 is as described in Table 3; and
[0369] NR.sup.6R.sup.7 is as described in Table 3.
[0370] In some embodiments, compounds described herein have the
following structure:
##STR00058##
[0371] wherein,
##STR00059##
is as described in Table 4;
[0372] R.sup.c is as described in Table 4; and
[0373] NR.sup.6R.sup.7 is as described in Table 4.
[0374] In some embodiments, compounds described herein have the
following structure:
##STR00060##
[0375] wherein,
[0376] R.sup.c is as described in Table 5;
[0377] R.sup.d is as described in Table 5;
[0378] R.sup.e is as described in Table 5; and
[0379] NR.sup.6R.sup.7 is as described in Table 5.
[0380] In some embodiments, compounds described herein have the
following structure:
##STR00061##
[0381] wherein,
[0382] NR.sup.6R.sup.7 is as described in Table 6.
[0383] In some embodiments, compounds described herein have the
following structure:
##STR00062##
[0384] wherein,
[0385] R.sup.c is as described in Table 7; and
[0386] NR.sup.6R.sup.7 is as described in Table 7.
[0387] In some embodiments, compounds described herein have the
following structure:
##STR00063##
[0388] wherein,
[0389] X is N or C--R.sup.a as described herein,
[0390] Y is N or CH,
[0391] Z is N or C--R.sup.c as described herein,
[0392] R.sup.d is
##STR00064##
as described herein,
[0393] R.sup.e is
##STR00065##
as described herein, and
[0394] R.sup.6 and R.sup.7 are as described herein.
[0395] In some embodiments, R.sup.d is
##STR00066##
as described herein.
[0396] In some embodiments, X is N. In some embodiments, X is
C--R.sup.a. In some embodiments, X is CH.
[0397] In some embodiments, Y is N. In some embodiments, Y is
CH.
[0398] In some embodiments, Z is N. In some embodiments, Z is
C--R.sup.c as described in Table 1, Table 2, Table 3, Table 4,
Table 5, Table 6, or Table 7. In some embodiments, Z is CH.
[0399] In some embodiments, X is CH, Y is N, and Z is C--R.sup.c as
described herein as described in Table 1, Table 2, Table 3, Table
4, or Table 5.
[0400] In some embodiments, X is CH, Y is CH, and Z is N.
[0401] In some embodiments, X is N, Y is CH, and Z is C--R.sup.c as
described herein as described in Table 7.
[0402] In some embodiments, R.sup.d is
##STR00067##
as described in Table 1, Table 2, Table 3, Table 4, Table 5, Table
6, or Table 7.
[0403] In some embodiments, R.sup.d is
##STR00068##
as described in Table 1, Table 5, Table 6, or Table 7. In some
embodiments, R.sup.d is
##STR00069##
as described in Table 1. In some embodiments, R.sup.d is
##STR00070## ##STR00071##
[0404] In some embodiments, R.sup.d is
##STR00072##
as described in Table 2. In some embodiments, R.sup.d is
##STR00073##
[0405] In some embodiments, R.sup.d is
##STR00074##
as described in Table 3. In some embodiments, R.sup.d is
##STR00075##
[0406] In some embodiments, R.sup.d is
##STR00076##
as described in Table 4. In some embodiments, R.sup.d is
##STR00077##
[0407] In some embodiments, R.sup.e is
##STR00078##
as described in Table 1, Table 2, Table 3, Table 4, Table 5, Table
6, or Table 7.
[0408] In some embodiments, R.sup.e is
##STR00079##
as described in Table 1, Table 2, Table 3, Table 4, Table 5, Table
6, or Table 7. In some embodiments, Re is
##STR00080##
[0409] In some embodiments, R.sup.e is
##STR00081##
as described in Table 1, Table 2, Table 3, Table 4, Table 6, or
Table 7. In some embodiments, R.sup.e is
##STR00082##
In some embodiments, R.sup.e is
##STR00083##
In some embodiments, R.sup.e is
##STR00084##
In some embodiments, R.sup.e is
##STR00085##
[0410] In some embodiments, R.sup.e is
##STR00086##
as described in Table 5. In some embodiments, R.sup.e is
##STR00087##
[0411] In some embodiments, R.sup.6 and R.sup.7 are as described in
Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7.
In some embodiments,
##STR00088##
is as described in Table 1, Table 2, Table 3, Table 4, Table 5,
Table 6, or Table 7. In some embodiments,
##STR00089## ##STR00090## ##STR00091##
In some embodiments,
##STR00092## ##STR00093##
[0412] Any combination of the groups described above for the
various variables is contemplated herein. Throughout the
specification, groups and substituents thereof are chosen by one
skilled in the field to provide stable moieties and compounds.
[0413] Exemplary compounds described herein include the compounds
described in the following Tables:
TABLE-US-00001 TABLE 1 ##STR00094## Compd No. R.sup.6R.sup.7N--
R.sup.4 R.sup.3 ##STR00095## R.sup.c 1-1 ##STR00096## H H
##STR00097## H 1-3 ##STR00098## H H ##STR00099## H 1-4 ##STR00100##
H CH.sub.3 ##STR00101## H 1-7 ##STR00102## H H ##STR00103## H 1-8
##STR00104## H H ##STR00105## H 1-9 ##STR00106## H H ##STR00107## H
1-10 ##STR00108## H --CH.sub.3 ##STR00109## H 1-11 ##STR00110## H
--CH.sub.3 ##STR00111## H 1-12 ##STR00112## H --CH.sub.3
##STR00113## H 1-13 ##STR00114## H --CH.sub.3 ##STR00115## H 1-14
##STR00116## H --CH.sub.3 ##STR00117## H 1-15 ##STR00118## H
--CH.sub.3 ##STR00119## H 1-16 ##STR00120## H --CH.sub.3
##STR00121## H 1-17 ##STR00122## H --CH.sub.3 ##STR00123## H 1-18
##STR00124## H --CH.sub.3 ##STR00125## H 1-19 ##STR00126## H
--CH.sub.3 ##STR00127## H 1-20 ##STR00128## H --CH.sub.3
##STR00129## H 1-21 ##STR00130## H --CH.sub.3 ##STR00131## H 1-22
##STR00132## H --CH.sub.3 ##STR00133## H 1-23 ##STR00134## H
--CH.sub.3 ##STR00135## H 1-24 ##STR00136## H --CH.sub.3
##STR00137## H 1-25 ##STR00138## H --CH.sub.3 ##STR00139## H 1-26
##STR00140## H --CH.sub.3 ##STR00141## H 1-27 ##STR00142## H
--CH.sub.3 ##STR00143## H 1-28 ##STR00144## H --CH.sub.3
##STR00145## H 1-29 ##STR00146## H --CH.sub.3 ##STR00147## H 1-30
##STR00148## H --CH.sub.3 ##STR00149## H 1-31 ##STR00150## H
--CH.sub.3 ##STR00151## H 1-32 ##STR00152## H --CH.sub.3
##STR00153## H 1-33 ##STR00154## H --CH.sub.3 ##STR00155## H 1-34
##STR00156## H --CH.sub.3 ##STR00157## H 1-35 ##STR00158## H
--CH.sub.3 ##STR00159## H 1-37 ##STR00160## F H ##STR00161## H 1-38
##STR00162## H --CH.sub.3 ##STR00163## H 1-39 ##STR00164## H
--CH.sub.3 ##STR00165## H 1-40 ##STR00166## H --CH.sub.3
##STR00167## H 1-41 ##STR00168## H --CH.sub.3 ##STR00169## H 1-42
##STR00170## H --CH.sub.3 ##STR00171## H 1-43 ##STR00172## H
--CH.sub.3 ##STR00173## H 1-44 ##STR00174## H --CH.sub.3
##STR00175## H 1-45 ##STR00176## H --CH.sub.3 ##STR00177## H 1-46
##STR00178## H --CH.sub.3 ##STR00179## H 1-47 ##STR00180## H
--CH.sub.3 ##STR00181## H 1-48 ##STR00182## H --CH.sub.3
##STR00183## --CN 1-49 ##STR00184## H --CH.sub.3 ##STR00185## --CN
1-50 ##STR00186## H --CH.sub.3 ##STR00187## H 1-51 ##STR00188## H
--CH.sub.3 ##STR00189## H 1-52 ##STR00190## H --CH.sub.3
##STR00191## H 1-53 ##STR00192## H --CH.sub.3 ##STR00193## H 1-54
##STR00194## H --CH.sub.3 ##STR00195## H 1-55 ##STR00196## H
--CH.sub.3 ##STR00197## H 1-56 ##STR00198## H --CH.sub.3
##STR00199## H 1-57 ##STR00200## H --CH.sub.3 ##STR00201## H 1-58
##STR00202## H --CH.sub.3 ##STR00203## H 1-59 ##STR00204## H
--CH.sub.3 ##STR00205## H 1-60 ##STR00206## H --CH.sub.3
##STR00207## H 1-61 ##STR00208## H H ##STR00209## H 1-62
##STR00210## H --CH.sub.3 ##STR00211## H 1-64 ##STR00212## H H
##STR00213## --CN 1-65 ##STR00214## H H ##STR00215## H 1-66
##STR00216## H H ##STR00217## --CN 1-67 ##STR00218## H H
##STR00219## --CN 1-68 ##STR00220## H H ##STR00221## --CN 1-69
##STR00222## H H ##STR00223## --CN 1-70 ##STR00224## H H
##STR00225## --CN 1-71 ##STR00226## H H ##STR00227## --CN 1-72
##STR00228## H H ##STR00229## --CN 1-73 ##STR00230## H H
##STR00231## --CN 1-74 ##STR00232## H --CH.sub.3 ##STR00233##
--CH.sub.3 1-76 ##STR00234## H --CH.sub.3 ##STR00235## --CN 1-77
##STR00236## H --CH.sub.3 ##STR00237## --CN 1-78 ##STR00238## H
--CH.sub.3 ##STR00239## --CN 1-79 ##STR00240## H --CH.sub.3
##STR00241## --CN 1-80 ##STR00242## H H ##STR00243## --CN 1-81
##STR00244## H H ##STR00245## --CN 1-82 ##STR00246## H H
##STR00247## --CN 1-83 ##STR00248## H --CH.sub.3 ##STR00249## H
1-84 ##STR00250## H H ##STR00251## --CN 1-85 ##STR00252## H
--CH.sub.3 ##STR00253## --CN 1-86 ##STR00254## H CH.sub.3
##STR00255## --CN 1-87 ##STR00256## H CH.sub.3 ##STR00257## --CN
1-88 ##STR00258## H CH.sub.3 ##STR00259## --CN 1-89 ##STR00260## H
CH.sub.3 ##STR00261## --CN 1-90 ##STR00262## H H ##STR00263## --CN
1-91 ##STR00264## H CH.sub.3 ##STR00265## --CN 1-92 ##STR00266## H
CH.sub.3 ##STR00267## --CN 1-93 ##STR00268## H CH.sub.3
##STR00269## --CN 1-94 ##STR00270## H --CH.sub.3 ##STR00271## H
1-95 ##STR00272## H H ##STR00273## --CN 1-96 ##STR00274## H
--CH.sub.3 ##STR00275## H 1-97 ##STR00276## H H ##STR00277## --CN
1-98 ##STR00278## H --CH.sub.2OH ##STR00279## --CN 1-101
##STR00280## F H ##STR00281## --CN 1-103 ##STR00282## H --CH.sub.3
##STR00283## --CN 1-104 ##STR00284## H --CH.sub.3 ##STR00285## --CN
1-105 ##STR00286## H --CH.sub.3 ##STR00287## --CN 1-106
##STR00288## H --CH.sub.3 ##STR00289## --CN 1-107 ##STR00290## H
--CH.sub.3 ##STR00291## --CN 1-108 ##STR00292## H --CH.sub.3
##STR00293## --CN 1-109 ##STR00294## H --CH.sub.3 ##STR00295## --CN
1-110 ##STR00296## H --CH.sub.3 ##STR00297## --CN 1-111
##STR00298## H --CH.sub.3 ##STR00299## --CN 1-112 ##STR00300## H
--CH.sub.3 ##STR00301## H 1-113 ##STR00302## H --CH.sub.3
##STR00303## --CN 1-114 ##STR00304## H --CH.sub.3 ##STR00305## --CN
1-115 ##STR00306## H --CH.sub.3 ##STR00307## --CN 1-116
##STR00308## H --CH.sub.2OMe ##STR00309## --CN 1-118 ##STR00310## H
--CH.sub.2CHF.sub.2 ##STR00311## --CN 1-120 ##STR00312## H
--CH.sub.3 ##STR00313## --CN 1-122 ##STR00314## H --CH.sub.3
##STR00315## --CH.sub.3 1-123 ##STR00316## H --CH.sub.3
##STR00317## --CH.sub.3 1-124 ##STR00318## H --CH.sub.3
##STR00319## --CH.sub.3 1-125 ##STR00320## H --CH.sub.3
##STR00321## --CH.sub.3 1-126 ##STR00322## H --CH.sub.3
##STR00323## --CN 1-127 ##STR00324## H --CH.sub.3 ##STR00325## --CN
1-130 ##STR00326## H --CH.sub.3 ##STR00327## --OCH.sub.3 1-132
##STR00328## H --CH.sub.3 ##STR00329## --CN 1-133 ##STR00330## H
--CH.sub.3 ##STR00331## --CN 1-135 ##STR00332## F H ##STR00333##
--CN 1-137 ##STR00334## H --CH.sub.3 ##STR00335## --OCH.sub.3 1-138
##STR00336## F H ##STR00337## --CN 1-140 ##STR00338## H --CH.sub.3
##STR00339## --OCH.sub.3
1-141 ##STR00340## H --CH.sub.3 ##STR00341## --OCH.sub.3 1-143
##STR00342## H --CH.sub.3 ##STR00343## H 1-144 ##STR00344## H
--CH.sub.3 ##STR00345## --OCH.sub.3 1-145 ##STR00346## H --CH.sub.3
##STR00347## --OCH.sub.3 1-146 ##STR00348## H --CH.sub.3
##STR00349## --CH.sub.3 1-147 ##STR00350## H --CH.sub.3
##STR00351## --CH.sub.3 1-149 ##STR00352## H --CH.sub.3
##STR00353## H 1-150 ##STR00354## H H ##STR00355## --OCH.sub.3
1-151 ##STR00356## H H ##STR00357## --OCH.sub.3 1-152 ##STR00358##
H H ##STR00359## --OCH.sub.3 1-153 ##STR00360## H --CH.sub.3
##STR00361## --OCH.sub.3 1-154 ##STR00362## H --CH.sub.3
##STR00363## --OCH.sub.3 1-164 ##STR00364## H --CH.sub.3
##STR00365## --OCH.sub.3 1-165 ##STR00366## H --CH.sub.3
##STR00367## --OCH.sub.3 1-168 ##STR00368## H --CH.sub.3
##STR00369## --CN 1-171 ##STR00370## H --CH.sub.3 ##STR00371##
--CH.sub.3 1-172 ##STR00372## H --CH.sub.3 ##STR00373## --CH.sub.3
1-173 ##STR00374## H --CH.sub.3 ##STR00375## --CH.sub.3 1-174
##STR00376## H --CH.sub.3 ##STR00377## --CH.sub.3 1-176
##STR00378## H --CH.sub.3 ##STR00379## --OCH.sub.2CH.sub.3 1-177
##STR00380## H --CH.sub.3 ##STR00381## --OCH.sub.2CHF.sub.2 1-178
##STR00382## H --CH.sub.3 ##STR00383## ##STR00384## 1-179
##STR00385## H --CH.sub.3 ##STR00386## --OCH.sub.2CH.sub.2OCH.sub.3
1-180 ##STR00387## H --CH.sub.3 ##STR00388## --CN 1-181
##STR00389## H --CH.sub.3 ##STR00390## --CH.sub.3 1-188
##STR00391## H --CH.sub.3 ##STR00392## --OCH.sub.3 1-189
##STR00393## H --CH.sub.3 ##STR00394## --CF.sub.3 1-190
##STR00395## H --CH.sub.3 ##STR00396## --OCH.sub.2CF.sub.3 1-191
##STR00397## H --CH.sub.3 ##STR00398## ##STR00399## 1-192
##STR00400## H --CH.sub.3 ##STR00401## --CN 1-193 ##STR00402## H H
##STR00403## --OCH.sub.3 1-194 ##STR00404## H H ##STR00405##
--OCH.sub.3 1-175 ##STR00406## H --CH.sub.3 ##STR00407## H 1-163
##STR00408## H --CH.sub.3 ##STR00409## H 1-184 ##STR00410## H
--CH.sub.3 ##STR00411## --OCH.sub.3 1-195 ##STR00412## H --CH.sub.3
##STR00413## --CF.sub.3 1-196 ##STR00414## H H ##STR00415##
--OCH.sub.3 1-197 ##STR00416## H --CH.sub.3 ##STR00417## --CF.sub.3
1-198 ##STR00418## H H ##STR00419## --CF.sub.3 1-199 ##STR00420## H
H ##STR00421## --CF.sub.3 1-200 ##STR00422## H H ##STR00423##
--OCH.sub.2CO.sub.2Et 1-201 ##STR00424## H H ##STR00425##
--OCH.sub.2CH.sub.2CO.sub.2Et 1-202 ##STR00426## H H ##STR00427##
--OCH.sub.2CH.sub.2--CH.sub.2CO.sub.2Et 1-203 ##STR00428## H H
##STR00429## --OCH.sub.2CO.sub.2H 1-204 ##STR00430## H H
##STR00431## --OCH.sub.2CH.sub.2CO.sub.2H 1-205 ##STR00432## H H
##STR00433## --OCH.sub.2CH.sub.2--CH.sub.2CO.sub.2H 1-209
##STR00434## H --CH.sub.3 ##STR00435## --CF.sub.3 1-210
##STR00436## H --CH.sub.3 ##STR00437## --CF.sub.3 1-211
##STR00438## H --CH.sub.3 ##STR00439## --CF.sub.3 1-212
##STR00440## H H ##STR00441## --CF.sub.3 1-213 ##STR00442## H H
##STR00443## --CF.sub.3 1-214 ##STR00444## H H ##STR00445##
--CF.sub.3 1-215 ##STR00446## H H ##STR00447## --CF.sub.3 1-216
##STR00448## H H ##STR00449## --CF.sub.3 1-217 ##STR00450## H
--CH.sub.3 ##STR00451## --CF.sub.3 1-218 ##STR00452## H --CH.sub.3
##STR00453## --CN 1-219 ##STR00454## H --CH.sub.3 ##STR00455## --CN
1-222 ##STR00456## H --CH.sub.3 ##STR00457## --CN 1-223
##STR00458## H --CH.sub.3 ##STR00459## --CH.sub.3 1-224
##STR00460## H --CH.sub.3 ##STR00461## --CH.sub.3 1-225
##STR00462## H --H ##STR00463## --CN 1-226 ##STR00464## H --H
##STR00465## --CN 1-227 ##STR00466## H H ##STR00467## --CN 1-228
##STR00468## H CH.sub.3 ##STR00469## --OCH.sub.3 1-229 ##STR00470##
H CH.sub.3 ##STR00471## --OCH.sub.3 1-230 ##STR00472## H H
##STR00473## --CH.sub.3 1-231 ##STR00474## H H ##STR00475##
--CH.sub.3 1-232 ##STR00476## H H ##STR00477## --CH.sub.3 1-233
##STR00478## H H ##STR00479## --CH.sub.3 1-234 ##STR00480## H
--CH.sub.3 ##STR00481## --CN 1-235 ##STR00482## H H ##STR00483##
--OCH.sub.3 1-236 ##STR00484## H H ##STR00485## --OCH.sub.3 1-237
##STR00486## H H ##STR00487## --OCH.sub.3 1-238 ##STR00488## H
--CH.sub.3 ##STR00489## --OCH.sub.3 1-239 ##STR00490## H --CH.sub.3
##STR00491## --OCH.sub.3 1-240 ##STR00492## H --CH.sub.3
##STR00493## --OCH.sub.3 1-241 ##STR00494## H --CH.sub.3
##STR00495## --OCH.sub.3 1-242 ##STR00496## H --CH.sub.3
##STR00497## --CH.sub.3 1-243 ##STR00498## H --CH.sub.3
##STR00499## --CH.sub.3 1-244 ##STR00500## H --CH.sub.3
##STR00501## --CN 1-245 ##STR00502## H --CH.sub.3 ##STR00503## --CN
1-246 ##STR00504## H --CH.sub.3 ##STR00505## --OCH.sub.2CH.sub.2OH
1-247 ##STR00506## H --CH.sub.3 ##STR00507## --OCH.sub.2CO.sub.2H
1-259 ##STR00508## H --CH.sub.3 ##STR00509## --OCH.sub.3 1-260
##STR00510## H --CH.sub.3 ##STR00511## --OCH.sub.3 1-261
##STR00512## H --CH.sub.3 ##STR00513## --OCH.sub.3 1-262
##STR00514## H --CH.sub.3 ##STR00515## --OCH.sub.3 1-263
##STR00516## H --CH.sub.3 ##STR00517## --OCH.sub.3 1-264
##STR00518## H --CH.sub.3 ##STR00519## --OCH.sub.2CH.sub.2CO.sub.2H
1-265 ##STR00520## H --CH.sub.3 ##STR00521##
--OCH.sub.2CH.sub.2--CH.sub.2CO.sub.2H 1-266 ##STR00522## H
--CH.sub.3 ##STR00523## ##STR00524## 1-267 ##STR00525## H
--CH.sub.3 ##STR00526## ##STR00527## 1-268 ##STR00528## H
--CH.sub.3 ##STR00529## --CH.sub.3 1-269 ##STR00530## H --CH.sub.3
##STR00531## --CH.sub.3 1-272 ##STR00532## H H ##STR00533##
--CH.sub.3 1-273 ##STR00534## H --CH.sub.3 ##STR00535## --OCH.sub.3
1-275 ##STR00536## H --CH.sub.3 ##STR00537## --CH.sub.3 1-276
##STR00538## H H ##STR00539## --CH.sub.3 1-277 ##STR00540## H H
##STR00541## --CH.sub.3 1-278 ##STR00542## H H ##STR00543##
--CH.sub.3 1-279 ##STR00544## H --CH.sub.3 ##STR00545## --CH.sub.3
1-280 ##STR00546## H --CH.sub.3 ##STR00547## --CH.sub.3 1-281
##STR00548## H --CH.sub.3 ##STR00549## ##STR00550## 1-282
##STR00551## H H ##STR00552## --OCH.sub.3 1-283 ##STR00553## H H
##STR00554## --OCH.sub.3 1-284 ##STR00555## H H ##STR00556##
--OCH.sub.3 1-285 ##STR00557## H H ##STR00558## --OCH.sub.3 1-286
##STR00559## H H ##STR00560## --OCH.sub.3 1-287 ##STR00561## H
--CH.sub.3 ##STR00562## --CH.sub.3 1-288 ##STR00563## H --CH.sub.3
##STR00564## --CH.sub.3 1-289 ##STR00565## H --CH.sub.3
##STR00566## --CH.sub.3 1-290 ##STR00567## H --CH.sub.3
##STR00568## ##STR00569##
[0414] Compounds in Table 1 are named: [0415] 1-1:
4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-car-
boxamide; [0416] 1-3:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-(3-chloro-5-fluorophenyl)-5-(3,5-dimeth-
ylphenyl)pyridine-3-carboxamide; [0417] 1-4:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-4-fluorophenyl)-N-(2--
fluorophenyl)pyridine-3-carboxamide; [0418] 1-7:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)-N-cyclohexylpyridine-3--
carboxamide; [0419] 1-8:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-cyanophenyl)-N-(1-methylcyclobutyl)p-
yridine-3-carboxamide; [0420] 1-9:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-benzyl-5-(3-cyanophenyl)pyridine-3-carb-
oxamide; [0421] 1-10:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyanophenyl)-N-(4,4-difluor-
ocyclohexyl)pyridine-3-carboxamide; [0422] 1-11:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-dimethylcyclohexyl)-5-(3,-
5-dimethylphenyl)pyridine-3-carboxamide; [0423] 1-12:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-dimethylphenyl)pyridine-3-carboxamide; [0424] 1-13:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3--
fluoro-5-methylphenyl)pyridine-3-carboxamide; [0425] 1-14:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclohexyl)-5-(3,-
5-dimethylphenyl)pyridine-3-carboxamide; [0426] 1-15:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-fluoro-5-methylphenyl)-N-[1-
-(trifluoromethyl)cyclopentyl]pyridine-3-carboxamide; [0427] 1-16:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide; [0428] 1-17:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2,3-dihydro-TH-inden-1-yl)-5--
(3-fluoro-5-methylphenyl)pyridine-3-carboxamide; [0429] 1-18:
N-(adamantan-2-yl)-4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-fluoro-5-
-methylphenyl)pyridine-3-carboxamide; [0430] 1-19:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-ethylcyclobutyl)-5-(3-fluor-
o-5-methylphenyl)pyridine-3-carboxamide; [0431] 1-20:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
4,5-trifluorophenyl)pyridine-3-carboxamide; [0432] 1-21:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5--
(3,5-difluorophenyl)pyridine-3-carboxamide; [0433] 1-22:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(3,3-di-
methylcyclobutyl)pyridine-3-carboxamide; [0434] 1-23:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopropyl-5-(3,5-difluorophe-
nyl)pyridine-3-carboxamide; [0435] 1-24:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclopropylethyl)-5-(3-fluo-
ro-5-methylphenyl)pyridine-3-carboxamide; [0436] 1-25:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-5-(3-flu-
oro-5-methylphenyl)pyridine-3-carboxamide; [0437] 1-26:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclopropylmethyl)-5-(3-fluor-
o-5-methylphenyl)pyridine-3-carboxamide; [0438] 1-27:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-fluoro-5-methylphenyl)-N-(1-
-methyl-1H-pyrazol-3-yl)pyridine-3-carboxamide; [0439] 1-28:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,2,2--
trifluoroethyl)pyridine-3-carboxamide; [0440] 1-29:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-tert-butyl-5-(3,5-difluorophen-
yl)pyridine-3-carboxamide; [0441] 1-30:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide; [0442] 1-31:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(pentan-
-3-yl)pyridine-3-carboxamide; [0443] 1-32:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1-met-
hylcyclopropyl)methyl]pyridine-3-carboxamide; [0444] 1-33:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclobutylmethyl)-5-(3,5-difl-
uorophenyl)pyridine-3-carboxamide; [0445] 1-34:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(1-meth-
ylcyclobutyl)pyridine-3-carboxamide; [0446] 1-35:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(3-
,3-difluorocyclobutyl)pyridine-3-carboxamide; [0447] 1-37:
4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-
-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0448] 1-38:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(3-meth-
ylbutan-2-yl)pyridine-3-carboxamide; [0449] 1-39:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,4-di-
methylpentan-3-yl)pyridine-3-carboxamide; [0450] 1-40:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2-cyclopropylpropan-2-yl)-5-(-
3,5-difluorophenyl)pyridine-3-carboxamide; [0451] 1-41:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)pyridine-3-carboxamide; [0452] 1-42:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(2,2-difluorocyclopropyl)meth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0453] 1-43:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2,2-d-
imethylcyclopropyl)methyl]pyridine-3-carboxamide; [0454] 1-44:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1R)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)pyridine-3-carboxamide; [0455] 1-45:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(1,1,1--
trifluoro-3-methylbutan-2-yl)pyridine-3-carboxamide; [0456] 1-46:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-meth-
ylpropyl)pyridine-3-carboxamide; [0457] 1-47:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1-flu-
orocyclobutyl)methyl]pyridine-3-carboxamide; [0458] 1-48:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(4,4-difluorocyclohexy-
l)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0459] 1-49:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6--
cyano-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0460] 1-50:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(3,3-difluorocyclobutyl)methy-
l]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0461] 1-51:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-5-(3,5-d-
ifluorophenyl)pyridine-3-carboxamide; [0462] 1-52:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[trans--
2-fluorocyclohexyl]pyridine-3-carboxamide; [0463] 1-53:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2R)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0464] 1-54:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0465] 1-55:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(trans-
-3-fluorocyclobutyl]pyridine-3-carboxamide; [0466] 1-56:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclobutyl-2,2,2-trifluoroe-
thyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0467] 1-57:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-meth-
ylbutyl)pyridine-3-carboxamide; [0468] 1-58:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2-ethy-
lbutyl)pyridine-3-carboxamide; [0469] 1-59:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[cis-3--
fluorocyclobutyl]pyridine-3-carboxamide; [0470] 1-60:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(4,4,4--
trifluorobutan-2-yl)pyridine-3-carboxamide; [0471] 1-61:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(dicyclopro-
pylmethyl)pyridine-3-carboxamide; [0472] 1-62:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-(2,2-di-
fluoropropyl)pyridine-3-carboxamide; [0473] 1-64:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(-
3,5-difluorophenyl)pyridine-3-carboxamide; [0474] 1-65:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(-
3-fluorophenyl)pyridine-3-carboxamide; [0475] 1-66:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-(-
3,4-difluorophenyl)pyridine-3-carboxamide; [0476] 1-67:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(4,4-difluorocyclohexyl)-5-(3,5-
-difluorophenyl)pyridine-3-carboxamide; [0477] 1-68:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(3,3-difluorocyclobutyl)-5-(3,5-
-difluorophenyl)pyridine-3-carboxamide; [0478] 1-69:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide; [0479] 1-70:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-(dicyclopropylmethyl)-5-(3,5-di-
fluorophenyl)pyridine-3-carboxamide; [0480] 1-71:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,-
1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0481] 1-72:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(pentan--
3-yl)pyridine-3-carboxamide; [0482] 1-73:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-cycloheptyl-5-(3,5-difluorophen-
yl)pyridine-3-carboxamide; [0483] 1-74:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5--
(3,5-difluorophenyl)-6-methylpyridine-3-carboxamide; [0484] 1-76:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(pentan-3-yl)pyridine-3-carboxamide; [0485] 1-77:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0486] 1-78:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-cyclopentyl-5-(3,5-dif-
luorophenyl)pyridine-3-carboxamide; [0487] 1-79:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(3,3-difluorocyclobuty-
l)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0488] 1-80:
4-[(3S)-3-aminopyrrolidin-1-yl]-3-(3,5-difluorophenyl)-5-(piperidine-1-ca-
rbonyl)pyridine-2-carbonitrile; [0489] 1-81:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-cyclohexyl-5-(3,5-difluoropheny-
l)pyridine-3-carboxamide; [0490] 1-82:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-N-cyclopentyl-5-(3,5-difluorophen-
yl)pyridine-3-carboxamide; [0491] 1-83:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[cis-2--
fluorocyclohexyl]pyridine-3-carboxamide; [0492] 1-84:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3-chloro-
phenyl)-6-cyanopyridine-3-carboxamide; [0493] 1-85:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(2-methylpropyl)pyridine-3-carboxamide; [0494] 1-86:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(cyclopropylmethyl)-5--
(3,5-difluorophenyl)pyridine-3-carboxamide; [0495] 1-87:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-cyclobutyl-5-(3,5-difl-
uorophenyl)pyridine-3-carboxamide; [0496] 1-88:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(oxan-4-yl)pyridine-3-carboxamide; [0497] 1-89:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(oxan-3-yl)pyridine-3-carboxamide; [0498] 1-90:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3-chloro-
-5-fluorophenyl)-6-cyanopyridine-3-carboxamide; [0499] 1-91:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(propan-2-yl)pyridine-3-carboxamide; [0500] 1-92:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; [0501] 1-93:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-cyclohexyl-5-(3,5-difl-
uorophenyl)pyridine-3-carboxamide; [0502] 1-94:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5--
(3-cyano-5-methoxyphenyl)pyridine-3-carboxamide; [0503] 1-95:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1S)-1--
(pyridin-2-yl)ethyl]pyridine-3-carboxamide; [0504] 1-96:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(-
1S)-1-cyclopropylethyl]pyridine-3-carboxamide; [0505] 1-97:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(1S)-1--
phenylethyl]pyridine-3-carboxamide; [0506] 1-98:
4-[(3S)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-
-1-yl}-6-cyano-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0507]
1-101:
4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-
-6-cyano-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0508]
1-103:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxamide; [0509] 1-104:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(1-methyl-1H-pyrazol-5-yl)methyl]pyridine-3-carboxamide; [0510]
1-105:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(1-methyl-1H-pyrazol-3-yl)methyl]pyridine-3-carboxamide; [0511]
1-106:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(1-methyl-1H-imidazol-2-yl)methyl]pyridine-3-carboxamide; [0512]
1-107:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(1-methyl-1H-pyrazol-4-yl)methyl]pyridine-3-carboxamide; [0513]
1-108:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(pyrimidin-2-yl)methyl]pyridine-3-carboxamide; [0514] 1-109:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-benzylpiperazine-1-carbonyl)-3-(3,5--
difluorophenyl)pyridine-2-carbonitrile; [0515] 1-110:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(3-pheny-
lpropyl)pyridine-3-carboxamide; [0516] 1-111:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(1-pheny-
lpiperidin-4-yl)pyridine-3-carboxamide; [0517] 1-112:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-5-(3,5-difluorophen-
yl)pyridine-3-carboxamide; [0518] 1-113:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-(2,2-dimethyloxan-4-yl)pyridine-3-carboxamide; [0519] 1-114:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(1,2-oxazol-3-yl)methyl]pyridine-3-carboxamide; [0520] 1-115:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2-hydroxyphenyl)methyl]pyridine-3-carboxamide; [0521] 1-116:
4-[(3R)-3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclo-
propylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0522]
1-118:
4-[(3S)-3-amino-3-(2,2-difluoroethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-c-
yclopropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
[0523] 1-120:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopr-
opylethyl]-5-[3-(difluoromethoxy)phenyl]pyridine-3-carboxamide;
[0524] 1-122:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-(3,5-difluorophenyl)-6-methylpyridine-3-carboxamide; [0525]
1-123:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-fluorophenyl)-N-[(1-
S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; [0526]
1-124:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
-fluorophenyl)-6-methylpyridine-3-carboxamide; [0527] 1-125:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; [0528]
1-126:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[1-(pyrimidin-2-yl)ethyl]pyridine-3-carboxamide; [0529] 1-127:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide; [0530]
1-130:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5--
(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide; [0531] 1-132:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[1-(1,2-oxazol-3-yl)ethyl]pyridine-3-carboxamide;
[0532] 1-133:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[1-(1-methyl-1H-1,2,3-triazol-4-yl)ethyl]pyridine-3-carboxamide;
[0533] 1-135:
4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cycl-
opropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0534]
1-137:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)-6-methoxypyridine-3-carboxamide; [0535] 1-138:
4-[(3R,4R)-3-amino-4-fluoropyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-
-cyano-N-[(1S)-1-cyclopropylethyl]pyridine-3-carboxamide; [0536]
1-140:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-
-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0537]
1-141:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-methoxypyridine-3-carboxamide; [0538] 1-143:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-
-(difluoromethoxy)-5-fluorophenyl]pyridine-3-carboxamide; [0539]
1-144:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-difluorophenyl)-6-methoxypyridine-3-carboxamide; [0540] 1-145:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-3,3-difluorocyclopentyl]-
-5-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide; [0541]
1-146:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)-6-methylpyridine-3-carboxamide; [0542] 1-147:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methyl--
N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0543]
1-149:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-
-(difluoromethoxy)phenyl]pyridine-3-carboxamide; [0544] 1-150:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluor-
ophenyl)-6-methoxypyridine-3-carboxamide; [0545] 1-151:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-N-[(2S)--
1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0546] 1-152:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-difluo-
rophenyl)-6-methoxypyridine-3-carboxamide; [0547] 1-153:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-fluorophenyl)-N-[(1-
S)-1-cyclopropylethyl]-6-methoxypyridine-3-carboxamide; [0548]
1-154:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-me-
thoxy-5-[3-(trifluoromethoxy)phenyl]pyridine-3-carboxamide; [0549]
1-163:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(2-
,2-difluoro-2H-1,3-benzodioxol-4-yl)pyridine-3-carboxamide; [0550]
1-164:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-[3-
-fluoro-5-(trifluoromethyl)phenyl]-6-methoxypyridine-3-carboxamide;
[0551] 1-165:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-[3-(difluoromethoxy)phenyl]-6-methoxypyridine-3-carboxamide;
[0552] 1-168:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-[3-(difluoromet-
hoxy)phenyl]-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0553] 1-171:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorop-
henyl]-6-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0554] 1-172:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-[3--
(difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide;
[0555] 1-173:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide;
[0556] 1-174:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-[3--
(difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide;
[0557] 1-175:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)pyridine-3-carboxamide;
[0558] 1-176:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-(3,5-difluorophenyl)-6-ethoxypyridine-3-carboxamide; [0559]
1-177:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-(2-
,2-difluoroethoxy)-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
[0560] 1-178:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-6-(cyclopropylmethoxy)-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
[0561] 1-179:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(2-methoxyethoxy)pyridine-3-carboxamide;
[0562] 1-180:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-[3-(difluoromet-
hoxy)-5-fluorophenyl]-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carbox-
amide; [0563] 1-181:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-difluorophenyl)-6-methylpyridine-3-carboxamide; [0564] 1-184:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(2,2-difluoro-2H-1,3-benzodiox-
ol-4-yl)-6-methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxami-
de; [0565] 1-188:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorop-
henyl]-6-methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide-
; [0566] 1-189:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide;
[0567] 1-190:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-(3,5-difluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide;
[0568] 1-191:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropoxy-N-[(1S)-1-cyclopr-
opylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0569]
1-192:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0570]
1-193:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methoxy-N-[4-(tr-
ifluoromethyl)cyclohexyl]pyridine-3-carboxamide; [0571] 1-194:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5--
(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide; [0572] 1-195:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide;
[0573] 1-196:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-{3-fluoro-
bicyclo[1.1.1]pentan-1-yl}-6-methoxypyridine-3-carboxamide; [0574]
1-197:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide;
[0575] 1-198:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S-
)-1-cyclopropylethyl]-6-(trifluoromethyl)pyridine-3-carboxamide;
[0576] 1-199:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-
-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; [0577]
1-200: ethyl
2-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carb-
amoyl]-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)acetate; [0578]
1-201: ethyl
3-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-
-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)propanoate; [0579] 1-202:
ethyl
4-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-
-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)butanoate; [0580] 1-203:
2-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-
-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)acetic acid [0581] 1-204:
3-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-
-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)propanoic acid; [0582]
1-205:
4-({4-[(3S)-3-aminopyrrolidin-1-yl]-5-[(4,4-difluorocyclohexyl)carbamoyl]-
-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)butanoic acid; [0583]
1-209:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,4-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide;
[0584] 1-210:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-5-(3,5-diflu-
orophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; [0585] 1-211:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; [0586]
1-212:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-(trifluoromethyl-
)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0587]
1-213:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-cyclohexyl-5-(3,5-difluorophenyl)-6-(tr-
ifluoromethyl)pyridine-3-carboxamide; [0588] 1-214:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluor-
ophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; [0589] 1-215:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3,5-dichlo-
rophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide; [0590] 1-216:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-{3-fluorobicyclo-
[1.1.1]pentan-1-yl}-6-(trifluoromethyl)pyridine-3-carboxamide;
[0591] 1-217:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N--
{3-fluorobicyclo[1.1.1]pentan-1-yl}-6-(trifluoromethyl)pyridine-3-carboxam-
ide; [0592] 1-218:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-(cyclopropylmethyl)-5--
(3,5-difluorophenyl)-N-methylpyridine-3-carboxamide; [0593] 1-219:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)-N-methylpyridine-3-carboxamide; [0594]
1-222:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2R)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0595]
1-223:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(1-hyd-
roxycyclopentyl)methyl]-6-methylpyridine-3-carboxamide; [0596]
1-224:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclopropyl-2-hydroxyethyl)-
-5-(3,5-difluorophenyl)-6-methylpyridine-3-carboxamide; [0597]
1-225:
4-(3-aminopyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N-(1,1,1-triflu-
oropropan-2-yl)pyridine-3-carboxamide; [0598] 1-226:
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-(1,1,1-t-
rifluoropropan-2-yl)pyridine-3-carboxamide; [0599] 1-227:
4-[(3R)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2R)-1,-
1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0600] 1-228:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-me-
thoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0601] 1-229:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluoropheny-
l)-N-[(1S)-1-cyclopropylethyl]-6-methoxypyridine-3-carboxamide;
[0602] 1-230:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3,5-difluorophenyl)-6-methyl-N--
[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0603]
1-231:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorophenyl]-6--
methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0604] 1-232:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-[3-(difluoromethoxy)phenyl]-6-me-
thyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0605] 1-233:
4-[(3S)-3-aminopyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5--
difluorophenyl)-6-methylpyridine-3-carboxamide; [0606] 1-234:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-{3-fluorobicyclo[1.1.1]pentan-1-yl}pyridine-3-carboxamide; [0607]
1-235:
(3S)-1-[3-(3,5-difluorophenyl)-2-methoxy-5-(piperidine-1-carbonyl)pyridin-
-4-yl]pyrrolidin-3-amine; [0608] 1-236:
(3S)-1-[3-(3,5-difluorophenyl)-5-(4,4-difluoropiperidine-1-carbonyl)-2-me-
thoxypyridin-4-yl]pyrrolidin-3-amine; [0609] 1-237:
(3S)-1-[3-(3,5-difluorophenyl)-5-(3,3-difluoropiperidine-1-carbonyl)-2-me-
thoxypyridin-4-yl]pyrrolidin-3-amine; [0610] 1-238:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-me-
thoxy-N-[(1,2-oxazol-3-yl)methyl]pyridine-3-carboxamide; [0611]
1-239:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5-fluorop-
henyl]-6-methoxy-N-[(1,2-oxazol-3-yl)methyl]pyridine-3-carboxamide;
[0612] 1-240:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluoropheny-
l)-6-methoxy-N-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxamide;
[0613] 1-241:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-[3-(difluoromethoxy)-5--
fluorophenyl]-6-methoxy-N-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxami-
de; [0614] 1-242:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-me-
thyl-N-[(1,2-oxazol-3-yl)methyl]pyridine-3-carboxamide; [0615]
1-243:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-me-
thyl-N-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxamide; [0616]
1-244:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-cy-
ano-N-[(1,2-oxazol-3-yl)methyl]pyridine-3-carboxamide; [0617]
1-245:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-cy-
ano-N-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxamide; [0618]
1-246:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(2-hydroxyethoxy)pyridine-3-carboxamide;
[0619] 1-247:
2-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropy-
lethyl]carbamoyl}-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)acetic
acid; [0620] 1-259:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,4-difluorophenyl)-6-methoxy-
-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0621]
1-260:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-3-fluorophenyl)-6-me-
thoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0622] 1-261:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluoropheny-
l)-6-methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0623] 1-262:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,4-difluorophenyl)-6-methoxypyridine-3-carboxamide; [0624] 1-263:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-chloro-3-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methoxypyridine-3-carboxamide; [0625]
1-264:
3-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropylethyl]-
carbamoyl}-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)propanoic acid;
[0626] 1-265:
4-({4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-{[(1S)-1-cyclopropy-
lethyl]carbamoyl}-3-(3,5-difluorophenyl)pyridin-2-yl}oxy)butanoic
acid; [0627] 1-266:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-[(oxetan-3-yl)methoxy]pyridine-3-carboxamide;
[0628] 1-267:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-(benzyloxy)-N-[(1S)-1-c-
yclopropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
[0629] 1-268:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxypheny-
l)-N-(4,4-difluorocyclohexyl)-6-methylpyridine-3-carboxamide;
[0630] 1-269:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxypheny-
l)-N-(3,3-difluorocyclobutyl)-6-methylpyridine-3-carboxamide;
[0631] 1-272:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S-
)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; [0632] 1-273:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-{3-fluo-
robicyclo[1.1.1]pentan-1-yl}-6-methoxypyridine-3-carboxamide;
[0633] 1-275:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxypheny-
l)-6-methyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0634] 1-276:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methyl-N-[(-
2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0635]
1-277:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(4,4-difluo-
rocyclohexyl)-6-methylpyridine-3-carboxamide;
[0636] 1-278:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-{3-fluorobi-
cyclo[1.1.1]pentan-1-yl}-6-methylpyridine-3-carboxamide; [0637]
1-279:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,4-difluorophenyl)-6-methyl--
N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0638]
1-280:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-cyano-5-methoxyphenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; [0639]
1-281:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-N-(4,4-difluorocyc-
lohexyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0640]
1-282:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-[(1S)-1-cyc-
lopropylethyl]-6-methoxypyridine-3-carboxamide; [0641] 1-283:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-methoxy-N-[-
(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0642]
1-284:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(4,4-difluo-
rocyclohexyl)-6-methoxypyridine-3-carboxamide; [0643] 1-285:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-(3,3-difluo-
rocyclobutyl)-6-methoxypyridine-3-carboxamide; [0644] 1-286:
4-[(3S)-3-aminopyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-N-{3-fluorobi-
cyclo[1.1.1]pentan-1-yl}-6-methoxypyridine-3-carboxamide; [0645]
1-287:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-6-me-
thyl-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0646] 1-288:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-5-(3,4-difluorophenyl)-6-methylpyridine-3-carboxamide; [0647]
1-289:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3-chloro-4-fluorophenyl)-N-[(-
1S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide; [0648]
1-290:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-5-(3,5-difluorophe-
nyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide.
[0649] In some embodiments, provided herein is a pharmaceutically
acceptable salt of a compound that is described in Table 1.
TABLE-US-00002 TABLE 2 ##STR00570## Compd No. R.sup.6R.sup.7N
##STR00571## R.sup.c 1-5 ##STR00572## ##STR00573## H 1-6
##STR00574## ##STR00575## H 1-121 ##STR00576## ##STR00577## --CN
1-128 ##STR00578## ##STR00579## --CN 1-129 ##STR00580##
##STR00581## --CN 1-131 ##STR00582## ##STR00583## H 1-134
##STR00584## ##STR00585## --CN 1-142 ##STR00586## ##STR00587## H
1-148 ##STR00588## ##STR00589## --CH.sub.3 1-155 ##STR00590##
##STR00591## --CH.sub.3 1-156 ##STR00592## ##STR00593## --CH.sub.3
1-157 ##STR00594## ##STR00595## --CH.sub.3 1-158 ##STR00596##
##STR00597## --CH.sub.3 1-159 ##STR00598## ##STR00599## --CH.sub.3
1-160 ##STR00600## ##STR00601## --CH.sub.3 1-166 ##STR00602##
##STR00603## --OCH.sub.3 1-167 ##STR00604## ##STR00605##
--OCH.sub.3 1-169 ##STR00606## ##STR00607## --CN 1-170 ##STR00608##
##STR00609## --CN 1-185 ##STR00610## ##STR00611## --OCH.sub.3 1-187
##STR00612## ##STR00613## --OCH.sub.3 1-206 ##STR00614##
##STR00615## --CF.sub.3 1-208 ##STR00616## ##STR00617## --CF.sub.3
1-248 ##STR00618## ##STR00619## --CN 1-249 ##STR00620##
##STR00621## --CN 1-250 ##STR00622## ##STR00623## --CN 1-251
##STR00624## ##STR00625## --CN 1-252 ##STR00626## ##STR00627## --CN
1-253 ##STR00628## ##STR00629## --CN 1-254 ##STR00630##
##STR00631## --CN 1-255 ##STR00632## ##STR00633## --CH.sub.3 1-256
##STR00634## ##STR00635## --CH.sub.3 1-257 ##STR00636##
##STR00637## --CH.sub.3 1-258 ##STR00638## ##STR00639## --CH.sub.3
1-270 ##STR00640## ##STR00641## --CN 1-271 ##STR00642##
##STR00643## --CN
[0650] Compounds in Table 2 are named: [0651] 1-5:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2'-cyano-N-(3-methylphenyl)-[3,4-
'-bipyridine]-5-carboxamide; [0652] 1-6: 4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,5-dimethylphenyl)-2'-methyl-[3,4-
'-bipyridine]-5-carboxamide; [0653] 1-121: 4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-
-(1-methyl-1H-pyrazol-3-yl)pyridine-3-carboxamide; [0654] 1-128:
4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropylethyl]-5-
-(2-methyl-1,3-thiazol-5-yl)pyridine-3-carboxamide; [0655] 1-129:
4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-[(1S)-1-cyclopropylethyl]-2-
'-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0656] 1-131:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2',6-
'-dimethyl-[3,4'-bipyridine]-5-carboxamide; [0657] 1-134:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(1,2-oxazol-4-yl)pyridine-3-carboxamide; [0658] 1-142:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5'-f-
luoro-[3,3'-bipyridine]-5-carboxamide; [0659] 1-148:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-me-
thyl-5-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carboxamide; [0660]
1-155:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-6-me-
thyl-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide;
[0661] 1-156:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(1-cyclopropyl-1H-pyrazol-4-yl-
)-N-[(1S)-1-cyclopropylethyl]-6-methylpyridine-3-carboxamide;
[0662] 1-157:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethy-
l]-2'-methoxy-2-methyl-[3,4'-bipyridine]-5-carboxamide; [0663]
1-158:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5'-chloro-N-[(1S)-1-cyclopropyle-
thyl]-2-methyl-[3,3'-bipyridine]-5-carboxamide; [0664] 1-159:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-me-
thyl-2'-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0665]
1-160:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5'-f-
luoro-2-methyl-[3,3'-bipyridine]-5-carboxamide; [0666] 1-166:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-me-
thoxy-2'-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0667]
1-167:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5'-chloro-N-[(1S)-1-cyclopropyle-
thyl]-2-methoxy-[3,3'-bipyridine]-5-carboxamide; [0668] 1-169:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-(trifluoromethyl)-N-[-
(2S)-1,1,1-trifluoropropan-2-yl]-[3,4'-bipyridine]-5-carboxamide;
[0669] 1-170:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-methoxy-N-[(2S-
)-1,1,1-trifluoropropan-2-yl]-[3,4'-bipyridine]-5-carboxamide;
[0670] 1-185:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-methoxy-5-(2-methylpyri-
midin-5-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0671] 1-187:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)-
-6-methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0672] 1-206:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2'-e-
thoxy-2-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0673]
1-208:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2'-m-
ethoxy-2-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0674]
1-248:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-cyclopentyl-2'-(triflu-
oromethyl)-[3,4'-bipyridine]-5-carboxamide; [0675] 1-249:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-(pentan-3-yl)-2'-(trif-
luoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0676] 1-250:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-(2-methylpropyl)-2'-(t-
rifluoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0677] 1-251:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-butyl-2-cyano-2'-(trifluoromet-
hyl)-[3,4'-bipyridine]-5-carboxamide; [0678] 1-252:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-cyclohexyl-2'-methoxy--
[3,4'-bipyridine]-5-carboxamide; [0679] 1-253:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-methoxy-N-(pentan-3-y-
l)-[3,4'-bipyridine]-5-carboxamide; [0680] 1-254:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-N-cyclopentyl-2'-methoxy-
-[3,4'-bipyridine]-5-carboxamide; [0681] 1-255:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-2'-methoxy-2-methyl-
-[3,4'-bipyridine]-5-carboxamide; [0682] 1-256:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-2'-methoxy-2-methy-
l-[3,4'-bipyridine]-5-carboxamide; [0683] 1-257:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-2-methyl-2'-(triflu-
oromethyl)-[3,4'-bipyridine]-5-carboxamide; [0684] 1-258:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-2-methyl-2'-(trifl-
uoromethyl)-[3,4'-bipyridine]-5-carboxamide; [0685] 1-270:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-methoxy-N-(2-methylpr-
opyl)-[3,4'-bipyridine]-5-carboxamide.
[0686] In some embodiments, provided herein is a pharmaceutically
acceptable salt of a compound that is described in Table 2.
TABLE-US-00003 TABLE 3 ##STR00644## Compd No. R.sup.6R.sup.7N
R.sup.11 R.sup.12 2-1 ##STR00645## --CH.sub.3 H 2-2 ##STR00646##
--CH.sub.3 H 2-3 ##STR00647## --CH.sub.3 H 2-4 ##STR00648##
--CH.sub.3 H 2-5 ##STR00649## --CH.sub.3 H 2-6 ##STR00650##
--CH.sub.3 H 2-7 ##STR00651## --CH.sub.3 H 2-8 ##STR00652##
--CH.sub.3 H 2-9 ##STR00653## --CH.sub.3 H 2-10 ##STR00654##
--CH.sub.3 H 2-11 ##STR00655## --CH.sub.3 H 2-12 ##STR00656##
--CH.sub.3 H 2-13 ##STR00657## --CH.sub.3 H 2-14 ##STR00658##
--CH.sub.3 H 2-15 ##STR00659## --CH.sub.3 H 2-16 ##STR00660##
--CH.sub.3 H 2-17 ##STR00661## --CH.sub.3 H 2-18 ##STR00662##
--CH.sub.3 H 2-19 ##STR00663## --CH.sub.3 H 2-20 ##STR00664##
--CH.sub.3 H 2-21 ##STR00665## --CH.sub.3 H 2-22 ##STR00666##
--CH.sub.3 H 2-23 ##STR00667## --CH.sub.3 H 2-24 ##STR00668## --F H
2-25 ##STR00669## --CH.sub.3 H 2-26 ##STR00670## --CH.sub.3 H 2-27
##STR00671## --CH.sub.3 H 2-28 ##STR00672## --CH.sub.3 H 2-29
##STR00673## --CH.sub.3 --F 2-30 ##STR00674## --CH.sub.3 --F 2-31
##STR00675## --CH.sub.3 H 2-32 ##STR00676## --CH.sub.3 H 2-33
##STR00677## --CH.sub.3 H 2-34 ##STR00678## --CH.sub.3 H 2-35
##STR00679## --CH.sub.3 H 2-36 ##STR00680## --CH.sub.3 H 2-37
##STR00681## --CH.sub.3 H 2-38 ##STR00682## --CH.sub.3 H 2-39
##STR00683## --CH.sub.3 H 2-40 ##STR00684## --CH.sub.3 H 2-41
##STR00685## --CH.sub.3 H 2-42 ##STR00686## --CH.sub.3 H 2-43
##STR00687## --CH.sub.3 H 2-44 ##STR00688## --CH.sub.3 H 2-45
##STR00689## --Cl H * racemic
[0687] Compounds in Table 3 are named: [0688] 2-1:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-ethyl-5-(4-methyl-1H-1,3-benzo-
diazol-2-yl)pyridine-3-carboxamide; [0689] 2-2:
(3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-(pyrrolidine-1-ca-
rbonyl)pyridin-4-yl]pyrrolidin-3-amine; [0690] 2-3:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-ethyl-N-methyl-5-(4-methyl-1H--
1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0691] 2-4:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-5-(4-methyl-1H-1,3-
-benzodiazol-2-yl)pyridine-3-carboxamide; [0692] 2-5:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-(oxolan-3-yl)pyridine-3-carboxamide; [0693] 2-6:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-phenylpyridine-3-carboxamide; [0694] 2-7:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide; [0695] 2-8:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2-methoxyethyl)-5-(4-methyl-1-
H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0696] 2-9:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(2-hydroxyethyl)-5-(4-methyl-1-
H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0697] 2-10:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-methyl-5-(4-methyl-1H-1,3-benz-
odiazol-2-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-carboxamide;
[0698] 2-11:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0699] 2-12:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopropyl-5-(4-methyl--
1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0700] 2-13:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclopropylmethyl)-5-(4-methy-
l-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0701] 2-14:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(1-cyclopropylethyl)-5-(4-meth-
yl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0702] 2-15:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5--
(4-methyl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0703]
2-16:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-N-methyl-5-(4-meth-
yl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0704] 2-17:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(4--
methyl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0705] 2-18:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-[(2R)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0706] 2-19:
(3S)-1-[3-(3,3-dimethylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-b-
enzodiazol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0707]
2-20:
(3S)-1-[3-(2,2-dimethylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodi-
azol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0708] 2-21:
(3S)-1-[3-(3,3-dimethylazetidine-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiaz-
ol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0709] 2-22:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopropyl-N-methyl-5-(4-meth-
yl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0710] 2-23:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclopropylmethyl)-N-methyl-5-
-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0711]
2-24:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-fluoro-1H-1,3-benzodiazol-2-
-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0712] 2-25:
(3S)-1-[3-(3,3-difluoropyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-b-
enzodiazol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0713]
2-26:
(3S)-1-(3-{2-azatricyclo[3.3.1.1.sup.3,7]decane-2-carbonyl}-5-(4-methyl-1-
H-1,3-benzodiazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine;
[0714] 2-27:
(3S)-1-[3-(3-tert-butylpyrrolidine-1-carbonyl)-5-(4-methyl-1H-1,3-b-
enzodiazol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0715]
2-28:
(3S)-1-{3-[(2R,6S)-2,6-dimethylmorpholine-4-carbonyl]-5-(4-methyl-1H-1,3--
benzodiazol-2-yl)pyridin-4-yl}-3-methylpyrrolidin-3-amine; [0716]
2-29:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-N-me-
thyl-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide;
[0717] 2-30:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,-
3-benzodiazol-2-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxam-
ide; [0718] 2-31:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(cyclobutylmethyl)-5-(4-methyl-
-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0719] 2-32:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-(4,4,4-trifluorobutan-2-yl)pyridine-3-carboxamide; [0720]
2-33:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[2.2.1]heptan-1-yl}-5--
(4-methyl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0721]
2-34:
(3S)-1-[3-(2,3-dihydro-1H-indole-1-carbonyl)-5-(4-methyl-1H-1,3-benzodiaz-
ol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0722] 2-35:
(3S)-1-(3-{2-azabicyclo[2.2.2]octane-2-carbonyl}-5-(4-methyl-1H-1,3-benzo-
diazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine; [0723] 2-36:
(3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-[2-(propan-2-yl)p-
yrrolidine-1-carbonyl]pyridin-4-yl]pyrrolidin-3-amine; [0724] 2-37:
(3S)-1-{3-[(3aR)-octahydrocyclopenta[b]pyrrole-1-carbonyl]-5-(4-methyl-TH-
-1,3-benzodiazol-2-yl)pyridin-4-yl}-3-methylpyrrolidin-3-amine;
[0725] 2-38:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-5-(4-methyl-1-
H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide; [0726] 2-39:
(3S)-1-(3-{5-azaspiro[2.4]heptane-5-carbonyl}-5-(4-methyl-TH-1,3-benzodia-
zol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine; [0727] 2-40:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-[(2S)-1,1,1-trifluorobutan-2-yl]pyridine-3-carboxamide;
[0728] 2-41:
(3S)-3-methyl-1-[3-(4-methyl-TH-1,3-benzodiazol-2-yl)-5-[(2S)-2-(tr-
ifluoromethyl)pyrrolidine-1-carbonyl]pyridin-4-yl]pyrrolidin-3-amine;
[0729] 2-42:
(3S)-1-[3-(3-cyclopropylpyrrolidine-1-carbonyl)-5-(4-methyl-TH-1,3-benzod-
iazol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0730] 2-43:
(3S)-1-[3-(2-cyclopropylpyrrolidine-1-carbonyl)-5-(4-methyl-TH-1,3-benzod-
iazol-2-yl)pyridin-4-yl]-3-methylpyrrolidin-3-amine; [0731] 2-44:
(3S)-3-methyl-1-[3-(4-methyl-1H-1,3-benzodiazol-2-yl)-5-[3-(trifluorometh-
yl)pyrrolidine-1-carbonyl]pyridin-4-yl]pyrrolidin-3-amine; [0732]
2-45:
(3S)-1-(3-{2-azatricyclo[3.3.1.1.sup.3,7]decane-2-carbonyl}-5-(7-chloro-1-
H-1,3-benzodiazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-amine.
[0733] In some embodiments, provided herein is a pharmaceutically
acceptable salt of a compound that is described in Table 3.
TABLE-US-00004 TABLE 4 ##STR00690## Compd No. R.sup.6R.sup.7N
##STR00691## R.sup.c 1-161 ##STR00692## ##STR00693## H 1-162
##STR00694## ##STR00695## H 1-182 ##STR00696## ##STR00697##
--OCH.sub.3 1-183 ##STR00698## ##STR00699## --OCH.sub.3 1-186
##STR00700## ##STR00701## --OCH.sub.3
[0734] Compounds in Table 4 are named: [0735] 1-161: 4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(1-meth-
yl-1H-indazol-6-yl)pyridine-3-carboxamide; [0736] 1-162: 4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(1-meth-
yl-1H-indazol-4-yl)pyridine-3-carboxamide; [0737] 1-182: 4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-6-methoxy-5-(1-methyl-1H-1,3-benzodia-
zol-6-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide;
[0738] 1-183: 4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-6-methoxy-5-(1-methyl-1H-indazol-4-yl-
)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide; [0739]
1-186: 4-[(3
S)-3-amino-3-methylpyrrolidin-1-yl]-5-(2,1,3-benzoxadiazol-5-yl)-6--
methoxy-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide.
[0740] In some embodiments, provided herein is a pharmaceutically
acceptable salt of a compound that is described in Table 4.
TABLE-US-00005 TABLE 5 ##STR00702## Compd No. R.sup.6R.sup.7N
R.sup.e R.sup.d R.sup.c 1-2 ##STR00703## ##STR00704## ##STR00705##
H 1-36 ##STR00706## ##STR00707## ##STR00708## H 1-63 ##STR00709##
##STR00710## ##STR00711## H 1-75 ##STR00712## ##STR00713## H --CN
1-99 ##STR00714## ##STR00715## ##STR00716## --CN 1-100 ##STR00717##
##STR00718## ##STR00719## --CN 1-102 ##STR00720## ##STR00721##
##STR00722## --CN 1-117 ##STR00723## ##STR00724## ##STR00725## --CN
1-119 ##STR00726## ##STR00727## ##STR00728## --CN 1-136
##STR00729## ##STR00730## ##STR00731## --CN 1-139 ##STR00732##
##STR00733## ##STR00734## --CN 1-220 ##STR00735## ##STR00736##
##STR00737## --CN 1-221 ##STR00738## ##STR00739## ##STR00740## --CN
1-274 ##STR00741## ##STR00742## Br --OCH.sub.3 * absolute
stereochemistry not determined
[0741] Compounds in Table 5 are named: [0742] 1-2:
4-[(3R)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-car-
boxamide; [0743] 1-36:
4-[3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl-
}-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0744] 1-63:
4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5-(3,5-di-
fluorophenyl)pyridine-3-carboxamide; [0745] 1-75:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6--
cyanopyridine-3-carboxamide; [0746] 1-99:
4-[(3R)-3-amino-3-(hydroxymethyl)pyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-
-1-yl}-6-cyano-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0747]
1-100:
4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-6-cyano-5-
-(3,5-difluorophenyl)pyridine-3-carboxamide; [0748] 1-102:
4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-
-6-cyano-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0749]
1-117:
4-[(3S)-3-amino-3-(methoxymethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclo-
propylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0750]
1-119:
4-[(3R)-3-amino-3-(2,2-difluoroethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-c-
yclopropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide;
[0751] 1-136:
4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cycl-
opropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0752]
1-139:
4-[(3S,4S)-3-amino-4-fluoropyrrolidin-1-yl]-5-(3-chloro-5-fluorophenyl)-6-
-cyano-N-[(1S)-1-cyclopropylethyl]pyridine-3-carboxamide; [0753]
1-220:
4-[(3S)-3-amino-3-(fluoromethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclop-
ropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0754]
1-221:
4-[(3R)-3-amino-3-(fluoromethyl)pyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclop-
ropylethyl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide; [0755]
1-274:
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-bromo-6-methoxy-N-[(2S)-1,1,1--
trifluoropropan-2-yl]pyridine-3-carboxamide.
[0756] In some embodiments, provided herein is a pharmaceutically
acceptable salt of a compound that is described in Table 5.
TABLE-US-00006 TABLE 6 ##STR00743## Compd No. R.sup.6R.sup.7N 3-1
##STR00744## 3-2 ##STR00745## 3-3 ##STR00746## 3-4 ##STR00747## 3-5
##STR00748## 3-6 ##STR00749## 3-7 ##STR00750## 3-8 ##STR00751##
[0757] Compounds in Table 6 are named: [0758] 3-1:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-(3-
,5-difluorophenyl)pyridine-4-carboxamide; [0759] 3-2:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclohexyl-2-(3,5-difluorophen-
yl)pyridine-4-carboxamide; [0760] 3-3:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-(3,5-difluorophenyl)-N-[(1S)-1-
-phenylethyl]pyridine-4-carboxamide; [0761] 3-4:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-2-(3,5-d-
ifluorophenyl)pyridine-4-carboxamide; [0762] 3-5:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[2.2.1]heptan-1-yl}-2--
(3,5-difluorophenyl)pyridine-4-carboxamide; [0763] 3-6:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cycloheptyl-2-(3,5-difluorophe-
nyl)pyridine-4-carboxamide; [0764] 3-7:
N-(adamantan-1-yl)-3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-(3,5-difluo-
rophenyl)pyridine-4-carboxamide; [0765] 3-8:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-cyclopentyl-2-(3,5-difluorophe-
nyl)pyridine-4-carboxamide.
[0766] In some embodiments, provided herein is a pharmaceutically
acceptable salt of a compound that is described in Table 6.
TABLE-US-00007 TABLE 7 ##STR00752## Compd No. R.sup.6R.sup.7N
R.sup.c 4-1 ##STR00753## --Cl 4-2 ##STR00754## --CH.sub.3 4-3
##STR00755## --CN 4-4 ##STR00756## --CO.sub.2CH.sub.3 4-5
##STR00757## --CONH.sub.2
[0767] Compounds in Table 7 are named: [0768] 4-1:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-chloro-N-[(1S)-1-cyclopropylet-
hyl]-4-(3,5-difluorophenyl)pyridine-2-carboxamide; [0769] 4-2:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-4-(3-
,5-difluorophenyl)-5-methylpyridine-2-carboxamide; [0770] 4-3:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-cyano-N-[(1S)-1-cyclopropyleth-
yl]-4-(3,5-difluorophenyl)pyridine-2-carboxamide; [0771] 4-4:
methyl
5-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-{[(1S)-1-cyclopropylethyl]
carbamoyl}-4-(3,5-difluorophenyl)pyridine-3-carboxylate; [0772]
4-5:
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N2-[(1S)-1-cyclopropylethyl]-4-(-
3,5-difluorophenyl)pyridine-2,5-dicarboxamide.
[0773] In some embodiments, provided herein is a pharmaceutically
acceptable salt of a compound that is described in Table 7.
[0774] In one aspect, compounds described herein are in the form of
pharmaceutically acceptable salts. As well, active metabolites of
these compounds having the same type of activity are included in
the scope of the present disclosure. In addition, the compounds
described herein can exist in unsolvated as well as solvated forms
with pharmaceutically acceptable solvents such as water, ethanol,
and the like. The solvated forms of the compounds presented herein
are also considered to be disclosed herein.
[0775] "Pharmaceutically acceptable," as used herein, refers 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 is 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.
[0776] The term "pharmaceutically acceptable salt" refers to a form
of a therapeutically active agent that consists of a cationic form
of the therapeutically active agent in combination with a suitable
anion, or in alternative embodiments, an anionic form of the
therapeutically active agent in combination with a suitable cation.
Handbook of Pharmaceutical Salts: Properties, Selection and Use.
International Union of Pure and Applied Chemistry, Wiley-VCH 2002.
S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977,
66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of
Pharmaceutical Salts: Properties, Selection and Use,
Weinheim/Zurich:Wiley-VCH/VHCA, 2002. Pharmaceutical salts
typically are more soluble and more rapidly soluble in stomach and
intestinal juices than non-ionic species and so are useful in solid
dosage forms. Furthermore, because their solubility often is a
function of pH, selective dissolution in one or another part of the
digestive tract is possible and this capability can be manipulated
as one aspect of delayed and sustained release behaviors. Also,
because the salt-forming molecule can be in equilibrium with a
neutral form, passage through biological membranes can be
adjusted.
[0777] In some embodiments, pharmaceutically acceptable salts are
obtained by reacting a compound of Formula (I) with an acid. In
some embodiments, the compound of Formula (I) (i.e. free base form)
is basic and is reacted with an organic acid or an inorganic acid.
Inorganic acids include, but are not limited to, hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
metaphosphoric acid. Organic acids include, but are not limited to,
1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid;
2-hydroxyethanesulfonic acid; 2-oxoglutaric acid;
4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic
acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid;
benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+);
capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic
acid (octanoic acid); carbonic acid; cinnamic acid; citric acid;
cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid;
ethanesulfonic acid; formic acid; fumaric acid; galactaric acid;
gentisic acid; glucoheptonic acid (D); gluconic acid (D);
glucuronic acid (D); glutamic acid; glutaric acid;
glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric
acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid;
malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic
acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid;
nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic
acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L);
salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric
acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid
(p); and undecylenic acid.
[0778] In some embodiments, a compound of Formula (I) is prepared
as a chloride salt, sulfate salt, bromide salt, mesylate salt,
maleate salt, citrate salt or phosphate salt.
[0779] In some embodiments, pharmaceutically acceptable salts are
obtained by reacting a compound of Formula (I) with a base. In some
embodiments, the compound of Formula (I) is acidic and is reacted
with a base. In such situations, an acidic proton of the compound
of Formula (I) is replaced by a metal ion, e.g., lithium, sodium,
potassium, magnesium, calcium, or an aluminum ion. In some cases,
compounds described herein coordinate with an organic base, such
as, but not limited to, ethanolamine, diethanolamine,
triethanolamine, tromethamine, meglumine, N-methylglucamine,
dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases,
compounds described herein form salts with amino acids such as, but
not limited to, arginine, lysine, 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, potassium
carbonate, sodium hydroxide, lithium hydroxide, and the like. In
some embodiments, the compounds provided herein are prepared as a
sodium salt, calcium salt, potassium salt, magnesium salt,
meglumine salt, N-methylglucamine salt or ammonium salt.
[0780] It should be understood that a reference to a
pharmaceutically acceptable salt includes the solvent addition
forms. In some embodiments, solvates contain either stoichiometric
or non-stoichiometric amounts of a solvent, and are 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 are
conveniently prepared or formed during the processes described
herein. In addition, the compounds provided herein optionally exist
in unsolvated as well as solvated forms.
[0781] The methods and formulations described herein include the
use of N-oxides (if appropriate), or pharmaceutically acceptable
salts of compounds having the structure of Formula (I), as well as
active metabolites of these compounds having the same type of
activity.
[0782] In some embodiments, sites on the organic radicals (e.g.
alkyl groups, aromatic rings) of compounds of Formula (I) are
susceptible to various metabolic reactions. Incorporation of
appropriate substituents on the organic radicals will reduce,
minimize or eliminate this metabolic pathway. In specific
embodiments, the appropriate substituent to decrease or eliminate
the susceptibility of the aromatic ring to metabolic reactions is,
by way of example only, a halogen, deuterium, an alkyl group, a
haloalkyl group, or a deuteroalkyl group.
[0783] In another embodiment, the compounds described herein are
labeled isotopically (e.g. with a radioisotope) or by another other
means, including, but not limited to, the use of chromophores or
fluorescent moieties, bioluminescent labels, or chemiluminescent
labels.
[0784] Compounds described herein include isotopically-labeled
compounds, which are identical to those recited in the various
formulae and structures presented herein, but for the fact that one
or more atoms are replaced by an atom having an atomic mass or mass
number different from the atomic mass or mass number usually found
in nature. Examples of isotopes that can be incorporated into the
present compounds include isotopes of hydrogen, carbon, nitrogen,
oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for
example, .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O,
.sup.7O, .sup.35S, .sup.18F, .sup.36Cl, .sup.123I, .sup.124I,
.sup.125I, .sup.131I .sup.32P and .sup.33P. In one aspect,
isotopically-labeled compounds described herein, for example those
into which radioactive isotopes such as .sup.3H and .sup.14C are
incorporated, are useful in drug and/or substrate tissue
distribution assays. In one aspect, substitution with isotopes such
as deuterium affords certain therapeutic advantages resulting from
greater metabolic stability, such as, for example, increased in
vivo half-life or reduced dosage requirements.
[0785] In some embodiments, the compounds of Formula (I) possess
one or more stereocenters and each stereocenter exists
independently in either the R or S configuration. In some
embodiments, the compound of Formula (I) exists in the R
configuration. In some embodiments, the compound of Formula (I)
exists in the S configuration. The compounds presented herein
include all diastereomeric, individual enantiomers, atropisomers,
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.
[0786] Individual stereoisomers are obtained, if desired, by
methods such as, stereoselective synthesis and/or the separation of
stereoisomers by chiral chromatographic columns or the separation
of diastereomers by either non-chiral or chiral chromatographic
columns or crystallization and recrystallization in a proper
solvent or a mixture of solvents. In certain embodiments, compounds
of Formula (I) 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 individual enantiomers. In some embodiments,
resolution of individual 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.
[0787] In some embodiments, compounds described herein are prepared
as prodrugs. A "prodrug" refers to an agent that is converted into
the parent drug in vivo. Prodrugs are often useful because, in some
situations, they are easier to administer than the parent drug.
They are, for instance, bioavailable by oral administration whereas
the parent is not. Further or alternatively, the prodrug also has
improved solubility in pharmaceutical compositions over the parent
drug. In some embodiments, the design of a prodrug increases the
effective water solubility. An example, without limitation, of a
prodrug is a compound described herein, which is administered as an
ester (the "prodrug") but then is metabolically hydrolyzed to
provide the active entity. A further example of a prodrug is a
short peptide (polyaminoacid) bonded to an acid group where the
peptide is metabolized to reveal the active moiety. In certain
embodiments, upon in vivo administration, a prodrug is chemically
converted to the biologically, pharmaceutically or therapeutically
active form of the compound. In certain embodiments, a prodrug is
enzymatically metabolized by one or more steps or processes to the
biologically, pharmaceutically or therapeutically active form of
the compound.
[0788] Prodrugs of the compounds described herein include, but are
not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl
derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl
derivatives, quaternary derivatives of tertiary amines, N-Mannich
bases, Schiff bases, amino acid conjugates, phosphate esters, and
sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.
Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al.,
Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and
Application of Prodrugs" in A Textbook of Drug Design and
Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter
5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review,
1992, 8, 1-38, each of which is incorporated herein by reference.
In some embodiments, a hydroxyl group in the compounds disclosed
herein is used to form a prodrug, wherein the hydroxyl group is
incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl
ester, alkyl ester, aryl ester, phosphate ester, sugar ester,
ether, and the like. In some embodiments, a hydroxyl group in the
compounds disclosed herein is a prodrug wherein the hydroxyl is
then metabolized in vivo to provide a carboxylic acid group. In
some embodiments, a carboxyl group is used to provide an ester or
amide (i.e. the prodrug), which is then metabolized in vivo to
provide a carboxylic acid group. In some embodiments, compounds
described herein are prepared as alkyl ester prodrugs.
[0789] Prodrug forms of the herein described compounds, wherein the
prodrug is metabolized in vivo to produce a compound of Formula (I)
as set forth herein are included within the scope of the claims. In
some cases, some of the herein-described compounds is a prodrug for
another derivative or active compound.
[0790] In some embodiments, any one of the hydroxyl group(s), amino
group(s) and/or carboxylic acid group(s) are functionalized in a
suitable manner to provide a prodrug moiety. In some embodiments,
the prodrug moiety is as described above.
[0791] In additional or further embodiments, the compounds
described herein are metabolized upon administration to an organism
in need to produce a metabolite that is then used to produce a
desired effect, including a desired therapeutic effect.
[0792] A "metabolite" of a compound disclosed herein is a
derivative of that compound that is formed when the compound is
metabolized. The term "active metabolite" refers to a biologically
active derivative of a compound that is formed when the compound is
metabolized. The term "metabolized," as used herein, refers to the
sum of the processes (including, but not limited to, hydrolysis
reactions and reactions catalyzed by enzymes) by which a particular
substance is changed by an organism. Thus, enzymes may produce
specific structural alterations to a compound. For example,
cytochrome P450 catalyzes a variety of oxidative and reductive
reactions while uridine diphosphate glucuronyltransferases catalyze
the transfer of an activated glucuronic-acid molecule to aromatic
alcohols, aliphatic alcohols, carboxylic acids, amines and free
sulfhydryl groups. Metabolites of the compounds disclosed herein
are optionally identified either by administration of compounds to
a host and analysis of tissue samples from the host, or by
incubation of compounds with hepatic cells in vitro and analysis of
the resulting compounds.
[0793] In some instances, heterocyclic rings may exist in
tautomeric forms. In such situations, it is understood that the
structures of said compounds are illustrated or named in one
tautomeric form but could be illustrated or named in the
alternative tautomeric form. The alternative tautomeric forms are
expressly included in this disclosure, such as, for example, the
structures illustrated below. For example, benzimidazoles or
imidazoles could exist in the following tautomeric forms:
##STR00758##
Synthesis of Compounds
[0794] Compounds of Formula (I) described herein are synthesized
using standard synthetic techniques or using methods known in the
art in combination with methods described herein.
[0795] Unless otherwise indicated, conventional methods of mass
spectroscopy, NMR, HPLC are employed.
[0796] Compounds are prepared using standard organic chemistry
techniques such as those described in, for example, March's
Advanced Organic Chemistry, 6.sup.th Edition, John Wiley and Sons,
Inc. Alternative reaction conditions for the synthetic
transformations described herein may be employed such as variation
of solvent, reaction temperature, reaction time, as well as
different chemical reagents and other reaction conditions.
[0797] In some embodiments, compounds described herein are prepared
as described in Scheme A.
##STR00759##
[0798] Nucleophilic substitution of I with protected
aminopyrrolidine afforded intermediate II, which was subsequently
converted to intermediate III by an organometallic coupling
reaction such as Suzuki-Miyaura reaction with a boronic acid
(R.sup.dB(OH).sub.2) or its ester or an organotrifluoroborate
(R.sup.dBF.sub.3K). Aldehyde III was treated with oxidative
reagents such as NaClO.sub.2 to generate the corresponding acid IV,
which was coupled with amines to produce amide intermediate V in
the presence of coupling reagents such as HATU or
1-Chloro-N,N,2-trimethyl-1-propenylamine (Ghosez's reagent).
Alternative, aldehyde II was treated with oxidative reagents such
as NaClO.sub.2 to generate acid VII, which could react with amines
to produce amide intermediate VIII in the presence of coupling
reagents such as HATU. This compound underwent organometallic
coupling reaction such as Suzuki-Miyaura reaction to generate
compound V. Rremoval of the protecting group using appropriate
de-protection methods yielded final compound VI.
[0799] In some other embodiments, compounds described herein are
prepared as described in Scheme B.
##STR00760## ##STR00761##
[0800] Nucleophilic substitution of IX with protected
aminopyrrolidine afforded intermediate X, which was halogenated to
afford compound XI. Subsequently, XI was converted to intermediate
XII by an organometallic coupling reaction such as Suzuki-Miyaura
reaction with a boronic acid (R.sup.dB(OH).sub.2) or its ester or
an organotrifluoroborate (R.sup.dBF.sub.3K). Compound XII was
converted to nitrile XIII using an organometallic cyanation
reaction, which was treated with oxidative reagents such as
NaClO.sub.2 to generate acid XIV. This compound could react with
amines to produce amide XV in the presence of coupling reagents
such as HATU. Alternatively, 4,6-dichloronicotinate XVII was
converted to nitrile XVIII by an organometallic cyanation reaction,
which underwent nucleophilic substitution with protected
aminopyrrolidine to produce intermediate XIX. Subsequently, this
compound was treated with halogenation reagents such as NBS or
1-bromopyrrolidine-2,5-dione to produce XX. Intermediate XX was
converted to XXI using an organometallic coupling reaction such as
Suzuki-Miyaura reaction, which was hydrolyzed to acid XIV in the
presence of base. Intermediate XIX could also be converted to acid
XXV, which was allowed to react with amines to generated amide
XXVI. Subsequent halogenation followed by an organometallic
coupling reaction such as Suzuki-Miyaura reaction produced
intermediate XV. Intermediate XXVI was also synthesized using a
different method. Nucleophilic substitution of XVII with protected
aminopyrrolidine afforded intermediate XXII, which was hydrolyzed
under basic conditions followed by coupling with appropriate amines
to produce amides XXIII. This compound was subject to
organometallic carbonylation conditions and the resulting ester XIV
was converted to corresponding amides which could be readily
dehydrated to nitrile XXVI. Removal of the protecting group of
intermediate XV using appropriate de-protection methods yielded
final compound XVI.
[0801] In some other embodiments, compounds described herein are
prepared as described in Scheme C.
##STR00762##
[0802] Nucleophilic substitution of IX with protected
aminopyrrolidine afforded intermediate X, which was brominated to
afford intermediate XI. Subsequently, compound XI was converted to
intermediate XII by an organometallic coupling reaction such as
Suzuki-Miyaura reaction, which underwent another organometallic
coupling reaction to introduce R group to afford XXVIII. This
compound was treated with oxidative reagents such as NaClO.sub.2 to
generate acid XXIX, which could react with amines to produce amide
XXX in the presence of coupling reagents such as HATU or Ghosez's
reagent. Alternatively, nucleophilic substitution of
4,6-dichloronicotinate XVII with protected aminopyrrolidine
afforded intermediate XXXII, which was hydrolyzed under basic
conditions followed by coupling with amines to produce amides
XXXIII. This compound was converted to intermediate XXXIV by an
organometallic coupling reaction to introduce R.sup.c group.
Halogenation of intermediate XXXIV led to the formation of
intermediate XXXV, which could be converted to compound XXX by an
organometallic coupling reaction such as Suzuki-Miyaura reaction.
Alternatively, 4,6-dichloronicotinate XVII was converted to XXXII,
then converted to XXXVI by an organometallic coupling reaction
followed by halogenation to afforded compound XXVII. This compound
was converted to intermediate XXXVIII by an organometallic coupling
reaction such as Suzuki-Miyaura reaction, which was hydrolyzed to
produce acid XXIX under basic conditions. Removing the protecting
group of intermediate XXX using appropriate de-protection methods
yielded final compound XXXI.
[0803] In some other embodiments, compounds described herein are
prepared as described in Scheme D.
##STR00763##
[0804] Nucleophilic substitution of 4,6-dichloronicotinate XVII
with protected aminopyrrolidine afforded intermediate XXXII, which
was treated with alkoxide with or without organometallic catalysts
to generated compound XXXIX. Subsequent halogenation followed an
organometallic coupling reaction such as Suzuki-Miyaura reaction
afforded intermediate XLI. This compound was converted to acid XLII
under basic conditions, which coupled with amines to produce amide
XLIII in the presence of coupling reagents such as HATU or Ghosez's
reagent. Removing the protecting group of intermediate XLIII using
appropriate de-protection methods yielded final compound XLIV.
Alternatively, ester XXXII was converted to acid XLV under basic
conditions, which coupled with amines to produce amide XLVI in the
presence of coupling reagents such as HATU or Ghosez's reagent.
Subsequent halogenation followed by an organometallic coupling
reaction such as Suzuki-Miyaura reaction afforded intermediate
XLVIII. Removal of protecting group using appropriate de-protection
methods followed by treating with alkoxide led to the formation of
final compound XLIV.
[0805] In some other embodiments, compounds described herein are
prepared as described in Scheme E.
##STR00764##
[0806] Nucleophilic substitution of I with protected
aminopyrrolidine afforded intermediate II, which was treated with
1,2-diaminobenzenes by heating in wet DMF or NMP or DMSO or other
solvents with or without Na.sub.2S.sub.2O.sub.5 under atmospheric
oxygen to yield benzimidazole LII. Subsequently, LII was converted
to ester LIII by an organometallic carbonylation reaction.
Alternative, compound II could be converted to ester L by an
organometallic carbonylation reaction, which was treated with
1,2-diaminobenzenes by heating in wet DMF or NMP or DMSO or other
solvents with or without Na.sub.2S.sub.2O.sub.5 under atmospheric
oxygen to yield benzimidazole LIII. Alternatively, aldehyde I could
react with 1,2-diaminobenzenes by heating in wet DMF or NMP or DMSO
or other solvents with or without Na.sub.2S.sub.2O.sub.5 under
atmospheric oxygen to yield imidazole LI, which underwent
nucleophilic substitution with protected aminopyrrolidine to
produce intermediate LII. Subsequently, ester LIII was converted to
acid LIV under basic conditions, which was treated with amines to
produce amide LV in the presence of coupling reagents such as HATU.
Removal of the protecting group using appropriate de-protection
methods yielded final compound LVI.
[0807] In some other embodiments, compounds described herein are
prepared as described in Scheme F.
##STR00765##
[0808] Nucleophilic substitution of LVII with protected
aminopyrrolidine afforded intermediate LVIII, which was converted
to compound LIX by an organometallic coupling reaction such as
Suzuki-Miyaura reaction. Basic hydrolysis of ester LIX led to the
formation of acid LX, which reacted with amines in the presence of
amide coupling reagents such as HATU to produce intermediate LXI.
Removal of the protecting group using appropriate de-protection
methods yielded final compound LXII.
[0809] In some other embodiments, compounds described herein are
prepared as described in Scheme G.
##STR00766##
[0810] Transition-metal catalyzed cyanation of bromo-pyridine LXIII
afforded nitrile intermediate LXIV, which underwent iodination to
generate LXV in the presence of strong base such as LDA. Compound
LXV was converted to intermediate LXVI by an organometallic
coupling reaction such as Suzuki-Miyaura reaction. Subsequent
nucleophilic substitution with protected aminopyrrolidine afforded
intermediate LXVII, which was hydrolyzed to acid LXVIII under basic
conditions. Compound LXVIII was treated with amines in the presence
of coupling reagents such as HATU to produce amide LXIX. Removal of
the protecting group using appropriate de-protection methods
yielded final compound LXX. Compound LXIX could be converted to
intermediate LXXI by an organometallic coupling reaction such as
Suzuki-Miyaura reaction. Removal of the protecting group using
appropriate de-protection methods yielded final compound LXXII.
[0811] In some embodiments, compounds are prepared as described in
the Examples.
Certain Terminology
[0812] Unless otherwise stated, the following terms used in this
application have the definitions given below. The 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.
[0813] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x. By way of example only, a
group designated as "C.sub.1-C.sub.6" indicates that there are one
to six carbon atoms in the moiety, i.e. groups containing 1 carbon
atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by
way of example only, "C.sub.1-C.sub.4 alkyl" indicates that there
are one to four carbon atoms in the alkyl group, i.e., the alkyl
group is selected from among methyl, ethyl, propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, and t-butyl.
[0814] An "alkyl" group refers to an aliphatic hydrocarbon group.
The alkyl group is branched or straight chain. In some embodiments,
the "alkyl" group has 1 to 10 carbon atoms, i.e. a
C.sub.1-C.sub.10alkyl. Whenever it appears herein, a numerical
range such as "1 to 10" refers to each integer in the given range;
e.g., "1 to 10 carbon atoms" means that the alkyl group consist of
1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 10 carbon atoms, although the present definition also
covers the occurrence of the term "alkyl" where no numerical range
is designated. In some embodiments, an alkyl is a
C.sub.1-C.sub.6alkyl. In one aspect the alkyl is methyl, ethyl,
propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or 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, or hexyl.
[0815] An "alkylene" group refers to a divalent alkyl radical. Any
of the above mentioned monovalent alkyl groups may be an alkylene
by abstraction of a second hydrogen atom from the alkyl. In some
embodiments, an alkelene is a C.sub.1-C.sub.6alkylene. In other
embodiments, an alkylene is a C.sub.1-C.sub.4alkylene. Typical
alkylene groups include, but are not limited to, --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the like. In some
embodiments, an alkylene is --CH.sub.2--.
[0816] An "alkoxy" group refers to a (alkyl)O-- group, where alkyl
is as defined herein.
[0817] The term "alkylamine" refers to the --N(alkyl).sub.xH.sub.y
group, where x is 0 and y is 2, or where x is 1 and y is 1, or
where x is 2 and y is 0.
[0818] An "hydroxyalkyl" refers to an alkyl in which one hydrogen
atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl
is a C.sub.1-C.sub.4hydroxyalkyl. Typical hydroxyalkyl groups
include, but are not limited to, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2OH, and the like.
[0819] An "aminoalkyl" refers to an alkyl in which one hydrogen
atom is replaced by an amino. In some embodiments, aminoalkyl is a
C.sub.1-C.sub.4aminoalkyl. Typical aminoalkyl groups include, but
are not limited to, --CH.sub.2NH.sub.2, --CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, and the like.
[0820] 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. In some embodiments, an alkenyl is selected from ethenyl
(i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl,
pentadienyl, and the like. 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.
[0821] 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 alkenyl 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. In some embodiments, an
alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl,
hexynyl, and the like. 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.
[0822] The term "heteroalkyl" refers to an alkyl group in which one
or more skeletal atoms of the alkyl are selected from an atom other
than carbon, e.g., oxygen, nitrogen (e.g. --NH--, --N(alkyl)-,
sulfur, or combinations thereof. A heteroalkyl is attached to the
rest of the molecule at a carbon atom of the heteroalkyl. In one
aspect, a heteroalkyl is a C.sub.1-C.sub.6heteroalkyl.
[0823] The term "aromatic" refers to a planar ring having a
delocalized .pi.-electron system containing 4n+2 .pi.electrons,
where n is an integer. The term "aromatic" includes both
carbocyclic 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.
[0824] The term "carbocyclic" or "carbocycle" refers to a ring or
ring system where the atoms forming the backbone of the ring are
all carbon atoms. The term thus distinguishes carbocyclic from
"heterocyclic" rings or "heterocycles" in which the ring backbone
contains at least one atom which is different from carbon. In some
embodiments, at least one of the two rings of a bicyclic carbocycle
is aromatic. In some embodiments, both rings of a bicyclic
carbocycle are aromatic. Carbocycles include aryls and
cycloalkyls.
[0825] As used herein, the term "aryl" refers to an aromatic ring
wherein each of the atoms forming the ring is a carbon atom. In one
aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl
is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl,
indanyl, indenyl, or tetrahyodronaphthyl. In some embodiments, an
aryl is a C.sub.6-C.sub.10aryl. Depending on the structure, an aryl
group is a monoradical or a diradical (i.e., an arylene group).
[0826] 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. In some
embodiments, cycloalkyls are spirocyclic or bridged compounds. In
some embodiments, cycloalkyls are optionally 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, cyclooctyl,
spiro[2.2]pentyl, norbomyl and bicycle[1.1.1]pentyl. In some
embodiments, a cycloalkyl is a C.sub.3-C.sub.6cycloalkyl. In some
embodiments, a cycloalkyl is a C.sub.3-C.sub.4cycloalkyl.
[0827] The term "halo" or, alternatively, "halogen" or "halide"
means fluoro, chloro, bromo or iodo. In some embodiments, halo is
fluoro, chloro, or bromo.
[0828] The term "fluoroalkyl" refers to an alkyl in which one or
more hydrogen atoms are replaced by a fluorine atom. In one aspect,
a fluoroalkyl is a C.sub.1-C.sub.6fluoroalkyl.
[0829] The term "heterocycle" or "heterocyclic" refers to
heteroaromatic rings (also known as heteroaryls) and
heterocycloalkyl rings containing one to four heteroatoms in the
ring(s), where each heteroatom in the ring(s) is selected from O, S
and N, wherein each heterocyclic group has from 3 to 10 atoms in
its ring system, and with the proviso that any ring does not
contain two adjacent O or S atoms. Non-aromatic heterocyclic groups
(also known as heterocycloalkyls) include rings having 3 to 10
atoms in its ring system and aromatic heterocyclic groups include
rings having 5 to 10 atoms in its ring system. The heterocyclic
groups include benzo-fused ring systems. Examples of non-aromatic
heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl,
piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl,
aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl,
oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl,
1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,
indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,
pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,
dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl,
3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl,
isoindolin-1-onyl, isoindoline-1,3-dionyl,
3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,
isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,
1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and
quinolizinyl. Examples of aromatic heterocyclic groups are
pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl,
pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The
foregoing groups are either C-attached (or C-linked) or N-attached
where such is possible. For instance, a group derived from pyrrole
includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
Further, a group derived from imidazole includes imidazol-1-yl or
imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or
imidazol-5-yl (all C-attached). The heterocyclic groups include
benzo-fused ring systems. Non-aromatic heterocycles are optionally
substituted with one or two oxo (.dbd.O) moieties, such as
pyrrolidin-2-one. In some embodiments, at least one of the two
rings of a bicyclic heterocycle is aromatic. In some embodiments,
both rings of a bicyclic heterocycle are aromatic.
[0830] 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 monocyclic heteroaryls and bicyclic
heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,
thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,
pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
Monocyclic heteroaryls include indolizine, indole, benzofuran,
benzothiophene, indazole, benzimidazole, purine, quinolizine,
quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,
quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments,
a heteroaryl contains 0-4 N atoms in the ring. In some embodiments,
a heteroaryl contains 1-4 N atoms in the ring. In some embodiments,
a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in
the ring. In some embodiments, a heteroaryl contains 1-4 N atoms,
0-1 O atoms, and 0-1 S atoms in the ring. 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.
[0831] A "heterocycloalkyl" group refers to a cycloalkyl group that
includes at least one heteroatom selected from nitrogen, oxygen and
sulfur. In some embodiments, a heterocycloalkyl is fused with an
aryl or heteroaryl. In some embodiments, the heterocycloalkyl is
oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, piperidin-2-onyl,
pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl,
imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. 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 is monocyclic or bicyclic. In some embodiments, a
heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or
8-membered ring. In some embodiments, a heterocycloalkyl is
monocyclic and is a 3, 4, 5, or 6-membered ring. In some
embodiments, a heterocycloalkyl is monocyclic and is a 3 or
4-membered ring. In some embodiments, a heterocycloalkyl contains
0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl
contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
[0832] 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.
[0833] 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.
[0834] The term "optionally substituted" or "substituted" means
that the referenced group is optionally substituted with one or
more additional group(s) individually and independently selected
from halogen, --CN, --NH.sub.2, --NH(alkyl), --N(alkyl).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 other
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.2(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-C.sub.4alkyl),
--C(.dbd.O)N(C.sub.1-C.sub.4alkyl).sub.2,
--S(.dbd.O).sub.2NH.sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-C.sub.4alkyl),
--S(.dbd.O).sub.2N(C.sub.1-C.sub.4alkyl).sub.2,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.1-C.sub.4fluoroalkyl, C.sub.1-C.sub.4heteroalkyl,
C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4fluoroalkoxy,
--SC.sub.1-C.sub.4alkyl, --S(.dbd.O)C.sub.1-C.sub.4alkyl, and
--S(.dbd.O).sub.2C.sub.1-C.sub.4alkyl. 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, --CHF.sub.2, --CF.sub.3,
--OCH.sub.3, --OCHF.sub.2, 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) includes oxo
(.dbd.O).
[0835] In some embodiments, each substituted alkyl, substituted
fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and
substituted heterocycle is substituted with one or more
R.sup.5groups independently selected from the group consisting of
halogen, C.sub.1-C.sub.6alkyl, monocyclic carbocycle, monocyclic
heterocycle, --CN, --OR.sup.21, --CO.sub.2R.sup.21,
--C(.dbd.O)N(R.sup.21).sub.2, --N(R.sup.21).sub.2,
--NR.sup.21C(.dbd.O)R.sup.22, --SR.sup.21, --S(.dbd.O)R.sup.22,
--SO.sub.2R.sup.22, or --SO.sub.2N(R.sup.21).sub.2; each R.sup.21
is independently selected from hydrogen, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two
R.sup.21 groups are taken together with the N atom to which they
are attached to form a N-containing heterocycle; each R.sup.22 is
independently selected from C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6heteroalkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6heterocycloalkyl, phenyl,
benzyl, 5-membered heteroaryl and 6-membered heteroaryl.
[0836] 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.
[0837] The term "modulate" as used herein, means to interact with a
target either directly or indirectly so as to alter the activity of
the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0838] The term "modulator" as used herein, refers to a molecule
that interacts with a target either directly or indirectly. The
interactions include, but are not limited to, the interactions of
an agonist, partial agonist, an inverse agonist, antagonist,
degrader, or combinations thereof. In some embodiments, a modulator
is an agonist.
[0839] The terms "administer," "administering", "administration,"
and the like, as used herein, refer to the methods that may be used
to enable delivery of compounds or compositions to the desired site
of biological action. These methods include, but are not limited to
oral routes, intraduodenal routes, parenteral injection (including
intravenous, subcutaneous, intraperitoneal, intramuscular,
intravascular or infusion), topical and rectal administration.
Those of skill in the art are familiar with administration
techniques that can be employed with the compounds and methods
described herein. In some embodiments, the compounds and
compositions described herein are administered orally.
[0840] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0841] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered, which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result includes reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired
alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition
comprising a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms. An appropriate
"effective" amount in any individual case is optionally determined
using techniques, such as a dose escalation study.
[0842] The terms "enhance" or "enhancing," as used herein, means to
increase or prolong either in potency or duration a desired effect.
Thus, in regard to enhancing the effect of therapeutic agents, the
term "enhancing" refers to the ability to increase or prolong,
either in potency or duration, the effect of other therapeutic
agents on a system. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of
another therapeutic agent in a desired system.
[0843] 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), 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),
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.
[0844] The terms "article of manufacture" and "kit" are used as
synonyms.
[0845] 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.
[0846] 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.
Pharmaceutical Compositions
[0847] 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 are used pharmaceutically. Proper formulation is dependent
upon the route of administration chosen. A summary of
pharmaceutical compositions described herein is 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.
[0848] In some embodiments, the compounds described herein are
administered either alone or in combination with pharmaceutically
acceptable carriers, excipients or diluents, in a pharmaceutical
composition. Administration of the compounds and compositions
described herein can be effected by any method that enables
delivery of the compounds to the site of action. These methods
include, though are not limited to delivery via enteral routes
(including oral, gastric or duodenal feeding tube, rectal
suppository and rectal enema), parenteral routes (injection or
infusion, including intraarterial, intracardiac, intradermal,
intraduodenal, intramedullary, intramuscular, intraosseous,
intraperitoneal, intrathecal, intravascular, intravenous,
intravitreal, epidural and subcutaneous), inhalational,
transdermal, transmucosal, sublingual, buccal and topical
(including epicutaneous, dermal, enema, eye drops, ear drops,
intranasal, vaginal) administration, although the most suitable
route may depend upon for example the condition and disorder of the
recipient. By way of example only, compounds described herein can
be administered locally to the area in need of treatment, by for
example, local infusion during surgery, topical application such as
creams or ointments, injection, catheter, or implant. The
administration can also be by direct injection at the site of a
diseased tissue or organ.
[0849] In some embodiments, pharmaceutical compositions suitable
for oral administration are presented as discrete units such as
capsules, cachets or tablets each containing a predetermined amount
of the active ingredient; as a powder or granules; as a solution or
a suspension in an aqueous liquid or a non-aqueous liquid; or as an
oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In
some embodiments, the active ingredient is presented as a bolus,
electuary or paste.
[0850] Pharmaceutical compositions which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. Tablets may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing in a suitable machine the active ingredient
in a free-flowing form such as a powder or granules, optionally
mixed with binders, inert diluents, or lubricating, surface active
or dispersing agents. Molded tablets may be made by molding in a
suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent. In some embodiments, the tablets are
coated or scored and are formulated so as to provide slow or
controlled release of the active ingredient therein. All
formulations for oral administration should be in dosages suitable
for such administration. The push-fit capsules can 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 soft capsules,
the active compounds may be dissolved or suspended in suitable
liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In some embodiments, stabilizers are added.
Dragee cores are provided with suitable coatings. For this purpose,
concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic solvents or solvent mixtures. Dyestuffs or
pigments may be added to the tablets or Dragee coatings for
identification or to characterize different combinations of active
compound doses.
[0851] In some embodiments, pharmaceutical compositions are
formulated for parenteral administration by injection, e.g., by
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 compositions
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents. The compositions
may be presented in unit-dose or multi-dose containers, for example
sealed ampoules and vials, and may be stored in powder form or in a
freeze-dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example, saline or sterile
pyrogen-free water, immediately prior to use. Extemporaneous
injection solutions and suspensions may be prepared from sterile
powders, granules and tablets of the kind previously described.
[0852] Pharmaceutical compositions for parenteral administration
include aqueous and non-aqueous (oily) sterile injection solutions
of the active compounds which may contain antioxidants, buffers,
bacteriostats and solutes which render the formulation isotonic
with the blood of the intended recipient; and aqueous and
non-aqueous sterile suspensions which may include suspending agents
and thickening agents. Suitable lipophilic solvents or vehicles
include fatty oils such as sesame oil, or synthetic fatty acid
esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase
the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or dextran. Optionally, the suspension may
also contain suitable stabilizers or agents which increase the
solubility of the compounds to allow for the preparation of highly
concentrated solutions.
[0853] Pharmaceutical compositions may also be formulated as a
depot preparation. Such long acting formulations may be
administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the compounds may be formulated with suitable polymeric or
hydrophobic materials (for example, as an emulsion in an acceptable
oil) or ion exchange resins, or as sparingly soluble derivatives,
for example, as a sparingly soluble salt.
[0854] For buccal or sublingual administration, the compositions
may take the form of tablets, lozenges, pastilles, or gels
formulated in conventional manner. Such compositions may comprise
the active ingredient in a flavored basis such as sucrose and
acacia or tragacanth.
[0855] Pharmaceutical compositions may be administered topically,
that is by non-systemic administration. This includes the
application of a compound of the present invention externally to
the epidermis or the buccal cavity and the instillation of such a
compound into the ear, eye and nose, such that the compound does
not significantly enter the blood stream. In contrast, systemic
administration refers to oral, intravenous, intraperitoneal and
intramuscular administration.
[0856] Pharmaceutical compositions suitable for topical
administration include liquid or semi-liquid preparations suitable
for penetration through the skin to the site of inflammation such
as gels, liniments, lotions, creams, ointments or pastes, and drops
suitable for administration to the eye, ear or nose. The active
ingredient may comprise, for topical administration, from 0.001% to
10% w/w, for instance from 1% to 2% by weight of the
formulation.
[0857] Pharmaceutical compositions for administration by inhalation
are conveniently delivered from an insufflator, nebulizer
pressurized packs or other convenient means of delivering an
aerosol spray. Pressurized packs may comprise a suitable propellant
such as dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation,
pharmaceutical preparations may take the form of a dry powder
composition, for example a powder mix of the compound and a
suitable powder base such as lactose or starch. The powder
composition may be presented in unit dosage form, in for example,
capsules, cartridges, gelatin or blister packs from which the
powder may be administered with the aid of an inhalator or
insufflator.
[0858] It should be understood that in addition to the ingredients
particularly mentioned above, the compounds and compositions
described herein may include other agents conventional in the art
having regard to the type of formulation in question, for example
those suitable for oral administration may include flavoring
agents.
Methods of Dosing and Treatment Regimens
[0859] In one embodiment, the compounds of Formula (I), or a
pharmaceutically acceptable salt thereof, are used in the
preparation of medicaments for the treatment of diseases or
conditions in a mammal that would benefit from modulation of
somatostatin activity. Methods for treating any of the diseases or
conditions described herein in a mammal in need of such treatment,
involves administration of pharmaceutical compositions that include
at least one compound of Formula (I) or a pharmaceutically
acceptable salt, active metabolite, prodrug, or pharmaceutically
acceptable solvate thereof, in therapeutically effective amounts to
said mammal.
[0860] In certain embodiments, the compositions containing the
compound(s) described herein are administered for prophylactic
and/or therapeutic treatments. In certain therapeutic applications,
the compositions are administered to a patient already suffering
from a disease or condition, in an amount sufficient to cure or at
least partially arrest at least one of the symptoms of the disease
or condition. Amounts effective for this use depend on the severity
and course of the disease or condition, previous therapy, the
patient's health status, weight, and response to the drugs, and the
judgment of the treating physician. Therapeutically effective
amounts are optionally determined by methods including, but not
limited to, a dose escalation and/or dose ranging clinical
trial.
[0861] In prophylactic applications, compositions containing the
compounds described herein are administered to a patient
susceptible to or otherwise at risk of a particular disease,
disorder or condition. Such an amount is defined to be a
"prophylactically effective amount or dose." In this use, the
precise amounts also depend on the patient's state of health,
weight, and the like. When used in patients, effective amounts for
this use will depend on the severity and course of the disease,
disorder or condition, previous therapy, the patient's health
status and response to the drugs, and the judgment of the treating
physician. In one aspect, prophylactic treatments include
administering to a mammal, who previously experienced at least one
symptom of the disease being treated and is currently in remission,
a pharmaceutical composition comprising a compound of Formula (I),
or a pharmaceutically acceptable salt thereof, in order to prevent
a return of the symptoms of the disease or condition.
[0862] In certain embodiments wherein the patient's condition does
not improve, upon the doctor's discretion the administration of the
compounds are administered chronically, that is, for an extended
period of time, including throughout the duration of the patient's
life in order to ameliorate or otherwise control or limit the
symptoms of the patient's disease or condition.
[0863] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, in
specific embodiments, the dosage or the frequency of
administration, or both, is reduced, as a function of the symptoms,
to a level at which the improved disease, disorder or condition is
retained. In certain embodiments, however, the patient requires
intermittent treatment on a long-term basis upon any recurrence of
symptoms.
[0864] The amount of a given agent that corresponds to such an
amount varies depending upon factors such as the particular
compound, disease condition and its severity, the identity (e.g.,
weight, sex) of the subject or host in need of treatment, but
nevertheless is determined according to the particular
circumstances surrounding the case, including, e.g., the specific
agent being administered, the route of administration, the
condition being treated, and the subject or host being treated.
[0865] In general, however, doses employed for adult human
treatment are typically in the range of 0.01 mg-2000 mg per day. In
one embodiment, the desired dose is conveniently presented in a
single dose or in divided doses administered simultaneously or at
appropriate intervals, for example as two, three, four or more
sub-doses per day.
[0866] In one embodiment, the daily dosages appropriate for the
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, described herein are from about 0.01 to about 50 mg/kg per
body weight. In some embodiments, the daily dosage or the amount of
active in the dosage form are lower or higher than the ranges
indicated herein, based on a number of variables in regard to an
individual treatment regime. In various embodiments, the daily and
unit dosages are altered depending on a number of variables
including, but not limited to, the activity of the compound used,
the disease or condition to be treated, the mode of administration,
the requirements of the individual subject, the severity of the
disease or condition being treated, and the judgment of the
practitioner.
[0867] Toxicity and therapeutic efficacy of such therapeutic
regimens are determined by standard pharmaceutical procedures in
cell cultures or experimental animals, including, but not limited
to, the determination of the LD.sub.50 and the ED.sub.50. The dose
ratio between the toxic and therapeutic effects is the therapeutic
index and it is expressed as the ratio between LD.sub.50 and
ED.sub.50. In certain embodiments, the data obtained from cell
culture assays and animal studies are used in formulating the
therapeutically effective daily dosage range and/or the
therapeutically effective unit dosage amount for use in mammals,
including humans. In some embodiments, the daily dosage amount of
the compounds described herein lies within a range of circulating
concentrations that include the ED.sub.50 with minimal toxicity. In
certain embodiments, the daily dosage range and/or the unit dosage
amount varies within this range depending upon the dosage form
employed and the route of administration utilized.
[0868] In any of the aforementioned aspects are further embodiments
in which the effective amount of the compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is: (a) systemically
administered to the mammal; and/or (b) administered orally to the
mammal; and/or (c) intravenously administered to the mammal; and/or
(d) administered by injection to the mammal; and/or (e)
administered topically to the mammal; and/or (f) administered
non-systemically or locally to the mammal.
[0869] In any of the aforementioned aspects are further embodiments
comprising single administrations of the effective amount of the
compound, including further embodiments in which (i) the compound
is administered once a day; or (ii) the compound is administered to
the mammal multiple times over the span of one day.
[0870] In any of the aforementioned aspects are further embodiments
comprising multiple administrations of the effective amount of the
compound, including further embodiments in which (i) the compound
is administered continuously or intermittently: as in a single
dose; (ii) the time between multiple administrations is every 6
hours; (iii) the compound is administered to the mammal every 8
hours; (iv) the compound is administered to the mammal every 12
hours; (v) the compound is administered to the mammal every 24
hours. In further or alternative embodiments, the method comprises
a drug holiday, wherein the administration of the compound is
temporarily suspended or the dose of the compound being
administered is temporarily reduced; at the end of the drug
holiday, dosing of the compound is resumed. In one embodiment, the
length of the drug holiday varies from 2 days to 1 year.
Combination Treatments
[0871] In certain instances, it is appropriate to administer at
least one compound of Formula (I), or a pharmaceutically acceptable
salt thereof, in combination with one or more other therapeutic
agents.
[0872] 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 has 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
agent (which also includes a therapeutic regimen) that also has
therapeutic benefit.
[0873] In one specific embodiment, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is co-administered with a
second therapeutic agent, wherein the compound of Formula (I), 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.
[0874] In any case, regardless of the disease, disorder or
condition being treated, the overall benefit experienced by the
patient is simply be additive of the two therapeutic agents or the
patient experiences a synergistic benefit.
[0875] 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.
[0876] 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).
[0877] The compounds of Formula (I), 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.
EXAMPLES
[0878] As used above, and throughout the description of the
invention, the following abbreviations, unless otherwise indicated,
shall be understood to have the following meanings:
Abbreviations
[0879] Pd(PPh.sub.3).sub.4:
tetrakis(triphenylphosphine)palladium(O); [0880]
Pd.sub.2(dba).sub.3.CHCl.sub.3:
Tris(dibenzylideneacetone)dipalladium(O)-chloroform adduct; [0881]
Pd(dppf)Cl.sub.2:
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride;
[0882] Pd(PPh.sub.3).sub.2Cl.sub.2:
bis(triphenylphosphine)palladium(II) dichloride; [0883] PdAMphos or
Pd(amphos)Cl.sub.2:
bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II);
[0884] Pd(DtBPF)Cl.sub.2:
[1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II);
[0885] DIEA or DIPEA: N,N-diisopropylethylamine; [0886] Prep-HPLC:
preparative high performance liquid chromatography; [0887] LCMS:
Liquid chromatography-mass spectrometry; [0888] MS: mass
spectrometry; [0889] AcOH: acetic acid; [0890] TFA: trifluoroacetic
acid; [0891] HCl: hydrochloric acid or hydrochloride; [0892] MeCN
or CH.sub.3CN or ACN: acetonitrile; [0893] H.sub.2O: water; [0894]
DMSO: dimethyl sulfoxide; [0895] DMF: dimethylformamide; [0896]
DCM: dichloromethane; [0897] NBS: N-bromosuccinimide; [0898]
Br.sub.2: bromine; [0899] NCS: N-chlorosuccinimide; [0900] rt: room
temperature; [0901] SST: somatostatin; [0902] SSTR: somatostatin
receptor; [0903] hrs: hours; [0904] h or hr: hour; [0905] min:
minute; [0906] N.sub.2: nitrogen gas; [0907] mg: milligrams; [0908]
mL: milliliter; [0909] eq. or equiv: equivalents; [0910] mmol:
millimole; [0911] .mu.mol: micromole; [0912] ppts: precipitates;
[0913] K.sub.2CO.sub.3: potassium carbonate; [0914] NaClO.sub.2:
sodium chlorite; [0915] t-BuOH: tert-butyl alcohol; [0916] EtOAc:
ethyl acetate; [0917] Na.sub.2SO.sub.4: sodium sulfate; [0918]
NaHSO.sub.4: sodium bisulfate; [0919] Na.sub.2S.sub.2O.sub.3:
sodium thiosulfate.
[0920] The following examples are provided for illustrative
purposes only and not to limit the scope of the claims provided
herein.
Synthesis of Compounds
Example 1.
4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyri-
dine-3-carboxamide (Compound 1-1)
##STR00767##
[0922] Step 1-1, preparation of tert-butyl
(S)-(1-(3-(3,5-dimethylphenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carba-
mate: to a mixture of tert-butyl
N-[(3S)-1-(3-bromo-5-formylpyridin-4-yl)pyrrolidin-3-yl]carbamate
(120 mg, 1.0 Eq, 0.32 mmol, "Step 9-1, Example 9"),
(3,5-dimethylphenyl)boronic acid (97 mg, 2.0 Eq, 0.65 mmol),
Pd.sub.2(dba).sub.3.CHCl.sub.3 (33 mg, 0.10 Eq, 0.032 mmol),
P(t-Bu).sub.3.HBF.sub.4 (19 mg, 0.20 Eq, 0.064 mmol) and
K.sub.3PO.sub.4 (206 mg, 3.0 Eq, 0.97 mmol) was added toluene (3.0
mL) and water (0.3 mL) under atmospheric nitrogen. The resulting
mixture was stirred at 70.degree. C. for 1 hour. The reaction
solution was concentrated under vacuum and the remaining residue
was purified by silica gel chromatography eluting with ethyl
acetate/petroleum ether (1:1) to afford 100 mg of the title
compound. MS (M+H).sup.+=396.5.
[0923] Step 1-2, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-dimethylphen-
yl)nicotinic acid: to a round-bottom flask was added tert-butyl
(S)-(1-(3-(3,5-dimethylphenyl)-5-formylpyridin-4-yl)pyrrolidin-3-yl)carba-
mate (100 mg, 1.0 Eq, 0.25 mmol), tert-butyl alcohol (4.2 mL), DCM
(4.2 mL), NaH.sub.2PO.sub.4 (91 mg, 3.0 Eq, 0.76 mmol),
2-methylbut-2-ene (532 mg, 30 Eq, 7.59 mmol), water (1.4 mL), and
NaClO.sub.2 (46 mg, 2.0 Eq, 0.51 mmol). The resulting mixture was
stirred at ambient temperature for 16 hours. The reaction mixture
was concentrated under vacuum and the remaining residue was diluted
with water (10 mL). The pH of resulting aqueous solution was
adjusted to .about.4 and solid product precipitated out. The
resulting suspension was filtered and solid was collected and dried
under vacuum. This resulted in 70 mg of the title compound as a
yellow solid. MS (M+H).sup.+=412.5.
[0924] Step 1-3, preparation of tert-butyl
(S)-(1-(3-(3,5-dimethylphenyl)-5-((3,5-dimethylphenyl)carbamoyl)pyridin-4-
-yl)pyrrolidin-3-yl)carbamate: to a DCM (3.0 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-dimethylphen-
yl)nicotinic acid (50 mg, 1.0 Eq, 0.12 mmol) was added Ghosez's
reagent (33 mg, 2.0 Eq, 0.24 mmol). The resulting mixture was
stirred at ambient temperature for 10 min followed by the addition
of pyridine (29 mg, 3.0 Eq, 0.36 mmol) and 3,5-dimethylaniline (18
mg, 1.2 Eq, 0.15 mmol). The reaction mixture was stirred at ambient
temperature for 2 hours. The reaction crude was concentrated under
vacuum and the remaining residue was purified by Prep-HPLC using
the following conditions: Column, XBridge Shield PR18 OBD, 5 .mu.m,
19.times.150 mm; mobile phase, water (10 mmol/L
NH.sub.4HCO.sub.3+0.1% NH.sub.3.H.sub.2O) and ACN (46% Phase B up
to 61% in 6 min); Detector, UV 220&254 nm. This resulted in 15
mg of the title compound as a light yellow solid. MS
(M+H).sup.+=515.2.
[0925] Step 1-4, preparation of
4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridine-3-car-
boxamide: to a DCM (1.0 mL) solution of tert-butyl
(S)-(1-(3-(3,5-dimethylphenyl)-5-((3,5-dimethylphenyl)carbamoyl)pyridin-4-
-yl)pyrrolidin-3-yl)carbamate was added TFA (1.0 mL). The resulting
mixture was stirred at ambient temperature for 1 hour. The reaction
crude was concentrated and dried under lyophilization to give 5.6
mg of the TFA salt of
4-[(3S)-3-aminopyrrolidin-1-yl]-N,5-bis(3,5-dimethylphenyl)pyridi-
ne-3-carboxamide as a light yellow solid. MS (M+H).sup.+=415.2.
[0926] The following compounds were prepared similarly to Example 1
with appropriate substituting reagents and substrates at different
steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
The coupling reaction with aniline can be carried out using other
coupling reagents such as HATU under appropriate conditions.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00008 Compound no. MS (M + H).sup.+ 1-2 415.3 1-3 439.1
1-4 434.2 1-5 413.2 1-6 416.1
Example 2.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohe-
xyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound
1-16)
##STR00768##
[0928] Step 2-1, preparation of tert-butyl
N-[(3S)-1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl]carbamat-
e: to an MeCN solution (100 mL) of
5-bromo-4-chloropyridine-3-carbaldehyde (12 g, 1.0 Eq, 54 mmol) was
added tert-butyl N-[(3S)-3-methylpyrrolidin-3-yl]carbamate (12 g,
1.1 Eq, 60 mmol) and DIPEA (21 g, 3.0 Eq, 160 mmol). The resulting
solution was stirred at 70.degree. C. for 24 hours. The reaction
mixture was quenched water and extracted with ethyl acetate. The
organic layers were combined, dried and concentrated. The remaining
residue was purified by silica gel column chromatography eluting
with petroleum ether/EtOAc (1:1) to afford tert-butyl
(S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(18 g, 86%) as a yellow solid. MS (M+H).sup.+=384.1, 386.1.
[0929] Step 2-2, preparation of
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)nic-
otinic acid: to a tert-butyl alcohol solution (9.0 mL) tert-butyl
(S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(190 mg, 1.0 Eq, 0.49 mmol) was added 2-methylbut-2-ene (0.66 mL,
12 Eq, 5.9 mmol), sodium chlorite (0.43 g, 7.8 Eq, 3.8 mmol, wt.
85%), sodium dihydrogen phosphate (0.35 g, 5.9 Eq, 2.9 mmol) and
water (2.8 mL). The resulting mixture was stirred at ambient
temperature for 1 hour. The reaction crude was concentrated to
remove most tert-butyl alcohol and saturated NaHSO.sub.4 (.about.2
mL) was added. The resulting aqueous solution was extracted with
ethyl acetate (3.times.20 mL), and the organic layers were
combined, dried and concentrated to give 160 mg of the title
compound as a light yellow solid. This material was used for next
step without further purification. MS (M+H).sup.+=400.1, 402.1.
[0930] Step 2-3, preparation of tert-butyl
(S)-(1-(3-bromo-5-((4,4-difluorocyclohexyl)carbamoyl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate: to a DMF (2.0 mL) solution of
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)nic-
otinic acid (250 mg, 1.0 Eq, 0.63 mmol) was added HATU (356 mg, 1.5
Eq, 0.94 mmol), DIPEA (0.60 mL, 5.5 Eq, 3.4 mmol) and
4,4-difluorocyclohexan-1-amine hydrochloride (161 mg, 1.5 Eq, 0.94
mmol). The resulting mixture was stirred at ambient temperature for
0.5 hour. The reaction crude was purified by C18 reverse phase
chromatography eluting with MeCN (0.1% TFA)/water (0.1% TFA)
(5-60%). Pure fractions were combined, concentrated to remove most
MeCN, neutralized with saturated NaHCO.sub.3 (5 mL), added solid
NaCl (15 g), and extracted with ethyl acetate (30 mL). Organic
layer was dried with MgSO.sub.4, filtered and concentrated to give
270 mg of the title compound. MS (M+H).sup.+=517.2, 519.2.
[0931] Step 2-4, preparation of tert-butyl
(S)-(1-(3-((4,4-difluorocyclohexyl)carbamoyl)-5-(3,5-difluorophenyl)pyrid-
in-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a mixture of
tert-butyl
(S)-(1-(3-bromo-5-((4,4-difluorocyclohexyl)carbamoyl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate (90 mg, 1.0 Eq, 0.17 mmol),
(3,5-difluorophenyl)boronic acid (55 mg, 2.0 Eq, 0.35 mmol),
K.sub.2CO.sub.3 (72 mg, 3.0 Eq, 0.52 mmol) and Pd(amphos)Cl.sub.2
(12 mg, 0.10 Eq, 0.017 mmol) was added dioxane (2.0 mL). Nitrogen
gas was bubbled through the reaction solution for 1 min followed by
the addition of water (0.20 mL). Nitrogen was bubbled for another 5
min. The resulting mixture was heated at 100.degree. C. for 1 hour.
The reaction crude was concentrated with silica gel and the
remaining residue was purified by silica gel chromatography to give
66 mg of the title compound as a clear oil. MS
(M+H).sup.+=551.4.
[0932] Step 2-5, preparation of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3,5-
-difluorophenyl)nicotinamide: to a DCM (0.8 mL) solution of
tert-butyl
(S)-(1-(3-((4,4-difluorocyclohexyl)carbamoyl)-5-(3,5-difluorophenyl)pyrid-
in-4-yl)-3-methylpyrrolidin-3-yl)carbamate (66 mg, 1.0 Eq, 0.12
mmol) was added TFA (0.8 mL). The resulting mixture was stirred at
ambient temperature for 0.5 hour. The reaction crude was
concentrated and the remaining residue was purified by C18 reverse
phase chromatography eluting with MeCN (0.1% TFA)/water (0.1% TFA)
(5-35%). Pure fractions were combined, neutralized with saturated
NaHCO.sub.3 (4 mL), added solid NaCl (8 g), and extracted with
ethyl acetate (25 mL). Organic layer was dried with MgSO.sub.4,
filtered and concentrated with 1.0 M HCl in ethyl acetate (0.3 mL)
to give 33 mg of the HCl salt of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3,5-
-difluorophenyl)nicotinamide as a white solid. MS
(M+H).sup.+=451.2.
[0933] The following compounds were prepared similarly to Example 2
with appropriate substituting reagents and substrates at different
steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00009 Compound no. MS (M + H).sup.+ 1-12 443.5 1-13 447.2
1-14 443.5 1-20 469.3 1-61 429.3 1-94 418.4 1-131 394.2 1-142 384.1
1-143 449.4 1-149 431.4 1-161 419.4 1-162 419.4 1-163 445.3 1-175
445.1
Example 3.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobu-
tyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound
1-30)
##STR00769##
[0935] Step 3-1, preparation of tert-butyl
(S)-(1-(3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-
-Yl)carbamate: to a mixture of tert-butyl
(S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(380 mg, 1.0 Eq, 0.989 mmol, "Step 2-1, Example 2"),
(3,5-difluorophenyl)boronic acid (312 mg, 2.0 Eq, 1.98 mmol),
K2CO.sub.3 (410 mg, 3.0 Eq, 2.97 mmol) and Pd(amphos)Cl.sub.2 (35
mg, 0.05 Eq, 0.050 mmol) was added dioxane (4.0 mL) and water (0.4
mL). Nitrogen was bubbled through the reaction solution for 5 min
and the resulting mixture was heated at 100.degree. C. for 1 hour.
The reaction crude was concentrated with silica gel and the
remaining residue was purified by silica gel chromatography to give
372 mg of the title compound as clear oil. MS
(M+H).sup.+=418.1.
[0936] Step 3-2, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)nicotinic acid: to a tert-butyl alcohol solution (11
mL) of tert-butyl
(S)-(1-(3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-
-yl)carbamate was added 2-methylbut-2-ene (1.2 mL, 12 Eq, 10.7
mmol), sodium chlorite (0.84 g, 8.9 Eq, 7.9 mmol, wt. 85%), sodium
dihydrogen phosphate (0.75 g, 7.0 Eq, 6.3 mmol) and water (4.0 mL).
The resulting mixture was stirred at ambient temperature for 1
hour. The reaction crude was concentrated to remove most tert-butyl
alcohol and saturated NaHSO.sub.4 (.about.3 mL) was added. The
resulting aqueous solution was extracted with ethyl acetate
(3.times.20 mL), and the organic layers were combined, dried and
concentrated to give 370 mg of the title compound. This material
was used for next step without further purification. MS
(M+H).sup.+=434.3.
[0937] Step 3-3, preparation of tert-butyl
(S)-(1-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyrid-
in-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF (0.6 mL)
solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)nicotinic acid (44 mg, 1.0 Eq, 0.10 mmol) was added
HATU (58 mg, 1.5 Eq, 0.15 mmol) and DIPEA (0.2 mL, 11 Eq, 1.0
mmol). The resulting mixture was stirred at ambient temperature for
5 min followed by the addition of 3,3-difluorocyclobutan-1-amine
hydrochloride (44 mg, 3.0 Eq, 0.30 mmol). The resulting mixture was
stirred at ambient temperature for 0.5 hour. The reaction crude was
purified by C18 reverse phase chromatography eluting with MeCN
(0.1% TFA)/water (0.1% TFA) (5-55%). Pure fractions were combined,
concentrated to remove most MeCN, neutralized with saturated
NaHCO.sub.3 (3 mL), added solid NaCl (5 g), and extracted with
ethyl acetate (2.times.10 mL). Organic layers were combined, dried
with MgSO.sub.4, filtered and concentrated to give 42 mg of the
title compound. MS (M+H).sup.+=534.1.
[0938] Step 3-4, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5-(3,-
5-difluorophenyl)pyridine-3-carboxamide: to a DCM (0.7 mL) solution
of tert-butyl
(S)-(1-(3-((3,3-difluorocyclobutyl)carbamoyl)-5-(3,5-difluorophenyl)pyrid-
in-4-yl)-3-methylpyrrolidin-3-yl)carbamate (42 mg, 1.0 Eq, 0.08
mmol) was added TFA (0.7 mL). The resulting mixture was stirred at
ambient temperature for 0.5 hour. The reaction crude was
concentrated, and the remaining residue was purified by C18 reverse
phase chromatography eluting with MeCN (0.1% TFA)/water (0.1% TFA)
(5-35%). Pure fractions were combined, neutralized with saturated
NaHCO.sub.3 (3 mL), added solid NaCl (5 g), and extracted with
ethyl acetate (2.times.10 mL). Organic layers were combined, dried
with MgSO.sub.4, filtered and concentrated with 1.0 M HCl in ethyl
acetate (0.10 mL) to give 25 mg of the HCl salt of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(3,3-difluorocyclobutyl)-5--
(3,5-difluorophenyl)pyridine-3-carboxamide as a white solid. MS
(M+H).sup.+=423.2.
[0939] The following compounds were prepared similarly to Example 3
with appropriate substituting reagents and substrates at different
steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00010 Compound no. MS (M + H).sup.+ 1-7 390.2 1-8 376.2
1-9 398.5 1-10 440.3 1-11 435.4 1-15 465.3 1-17 445.3 1-18 463.2
1-19 411.5 1-21 398.9, 399.1 1-22 415.4 1-23 373.2 1-24 397.0 1-25
423.3 1-26 382.9 1-27 409.5 1-28 415.3 1-29 389.5 1-31 403.3 1-32
401.4 1-33 401.2 1-34 401.1 1-35 439.3 1-36 429.2 1-37 403.2 1-38
403.5 1-39 431.5 1-40 415.3 1-41 401.1 1-42 423.0 1-43 415.2 1-44
401.1 1-45 457.3 1-46 389.3 1-47 419.2 1-50 437.2 1-51 427.3 1-52
433.3 1-53 429.3 1-55 405.3 1-56 469.4 1-57 403.4 1-58 417.4 1-59
405.3 1-60 443.5 1-62 411.4 1-83 433.4 1-96 420.3 1-112 415.2
Example 4.
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)--
N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide (Compound
1-71)
##STR00770##
[0941] Step 4-1, preparation of tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate: to
a DMF (70 mL) solution was added 4,6-dichloronicotinaldehyde (6.8
g, 1.0 Eq, 39 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (7.6
g, 1.1 Eq, 41 mmol) and TEA (16 mL, 3.1 Eq, 120 mmol). The
resulting mixture was stirred at 50.degree. C. for 4 hours. The
reaction crude was quenched with water (100 mL) and extracted with
ethyl acetate (3.times.40 mL). The organic layers were combined,
washed with brine, dried and concentrated under vacuum. The
remaining residue was purified by silica gel chromatography eluting
with ethyl acetate/petroleum ether (1/3) to afford tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate
(5.3 g, 42%) as a yellow solid. MS (M+H).sup.+=326.2.
[0942] Step 4-2, preparation of tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate:
to an AcOH (60 mL) solution of tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate
(5.3 g, 1.0 Eq, 16 mmol) was added NBS (3.1 g, 1.1 Eq, 17 mmol) at
10.degree. C. The resulting mixture was stirred at the same
temperature for 1 hour. The reaction mixture was quenched with
saturated NaHCO.sub.3and extracted with ethyl acetate (3.times.40
mL). The organic layers were combined, washed with brine, dried and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with ethyl acetate/petroleum
ether (1/4) to afford tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate
(3.5 g, 53%) as a yellow solid. MS (M+H).sup.+=404.1, 406.1.
[0943] Step 4-3, preparation of tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-
-yl)carbamate: to a mixture of tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate
(3.5 g, 1.0 Eq, 8.6 mmol), (3,5-difluorophenyl)boronic acid (0.88
Eq, 7.6 mmol, 1.2 g), Pd(DtBPF)Cl.sub.2 (300 mg, 0.05 Eq, 0.46
mmol) and potassium phosphate (5.4 g, 2.9 Eq, 25 mmol) was added
Toluene (140 mL) and water (14 mL) under atmospheric nitrogen. The
resulting mixture was stirred at 40.degree. C. for 2 hours. The
reaction crude was concentrated under reduced pressure and the
remaining residue was purified by silica gel column chromatography
eluting with petroleum ether/EtOAc (3:1) to afford tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-
-yl)carbamate (2.7 g, 71%) as a yellow solid. MS (M+H).sup.+=438.0,
440.0.
[0944] Step 4-4, preparation of tert-butyl
(S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3--
yl)carbamate: to a mixture of tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3-
-yl)carbamate (2.7 g, 1.0 Eq, 6.2 mmol),
Pd.sub.2(dba).sub.3.CHCl.sub.3 (310 mg, 0.05 Eq, 0.31 mmol),
Zn(CN).sub.2 (1.4 g, 1.9 Eq, 12 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (720 mg,
0.20 Eq, 1.24 mmol) was added DMF (30 mL) under atmospheric
nitrogen. The resulting mixture was heated under microwave
radiation conditions at 135.degree. C. for 1 hour. The reaction
crude was quenched with water (100 mL) and extracted with EtOAc
(3.times.40 mL). Organic layers were combined, washed with brine,
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under vacuum. The remaining residue was purified by silica gel
chromatography eluting with petroleum ether/EtOAc (1:1) to afford
tert-butyl
(S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3--
yl)carbamate (2.2 g, 83%) as a yellow solid. MS
(M+H).sup.+=429.2.
[0945] Step 4-5, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-cyano-5-(3,5-difl-
uorophenyl)nicotinic acid: to a tert-butyl alcohol solution (20 mL)
of
(S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)pyrrolidin-3--
yl)carbamate (2.4 g, 1.0 Eq, 5.1 mmol) was added sodium dihydrogen
phosphate (2.4 g, 3.0 Eq, 15 mmol) 2-methylbut-2-ene (11.0 g, 31
Eq, 157 mmol), sodium chlorite (1.0 g, 2.2 Eq, 11 mmol) and water
(6.6 mL). The resulting mixture was stirred at ambient temperature
for 1 hour. The reaction mixture was quenched with saturated
NaHSO.sub.4 (50 mL) and extracted with ethyl acetate (3.times.40
mL). The organic layers were combined, washed with brine, dried and
concentrated under vacuum to afford
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-cyano-5-(3-
,5-difluorophenyl)nicotinic acid (2.0 g, 88%) as a yellow solid.
This material was used for next step without purification. MS
(M+H).sup.+=445.2.
[0946] Step 4-6, preparation of tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl-
)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate: to a DMF
solution (2.0 mL) of
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-cyano-5-(3-
,5-difluorophenyl)nicotinic acid (70 mg, 1.0 Eq, 0.16 mmol) was
added (S)-1,1,1-trifluoropropan-2-amine hydrochloride (35 mg, 1.5
Eq, 0.23 mmol), N-ethyl-N-isopropylpropan-2-amine (4.4 Eq, 0.70
mmol, 0.12 mL) and HATU (60 mg, 1.0 Eq, 0.16 mmol). The resulting
mixture was stirred at ambient temperature for 2 hours. The
reaction crude was purified by Prep-HPLC using the following
conditions: SunFire Prep C18 OBD Column, 19*150 mm 5 .mu.m; mobile
phase, Water (0.1% FA) and ACN (24.0% ACN up to 46.0% in 7 min);
Total flow rate, 20 mL/min; Detector, UV 220 nm. This resulted in
tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl-
)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate (45 mg, 53%) as a
light yellow solid. MS (M+H).sup.+=540.3.
[0947] Step 4-7, preparation of
4-((S)-3-aminopyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N--((S)-1,1-
,1-trifluoropropan-2-yl)nicotinamide: to a DCM solution (2.0 mL) of
tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl-
)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate (45 mg, 1.0 Eq,
0.083 mmol) was added TFA (1.0 mL). The resulting mixture was
stirred at ambient temperature for 2 hours. The reaction solution
was concentrated and freeze-dried under vacuum to afford the TFA
salt of
4-((S)-3-aminopyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N--((S)-1,1-
,1-trifluoropropan-2-yl)nicotinamide bis(2,2,2-trifluoroacetate)
(40.2 mg, 72%) as a light yellow solid. MS (M+H).sup.+=440.2.
[0948] The following compounds were prepared similarly to Example 4
with appropriate substituting reagents and substrates at different
steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00011 Compound no. MS (M + H).sup.+ 1-48 476.3 1-49 424.2
1-64 410.2 1-65 392.2 1-66 410.2 1-67 462.2 1-68 434.2 1-69 412.2,
1-70 438.2 1-72 414.2 1-73 440.2 1-76 428.3 1-78 426.2 1-79 448.1
1-80 412.3 1-81 426.3 1-82 412.3 1-84 408.2 1-85 414.2 1-86 412.2
1-87 412.2 1-88 442.2 1-89 442.2 1-90 426.1 1-91 400.2 1-92 440.2
1-93 440.2 1-95 449.3 1-97 448.1 1-98 440.2 1-99 440.2 1-100 424.2
1-101 428.2 1-102 428.2
Example 5.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluor-
ophenyl)-N-[(1S)-1-(pyridin-2-yl)ethyl]pyridine-3-carboxamide
(Compound 1-103)
##STR00771##
[0950] Step 5-1, preparation of ethyl 4-chloro-6-cyanonicotinate:
to a mixture of ethyl 4,6-dichloronicotinate (200.0 g, 1.0 Eq, 909
mmol), zinc(II) cyanide (0.600 Eq, 545 mmol, 64 g),
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (9.41 g,
0.01 Eq, 9.09 mmol),
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (10.5 g,
0.02 Eq, 18.1 mmol) was added DMF (1600 mL) under atmospheric
nitrogen. The reaction mixture was stirred at 130.degree. C. for 2
hours. The reaction mixture was poured into water (3000 mL),
extracted with EtOAc (3.times.1000 mL). Organic layers were
combined, washed with water (3.times.2000 mL) and brine (1000 mL),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The
remaining residue was purified by silica gel chromatography eluting
with petroleum ether/EtOAc/DCM (10/1/2). This resulted in a pure
batch (78 g, 95% purity) and a less pure batch (63 g, 50% purity).
MS (M+H).sup.+=211.1, 212.1.
[0951] Step 5-2, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinate: to a mixture of ethyl 4-chloro-6-cyanonicotinate (15 g,
1.0 Eq, 71 mmol), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine
(10 g, 0.92 Eq, 66 mmol) and tert-butyl
(S)-(3-methylpyrrolidin-3-yl)carbamate (30 g, 2.1 Eq, 150 mmol) was
added MeCN (200 mL). The resulting mixture was stirred at
50.degree. C. for 1 hour. The reaction crude was quenched with
water (100 mL) and extracted with EtOAc (3.times.40 mL). The
organic layers were combined, washed with brine, dried and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with petroleum ether/EtOAc(3/1)
to afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinate (16.0 g, 60%) as a yellow solid. MS (M+H).sup.+=375.1.
[0952] Step 5-3, preparation of ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
cyanonicotinate: to a round-bottom flask was added ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinate (3.0 g, 1.0 Eq, 8.0 mmol), AcOH (60 mL) and DCM (12 mL). At
0.degree. C., 1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (5.8 g
2.0 Eq, 16 mmol) was added portion-wise. The resulting mixture was
stirred at the same temperature for 30 min. The reaction crude was
quenched with aqueous NaHSO.sub.3 at 0.degree. C. The resulting
suspension was filtered, and the filtrate was extracted with EtOAc
(3.times.100 mL). The organic layers were combined, and washed with
water (3.times.30 mL) and aqueous NaHCO.sub.3. The organic layer
were dried and concentrated under vacuum. The remaining residue was
purified by silica gel chromatography eluting with petroleum
ether/EtOAc/(4/1) to afford ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
cyanonicotinate (2.2 g, 61%) as a yellow solid. MS
(M+H).sup.+=453.0, 455.0.
[0953] Step 5-4, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinate: to a mixture of ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
cyanonicotinate (5.0 g, 1.0 Eq, 11 mmol),
(3,5-difluorophenyl)boronic acid (3.5 g, 2.0 Eq, 22 mmol),
potassium phosphate (7.2 g, 3.1 Eq, 34 mmol) and Pd(DtBPF)Cl.sub.2
(350 mg, 0.049 Eq, 0.537 mmol) was added Toluene (50 mL) and water
(5 mL) under atmospheric nitrogen. The resulting mixture was
stirred at 80.degree. C. for 1 hour. The reaction mixture was
concentrated under reduced pressure and the remaining residue was
purified by silica gel column chromatography eluting with petroleum
ether/EtOAc (5:1) to afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinate (4.4 g, 82%) as a yellow solid. MS
(M+H).sup.+=487.4.
[0954] Step 5-5, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid: to a MeOH solution (50 mL) of
ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinate (5.0 g, 1.0 Eq, 10 mmol) was added
water (5.0 mL). The resulting mixture was cooled to 10.degree. C.
and lithium hydroxide (2.5 g, 10 Eq, 100 mmol) was added
portion-wise. The reaction mixture was stirred at 50.degree. C. for
3 hours. The reaction crude was concentrated under vacuum and
saturated NaHSO.sub.4 was added until the crude solution is acidic
(pH 4-5). The resulting mixture was extracted with EtOAc
(3.times.40 mL). Organic layers were combined, washed with water,
dried and concentrated under vacuum to afford
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid (4.0 g, 85%) as a yellow solid.
This material was used for next step without further purification.
MS (M+H).sup.+=459.2.
[0955] Step 5-6, preparation of tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1-(pyridin-2-yl)ethyl)carb-
amoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a mixture
of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid (90 mg, 1.0 Eq, 0.20 mmol), HATU
(0.11 g, 1.5 Eq, 0.29 mmol) and (S)-1-(pyridin-2-yl)ethan-1-amine
(36 mg, 1.50 Eq, 0.29 mmol) was added DMF (0.8 mL) and DIPEA (0.10
mL, 3.0 Eq, 0.59 mmol). The resulting mixture was stirred at
ambient temperature for 0.5 hour. The reaction crude was purified
by C18 reverse phase chromatography eluting with MeCN (0.1%
TFA)/water (0.1% TFA) (5-65%). Pure fractions were combined,
neutralized with saturated NaHCO.sub.3 (3 mL), solid NaCl (5 g) was
added, and extracted with ethyl acetate (20 mL). The organic layer
was dried with MgSO.sub.4, filtered and concentrated to give 75 mg
of tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1-(pyridin-2-yl)ethyl)carb-
amoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate as a clean
oil. MS (M+H).sup.+=563.5.
[0956] Step 5-7, preparation of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N--
-((S)-1-(pyridin-2-yl)ethyl)nicotinamide: to a DCM (0.6 mL)
solution of tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1-(pyridin-2-yl)ethyl)carb-
amoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (75 mg, 1.0
Eq, 0.13 mmol) was added TFA (0.6 mL). The resulting mixture was
stirred at ambient temperature for 0.5 h. The reaction crude was
concentrated, and the remaining residue was purified by C18 reverse
phase chromatography eluting with MeCN (0.1% TFA)/water (0.1% TFA)
(5-35%). Pure fractions were combined, neutralized with saturated
NaHCO.sub.3 (3 mL), added solid NaCl (5 g), and extracted with
ethyl acetate (20 mL). The organic layer was dried with MgSO.sub.4,
filtered and concentrated with 1.0 M HCl in ethyl acetate (0.2 mL)
to give the HCl salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N--
-((S)-1-(pyridin-2-yl)ethyl)nicotinamide as a white solid. MS
(M+H).sup.+=463.2.
[0957] The following compounds were prepared similarly to Example 5
with appropriate substituting reagents and substrates at different
steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00012 Compound no. MS (M + H).sup.+ 1-104 452.2 1-105
452.2 1-106 452.2 1-107 452.2 1-108 450.2 1-109 503.2 1-110 462.2
1-111 503.3 1-113 470.5 1-114 439.2 1-115 464.3 1-116 456.2 1-117
456.2 1-118 476.2 1-119 476.2 1-126 464.4 1-132 453.1 1-133 467.0
1-135 430.2 1-136 430.2 1-138 446.2 1-139 446.2 1-168 484.2 1-169
487.1 1-180 502.1 1-218 426.2 1-219 440.2 1-220 444.1 1-221 444.1
1-222 454.1 1-225 440.1 1-226 440.1 1-227 440.1 1-234 442.2 1-244
455.1 1-245 479.1 1-248 459.2 1-249 461.1 1-250 447.1 1-251 447.1
1-252 435.2 1-253 423.2 1-254 421.2 1-270 409.2 1-271 409.2
Example 6.
4-[3-(1-aminoethyl)azetidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-
-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound 1-63)
##STR00772##
[0959] Step 6-1, preparation of 1-(azetidin-3-yl)ethan-1-one: to a
DCM (5 mL) solution of tert-butyl 3-acetylazetidine-1-carboxylate
(500 mg, 1.0 Eq, 2.51 mmol) was added TFA (5 mL). The resulting
mixture was stirred at ambient temperature for 3 hours. The
reaction mixture was concentrated under reduced pressure. The
mixture was diluted with water (30 mL) and saturated
NaHCO.sub.3solution was added until pH is .about.7.0. The resulting
mixture was concentrated under reduced pressure and the remaining
residue was washed with DCM/MeOH (3.times.50 mL). Organic layers
were combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under vacuum. This resulted in 280 mg of
1-(azetidin-3-yl)ethan-1-one (80% purity) as colorless oil. This
material was used for next step without further purification.
[0960] Step 6-2, preparation of
4-(3-acetylazetidin-1-yl)-5-bromonicotinaldehyde: to a mixture of
1-(azetidin-3-yl)ethan-1-one (280 mg, 1.0 Eq, 2.3 mmol),
5-bromo-4-chloronicotinaldehyde (446 mg, 0.90 Eq, 2.02 mmol),
N-ethyl-N-isopropylpropan-2-amine (1.00 g, 3.4 Eq, 7.74 mmol) was
added MeCN (5 mL). The resulting mixture was stirred at 80.degree.
C. for 2 hours. The reaction mixture was concentrated under reduced
pressure and the remaining residue was purified by silica gel
chromatography eluting with petroleum ether/EtOAc (5:1) to afford
4-(3-acetylazetidin-1-yl)-5-bromonicotinaldehyde (250 mg, 39%) as
colorless oil. MS (M+H).sup.+=285.0.
[0961] Step 6-3, preparation of
4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinaldehyde: to
a mixture of 4-(3-acetylazetidin-1-yl)-5-bromonicotinaldehyde (90
mg, 1.0 Eq, 0.32 mmol), (3,5-difluorophenyl)boronic acid (150 mg,
3.0 Eq, 0.95 mmol), potassium phosphate (200 mg, 3.0 Eq, 0.942
mmol), and
dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (21
mg, 0.10 Eq, 0.032 mmol) was added 1,4-dioxane (1.0 mL) and Water
(0.1 mL) under atmospheric nitrogen. The reaction mixture was
stirred at 80.degree. C. for 1 hour. The resulting mixture was
concentrated under reduced pressure and the remaining residue was
purified by silica gel chromatography. This resulted in 65 mg of
4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinaldehyde
(65%) as a yellow solid. MS (M+H).sup.+=317.1.
[0962] Step 6-4, preparation of
4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid: to
a tert-butyl alcohol (6.0 mL) solution of
4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinaldehyde
(150 mg, 1.0 Eq, 0.474 mmol) was added 2-methylbut-2-ene (1.66 g,
50 Eq, 23.7 mmol), sodium chlorite (86 mg, 2.0 Eq, 0.95 mmol),
sodium dihydrogen phosphate dihydrate (222 mg, 3.0 Eq, 1.42 mmol)
and water (2 mL). The resulting mixture was stirred at ambient
temperature for 1 hour. The reaction mixture was purified by
Prep-HPLC using the following conditions: Column, C18; mobile
phase, Water (0.1% TFA) and ACN (25% ACN up to 45% in 8 min); Total
flow rate, 70 mL/min; Detector, UV 220 nm. This resulted in 120 mg
of 4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid
as colorless oil. MS (M+H).sup.+=333.1.
[0963] Step 6-5, preparation of
4-(3-acetylazetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluoroph-
enyl)nicotinamide: to a DMF (2.0 mL) solution of
4-(3-acetylazetidin-1-yl)-5-(3,5-difluorophenyl)nicotinic acid (120
mg, 1.0 Eq, 0.361 mmol) was added bicyclo[1.1.1]pentan-1-amine
hydrochloride (65 mg, 1.5 Eq, 0.54 mmol),
N-ethyl-N-isopropylpropan-2-amine (163 mg, 3.49 Eq, 1.26 mmol), and
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (206 mg, 1.50 Eq, 0.54 mmol). The reaction
mixture was stirred at ambient temperature for 1 hour. The reaction
crude was purified by Prep-HPLC using the following conditions:
Column, C18; mobile phase, Water (0.1% TFA) and ACN (35% ACN up to
60% in 8 min); Total flow rate, 70 mL/min; Detector, UV 220 nm.
This resulted in
4-(3-acetylazetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluoroph-
enyl)nicotinamide (110 mg, 76.6%) as a yellow solid. MS
(M+H).sup.+=398.3.
[0964] Step 6-6, preparation of
N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-4-(3-(1-((2,4-dimeth-
oxybenzyl)amino)ethyl)azetidin-1-yl)nicotinamide: to a DCE (2.0 mL)
solution of
4-(3-acetylazetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluoroph-
enyl)nicotinamide (100 mg, 1.0 Eq, 0.252 mmol) was added acetic
acid (15 mg, 0.99 Eq, 0.25 mmol), (2,4-dimethoxyphenyl)methanamine
(63 mg, 1.5 Eq, 0.38 mmol), and sodium triacetoxyhydroborate (160
mg 3.0 Eq, 0.755 mmol). The resulting mixture was stirred at
ambient temperature for 6 hours. The reaction crude was
concentrated under reduced pressure and the remaining residue was
purified by Prep-HPLC using the following conditions: Column, C18;
mobile phase, Water (0.1% TFA) and ACN (30% ACN up to 60% in 8
min); Total flow rate, 70 mL/min; Detector, UV 220 nm. This
resulted in
N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-4-(3-(1-((2,4-dimeth-
oxybenzyl)amino)ethyl)azetidin-1-yl)nicotinamide (110 mg, 72%, 90%
purity) as yellow oil. MS (M+H).sup.+=549.3.
[0965] Step 6-7, preparation of
4-(3-(1-aminoethyl)azetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-di-
fluorophenyl)nicotinamide:
N-(bicyclo[1.1.1]pentan-1-yl)-5-(3,5-difluorophenyl)-4-(3-(1-((2,4-dimeth-
oxybenzyl)amino)ethyl)azetidin-1-yl)nicotinamide (100 mg, 1.0 Eq,
0.182 mmol) was combined with TFA (2.0 mL) and the resulting
mixture was heated at 80.degree. C. for 16 hours. The mixture was
concentrated under reduced pressure and the remaining residue was
purified by Prep-HPLC using the following conditions: Column,
SunFire Prep C18 OBD, 19*150 mm, 5 .mu.m; mobile phase, Water (0.1%
TFA) and ACN (12% ACN up to 17% in 7 min); Total flow rate, 20
mL/min; Detector, UV 220 nm. This resulted in the TFA salt of
4-(3-(1-aminoethyl)azetidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-
-(3,5-difluorophenyl)nicotinamide (38.8 mg, 34.0%) as a white
solid. MS (M+H).sup.+=399.2.
Example 7.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]penta-
n-1-yl}-5-(3,5-difluorophenyl)-6-methylpyridine-3-carboxamide
(Compound 1-74)
##STR00773##
[0967] Step 7-1, preparation of tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate:
from 4,6-dichloronicotinaldehyde (5.0 g, 1.0 Eq, 28 mmol) and
tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (6.0 g, 1.1 Eq,
30 mmol), the title compound (3.4 g, 35%) was prepared using a
similar method to the one described in "Example 4, Step 4-1". MS
(M+H).sup.+=340.1, 342.1.
[0968] Step 7-2, preparation of tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)ca-
rbamate: from tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(3.4 g, 1.0 Eq, 10 mmol), the title compound (2.3 g, 55%) was
prepared using a similar method to the one described in "Example 4,
Step 4-2". MS (M+H).sup.+=418.0, 420.0.
[0969] Step 7-3, preparation of tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyr-
rolidin-3-yl)carbamate: from tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)ca-
rbamate (2.3 g, 1.0 Eq, 5.5 mmol) and (3,5-difluorophenyl)boronic
acid (0.80 g, 0.92 Eq, 5.07 mmol), the title compound (1.7 g, 68%)
was prepared using a similar method to the one described in
"Example 4, Step 4-3". MS (M+H).sup.+=452.2, 454.2.
[0970] Step 7-4, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloro-5-
-(3,5-difluorophenyl)nicotinic acid: from tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyr-
rolidin-3-yl)carbamate (80 mg, 1.0 Eq, 0.18 mmol), the title
compound (100 mg, 97%, 80& purity) was prepared using a similar
method to the one described in "Example 4, Step 4-5". MS
(M+H)==539.7, 541.7.
[0971] Step 7-5, preparation of tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluoroph-
enyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: from
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloro-5-
-(3,5-difluorophenyl)nicotinic acid (100 mg, 1.0 Eq, 0.17 mmol, 80%
purity), the title compound (60 mg, 66%) was prepared using a
similar method to the one described in "Example 4, Step 4-6". MS
(M+H).sup.+=533.2, 535.2.
[0972] Step 7-6, preparation of tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(3,5-difluorophenyl)-2-m-
ethylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a mixture
of tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluoroph-
enyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (35 mg, 1.0
Eq, 0.066 mmol), potassium carbonate (28 mg, 3.1 Eq, 0.20 mmol),
2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (30 mg, 3.6 Eq, 0.24
mmol), and Pd(amphos)Cl.sub.2 (15 mg, 0.11 Eq, 0.007 mmol) was
added dioxane (1.0 mL) under atmospheric nitrogen. The resulting
solution was stirred at 100.degree. C. for 1 hour. The reaction
mixture was concentrated under vacuum and the remaining residue was
purified by silica gel column eluting with ethyl acetate/petroleum
ether (1:1). This resulted in tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(3,5-difluorophenyl)-2-m-
ethylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 59%)
as a yellow solid. MS (M+H).sup.+=513.1.
[0973] Step 7-7, preparation of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(-
3,5-difluorophenyl)-6-methylnicotinamide: to a DCM solution (2.0
mL) of tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-3-(3,5-difluorophenyl)-2-m-
ethylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 1.0
Eq, 0.039 mmol) was added TFA (1.0 mL). The resulting mixture was
stirred at ambient temperature for 2 hours. The reaction solution
was concentrated under vacuum and the remaining residue was
purified by Prep-HPLC using the following conditions: Column,
SunFire Prep C18 OBD, 19*150 mm 5 .mu.m 10 nm; mobile phase, Water
(0.05% TFA) and ACN (16% ACN up to 33% in 7 min); Total flow rate,
20 mL/min; Detector, UV 220 nm. This resulted in the TFA salt of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-5-(-
3,5-difluorophenyl)-6-methylnicotinamide (11.8 mg, 47%) as a white
solid. MS (M+H).sup.+=413.2.
Example 8.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]penta-
n-1-yl}-6-cyanopyridine-3-carboxamide (Compound 1-75)
##STR00774##
[0975] Step 8-1, preparation of tert-butyl
(S)-(1-(2-cyano-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate:
from tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(50 mg, 1.0 Eq, 0.10 mmol), the title compound (20 mg, 59%) was
prepared using a similar method to the one described in "Example 4,
Step 4-4". MS (M+H).sup.+=331.3.
[0976] Step 8-2, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinic acid: from tert-butyl
(S)-(1-(2-cyano-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(20 mg, 1.0 Eq, 0.061 mmol), the title compound (25 mg, 83%) was
prepared using a similar method to the one described in "Example 4,
Step 4-5". MS (M+H).sup.+=347.1.
[0977] Step 8-3, preparation of tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-cyanopyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate: form
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinic acid (25 mg, 1.0 Eq, 0.051 mmol), the title compound (10 mg,
48%) was prepared using a similar method to the one described in
"Example 4, Step 4-6". MS (M+H).sup.+=412.2.
[0978] Step 8-4, preparation of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-6-c-
yanonicotinamide: from tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-cyanopyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate (10 mg, 1.0 Eq, 0.024 mmol), the TFA
salt of the title compound (2.7 mg, 21%) was prepared using a
similar method to the one described in "Example 4, Step 4-7". MS
(M+H).sup.+=312.2.
Example 9.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cycl-
opropylethyl]-5-[3-(difluoromethoxy)phenyl]pyridine-3-carboxamide
(Compound 1-120)
##STR00775##
[0980] Step 9-1, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate: to a mixture of ethyl 4,6-dichloronicotinate (5.00 g, 1.0
Eq, 22.7 mmol), tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate
(4.55 g, 1.0 Eq, 22.7 mmol), and N-ethyl-N-isopropylpropan-2-amine
(8.81 g, 3.0 Eq, 68.2 mmol) was added MeCN (50 mL). The resulting
mixture was stirred at 0.degree. C. for 16 hours. The reaction
mixture was concentrated under reduced pressure and the remaining
residue was purified by recrystallization. This resulted in 6.0 g
of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate (68%). MS (M+H).sup.+=384.3.
[0981] Step 9-2, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinic acid: to a MeOH (50 mL) solution of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate (6.0 g, 1.0 Eq, 15.6 mmol) was added lithium hydroxide
(3.74 g, 9.99 Eq, 156 mmol) and Water (5.0 mL). The resulting
mixture was stirred at 50.degree. C. for 1 hour. The organic layer
was separated and concentrated under vacuum to afford crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinic acid (5.60 g, 93%). This material was used for next step
without further purification. MS (M+H).sup.+=356.2.
[0982] Step 9-3, preparation of tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate: to a DMF (50 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinic acid (1.0 Eq, 15.5 mmol, 5.5 g) was added
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (8.82 g, 1.50 Eq, 23.2 mmol) and
N-ethyl-N-isopropylpropan-2-amine (3.0 Eq, 46.3 mmol, 5.99 g). The
resulting mixture was stirred at ambient temperature for 10 min
followed by the addition of (S)-1-cyclopropylethan-1-amine (2.63 g,
2.00 Eq, 30.9 mmol). The resulting mixture was stirred at ambient
temperature for 1 hour. Reaction solution was diluted with water
(100 mL) and extracted with ethyl acetate (3.times.100 mL). Organic
layers were combined, washed with brine (2.times.100 mL), dried
over anhydrous sodium sulfate and concentrated under vacuum. The
remaining residue was purified by silica gel chromatography eluting
with ethyl acetate/petroleum ether (1:2). This resulted in
tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate (6.0 g, 87%). MS
(M+H).sup.+=423.3.
[0983] Step 9-4, preparation of methyl
4-((S)-3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(((S)-1--
cyclopropylethyl)carbamoyl)picolinate: to a MeOH (20 mL) solution
of tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate (1.2 g, 1.0 Eq, 2.8 mmol) was added
triethylamine (1.0 g, 3.5 Eq, 9.9 mmol), Pd(dppf)Cl.sub.2 (200 mg,
0.096 Eq, 0.273 mmol) under atmospheric nitrogen. The resulting
mixture was heated at 130.degree. C. under 20 bar of carbon
monoxide for 8 hours. The reaction mixture was concentrated under
reduced pressure and the remaining residue was purified by silica
gel chromatography eluting with petroleum ether/EtOAc (1:2) to
afford methyl
4-((S)-3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(((S)-1--
cyclopropylethyl)carbamoyl)picolinate (1.0 g, 79%). MS
(M+H).sup.+=447.4.
[0984] Step 9-5, preparation of tert-butyl
((S)-1-(2-carbamoyl-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3--
methylpyrrolidin-3-yl)carbamate: to a sealed tube was added methyl
4-((S)-3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(((S)-1--
cyclopropylethyl)carbamoyl)picolinate (1.3 g, 1.0 Eq, 2.9 mmol) and
ammonia in MeOH (7.0 M) (12 mL, 28 Eq, 82.2 mmol). The resulting
mixture was stirred at 80.degree. C. for 2 hours. The reaction
solution was concentrated under vacuum to afford crude tert-butyl
((S)-1-(2-carbamoyl-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3--
methylpyrrolidin-3-yl)carbamate (1.0 g, 80%). This material was
used for next step without further purification. MS
(M+H).sup.+=432.2.
[0985] Step 9-6, preparation of tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate: to a DCM (30 mL) solution of
tert-butyl
((S)-1-(2-carbamoyl-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3--
methylpyrrolidin-3-yl)carbamate (1.0 g, 1.0 Eq, 2.3 mmol) was added
TEA (1.1 mL, 3.4 Eq, 7.82 mmol) and TFAA (1.3 mL, 4.1 Eq, 9.5 mmol)
drop-wise at 0.degree. C. The resulting mixture was stirred at
0.degree. C. for 1 hour. The reaction mixture was quenched with
aqueous K.sub.2CO.sub.3 and extracted with EtOAc (3.times.40 mL).
The organic layers were combined, washed with brine, dried and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with ethyl acetate/petroleum
ether (1/1) to afford tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate (700 mg, 73%) as a yellow solid. MS
(M+H).sup.+=414.2.
[0986] Step 9-7, preparation of tert-butyl
((S)-1-(3-bromo-2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl-
)-3-methylpyrrolidin-3-yl)carbamate: to a DCM (4.0 mL) solution of
tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate (700 mg, 1.0 Eq, 1.69 mmol) was added
AcOH (20 mL). 1,3,5-Tribromo-1,3,5-triazinane-2,4,6-trione (620 mg,
1.0 Eq, 1.70 mmol) was added at 0.degree. C. and the resulting
mixture was stirred at the same temperature for 20 min. The
reaction crude was quenched with saturated Na.sub.2SO.sub.3 (10 mL)
and extracted with EtOAc (3.times.40 mL). Organic layers were
combined, washed with brine, dried and concentrated under vacuum.
The remaining residue was purified by silica gel chromatography
eluting with ethyl acetate/petroleum ether (1/3) to afford
tert-butyl
((S)-1-(3-bromo-2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl-
)-3-methylpyrrolidin-3-yl)carbamate (410 mg, 49.2%) as a yellow
solid. MS (M+H).sup.+=492.1, 494.1.
[0987] Step 9-8, preparation of tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3-(difluorometho-
xy)phenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a
mixture of tert-butyl
((S)-1-(3-bromo-2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl-
)-3-methylpyrrolidin-3-yl)carbamate (50 mg, 1.0 Eq, 0.10 mmol),
(3-(difluoromethoxy)phenyl)boronic acid (45 mg, 2.2 Eq, 0.22 mmol),
potassium phosphate (66 mg, 3.1 Eq, 0.31 mmol) and
Pd(DtBPF)Cl.sub.2 (7.0 mg, 0.11 Eq, 0.011 mmol) was added Toluene
(2.0 mL) and water (0.2 mL) under atmospheric nitrogen. The
resulting mixture was stirred at 80.degree. C. for 1 hour. The
reaction mixture was concentrated under reduced pressure and the
remaining residue was purified by silica gel chromatography eluting
with ethyl acetate/petroleum ether (1:1) to afford crude product.
This material was re-purified by Prep-HPLC using the following
conditions: Column, SunFire prep OBD 19*150 mm 5 .mu.m C-01; mobile
phase, Water (0.05% TFA) and ACN (30% ACN up to 44% in 14 min);
Detector, 254 nm. This resulted in tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3-(difluorometho-
xy)phenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (30 mg,
52%) as a white solid. MS (M+H).sup.+=574.4.
[0988] Step 9-9, preparation of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-N--((S)-1-cyclopropylethy-
l)-5-(3-(difluoromethoxy)phenyl)nicotinamide: to a DCM (3.0 mL)
solution of tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3-(difluorometho-
xy)phenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (21 mg,
1.0 Eq, 0.037 mmol) was added TFA (1.0 mL). The resulting mixture
was stirred at 25.degree. C. for 1 hour. The reaction solution was
concentrated and freeze-dried under vacuum to afford the TFA salt
of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-N--((S)-1-cyclopropylethy-
l)-5-(3-(difluoromethoxy)phenyl)nicotinamide (12.4 mg, 48%) as a
white solid. MS (M+H).sup.+=474.2.
[0989] The following compounds were prepared similarly to Example 9
with appropriate substituting reagents and substrates at different
steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00013 Compound no. MS (M + H).sup.+ 1-121 394.3 1-127
474.2 1-128 411.2 1-129 459.2 1-134 381.2
Example 10.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-methylpyridine-3-carboxamide (Compound
1-122)
##STR00776##
[0991] Step 10-1, preparation of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-met-
hylpyrrolidin-3-Yl)carbamate: to a mixture of tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate (400 mg, 1.0 Eq, 0.946 mmol, "Example
9, step 9-3"),
tetrachlorobis{[4-(N,N-dimethylamino)phenyl]-di-t-butylphosphino}d-
ipalladium(II) (67.0 mg, 0.10 Eq, 0.095 mmol), potassium carbonate
(392 mg, 3.0 Eq, 2.84 mmol), and
2,4-dimethyl-1,3,5,2,4,6-trioxatriborinane (2.0 Eq, 1.89 mmol, 209
mg) was added 1,4-Dioxane (5.0 mL) under atmospheric nitrogen. The
resulting mixture was stirred at 80.degree. C. for 1 hour. The
reaction mixture was concentrated, diluted with water (20 mL), and
extracted with ethyl acetate (3.times.20 mL). Organic layers were
combined, washed with brine (2.times.20 mL), dried over anhydrous
sodium sulfate and concentrated under vacuum. The remaining residue
was purified by silica gel chromatography eluting with ethyl
acetate/petroleum ether (2:1) to afford tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate (400 mg, 95%). MS
(M+H).sup.+=403.4.
[0992] Step 10-2, preparation of tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-y-
l)-3-methylpyrrolidin-3-yl)carbamate: to a mixture of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate (400 mg, 1.0 Eq, 0.994 mmol), AcOH
(5.0 mL) and DCM (1.0 mL) was added
1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (550 mg, 1.51 Eq, 1.50
mmol) at 0.degree. C. The resulting mixture was stirred at the same
temperature for 15 min. The reaction mixture was quenched with
aqueous NaHSO.sub.3 at .degree. C. and solids were filtered out.
The filtrate was collected and extracted with EtOAc (3.times.30
mL). Organic layers were combined, washed with water (3.times.30
mL) and aqueous NaHCO.sub.3, dried and concentrated under vacuum.
The remaining residue was purified by silica gel chromatography
eluting with ethyl acetate/petroleum ether (1/2) to afford
tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-y-
l)-3-methylpyrrolidin-3-yl)carbamate (300 mg, 60%). MS
(M+H).sup.+=481.2, 483.2.
[0993] Step 10-3, preparation of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a mixture
of tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methylpyridin-4-y-
l)-3-methylpyrrolidin-3-yl)carbamate (110 mg, 1.0 Eq, 0.228 mmol),
(3,5-difluorophenyl)boronic acid (72 mg, 2.0 Eq, 0.457 mmol),
dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) (15
mg, 0.10 Eq, 0.023 mmol) and potassium phosphate (145 mg 3.0 Eq,
0.683 mmol) was added Toluene (3.0 mL) and water (0.3 mL) under
atmospheric nitrogen. The resulting mixture was heated at
70.degree. C. for 1 hour. The reaction crude was purified by
Prep-HPLC using the following conditions: Column, SunFire Prep C18
OBD Column, 19*150 mm 5 .mu.m; mobile phase, Water (0.05% TFA) and
ACN (22.0% ACN up to 45.0% in 7 min); Total flow rate, 20 mL/min;
Detector, UV 220 nm. This resulted in tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (40 mg, 33%).
MS (M+H).sup.+=515.4.
[0994] Step 10-4, preparation of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-N--((S)-1-cyclopropylethyl)-5-(3,-
5-difluorophenyl)-6-methylnicotinamide: to a DCM (4.0 mL) of
tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (40 mg, 1.0 Eq,
0.078 mmol) was added TFA (2.0 mL). The resulting mixture was
stirred at 25.degree. C. for 1 hour. The reaction solution was
concentrated and lyophilized under vacuum to give the TFA salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-N--((S)-1-cyclopropylethyl)-5-(3,-
5-difluorophenyl)-6-methylnicotinamide as an off-white solid. MS
(M+H).sup.+=415.2.
[0995] The following compounds were prepared similarly to Example
10 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00014 Compound no. MS (M + H).sup.+ 1-121 394.3 1-123
422.2 1-124 397.2 1-125 431.2 1-146 437.2 1-147 443.2 1-148 383.3
1-155 451.3 1-156 409.3 1-157 410.3 1-158 414.2 1-159 448.3 1-160
398.3
Example 11.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-difluorophenyl)-6-methoxypyridine-3-carboxamide (Compound
1-144)
##STR00777##
[0997] Step 11-1, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate: to a mixture of methyl 4,6-dichloronicotinate (1.10 g,
1.0 Eq, 5.34 mmol) and tert-butyl
(S)-(3-methylpyrrolidin-3-yl)carbamate (1.05 g, 0.982 Eq, 5.24
mmol) was added MeCN (10 mL). At 0.degree. C., DIPEA (2.8 mL, 3.0
Eq, 16.0 mmol) was added and the resulting mixture was stirred at
the same temperature for 2 hours. The reaction solution was stirred
at ambient temperature for overnight. The reaction crude was
concentrated and purified by silica gel chromatography eluting with
EtOAc/Hexane (0-60%) to give methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate (1.97 g, 98%). MS (M+H).sup.+=370.3.
[0998] Step 11-2, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinate: to a MeOH (5 mL) solution of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate (1.95 g, 1.0 Eq, 5.27 mmol) was added 25% sodium methoxide
in MeOH (10.0 mL, 8.3 Eq, 44 mmol). The resulting mixture was
heated at 65.degree. C. for overnight. The reaction mixture was
concentrated, diluted with ethyl acetate (30 mL), washed with
saturated NH.sub.4Cl and brine. The organic layer was concentrated
and the remaining residue was purified by C18 reverse phase
chromatography eluting with MeCN (0.1% TFA)/water (0.1% TFA)
(5-45%). Pure fractions were combined, concentrated, neutralized
with saturated NaHCO.sub.3 (5.0 mL), added solid NaCl (10 g), and
extracted with ethyl acetate (2.times.20 mL). Organic layers were
combined, dried with MgSO.sub.4, filtered and concentrated to give
methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinate (1.1 g, 57%) as a clear oil. MS (M+H).sup.+=366.2.
[0999] Step 11-3, preparation of methyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
methoxynicotinate: to a DMF (5.0 mL) solution of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinate (1.06 g, 1.0 Eq, 2.90 mmol) was added NBS (568 mg, 1.1
Eq, 3.19 mmol) portion-wise. The resulting mixture was stirred at
ambient temperature for 15 min and LCMS showed complete conversion
to desired product. The crude reaction mixture was purified by C18
reverse phase chromatography eluting with MeCN (0.1% TFA)/water
(0.1% TFA) (5-85%). Pure fractions were dried under vacuum to
remove water and MeCN. The resulting residue was re-dissolved in
ethyl acetate, washed with saturated NaHCO.sub.3 (5.0 mL) and
brine, dried and concentrated to give
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
methoxynicotinate (809 mg, 63%) as a clear oil. MS
(M+H).sup.+=444.3, 446.1.
[1000] Step 11-4, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)-6-methoxynicotinate: to a mixture of methyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
methoxynicotinate (754 mg, 1.0 Eq, 1.70 mmol),
(3,5-difluorophenyl)boronic acid (1.07 g, 4.0 Eq, 6.79 mmol),
potassium carbonate (1.17 g, 5.0 Eq, 8.48 mmol) and
Pd(amphos)Cl.sub.2 (120 mg, 0.10 Eq, 0.170 mmol) was added
1,4-Dioxane (7.0 mL) and water (0.7 mL) under atmospheric nitrogen.
The resulting mixture was heated at 95.degree. C. for 1 hour. LCMS
showed .about.50% conversion. Second batch of
(3,5-difluorophenyl)boronic acid (1.07 g, 4.0 Eq, 6.79 mmol),
potassium carbonate (1.17 g, 5.0 Eq, 8.48 mmol) and
Pd(amphos)Cl.sub.2 (120 mg, 0.10 Eq, 0.170 mmol) were added under
atmospheric nitrogen, and the resulting mixture was heated at
95.degree. C. for another 1 hour. The reaction crude was diluted
with ethyl acetate, washed with brine, concentrated and dried. The
remaining residue was purified by silica gel chromatography eluting
with EtOAc/Hexane (0-35%) to give methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)-6-methoxynicotinate (286 mg, 35%) as a clear oil. MS
(M+H).sup.+=478.2.
[1001] Step 11-5, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)-6-methoxynicotinic acid: to a MeOH (5 mL) solution of
methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)-6-methoxynicotinate (286 mg, 1.0 Eq, 0.599 mmol) was
added lithium hydroxide hydrate (276 mg, 11.0 Eq, 6.59 mmol) and
water (1.0 mL). The resulting mixture was stirred at 50.degree. C.
for 24 hours. The reaction crude was concentrated, diluted with
ethyl acetate, washed with saturated NaHSO.sub.4, dried and
concentrated to give crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)-6-methoxynicotinic acid (220 mg, 79%) as a white
solid. This material was used for next step without further
purification. MS (M+H).sup.+=464.4.
[1002] Step 11-6, preparation of tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thoxypyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF (0.5
mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)-6-methoxynicotinic acid (30 mg, 1.0 Eq, 0.065 mmol)
was added
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (37 mg, 1.5 Eq, 0.097 mmol),
4,4-difluorocyclohexan-1-amine hydrochloride (17 mg, 1.5 Eq, 0.097
mmol) and N-ethyl-Nisopropylpropan-2-amine (0.045 mL, 4.0 Eq, 0.26
mmol). The resulting mixture was stirred at room temperature for 30
minutes. The reaction mixture was diluted with ethyl acetate,
washed with water and brine, concentrated and purified by silica
gel chromatography eluting with EtOAc/hexane (0-80%). This resulted
in 30 mg of tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thoxypyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate as a white
solid. MS (M+H).sup.+=581.2.
[1003] Step 11-7, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-difluorophenyl)-6-methoxypyridine-3-carboxamide: to a DCM (0.6
mL) solution of tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thoxypyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (30 mg, 1.0
Eq, 0.051 mmol) was added TFA (0.5 mL). The resulting mixture was
stirred at ambient temperature for 0.5 hour. The reaction crude was
concentrated and the remaining residue was purified by C18 reverse
phase chromatography eluting with MeCN (0.10% TFA)/water (0.10%
TFA). Pure fractions were combined, dried under vacuum and treated
with 2.0 N HCl in ether (1.0 mL) for 1 hour. The resulting mixture
as concentrated and dried under vacuum to the HCl salt of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,-
5-difluorophenyl)-6-methoxypyridine-3-carboxamide. MS
(M+H).sup.+=481.3.
[1004] The following compounds were prepared similarly to Example
11 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00015 Compound no. MS (M + H).sup.+ 1-137 453.2 1-140
459.2 1-141 431.5 1-145 467.4 1-151 445.2 1-152 417.4 1-193 499.1
1-194 471.2 1-228 475.3 1-229 447.2 1-235 417.3 1-236 453.3 1-237
453.2 1-238 460.1 1-239 492.1 1-240 484.1 1-241 516.2 1-259 459.3
1-260 475.3 1-261 475.0 1-262 431.5 1-263 447.3 1-273 447.4 1-274
425.1 1-282 433.2 1-283 461.1 1-284 483.2 1-285 455.1 1-286
449.2
Example 12.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5--
(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide (Compound
1-130)
##STR00778##
[1006] Step 12-1, preparation of tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluoroph-
enyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF (2.0
mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloro-5-
-(3,5-difluorophenyl)nicotinic acid (100 mg, 1.0 Eq, 0.17 mmol,
"Step 7-3, Example 7") was added
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (65 mg, 1.0 Eq, 0.17 mmol). The resulting
mixture was stirred at 30.degree. C. for 5 min followed by the
addition of N-ethyl-N-isopropylpropan-2-amine (90 mg, 4.1 Eq, 0.70
mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (25 mg, 1.2
Eq, 0.21 mmol). The reaction mixture was stirred at 30.degree. C.
for 2 hours. The resulting solution was diluted with water (20 mL)
and extracted with ethyl acetate (3.times.30 mL). Organic layers
were combined, washed with brine (2.times.20 mL), dried over
anhydrous sodium sulfate and concentrated under vacuum. The
remaining residue (60 mg, 66%) was used for next step without
further purification. MS (M+H).sup.+=533.2, 535.2.
[1007] Step 12-2, preparation of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-6-c-
hloro-5-(3,5-difluorophenyl)nicotinamide: to a DCM (3.0 mL) of
tert-butyl
(S)-(1-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-2-chloro-3-(3,5-difluoroph-
enyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 1.0
Eq, 0.038 mmol) was added TFA (1.0 mL). The resulting mixture was
stirred at 25.degree. C. for 2 hours. The reaction solution was
concentrated and the remaining residue was purified by Prep-HPLC
using the following conditions: Column, SunFire Prep C18 OBD
Column, 19*150 mm 5 .mu.m 10 nm; mobile phase, Water (0.05% TFA)
and ACN (15% ACN up to 27% in 7 min); Total flow rate, 20 mL/min;
Detector, UV 220 nm. This resulted in the TFA salt of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-
-yl)-6-chloro-5-(3,5-difluorophenyl)nicotinamide (14.1 mg, 57%) as
a white solid. MS (M+H).sup.+=433.2, 435.2.
[1008] Step 12-3, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-{bicyclo[1.1.1]pentan-1-yl}-5--
(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide: to a MeOH
(0.4 mL) solution of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(bicyclo[1.1.1]pentan-1-yl)-6-c-
hloro-5-(3,5-difluorophenyl)nicotinamide
bis(2,2,2-trifluoroacetate) (11 mg, 1.0 Eq, 0.017 mmol) was added
25% sodium methoxide (0.038 mL, 10 Eq, 0.17 mmol). The resulting
mixture as stirred at 65.degree. C. for overnight. LCMS showed most
starting material was converted to the desired product. The
reaction crude was concentrated, 0.5 mL of 25% sodium methoxide was
added, and the resulting mixture was heated at 65.degree. C. for
another 6 hours. The reaction crude was concentrated, diluted with
EtOAc, washed with saturated NaHSO.sub.4 and brine, dried and
concentrated. The remaining residue was combined with 2 N HCl in
ether (1.0 mL) and stirred at ambient temperature for 1 hour. The
resulting suspension was filtered and solid was collected and dried
under vacuum to afford the HCl salt of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N--{bicyclo[1.1.1]pentan-1-yl}-5-
-(3,5-difluorophenyl)-6-methoxypyridine-3-carboxamide as a white
solid. MS (M+H).sup.+=429.4.
[1009] The following compounds were prepared similarly to Example
12 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00016 Compound no. MS (M + H).sup.+ 1-176 445.2 1-177
481.2 1-178 471.2 1-179 475.2
Example 13.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide
(Compound 2-11)
##STR00779##
[1011] Step 13-1, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate: to a mixture of tert-butyl
(S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(1.50 g, 1.0 Eq, 3.9 mmol "Step 2-1, Example 2"),
3-methylbenzene-1,2-diamine (1.40 g, 2.9 Eq, 11.0 mmol) and sodium
metabisulfite (1.50 g, 2.0 Eq, 7.9 mmol) was added DMSO (15 mL).
The resulting mixture was stirred at 50.degree. C. for 1 hour. The
reaction mixture was concentrated under reduced pressure and the
remaining residue was purified by silica gel chromatography eluting
with petroleum ether/EtOAc (3:1) to afford tert-butyl
(S)-(1-(3-bromo-5-(4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate (960 mg, 49%). MS (M+H).sup.+=486.2,
488.2.
[1012] Step 13-2, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinate: to a EtOH (10 mL) solution
of tert-butyl
(S)-(1-(3-bromo-5-(4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate (400 mg, 1.0 Eq, 0.822 mmol) was added
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (68 mg, 0.10 Eq, 0.083 mmol) and
triethylamine (250 mg, 3.0 Eq, 2.47 mmol). The resulting mixture
was saturated with CO and then heated at 120.degree. C. for 12
hours under 20 bar of CO. The reaction mixture was concentrated
under vacuum and the remaining residue was purified by purified by
silica gel chromatography eluting with petroleum ether/EtOAc (1:1).
This resulted in ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinate (120 mg, 30.4%) as a brown
solid. MS (M+H).sup.+=480.3.
[1013] Step 13-3, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinic acid: to a EtOH (1.5 mL)
solution of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-
-methyl-1H-benzo[d]imidazol-2-yl)nicotinate (100 mg, 1.0 Eq, 0.209
mmol) was added sodium hydroxide (125 mg, 15.0 Eq, 3.13 mmol) and
water (0.5 mL). The resulting mixture was stirred at 50.degree. C.
for 36 hours. The reaction mixture was concentrated under reduced
pressure followed by the addition of acetic acid until pH is about
5. The resulting mixture was separated, and the aqueous layer was
treated with NaHCO.sub.3until pH is about 7. The aqueous solution
was washed with methanol/DCM (1/10) three times to remove remaining
starting material. The aqueous phase was spin-dried, and the salts
crashed out were removed. The liquid layer was concentrated to
afford 100 mg of crude product. This material was used for next
step without further purification. MS (M+H).sup.+=452.3.
[1014] Step 13-4, preparation of tert-butyl
((S)-3-methyl-1-(3-(4-methyl-1H-benzo[d]imidazol-2-yl)-5-(((S)-1,1,1-trif-
luoropropan-2-yl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate:
to a DMF (2.0 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinic acid (70 mg, 1.0 Eq, 0.16
mmol) was added HATU (60 mg, 1.0 Eq, 0.16 mmol),
(S)-1,1,1-trifluoropropan-2-amine hydrochloride (25 mg, 1.1 Eq,
0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (70 mg, 3.5 Eq,
0.54 mmol). The resulting mixture was stirred at 50.degree. C. for
1.5 hours. The crude product was purified by Prep-HPLC using the
following conditions: Column, SunFire Prep C18 OBD Column, 19*150
mm 5 .mu.m; mobile phase, Water (0.1% TFA) and ACN (35.0% ACN up to
42.0% in 6 min); Total flow rate, 20 mL/min; Detector, UV 220 nm.
This resulted in the TFA salt of tert-butyl
((S)-3-methyl-1-(3-(4-methyl-1H-benzo[d]imidazol-2-yl)-5-(((S)-1,1,1-trif-
luoropropan-2-yl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate
(60 mg, 59%) as a white solid. MS (M+H).sup.+=547.3.
[1015] Step 13-5, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-
-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide: to
a DCM (3.0 mL) solution of tert-butyl
((S)-3-methyl-1-(3-(4-methyl-1H-benzo[d]imidazol-2-yl)-5-(((S)-1,1,1-trif-
luoropropan-2-yl)carbamoyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate
2,2,2-trifluoroacetate (60 mg, 1.0 Eq, 0.091 mmol) was added TFA
(1.0 mL). The resulting mixture was stirred at 25.degree. C. for 2
hours. The reaction solution was concentrated and the remaining
residue was purified by Prep-HPLC with the following conditions:
Column, SunFire Prep C18 OBD Column, 19*150 mm 5 .mu.m 10 nm;
mobile phase, Water (0.1% TFA) and ACN (26% ACN up to 38% in 6
min); Total flow rate, 20 mL/min; Detector, UV 220 nm. This
resulted in the TFA salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-5-(4-methyl-1H-benzo[d]imidazol-2-
-yl)-N--((S)-1,1,1-trifluoropropan-2-yl)nicotinamide (54.0 mg, 88%)
as a white solid. MS (M+H).sup.+=447.2.
[1016] The following compounds were prepared similarly to Example
13 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00017 Compound no. MS (M + H).sup.+ 2-1 379.2 2-2 405.3
2-3 393.2 2-4 419.2 2-5 421.3 2-6 427.2 2-7 433.2 2-8 409.2 2-9
395.2 2-10 447.2 2-24 451.2 2-25 441.5 2-27 461.5 2-28 449.3 2-31
419.2 2-32 461.3 2-33 445.3 2-34 453.3 2-35 445.3 2-36 447.4 2-37
445.5 2-38 433.5 2-39 431.0 2-40 461.3 2-41 473.3 2-42 445.3 2-43
445.3 2-44 473.7
Example 14.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(7-fluoro-4-methyl-1H-1,3-benz-
odiazol-2-yl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide
(Compound 2-30)
##STR00780##
[1018] Step 14-1, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-formylni-
cotinate: to a MeOH (20 mL) solution of tert-butyl
(S)-(1-(3-bromo-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(1.9 g, 1.0 Eq, 4.9 mmol, "Step 2-1, Example 2") was added
Pd(dppf)Cl.sub.2 (0.30 g, 0.08 Eq, 0.4 mmol) and triethylamine (1.5
g, 3.0 Eq, 15 mmol) under atmospheric of CO. The resulting mixture
was stirred at 100.degree. C. for 2 hours under 15 bar of CO. The
reaction mixture was concentrated under vacuum. The remaining
residue was purified by silica gel chromatography eluting with
ethyl acetate/petroleum ether (2:1) to afford methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-formylni-
cotinate (1.75 g, 97%) as a yellow solid. MS (M+H).sup.+=364.1.
[1019] Step 14-2, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(7-fluor-
o-4-methyl-1H-benzo[d]imidazol-2-yl)nicotinate: to a mixture of
methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-formylni-
cotinate (130 mg, 1.0 Eq, 0.358 mmol), Na.sub.2S.sub.2O.sub.5 (102
mg, 1.50 Eq, 0.537 mmol) and 3-fluoro-6-methylbenzene-1,2-diamine
(100 mg, 1.99 Eq, 0.713 mmol) was added DMSO (2.0 mL). The
resulting mixture was stirred at 80.degree. C. for 2 hours. The
reaction crude mixtures were purified by Prep-HPLC using the
following conditions: Column, C18 120 g; mobile phase, Water (0.1%
FA) and ACN (30% ACN up to 80% in 8 min); Total flow rate, 70
mL/min; Detector, UV 220 nm. This resulted in methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(7-fluor-
o-4-methyl-1H-benzo[d]imidazol-2-yl)nicotinate (160 mg, 74%) as a
yellow oil. MS (M+H).sup.+=484.3.
[1020] Step 14-3, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(7-fluor-
o-4-methyl-1H-benzo[d]imidazol-2-yl)nicotinic acid: to a mixture of
methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(7-fluor-
o-4-methyl-1H-benzo[d]imidazol-2-yl)nicotinate (160 mg, 1.0 Eq,
0.26 mmol) and NaOH (160 mg, 15 Eq, 4.0 mmol) was added MeOH (5.0
mL) and water (0.5 mL). The resulting mixture was stirred at
60.degree. C. for 16 hours. The reaction mixture was concentrated
under reduced pressure, diluted with DCM/MeOH (100 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum.
This resulted in the crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(7-fluor-
o-4-methyl-TH-benzo[d]imidazol-2-yl)nicotinic acid (110 mg, 89%) as
a yellow oil. This material was used for next step without further
purification. MS (M+H).sup.+=470.2.
[1021] Step 14-4, preparation of tert-butyl
((S)-1-(3-(7-fluoro-4-methyl-1H-benzo[d]imidazol-2-yl)-5-(((S)-1,1,1-trif-
luoropropan-2-yl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate-
: to a NMP (3.0 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(7-fluor-
o-4-methyl-1H-benzo[d]imidazol-2-yl)nicotinic acid (110 mg, 1.0 Eq,
0.234 mmol) was added HATU (134 mg, 1.50 Eq, 0.352 mmol) and DIEA
(106 mg, 3.50 Eq, 0.820 mmol). The resulting mixture was stirred at
20.degree. C. for 15 minutes followed by the addition of
(S)-1,1,1-trifluoropropan-2-amine hydrochloride (53 mg, 1.50 Eq,
0.35 mmol). The resulting mixture was stirred at 50.degree. C. for
5 hours. The reaction crude was purified by Prep-HPLC using the
following conditions: Column, SunFire Prep C18 OBD Column, 19*150
mm, 5 .mu.m; mobile phase, Water (0.1% TFA) and ACN (30% ACN up to
70% in 8 min); Total flow rate, 20 mL/min; Detector, UV 220 nm.
This resulted in tert-butyl
((S)-1-(3-(7-fluoro-4-methyl-TH-benzo[d]imidazol-2-yl)-5-(((S)-1,1,1-trif-
luoropropan-2-yl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(60 mg, 45%) as a white solid. MS (M+H).sup.+=565.4.
[1022] Step 14-5, preparation of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-5-(7-fluoro-4-methyl-1H-benzo[d]i-
midazol-2-yl)-N--((S)-1,1,1-trifluoropropan-2-yl)nicotinamide: to a
DCM (2.0 mL) solution of tert-butyl
((S)-1-(3-(7-fluoro-4-methyl-TH-benzo[d]imidazol-2-yl)-5-(((S)-1,1,1-trif-
luoropropan-2-yl)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(60 mg, 1.0 Eq, 0.11 mmol) was added TFA (2.0 mL). The reaction
mixture was stirred at 20.degree. C. for 1 hour. The reaction crude
was concentrated under reduced pressure and lyophilized. This
resulted in the TFA salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-5-(7-fluoro-4-methyl-1H-benzo[d]i-
midazol-2-yl)-N--((S)-1,1,1-trifluoropropan-2-yl)nicotinamide (45.3
mg, 62%) as light brown solid. MS (M+H).sup.+=465.2.
[1023] The following compounds were prepared similarly to Example
14 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00018 Compound no. MS (M + H).sup.+ 2-45 491.2
Example 15.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-N-me-
thyl-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide
(Compound 2-29)
##STR00781##
[1025] Step 15-1, preparation of
2-(5-bromo-4-chloropyridin-3-yl)-4-methyl-1H-benzo[d]imidazole: to
a mixture of 5-bromo-4-chloronicotinaldehyde (250 mg, 1.0 Eq, 1.13
mmol) and 3-methylbenzene-1,2-diamine (208 mg, 1.50 Eq, 1.70 mmol)
was added DMSO (5.0 mL). The reaction mixture was stirred at
50.degree. C. for 1 hour. The reaction mixture was poured into
water (50 mL) and extracted with EtOAc (3.times.50 mL). Organic
layers were combined, washed with water (2.times.50 mL) and brine
(50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure. This resulted in crude
2-(5-bromo-4-chloropyridin-3-yl)-4-methyl-1H-benzo[d]imidazole (320
mg, 44%) as a brown solid. This material was used for next step
without further purification. MS (M+H).sup.+=322.1, 324.1.
[1026] Step 15-2, preparation of tert-butyl
(S)-(1-(3-bromo-5-(4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate: to a mixture of
2-(5-bromo-4-chloropyridin-3-yl)-4-methyl-1H-benzo[d]imidazole (200
mg, 1.0 Eq, 0.620 mmol) and tert-butyl
(S)-(3-methylpyrrolidin-3-yl)carbamate (130 mg, 1.05 Eq, 0.649
mmol) was added MeCN (5.0 mL) and DIEA (0.34 mL, 3.12 Eq, 1.93
mmol). The resulting solution was stirred for at 80.degree. C. for
2 hours. The reaction mixture was cooled to room temperature and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with ethyl acetate/petroleum
ether (1:3) to afford tert-butyl
(S)-(1-(3-bromo-5-(4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate (210 mg, 69.6%) as a yellow oil. MS
(M+H).sup.+=486.0, 488.0.
[1027] Step 15-3, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinate: from tert-butyl
(S)-(1-(3-bromo-5-(4-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-3-meth-
ylpyrrolidin-3-yl)carbamate (210 mg, 1.0 Eq, 0.432 mmol), the title
compound (200 mg, 77%) was prepared using a similar method to the
one described in as described in "Step 13-2, Example 13". MS
(M+H).sup.+=466.2.
[1028] Step 15-4, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinic acid: from methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinate (200 mg, 1.0 Eq, 0.33 mmol),
the title compound (140 mg, 94%) was prepared using a similar
method to the one described in as described in "Step 13-3, Example
13". MS (M+H).sup.+=452.2.
[1029] Step 15-5, preparation of tert-butyl
((S)-1-(3-(((S)-1-cyclopropylethyl)(methyl)carbamoyl)-5-(4-methyl-1H-benz-
o[d]imidazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate:
from
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(4-methy-
l-1H-benzo[d]imidazol-2-yl)nicotinic acid (65 mg, 1.0 Eq, 0.14
mmol), the title compound (25 mg, 33%) was prepared using a similar
method to the one described in as described in "Step 13-4, Example
13". MS (M+H).sup.+=533.3.
[1030] Step 15-6, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-N-me-
thyl-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridine-3-carboxamide:
from tert-butyl
((S)-1-(3-(((S)-1-cyclopropylethyl)(methyl)carbamoyl)-5-(4-methyl-1H-benz-
o[d]imidazol-2-yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(25 mg, 1.0 Eq, 0.047 mmol), the title compound (25 mg, 33%) was
prepared using a similar method to the one described in as
described in "Step 13-5, Example 13". MS (M+H).sup.+=433.3.
[1031] The following compounds were prepared similarly to Example
15 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00019 Compound no. MS (M + H).sup.+ 2-12 391.3 2-13 405.3
2-14 419.3 2-15 417.3 2-16 433.4 2-17 469.3 2-18 447.3 2-19 433.3
2-20 433.3 2-21 419.3 2-22 405.3 2-23 419.3 2-26 471.3
Example 16.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-[3--
(difluoromethoxy)-5-fluorophenyl]-6-methylpyridine-3-carboxamide
(Compound 1-174)
##STR00782##
[1033] Step 16-1, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methylni-
cotinate: to a 1,4-dioxane (30 mL) solution of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate (3.00 g, 1 Eq, 7.82 mmol, "Step 9-2, Example 9") was added
2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (20.0 g, 10 Eq, 80
mmol) (50% w/w in THF), Pd(amphos)Cl.sub.2 (277 mg, 0.0501 Eq, 391
.mu.mol) and potassium carbonate ((3.24 g, 3.00 Eq, 23.4 mmol)
under atmospheric nitrogen. The resulting mixture was stirred at
80.degree. C. for 2 hours. The reaction mixture was quenched with
water (100 mL) and extracted with EtOAc (3.times.100 mL). Organic
layers were combined, washed with brine (100 mL), dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The remaining residue was purified by silica gel chromatography
eluting with DCM/MeOH (8/1) to afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methylni-
cotinate (3.02 g, 96%, 90% purity) as a yellow solid. MS
(M+H).sup.+=364.2.
[1034] Step 16-2, preparation of ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
methylnicotinate: to a mixture of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methylni-
cotinate (900 mg, 1 Eq, 2.48 mmol) and
1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (1.18 g, 1.30 Eq, 3.23
mmol) was added AcOH (25 mL) and DCM (5.0 mL). The resulting
mixture was stirred at 0.degree. C. for 10 min. The reaction
mixture was quenched with saturated NaHSO.sub.3 solution (100 mL),
extracted with EtOAc (2.times.100 mL), washed with water
(2.times.100 mL), saturated NaHCO.sub.3solution (100 mL), brine (20
mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The
remaining residue was purified by silica gel chromatography eluting
with petroleum ether/EtOAc (2/1) to afford ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
methylnicotinate (400 mg, 36.5%) as a yellow solid. MS
(M+H).sup.+=442.1, 444.1.
[1035] Step 16-3, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3-(difl-
uoromethoxy)-5-fluorophenyl)-6-methylnicotinate: to a mixture of
ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
methylnicotinate ((400 mg, 1 Eq, 904 .mu.mol),
(3-(difluoromethoxy)-5-fluorophenyl)boronic acid (372 mg, 2.00 Eq,
1.81 mmol), Pd(DtBPF)Cl.sub.2 (59 mg, 0.10 Eq, 91 .mu.mol) and
potassium phosphate (576 mg, 3.00 Eq, 2.71 mmol) was added Toluene
(8.0 mL) and water (0.8 mL) under atmospheric nitrogen. The
resulting mixture was stirred at 80.degree. C. for 1 hour. The
reaction mixture was concentrated and purified by silica gel
chromatography eluting with petroleum ether/EtOAc (3/1) to afford
ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3-(difl-
uoromethoxy)-5-fluorophenyl)-6-methylnicotinate (270 mg, 57.0%) as
a yellow solid. MS (M+H).sup.+=524.2.
[1036] Step 16-4, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3-(difl-
uoromethoxy)-5-fluorophenyl)-6-methylnicotinic acid: to a MeOH (4.0
mL) solution of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3-(difl-
uoromethoxy)-5-fluorophenyl)-6-methylnicotinate (270 mg, 1 Eq, 516
.mu.mol) was added LiOH (185 mg, 15.0 Eq, 7.72 mmol) and water (2.0
mL). The reaction mixture was stirred at 60.degree. C. for 2 hours.
The reaction mixture was concentrated under reduced pressure to
remove most of MeOH, and the remaining residue was diluted with
water (5 mL). Saturated NaHSO.sub.4 solution was added until pH is
.about.6.0. The resulting mixture was extracted with EtOAc
(3.times.50 mL). Organic layers were combined, washed with brine
(50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under vacuum to afford
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3-(difl-
uoromethoxy)-5-fluorophenyl)-6-methylnicotinic acid (250 mg, 97.8%)
as light yellow solid. This material was used for next step without
further purification. MS (M+H).sup.+=496.4.
[1037] Step 16-5, preparation of tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3-(difluoromethoxy)-5-fl-
uorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-Yl)carbamate:
to a DMF (2.0 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3-(difl-
uoromethoxy)-5-fluorophenyl)-6-methylnicotinic acid (80 mg, 1 Eq,
0.16 mmol) was added HATU (92 mg, 1.5 Eq, 0.24 mmol), and DIEA
(0.11 mL, 4.0 Eq, 0.64 mmol). The resulting mixture was stirred at
25.degree. C. for 15 min, followed by the addition of
4,4-difluorocyclohexan-1-amine hydrochloride (55 mg, 2.0 Eq, 0.32
mmol). The reaction mixture was stirred at 25.degree. C. for 1
hour. The crude product was purified by Prep-HPLC using the
following conditions: Column, SunFire Prep C18 OBD Column, 19*150
mm 5 .mu.m; mobile phase, Water (0.05% NH.sub.3H.sub.2O) and ACN
(40.0% ACN up to 65.0% in 7 min); Total flow rate, 20 mL/min;
Detector, UV 220 nm. This resulted in tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3-(difluoromethoxy)-5-fl-
uorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(65 mg, 66%) as a white solid. MS (M+H).sup.+=613.4.
[1038] Step 16-5, preparation of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3-(-
difluoromethoxy)-5-fluorophenyl)-6-methylnicotinamide: to a DCM
(3.0 mL) of tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3-(difluoromethoxy)-5-fl-
uorophenyl)-2-methylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(65 mg, 1 Eq, 0.11 mmol) was added TFA (2.0 mL). The resulting
mixture was stirred at 25.degree. C. for 1 hour. The reaction
mixture was concentrated and lyophilized under vacuum to afford the
TFA salt of
(S)-4-(3-amino-3-methylpyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3-(-
difluoromethoxy)-5-fluorophenyl)-6-methylnicotinamide (62.2 mg,
79%) as a white solid. MS (M+H).sup.+=513.2.
[1039] The following compounds were prepared similarly to Example
16 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00020 Compound no. MS (M + H).sup.+ 1-171 491.1 1-172
485.2 1-173 463.2 1-181 465.2 1-223 445.2 1-224 431.2 1-230 429.1
1-231 477.1 1-232 459.1 1-233 451.2 1-242 444.1 1-243 468.2 1-255
424.2 1-256 410.2 1-257 462.2 1-258 448.2 1-268 484.3 1-269 456.2
1-272 417.2 1-275 462.1 1-276 445.1 1-277 467.2 1-278 433.2 1-279
443.1 1-280 435.3 1-287 459.2 1-288 415.2 1-289 431.2
Example 17.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-me-
thoxy-2'-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide
(Compound 1-166)
##STR00783##
[1041] Step 17-1, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinate: to a MeOH (10 mL) solution of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate (2.0 g, 1 Eq, 5.2 mmol, "Step 9-1, Example 9") was added
sodium methanolate (2.4 g, 8.5 Eq, 44 mmol). The resulting mixture
was stirred at 65.degree. C. for 16 hours. The reaction mixture was
quenched with water (100 mL), extracted with AcOEt (3.times.40 mL).
Organic layers were combined, washed with brine, dried and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with ethyl acetate/petroleum
ether (1/3) to afford methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinate (930 mg, 49%) as a yellow solid. MS
(M+H).sup.+=366.3.
[1042] Step 17-2, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinic acid: from methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinate (900 mg, 1.0 Eq, 2.46 mmol), the title compound (865 mg)
was prepared using a similar method to the one described in "Step
11-5, Example 11". MS (M+H).sup.+=352.2.
[1043] Step 17-3, preparation of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxypyridin-4-yl)-3-me-
thylpyrrolidin-3-yl)carbamate: to a DMF (10 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-methoxyn-
icotinic acid (900 mg, 1 Eq, 2.56 mmol) was added DIEA (1.0 g, 1.4
mL, 3.0 Eq, 7.7 mmol) and HATU (1.2 g, 1.2 Eq, 3.2 mmol). The
resulting mixture was stirred at room temperature for 10 min
followed by the addition of (S)-1-cyclopropylethan-1-amine
hydrochloride (600 mg, 1.93 Eq, 4.93 mmol). The reaction mixture
was stirred at ambient temperature for 16 hours. The reaction crude
was purified by Prep-HPLC using the following conditions: Column,
SunFire prep OBD 19*150 mm 5 .mu.m C-01; mobile phase, Water (0.05%
FA) and ACN (40% ACN up to 80% in 7 min); Detector 254 nm & 220
nm; flow rate 20 mL/min. This resulted in tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxypyridin-4-yl)-3-me-
thylpyrrolidin-3-yl)carbamate (700 mg, 65.3%) as a white solid. MS
(M+H).sup.+=420.2.
[1044] Step 17-4, preparation of tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxypyridin-4--
yl)-3-methylpyrrolidin-3-yl)carbamate: to a DCM (4.0 mL) of
tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxypyridin-4-yl)-3-me-
thylpyrrolidin-3-yl)carbamate (700 mg, 1 Eq, 1.67 mmol) was added
AcOH (20 mL) and 1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (600
mg, 0.981 Eq, 1.64 mmol) at 0.degree. C. The resulting mixture was
stirred at 0.degree. C. for 20 min. The reaction crude was quenched
with NaHSO.sub.3 (10 mL) and extracted with AcOEt (3.times.40 mL).
Organic layers were combined, washed with brine, dried and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with ethyl acetate/petroleum
ether (1/3) to afford tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxypyridin-4--
yl)-3-methylpyrrolidin-3-yl)carbamate (500 mg, 60.1%) as a yellow
solid. MS (M+H).sup.+=500.2, 502.2.
[1045] Step 17-5, preparation of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxy-2'-(trifluorometh-
yl)-[3,4'-bipyridin]-4-yl)-3-methylpyrrolidin-3-Yl)carbamate: to a
mixture of tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxypyridin-4--
yl)-3-methylpyrrolidin-3-yl)carbamate (70 mg, 1 Eq, 0.14 mmol),
(2-(trifluoromethyl)pyridin-4-yl)boronic acid (60 mg, 2.2 Eq, 0.31
mmol), Pd(dppf)Cl.sub.2 (10 mg, 0.097 Eq, 14 .mu.mol) and potassium
phosphate (90 mg, 3.0 Eq, 0.42 mmol) was added 1,4-Dioxane (2.0 mL)
and water (0.2 mL) under atmospheric nitrogen. The resulting
mixture was stirred at 80.degree. C. for 1 hour. The reaction
mixture was concentrated under reduced pressure. The remaining
residue was purified by silica gel column chromatography eluting
with DCM/MeOH (5:1) to afford crude product. This material was
re-purified by Prep-HPLC using the following conditions: Column,
SunFire prep OBD 19*150 mm 5 .mu.m C-01; mobile phase, Water (0.05%
FA) and MeCN (27% MeCN up to 47% in 7 min); Detector, 254 nm; flow
rate 20 mE/min. This resulted in tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxy-2'-(trifluorometh-
yl)-[3,4'-bipyridin]-4-yl)-3-methylpyrrolidin-3-yl)carbamate (45
mg, 59%) as a white solid. MS (M+H).sup.+=564.5.
[1046] Step 17-6, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-2-me-
thoxy-2'-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide: to a
DCM (3.0 mL) solution of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-methoxy-2'-(trifluorometh-
yl)-[3,4'-bipyridin]-4-yl)-3-methylpyrrolidin-3-yl)carbamate (45
mg, 1 Eq, 80 .mu.mol) was added TFA (1.0 mL). The resulting mixture
was stirred at ambient temperature for 1 hour. The reaction
solution was concentrated and freeze-dried under vacuum to afford
the TFA salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-N--((S)-1-cyclopropylethyl)-2-met-
hoxy-2'-(trifluoromethyl)-[3,4'-bipyridine]-5-carboxamide as a
light yellow solid. MS (M+H).sup.+=464.2.
[1047] The following compounds were prepared similarly to Example
17 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt maybe
obtained.
TABLE-US-00021 Compound no. MS (M + H).sup.+ 1-153 438.3 1-154
479.2 1-164 481.2 1-165 461.2 1-167 430.2 1-182 477.3 1-183 477.1
1-184 503.3 1-185 439.3 1-186 465.3 1-187 442.4 1-188 507.1
Example 18.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide
(Compound 1-190)
##STR00784##
[1049] Step 18-1, preparation of 1 tert-butyl
((S)-1-(3-bromo-2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-y-
l)-3-methylpyrrolidin-3-yl)carbamate: from tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-yl)-3-met-
hylpyrrolidin-3-yl)carbamate (1.6 g, 1 Eq, 4.5 mmol, "Step 9-3,
Example 9"), the title compound (1.30 g) was prepared using a
similar method to the one described in "Step 5-3, Example 5". MS
(M+H).sup.+=503.2.
[1050] Step 18-2, preparation of tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophe-
nyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a mixture
of tert-butyl
((S)-1-(3-bromo-2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)pyridin-4-y-
l)-3-methylpyrrolidin-3-yl)carbamate (1.3 g, 1 Eq, 2.6 mmol),
(3,5-difluorophenyl)boronic acid (420 mg, 1.0 Eq, 2.66 mmol),
K.sub.3PO.sub.4 (1.6 g, 2.9 Eq, 7.5 mmol) and Pd(DtBPF)Cl.sub.2
(180 mg, 0.11 Eq, 276 .mu.mol) was added Toluene (20 mL) and water
(2.0 mL). The resulting mixture was stirred at 60.degree. C. for 30
min. The reaction mixture was concentrated and the remaining
residue was purified by silica gel chromatography eluting with
DCM/MeOH (5:1) to afford tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophe-
nyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (1.0 g, 72%) as
a yellow solid. MS (M+H).sup.+=535.2.
[1051] Step 18-3, preparation of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-(2-
,2,2-trifluoroethoxy)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate:
to a mixture of tert-butyl
((S)-1-(2-chloro-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophe-
nyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (40 mg, 1 Eq,
75 .mu.mol), cesium carbonate (70 mg, 2.9 Eq, 0.21 mmol),
2,2,2-trifluoroethan-1-ol (80 mg, 11 Eq, 0.80 mmol) and
Pd.sub.2(dba).sub.3.CHCl.sub.3 (8 mg, 0.1 Eq, 9 .mu.mol) and BINAP
(15 mg, 0.32 Eq, 24 .mu.mol) was added Toluene (2.0 mL) under
atmospheric nitrogen. The resulting mixture was stirred at
100.degree. C. for 16 hours. The reaction mixture was concentrated
and the remaining residue was purified by silica gel chromatography
eluting with DCM/MeOH (20:1) to afford tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-(2-
,2,2-trifluoroethoxy)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(20 mg, 45%) as a light yellow solid. MS (M+H).sup.+=599.4.
[1052] Step 18-4, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide:
to a DCM (3.0 mL) solution of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-(2-
,2,2-trifluoroethoxy)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(30 mg, 1 Eq, 50 .mu.mol) was added TFA (1.0 mL). The resulting
mixture was stirred at 25.degree. C. for 1 hour. The reaction
solution was concentrated and the remaining residue was purified by
Prep-HPLC using the following conditions: Column, SunFire prep OBD
19*150 mm 5 .mu.m C-01; mobile phase, Water (0.05% FA) and ACN(15%
ACN up to 38% in 7 min); Detector, 254 nm. This resulted in the
formic acid salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-N--((S)-1-cyclopropylethyl)-5-(3,-
5-difluorophenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide (21.6 mg,
79%) as a white solid. MS (M+H).sup.+=499.2.
[1053] The following compounds were prepared similarly to Example
18 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00022 Compound no. MS (M + H).sup.+ 1-191 457.2 1-200
539.2 1-201 553.3 1-202 567.4 1-203 511.3 1-204 525.3 1-205 539.3
1-246 461.2 1-247 475.1 1-264 489.2 1-265 503.3 1-266 487.2 1-267
507.2
Example 19.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide
(Compound 1-189)
##STR00785##
[1055] Step 19-1, preparation of tert-butyl
(S)-(1-(5-formyl-2-(trifluoromethyl)pyridin-4-yl)-3-methylpyrrolidin-3-Yl-
)carbamate: to a mixture of
4-chloro-6-(trifluoromethyl)nicotinaldehyde (100 mg, 1 Eq, 477
.mu.mol), tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (110
mg, 1.15 Eq, 549 .mu.mol), and N-ethyl-N-isopropylpropan-2-amine
(200 mg, 3.24 Eq, 1.55 mmol) was added MeCN (2.0 mL). The resulting
mixture was stirred at 80.degree. C. for 1 hour. The reaction
mixture was concentrated and the remaining residue was purified by
silica gel chromatography eluting with petroleum/EtOAc (3/1) to
afford tert-butyl
(S)-(1-(5-formyl-2-(trifluoromethyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl-
)carbamate (100 mg, 56.1%) as a yellow solid. MS
(M+H).sup.+=374.1.
[1056] Step 19-2, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-(trifluo-
romethyl)nicotinic acid: to a mixture of tert-butyl
(S)-(1-(5-formyl-2-(trifluoromethyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl-
)carbamate (90 mg, 1 Eq, 0.24 mmol), 2-methylbut-2-ene (500 mg, 30
Eq, 7.13 mmol), NaH.sub.2PO.sub.4.2H.sub.2O (100 mg, 2.7 Eq, 641
.mu.mol), and sodium chlorite (36 mg, 1.7 Eq, 0.40 mmol) was added
2-methylpropan-2-ol (2.0 mL) and water (0.4 mL). The resulting
mixture was stirred at 30.degree. C. for 1 hour. The resulting
solution was diluted with saturated NaHSO.sub.4 (20 mL) and
extracted with ethyl acetate (3.times.20 mL). Organic layers were
combined, washed with brine (2.times.20 mL), dried over anhydrous
sodium sulfate and concentrated under vacuum. This resulted in
crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-(trifluo-
romethyl)nicotinic acid (95 mg, 81%) as a yellow solid. This
material was used for next step without further purification. MS
(M+H).sup.+=390.1.
[1057] Step 19-3, preparation of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-(trifluoromethyl)pyridin--
4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF (2.0 mL) solution
of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-(trifluo-
romethyl)nicotinic acid (95 mg, 1 Eq, 0.24 mmol) was added HATU
(100 mg, 1.1 Eq, 263 .mu.mol) and DIEA (100 mg, 0.14 mL, 3.2 Eq,
774 .mu.mol). The resulting mixture was stirred at ambient
temperature for 15 min followed by the addition of
(S)-1-cyclopropylethan-1-amine hydrochloride (40 mg, 1.3 Eq, 0.33
mmol). The reaction mixture was stirred at ambient temperature for
1 hour. The resulting solution was diluted with saturated
NaHCO.sub.3 (20 mL) and extracted with ethyl acetate (3.times.20
mL). Organic layers were combined, washed with brine (2.times.20
mL), dried over anhydrous sodium sulfate and concentrated under
vacuum. The remaining residue was purified by silica gel
chromatography eluting with petroleum/EtOAc (2/1). This resulted in
tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-(trifluoromethyl)pyridin--
4-yl)-3-methylpyrrolidin-3-yl)carbamate (80 mg, 72%) as a yellow
solid. MS (M+H).sup.+=457.2.
[1058] Step 19-4, preparation of tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-(trifluoromethyl)-
pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DCM (0.5 mL)
solution of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-2-(trifluoromethyl)pyridin--
4-yl)-3-methylpyrrolidin-3-yl)carbamate (75 mg, 1 Eq, 0.16 mmol)
was added AcOH (2.5 mL)
1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (75 mg, 1.2 Eq, 0.21
mmol) at 0.degree. C. The resulting mixture was stirred at
0.degree. C. for 15 min. The reaction solution was quenched with
saturated Na.sub.2CO.sub.3 (20 mL) followed by the addition of
saturated NaHSO.sub.4 until pH was adjusted to 6-7. The resulting
solution was extracted with ethyl acetate (3.times.20 mL) and
organic layers were combined. The organic was washed with brine
(2.times.20 mL), dried over anhydrous sodium sulfate and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with ethyl acetate/petroleum
ether (1:3) to afford tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-(trifluoromethyl)-
pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (75 mg, 85%). MS
(M+H).sup.+=535.2, 537.2.
[1059] Step 19-5, preparation of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-(t-
rifluoromethyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to
a mixture of tert-butyl
((S)-1-(3-bromo-5-(((S)-1-cyclopropylethyl)carbamoyl)-2-(trifluoromethyl)-
pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (30 mg, 1 Eq, 56
.mu.mol), (3,5-difluorophenyl)boronic acid (20 mg, 2.3 Eq, 0.13
mmol), Pd(DtBPF)Cl.sub.2 (5.0 mg, 0.14 Eq, 7.7 .mu.mol) and
K.sub.3PO.sub.4 (40 mg, 3.4 Eq, 0.19 mmol) was added Toluene (1.0
mL) and water (0.1 mL) under atmospheric nitrogen. The resulting
mixture was stirred at ambient temperature for 0.5 hour. The
reaction mixture was concentrated and the remaining residue was
purified by silica gel chromatography eluting with petroleum
ether/EtOAc (2/1). The crude product was purified again by
Prep-HPLC using the following conditions: Column, SunFire Prep C18
OBD Column, 19*150 mm 5 .mu.m; mobile phase, Water (0.1% FA) and
ACN (18.0% ACN up to 30.0% in 7 min); Total flow rate, 20 mL/min;
Detector, UV 220 nm. This resulted in tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-(t-
rifluoromethyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (6.0
mg, 19%) as a white solid. MS (M+H).sup.+=498.4.
[1060] Step 19-6, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-5-(3-
,5-difluorophenyl)-6-(trifluoromethyl)pyridine-3-carboxamide: to a
DCM (2.0 mL) of tert-butyl
((S)-1-(5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophenyl)-2-(t-
rifluoromethyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (6.0
mg, 1 Eq, 11 .mu.mol) was added TFA (1.0 mL). The reaction mixture
was stirred at ambient temperature for 1 hour. The resulting
solution was concentrated and freeze-dried under vacuum. This
resulted in the TFA salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-N--((S)-1-cyclopropylethyl)-5--
(3,5-difluorophenyl)-6-(trifluoromethyl)nicotinamide (4.5 mg, 61%)
as a white solid. MS (M+H).sup.+=469.2.
[1061] The following compounds were prepared similarly to Example
19 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00023 Compound no. MS (M + H).sup.+ 1-189 469.2 1-195
485.2 1-197 488.3 1-198 471.1 1-199 455.2 1-206 478.3 1-208 464.2
1-209 469.2 1-210 483.2 1-211 519.2 1-212 483.2 1-213 469.2 1-214
505.2 1-215 487.2 1-216 471.2 1-217 485.2
Example 20.
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-(dicyclopropylmethyl)-2-(3,5-d-
ifluorophenyl)pyridine-4-carboxamide (Compound 3-4)
##STR00786##
[1063] Step 20-1, preparation of methyl
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-chlorois-
onicotinate: to a 1,4-Dioxane (10 mL) solution of methyl
2-chloro-3-fluoroisonicotinate (431.5 mg, 1 Eq, 2.276 mmol) was
added tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (21.13 mg,
1 Eq, 105.5 .mu.mol) and potassium carbonate (786.4 mg, 2.5 Eq,
5.691 mmol). The resulting mixture was stirred at 70.degree. C. for
24 hours. The reaction mixture was quenched with water, extracted
with EtOAc, washed with brine and concentrated. The remaining
residue was purified by silica gel chromatography eluting with
EtOAc/Hexane (0-70%) to give methyl
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-chlorois-
onicotinate (501 mg, 59.5%) as an off-white solid. MS
(M+H).sup.+=370.3.
[1064] Step 20-2, preparation of methyl
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-(3,5-dif-
luorophenyl)isonicotinate: to a mixture of methyl
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-chlorois-
onicotinate (497 mg, 1 Eq, 1.34 mmol), (3,5-difluorophenyl)boronic
acid (424 mg, 2 Eq, 2.69 mmol), potassium carbonate (557 mg, 3 Eq,
4.03 mmol) and Pd(amphos)Cl.sub.2 (47.6 mg, 0.05 Eq, 67.2 .mu.mol)
was added 1,4-Dioxane (6.0 mL) and Water (0.7 mL) under atmospheric
nitrogen. The resulting mixture was heated at 100.degree. C. for 1
hour. The reaction mixture was quenched with water, extracted with
ethyl acetate, washed with brine and concentrated. The remaining
residue was purified by silica gel chromatography eluting with
EtOAc/hexane (0-30%) to methyl
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-(3,5-dif-
luorophenyl)isonicotinate (550 mg, 91.5%) as an off-white solid. MS
(M+H).sup.+=448.0.
[1065] Step 20-3, preparation of
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-(3,5-dif-
luorophenyl)isonicotinic acid: to a solution of methyl
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-(3,5-dif-
luorophenyl)isonicotinate (580 mg, 1 Eq, 1.30 mmol) in THF/H.sub.2O
(4:1) was added lithium hydroxide (310 mg, 10 Eq, 13.0 mmol). The
resulting mixture was stirred at 60.degree. C. for overnight. The
reaction crude was acidified by saturated NaHSO.sub.4, extracted
with ethyl acetate, washed with brine, dried over MgSO.sub.4 and
concentrated to give the crude
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-(3-
,5-difluorophenyl)isonicotinic acid (510 mg, 90.8%) as a light
yellow solid. This material was used for next step without further
purification. MS (M+H).sup.+=434.4.
[1066] Step 20-4, preparation of tert-butyl
(S)-(1-(4-((dicyclopropylmethyl)carbamoyl)-2-(3,5-difluorophenyl)pyridin--
3-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF (0.5 mL) solution
of
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-(3,5-dif-
luorophenyl)isonicotinic acid (30 mg, 1 Eq, 69 .mu.mol) was added
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (39 mg, 1.5 Eq, 0.10 mmol),
dicyclopropylmethanamine hydrochloride (15 mg, 1.5 Eq, 0.10 mmol)
and N-ethyl-Nisopropylpropan-2-amine (36 mg, 48 .mu.L, 4 Eq, 0.28
mmol). The resulting mixture was stirred at 40.degree. C. for 2
hours. The reaction mixture was diluted with ethyl acetate, washed
with water and brine, dried and concentrated to give crude
tert-butyl
(S)-(1-(4-((dicyclopropylmethyl)carbamoyl)-2-(3,5-difluorophenyl)pyridin--
3-yl)-3-methylpyrrolidin-3-yl)carbamate. This material was used for
next step without purification.
[1067] Step 20-5, preparation of
(S)-3-(3-amino-3-methylpyrrolidin-1-yl)-N-(dicyclopropylmethyl)-2-(3,5-di-
fluorophenyl)isonicotinamide: to a DCM (0.6 mL) solution of crude
tert-butyl
(S)-(1-(4-((dicyclopropylmethyl)carbamoyl)-2-(3,5-difluorophenyl)pyridin--
3-yl)-3-methylpyrrolidin-3-yl)carbamate was added TFA (0.5 mL). The
resulting mixture was stirred at ambient temperature for 0.5 hour.
The reaction crude was concentrated and the remaining residue was
purified by C18 reverse phase chromatography eluting with MeCN
(0.1% TFA)/water (0.10% TFA). Pure fractions were combined and
concentrated under vacuum. The remaining residue was stirred in 2.0
N HCl in ether (1.0 mL) for 1 hour. The resulting mixture was
concentrated and dried under vacuum to give the HCl salt of
(S)-3-(3-amino-3-methylpyrrolidin-1-yl)-N-(dicyclopropylmethyl)-2-(3,5-di-
fluorophenyl)isonicotinamide. MS (M+H).sup.+=427.4.
[1068] The following compounds were prepared similarly to Example
20 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00024 Compound no. MS (M + H).sup.+ 3-1 401.5 3-2 415.6
3-3 437.3 3-5 427.4 3-6 428.8 3-7 468.2 3-8 401.3
Example 21.
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-chloro-N-[(1S)-1-cyclopropylet-
hyl]-4-(3,5-difluorophenyl)pyridine-2-carboxamide (Compound
4-1)
##STR00787##
[1070] Step 21-1, preparation of 5-chloro-3-fluoropicolinonitrile:
to a mixture of 2-bromo-5-chloro-3-fluoropyridine (5.00 g, 1 Eq,
23.8 mmol), zinc(II) cyanide (1.67 g, 0.599 Eq, 14.2 mmol),
Pd.sub.2(dba).sub.3.CHCl.sub.3 (246 mg, 0.0100 Eq, 238 .mu.mol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (275 mg,
0.0200 Eq, 475 .mu.mol) was added DMF (60 mL). The reaction mixture
was stirred at 120.degree. C. for 2 hours. The reaction mixture was
quenched with water (200 mL) and extracted with EtOAc (3.times.100
mL). Organic layers were combined, washed with water (2.times.100
mL) and brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The remaining residue was purified by silica gel
chromatography eluting with petroleum/EtOAc (5/1) to afford
5-chloro-3-fluoropicolinonitrile (2.80 g, 75.3%) as a white solid.
.sup.1H NMR (300 MHz, Chloroform-d) .delta. 8.54 (dd, J=1.9, 0.8
Hz, 1H), 7.70 (dd, J=8.0, 1.9 Hz, 1H).
[1071] Step 21-2, preparation of
5-chloro-3-fluoro-4-iodopicolinonitrile: to a mixture of
di-isopropylamine (1.86 g, 1.20 Eq, 18.4 mmol) in THF (80 mL) was
added n-butyl lithium (1.18 g, 7.4 mL, 1.20 Eq, 18.4 mmol) (2.5 M
in n-hexane) at -78.degree. C. under atmospheric nitrogen. The
resulting mixture was stirred at -30.degree. C. for 25 min,
followed by the addition of 5-chloro-3-fluoropicolinonitrile (2.40
g, 1 Eq, 15.3 mmol) in THF (40 mL) drop-wise at -78.degree. C. The
reaction mixture was stirred at -78.degree. C. for 20 min. At
-78.degree. C., an iodine solution (5.84 g, 1.50 Eq, 23.0 mmol) in
THF (20 mL) was added rapidly and the reaction mixture was stirred
at the same temperature for 20 min. The reaction mixture was
quenched with 200 mL of Na.sub.2S.sub.2O.sub.3 solution and
extracted with EtOAc (3.times.100 mL). Organic layers were
combined, washed with brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under vacuum. This resulted in
crude 5-chloro-3-fluoro-4-iodopicolinonitrile (4.10 g, 73%, LCMS
77% purity) as a yellow solid. This material was used for next step
without further purification.
[1072] Step 21-3, preparation of
5-chloro-4-(3,5-difluorophenyl)-3-fluoropicolinonitrile: to a
mixture of crude 5-chloro-3-fluoro-4-iodopicolinonitrile (1.00 g, 1
Eq, 2.7 mmol, 77% purity), (3,5-difluorophenyl)boronic acid (860
mg, 2.0 Eq, 5.45 mmol), potassium phosphate (2.00 g, 3.5 Eq, 9.42
mmol), and Pd(DtBPF)Cl.sub.2 (270 mg, 0.15 Eq, 414 .mu.mol) was
added Toluene (15 mL) and water (1.5 mL) under atmospheric
nitrogen. The reaction mixture was stirred at 45.degree. C. for 5
hours. The resulting mixture was purified by silica gel
chromatography eluting with petroleum ether/EtOAc (4/1). This
resulted in 5-chloro-4-(3,5-difluorophenyl)-3-fluoropicolinonitrile
(546 mg, 52%) (70% purity) as a yellow oil.
[1073] Step 21-4, preparation of tert-butyl
(S)-(1-(5-chloro-2-cyano-4-(3,5-difluorophenyl)pyridin-3-yl)-3-methylpyrr-
olidin-3-yl)carbamate: to a mixture of
5-chloro-4-(3,5-difluorophenyl)-3-fluoropicolinonitrile (546 mg, 1
Eq, 1.4 mmol), tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate
(400 mg, 1.4 Eq, 2.00 mmol), and N-ethyl-N-isopropylpropan-2-amine
(740 mg, 4.0 Eq, 5.73 mmol) was added MeCN (10 mL). The reaction
mixture was stirred at 80.degree. C. for 1 hour. The resulting
mixture was concentrated under reduced pressure and the remaining
residue was purified by silica gel chromatography eluting with
petroleum ether/EtOAc (5/1) to afford tert-butyl
(S)-(1-(5-chloro-2-cyano-4-(3,5-difluorophenyl)pyridin-3-yl)-3-methylpyrr-
olidin-3-yl)carbamate (440 mg, 69%) as a yellow solid. MS
(M+H).sup.+=449.2, 451.2.
[1074] Step 21-5, preparation of
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-chloro-4-
-(3,5-difluorophenyl)picolinic acid: to a EtOH (2.5 mL) solution of
tert-butyl
(S)-(1-(5-chloro-2-cyano-4-(3,5-difluorophenyl)pyridin-3-yl)-3-methylpyrr-
olidin-3-yl)carbamate (200 mg, 1 Eq, 446 .mu.mol) was added
potassium hydroxide (250 mg, 10.0 Eq, 4.46 mmol) and water (1.25
mL). The resulting mixture was stirred at 100.degree. C. for 16
hours. The reaction mixture was poured into water (30 mL), the pH
was adjusted to 5.about.6 by adding saturated NaHSO.sub.4, and
extracted with EtOAc (3.times.30 mL). Organic layers were combined,
washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure. This resulted in
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-chlor-
o-4-(3,5-difluorophenyl)picolinic acid (102 mg, 37%, 75% purity) as
a yellow oil. MS (M+H).sup.+=468.3.
[1075] Step 21-6, preparation of tert-butyl
((S)-1-(5-chloro-2-(((S)-1-cyclopropylethyl)carbamoyl)-4-(3,5-difluorophe-
nyl)pyridin-3-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF (2.0
mL) solution of
(S)-3-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-chloro-4-
-(3,5-difluorophenyl)picolinic acid (102 mg, 1 Eq, 0.16 mmol) was
added DIEA (85 mg, 4.0 Eq, 0.66 mmol), HATU (93 mg, 1.5 Eq, 0.24
mmol) and (S)-1-cyclopropylethan-1-amine hydrochloride (40 mg, 2.0
Eq, 0.33 mmol). The resulting mixture was stirred at ambient
temperature for 1 hour. The reaction crude was purified by
Prep-HPLC using the following conditions: Column, SunFire Prep C18
OBD Column, 19*150 mm, 5 .mu.m; mobile phase, Water (0.1% TFA) and
ACN (70% ACN up to 90% in 7 min); Total flow rate, 20 mL/min;
Detector, UV 220 nm. This resulted in tert-butyl
((S)-1-(5-chloro-2-(((S)-1-cyclopropylethyl)carbamoyl)-4-(3,5-difluorophe-
nyl)pyridin-3-yl)-3-methylpyrrolidin-3-yl)carbamate (32 mg, 37%) as
a light yellow solid. MS (M+H).sup.+=535.3.
[1076] Step 21-7, preparation of
3-((S)-3-amino-3-methylpyrrolidin-1-yl)-5-chloro-N--((S)-1-cyclopropyleth-
yl)-4-(3,5-difluorophenyl)picolinamide: to a DCM (1.0 mL) solution
of tert-butyl
((S)-1-(5-chloro-2-(((S)-1-cyclopropylethyl)carbamoyl)-4-(3,5-difluorophe-
nyl)pyridin-3-yl)-3-methylpyrrolidin-3-yl)carbamate (15 mg, 1 Eq,
28 .mu.mol) was added TFA (1.0 mL). The reaction mixture was
stirred at ambient temperature for 1 hour. The reaction mixture was
concentrated under reduced pressure and lyophilized under vacuum.
This resulted in the TFA salt of
3-((S)-3-amino-3-methylpyrrolidin-1-yl)-5-chloro-N--((S)-1-cyclopropyleth-
yl)-4-(3,5-difluorophenyl)picolinamide (15.9 mg, 86%) as a light
yellow solid. MS (M+H).sup.+=435.1.
Example 22.
3-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-N-[(1S)-1-cyclopropylethyl]-4-(3-
,5-difluorophenyl)-5-methylpyridine-2-carboxamide (Compound
4-2)
##STR00788##
[1078] Step 22-1, preparation of tert-butyl
((S)-1-(2-(((S)-1-cyclopropylethyl)carbamoyl)-4-(3,5-difluorophenyl)-5-me-
thylpyridin-3-yl)-3-methylpyrrolidin-3-Yl)carbamate: to a mixture
of tert-butyl
((S)-1-(5-chloro-2-(((S)-1-cyclopropylethyl)carbamoyl)-4-(3,5-difluorophe-
nyl)pyridin-3-yl)-3-methylpyrrolidin-3-yl)carbamate (15 mg, 1 Eq,
28 .mu.mol, "Step 21-6, Example 21"),
2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (35 mg, 9.9 Eq, 0.28
mmol) (50% w/w in THF), Pd(Amphos)Cl.sub.2 (2.0 mg, 0.10 Eq, 2.8
.mu.mol) and potassium carbonate (12 mg, 3.1 Eq, 87 .mu.mol) was
added 1,4-Dioxane (0.5 mL) under atmospheric nitrogen. The reaction
mixture was stirred at 80.degree. C. for 2 hours. The reaction
mixture was purified by silica gel chromatography eluting with
petroleum ether/EtOAc (3/1). The resulting material was further
re-purified by Prep-HPLC using the following conditions: Column,
SunFire Prep C18 OBD Column, 19*150 mm, 5 .mu.m; mobile phase,
Water (0.05% NH.sub.3.H.sub.2O) and ACN (50% ACN up to 85% in 7
min); Total flow rate, 20 mL/min; Detector, UV 220 nm. This
resulted in tert-butyl
((S)-1-(2-(((S)-1-cyclopropylethyl)carbamoyl)-4-(3,5-difluorophenyl)-5-me-
thylpyridin-3-yl)-3-methylpyrrolidin-3-yl)carbamate (10 mg, 69%) as
white solid. MS (M+H).sup.+=515.4.
[1079] Step 22-2, preparation of
3-((S)-3-amino-3-methylpyrrolidin-1-yl)-N--((S)-1-cyclopropylethyl)-4-(3,-
5-difluorophenyl)-5-methylpicolinamide: to a DCM (2.0 mL) of
tert-butyl
((S)-1-(2-(((S)-1-cyclopropylethyl)carbamoyl)-4-(3,5-difluorophenyl)-5-me-
thylpyridin-3-yl)-3-methylpyrrolidin-3-yl)carbamate (10 mg, 1 Eq,
19 .mu.mol) was added TFA (2.0 mL). The resulting mixture was
stirred at 25.degree. C. for 1 hour. The reaction mixture was
concentrated under reduced pressure and lyophilized under vacuum.
This resulted in the TFA salt of
3-((S)-3-amino-3-methylpyrrolidin-1-yl)-N--((S)-1-cyclopropylethy-
l)-4-(3,5-difluorophenyl)-5-methylpicolinamide (9.0 mg, 72%) as an
off-white solid. MS (M+H).sup.+=414.2.
Example 23.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound
1-77)
##STR00789##
[1081] Step 23-1, preparation of tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-Yl)carbamate:
to a mixture of 4,6-dichloronicotinaldehyde (5.0 g, 1 Eq, 28 mmol),
tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (6.0 g, 1.1 Eq,
30 mmol) and TEA (9.0 g, 12 mL, 3.1 Eq, 89 mmol) was added DMF (60
mL). The resulting mixture was stirred at 50.degree. C. for 4
hours. The reaction mixture was quenched with water (100 mL) and
extracted EtOAc (3.times.40 mL). Organic layers were combined,
washed with brine, dried and concentrated under vacuum. The
remaining residue was purified by silica gel chromatography eluting
with EtOAc/petroleum ether (1/3) to afford tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(3.4 g, 35%) as a yellow solid. MS (M+H).sup.+=340.1, 342.1.
[1082] Step 23-2, preparation of tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-Yl)ca-
rbamate: to an acetic acid (40 mL) solution of tert-butyl
(S)-(1-(2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate
(3.4 g, 1 Eq, 10 mmol) was added NBS (2.0 g, 1.1 Eq, 11 mmol) at
10.degree. C. portion-wise. The resulting mixture was stirred at
the same temperature for 2 hours. The reaction solution was
quenched with saturated NaHCO.sub.3and extracted with EtOAc
(3.times.40 mL). Organic layers were combined, washed with brine,
dried and concentrated under vacuum. The remaining residue was
purified by silica gel chromatography eluting with EtOAc/petroleum
ether (1/4) to afford tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)ca-
rbamate (2.3 g, 55%) as a yellow solid. MS (M+H).sup.+=418.0,
420.0.
[1083] Step 23-3, preparation of tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyr-
rolidin-3-yl)carbamate: to a mixture of tert-butyl
(S)-(1-(3-bromo-2-chloro-5-formylpyridin-4-yl)-3-methylpyrrolidin-3-yl)ca-
rbamate (2.3 g, 1 Eq, 5.5 mmol), (3,5-difluorophenyl)boronic acid
(800 mg, 0.92 Eq, 5.07 mmol), potassium phosphate (3.7 g, 3.2 Eq,
17 mmol) and Pd(DtBPF)Cl.sub.2 (370 mg, 0.10 Eq, 568 .mu.mol) was
added Toluene (92 mL) and water (9.2 mL) under atmospheric
nitrogen. The resulting mixture was stirred at 40.degree. C. for
1.5 hours. The resulting mixture was concentrated under reduced
pressure. The remaining residue was purified by silica gel
chromatography eluting with EtOAc/petroleum ether (1:2) to afford
tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyr-
rolidin-3-yl)carbamate (1.7 g, 68%) as a yellow solid. MS
(M+H).sup.+=452.2, 454.2.
[1084] Step 23-4, preparation of tert-butyl
(S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrr-
olidin-3-yl)carbamate: to a mixture of tert-butyl
(S)-(1-(2-chloro-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyr-
rolidin-3-yl)carbamate (1.7 g, 1 Eq, 3.8 mmol), zinc(II) cyanide
(900 mg, 2.0 Eq, 7.66 mmol), Pd.sub.2(dba).sub.3.CHCl.sub.3 (400
mg, 0.10 Eq, 386 .mu.mol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (440 mg,
0.20 Eq, 760 .mu.mol) was added DMF (20 mL) under atmospheric
nitrogen. The resulting mixture was heated under microwave
radiation at 135.degree. C. for 1 hour. The reaction mixture was
quenched with water (100 mL) and extracted with EtOAc (3.times.40
mL). Organic layers were combined, washed with brine, dried and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with EtOAc/petroleum ether (1/1)
to afford tert-butyl
(S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrr-
olidin-3-yl)carbamate (720 mg, 43%) as a yellow solid. MS
(M+H).sup.+=443.1.
[1085] Step 23-5, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid: to a 2-methylpropan-2-ol (10
mL) solution of tert-butyl
(S)-(1-(2-cyano-3-(3,5-difluorophenyl)-5-formylpyridin-4-yl)-3-methylpyrr-
olidin-3-yl)carbamate (720 mg, 1 Eq, 1.63 mmol) was added sodium
dihydrogen phosphate dihydrate (800 mg, 3.15 Eq, 5.13 mmol),
2-methylbut-2-ene (3.4 g, 30 Eq, 48 mmol), sodium chlorite (300 mg,
2.04 Eq, 3.32 mmol) and water (3.3 mL). The resulting mixture was
stirred at ambient temperature for 1 hour. The reaction mixture was
quenched with saturated NaHSO.sub.4 (50 mL) and extracted with
EtOAc (3.times.40 mL). Organic layers were combined, washed with
brine, dried and concentrated under vacuum to afford crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid (670 mg, 89.8%) as a yellow
solid. This material was used for next step without further
purification. MS (M+H).sup.+=459.2.
[1086] Step 23-6, preparation of tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophen-
yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: from
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid (70 mg, 1.0 Eq, 0.15 mmol), the
title compound (54 mg, 67%) was prepared using a similar method to
the one described in "Example 5, Step 5-6". MS
(M+H).sup.+=526.3.
[1087] Step 23-7, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-N-[(1S)-1-cyclopropyleth-
yl]-5-(3,5-difluorophenyl)pyridine-3-carboxamide: from tert-butyl
((S)-1-(2-cyano-5-(((S)-1-cyclopropylethyl)carbamoyl)-3-(3,5-difluorophen-
yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (54 mg, 1.0 Eq,
0.10 mmol), the HCl salt of the title compound (28 mg, 67%) was
prepared using a similar method to the one described in "Example 5,
Step 5-7". MS (M+H).sup.+=426.3.
Example 24.
4-[(3S)-3-aminopyrrolidin-1-yl]-N-(4,4-difluorocyclohexyl)-5-(3,5-difluor-
ophenyl)-6-methoxypyridine-3-carboxamide (Compound 1-150)
##STR00790##
[1089] Step 24-1, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-chloronicotinate:
to a mixture of methyl 4,6-dichloronicotinate (1.20 g, 1 Eq, 5.82
mmol) and MeCN (7.0 mL) was added tert-butyl
(S)-pyrrolidin-3-ylcarbamate (1.19 g, 1.1 Eq, 6.41 mmol) and DIPEA
(2.26 g, 3.1 mL, 3 Eq, 17.5 mmol). The resulting mixture was
stirred at ambient temperature for 24 hours. The reaction crude was
concentrated and the remaining residue was purified by silica gel
chromatography eluting with EtOAc/hexane (0-50%) to give methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-chloronico-
tinate (2.07 g, 97%) as a white solid. MS (M+H).sup.+=356.2.
[1090] Step 24-2, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-methoxynicotinate-
: to a mixture of MeOH (3.0 mL) and methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-chloronicotinate
(2.0 g, 1 Eq, 5.6 mmol) was added sodium methoxide solution in MeOH
(25% Wt, 13 mL, 10 Eq, 56 mmol). The resulting mixture was heated
at 65.degree. C. for 6 hours. The reaction crude was concentrated,
diluted with saturated NH.sub.4Cl (20 mL), and extracted with ethyl
acetate (3.times.20 mL). Organic layers were combined and
concentrated. The remaining residue was purified by silica gel
chromatography eluting with EtOAc/hexane (0-50%) to give methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-methoxynicotinate
(1.15 g, 58%) as a clear oil. (M+H).sup.+=352.3.
[1091] Step 24-3, preparation of methyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-methoxyni-
cotinate: to a DMF (5 mL) solution of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-methoxynicotinate
(1.15 g, 1 Eq, 3.27 mmol) was added NBS (699 mg, 1.2 Eq, 3.93 mmol)
portion-wise at ambient temperature. The resulting mixture was
stirred at the same temperature for 0.5 hour. The reaction crude
was purified by C18 reverse phase chromatography eluting with MeCN
(0.1% TFA)/water (0.1% TFA) (5-75%). Pure fractions were combined,
neutralized with saturated NaHCO.sub.3 (5 mL), added solid NaCl (15
g), and extracted with ethyl acetate (2.times.20 mL). Organic layer
was dried with MgSO.sub.4, filtered and concentrated. The resulting
residue was re-purified by silica gel chromatography eluting with
EtOAc/hexane (0-50%) to give methyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-me-
thoxynicotinate (801 mg, 57%) as a clear oil. (M+H).sup.+=430.3,
432.3.
[1092] Step 24-4, preparation of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-difluorophen-
yl)-6-methoxynicotinate: to a 1,4-Dioxane (7.0 mL) solution of
methyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-6-methoxyni-
cotinate (760 mg, 1 Eq, 1.77 mmol) was added
(3,5-difluorophenyl)boronic acid (837 mg, 3 Eq, 5.30 mmol),
potassium carbonate (976 mg, 4 Eq, 7.06 mmol), Pd(amphos)Cl.sub.2
(62.5 mg, 0.05 Eq, 88.3 .mu.mol) and Water (0.7 mL) under
atmospheric nitrogen. The resulting mixture was heated at
100.degree. C. for 1 hour. The reaction crude was concentrated and
the remaining residue was purified by silica gel chromatography to
give methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-diflu-
orophenyl)-6-methoxynicotinate (631 mg, 77.1%) as a gummy oil. MS
(M+H).sup.+=464.4.
[1093] Step 24-5, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-difluorophen-
yl)-6-methoxynicotinic acid: to a MeOH (5.0 mL) solution of methyl
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-difluorophen-
yl)-6-methoxynicotinate (631 mg, 1 Eq, 1.36 mmol) was added lithium
hydroxide hydrate (628 mg, 11 Eq, 15.0 mmol) and Water (0.5 mL).
The resulting mixture was heated at 50.degree. C. for 24 hours. The
resulting mixture was concentrated, diluted with ethyl acetate,
washed with saturated NaHSO.sub.4, dried and concentrated to give
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-difluorophen-
yl)-6-methoxynicotinic acid (580 mg, 94.8%) as a yellow solid. This
material was used for next step without further purification. MS
(M+H).sup.+=450.2.
[1094] Step 24-6, preparation of tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thoxypyridin-4-yl)pyrrolidin-3-yl)carbamate: to a solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-5-(3,5-difluorophen-
yl)-6-methoxynicotinic acid (30 mg, 1 Eq, 67 .mu.mol) and
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate (V) (38 mg, 1.5 Eq, 0.10 mmol) in DMF was added
4,4-difluorocyclohexan-1-amine hydrochloride (17 mg, 1.5 Eq, 0.10
mmol) and DIPEA (35 mg, 47 .mu.L, 4 Eq, 0.27 mmol). The reaction
mixture was stirred at 40.degree. C. for overnight. The reaction
mixture was diluted with ethyl acetate, washed with water and
brine, dried and concentrated to give 38 mg of the crude product.
This material was used for next step without further purification.
MS (M+H).sup.+=567.1.
[1095] Step 24-7, preparation of
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3,5-difluoro-
phenyl)-6-methoxynicotinamide: to a DCM (0.6 mL) solution of
tert-butyl
(S)-(1-(5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluorophenyl)-2-me-
thoxypyridin-4-yl)pyrrolidin-3-yl)carbamate (38 mg, 1 Eq, 67
.mu.mol) was added TFA (0.7 g, 0.5 mL, 102 Eq, 6 mmol). The
resulting mixture was stirred at ambient temperature for 0.5 hour.
The reaction crude was concentrated and the remaining residue was
purified by C18 reverse phase chromatography eluting with MeCN
(0.1% TFA)/water (0.1% TFA). Pure fractions were combined and dried
under vacuum. The remaining residue was treated with 2.0 N HCl in
ether (1.0 mL) for 1 hour and concentrated to give the HCl salt of
(S)-4-(3-aminopyrrolidin-1-yl)-N-(4,4-difluorocyclohexyl)-5-(3,5-difluoro-
phenyl)-6-methoxynicotinamide as a white solid (32 mg, 88%). MS
(M+H).sup.+=467.1.
[1096] The following compounds were prepared similarly to Example
24 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00025 Compound no. MS (M + H).sup.+ 1-196 433.3
Example 25.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-2-cyano-2'-methoxy-N-[(2S)-1,1,1-
-trifluoropropan-2-yl]-[3,4'-bipyridine]-5-carboxamide (Compound
1-170)
##STR00791##
[1098] Step 25-1, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-cyano-2'-
-methoxy-[3,4'-bipyridine]-5-carboxylate: to a mixture of ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
cyanonicotinate (100 mg, 1 Eq, 221 .mu.mol, "Step 5-3, Example 5"),
(2-methoxypyridin-4-yl)boronic acid (50 mg, 1.5 Eq, 0.33 mmol),
potassium phosphate (150 mg, 3.20 Eq, 707 .mu.mol) and
Pd(DTBPF)Cl.sub.2 (20 mg, 0.14 Eq, 31 .mu.mol) was added toluene
(2.0 mL) and water (0.2 mL) under atmospheric nitrogen. The
resulting mixture was stirred at 80.degree. C. for 1 hour. The
reaction mixture was concentrated under vacuum and the remaining
residue was purified by silica gel chromatography eluting with
ethyl acetate/petroleum ether (1/2). This resulted in ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-cyano-2'-
-methoxy-[3,4'-bipyridine]-5-carboxylate (70 mg, 66%) as a yellow
oil. MS (M+H).sup.+=482.2.
[1099] Step 25-2, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-cyano-2'-
-methoxy-[3,4'-bipyridine]-5-carboxylic acid: to a MeOH (2.0 mL)
solution of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-
-cyano-2'-methoxy-[3,4'-bipyridine]-5-carboxylate (70 mg, 1 Eq,
0.15 mmol) was added LiOH (40 mg, 11 Eq, 1.7 mmol) and water (0.2
mL). The resulting solution was stirred at 50.degree. C. for 1
hour. The reaction mixture was cooled to room temperature and
concentrated under vacuum. The remaining residue was diluted with
water (30 ml) and the pH was adjusted to 6-7 using saturated
NaHCO.sub.3solution. The resulting mixture was extracted with ethyl
acetate (3.times.30 mL). Organic layers were combined, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-cyano-2'-
-methoxy-[3,4'-bipyridine]-5-carboxylic acid (50 mg, 76%) as a
yellow oil. MS (M+H).sup.+=454.2.
[1100] Step 25-3, preparation of tert-butyl
((S)-1-(2-cyano-2'-methoxy-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamoyl)--
[3,4'-bipyridin]-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF
(2.0 mL) solution was added
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-2-cyano-2'-
-methoxy-[3,4'-bipyridine]-5-carboxylic acid (50 mg, 1 Eq, 0.11
mmol),
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate (V) (45 mg, 1.1 Eq, 0.12 mmol) and
N-ethyl-N-isopropylpropan-2-amine (50 mg, 3.5 Eq, 0.39 mmol). The
resulting mixture was stirred at 25.degree. C. for 5 min followed
by the addition of (S)-1,1,1-trifluoropropan-2-amine hydrochloride
(25 mg, 1.5 Eq, 0.17 mmol). The reaction mixture was stirred at
25.degree. C. for 1 hour. The reaction crude was purified by
Prep-HPLC using the following conditions: Column, SunFire Prep C18
OBD Column, 19*150 mm 5 um; mobile phase, Water (0.1%
NH.sub.3.H.sub.2O) and ACN (22.0% ACN up to 35.0% in 6 min); Total
flow rate, 20 mL/min; Detector, UV 220 nm. This resulted in
tert-butyl
((S)-1-(2-cyano-2'-methoxy-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamoyl)--
[3,4'-bipyridin]-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg,
33%) as a white solid. MS (M+H).sup.+=549.3.
[1101] Step 25-4, preparation of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-2-cyano-2'-methoxy-N--((S)-1,1,1--
trifluoropropan-2-yl)-[3,4'-bipyridine]-5-carboxamide: to a DCM (2
mL) solution of tert-butyl
((S)-1-(2-cyano-2'-methoxy-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamoyl)--
[3,4'-bipyridin]-4-yl)-3-methylpyrrolidin-3-yl)carbamate (20 mg, 1
Eq, 36 .mu.mol) was added TFA (1.0 mL). The resulting mixture was
stirred at ambient temperature for 1 hour. The reaction solution
was concentrated and dried under lyophilization. This resulted in
the TFA salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-2-cyano-2'-methoxy-N--((S)-1,1,1--
trifluoropropan-2-yl)-[3,4'-bipyridine]-5-carboxamide (18.1 mg,
73%) as a white solid. MS (M+H).sup.+=449.1.
Example 26.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-
-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide (Compound
1-192)
##STR00792##
[1103] Step 26-1, preparation of ethyl 4-chloro-6-cyanonicotinate:
to a mixture of ethyl 4,6-dichloronicotinate (100 g, 1 Eq, 454
mmol), zinc(II) cyanide (32.0 g, 0.60 Eq, 273 mmol),
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (4.71 g,
0.010 Eq, 4.55 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (5.26 g,
0.020 Eq, 9.09 mmol) was added DMF (800 mL) under atmospheric
nitrogen. The reaction mixture was stirred at 130.degree. C. for 2
hours. The reaction mixture was poured into water (3000 mL) and
extracted with EtOAc (3.times.1000 mL). Organic layers were
combined, washed with water (3.times.1500 mL) and brine (1000 mL),
dried over anhydrous Na.sub.2SO.sub.4, and concentrated under
reduced pressure. The remaining residue was purified by silica gel
chromatography eluting with petroleum ether /EtOAc/DCM=10/1/1. This
resulted in ethyl 4-chloro-6-cyanonicotinate (68.0 g, 0.23 mol,
50%, 70% Purity) as a yellow solid. MS (M+H).sup.+=211.1,
212.1.
[1104] Step 26-2, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinate: to an MeCN (200 mL) solution of ethyl
4-chloro-6-cyanonicotinate (15 g, 1 Eq, 71 mmol) was added
2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (10 g, 0.92 Eq, 66
mmol) and tert-butyl (S)-(3-methylpyrrolidin-3-yl)carbamate (30 g,
2.1 Eq, 0.15 mol). The resulting mixture was stirred at 50.degree.
C. for 1 hour. The reaction crude was quenched with water (100 mL)
and extracted with EtOAc (3.times.40 mL). The organic layers were
combined, washed with brine, dried and concentrated under vacuum.
The remaining residue was purified by silica gel chromatography
eluting with ethyl acetate/petroleum ether (1/3) to afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinate (16.0 g, 42.7 mmol, 60%) as a yellow solid. MS
(M+H).sup.+=375.1.
[1105] Step 26-3, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-chloro-6-
-cyanonicotinate: to an AcOH (130 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyanonic-
otinate (13.0 g, 1 Eq, 34.7 mmol) was added
1-chloropyrrolidine-2,5-dione (14 g, 3.0 Eq, 0.10 mol). The
resulting mixture was stirred at 35.degree. C. for 3 hours. The
reaction crude was quenched with aqueous NaHCO.sub.3and extracted
with DCM (3.times.200 mL). The organic layers were combined, washed
with brine, dried and concentrated under vacuum. The remaining
residue was purified by silica gel chromatography eluting with
ethyl acetate/petroleum ether (1/4) to afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-chloro-6-
-cyanonicotinate (8.2 g, 20 mmol, 58%) as a yellow solid. MS
(M+H).sup.+=409.2.
[1106] Step 26-4, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinate: to a mixture of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-chloro-6-
-cyanonicotinate (7.5 g, 1 Eq, 18 mmol),
(3,5-difluorophenyl)boronic acid (8.5 g, 2.9 Eq, 54 mmol),
potassium carbonate (7.6 g, 3.0 Eq, 55 mmol) and Pd(amphos)Cl.sub.2
(800 mg, 0.062 Eq, 1.13 mmol) was added 1,4-Dioxane (80 mL) and
Water (8 mL) under atmospheric nitrogen. The resulting mixture was
stirred at 120.degree. C. for 1 hour. The reaction crude was
concentrated under reduced pressure. The remaining residue was
purified by silica gel chromatography eluting with EtOAc/petroleum
ether (1:5) to afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinate (5.2 g, 11 mmol, 58%) as a yellow
solid. MS (M+H).sup.+=487.3.
[1107] Step 26-5, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid: to a MeOH (60 mL) solution of
ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinate (5.2 g, 1 Eq, 11 mmol) was added
LiOH (2.6 g, 10 Eq, 0.11 mol) and Water (6 mL). The resulting
mixture was stirred at 50.degree. C. for 3 hours. The reaction
crude was quenched with aqueous NaHSO.sub.4 and extracted with
EtOAc (3.times.40 mL). The organic layers were combined, washed
with brine, dried and concentrated under vacuum to afford crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid (3.7 g, 8.1 mmol, 76%) as a
yellow solid. This material was used for next step without further
purification. MS (M+H).sup.+=459.3.
[1108] Step 26-6, preparation of tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1.1.1-trifluoropropan-2-yl-
)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a
NMP (7.0 mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyano-5--
(3,5-difluorophenyl)nicotinic acid (500 mg, 1 Eq, 1.09 mmol) was
added
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate (V) (430 mg, 1.04 Eq, 1.13 mmol),
N-ethyl-N-isopropylpropan-2-amine (550 mg, 3.90 Eq, 4.26 mmol) and
(S)-1,1,1-trifluoropropan-2-amine hydrochloride (200 mg, 1.23 Eq,
1.34 mmol). The resulting mixture was stirred at 50.degree. C. for
2 hours. The reaction solution was diluted with saturated
Na.sub.2CO.sub.3 (50 mL) and extracted with ethyl acetate
(3.times.50 mL). Organic layers were combined, washed with brine
(2.times.50 mL), dried over anhydrous sodium sulfate and
concentrated under vacuum. The remaining residue was purified by
silica gel chromatography eluting with ethyl acetate/petroleum
ether (1/3) to give crude product. This material was re-purified by
Prep-HPLC using the following conditions: Column, C18 silica gel;
mobile phase, Water (0.1% FA) and ACN (45.0% up to 85.0% in 8 min);
Total flow rate, 70 mE/min; Detector, UV 220 nm. This resulted in
tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl-
)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (360 mg,
59.6%) as a yellow solid. MS (M+H).sup.+=554.2.
[1109] Step 26-7, preparation of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N--
-((S)-1,1,1-trifluoropropan-2-yl)nicotinamide: 4.0 M HCl in dioxane
(10 mL) was added into tert-butyl
((S)-1-(2-cyano-3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl-
)carbamoyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate with
stirring. The resulting mixture was stirred at 30.degree. C. for
1.5 hour. The reaction mixture was concentrated and dried under
lyophilization (twice). This resulted in the HCl salt of
4-((S)-3-amino-3-methylpyrrolidin-1-yl)-6-cyano-5-(3,5-difluorophenyl)-N--
-((S)-1,1,1-trifluoropropan-2-yl)nicotinamide (317.4 mg, 86.7%) as
a light yellow solid. MS (M+H).sup.+=454.2.
Example 27.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide (Compound
1-54)
##STR00793##
[1111] Step 27-1, preparation of tert-butyl
((S)-1-(3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamo-
yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate: to a DMF (1.3
mL) solution of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-5-(3,5-dif-
luorophenyl)nicotinic acid (57 mg, 1 Eq, 0.132 mmol, "Step 3-2,
Example 3") was added
2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate (V) (60 mg, 1.20 Eq, 0.159 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.222 mL, 10.1 Eq, 1.33 mmol)
and (S)-1,1,1-trifluoropropan-2-amine hydrochloride (120 mg, 6.0
Eq, 0.793 mmol) under atmospheric nitrogen. The resulting mixture
was stirred at 60.degree. C. for 2 hours. The reaction mixture was
diluted with ethyl acetate (30 mL), washed with saturated
NH.sub.4Cl, NaHCO.sub.3and brine, dried over anhydrous sodium
sulfate and concentrated. The remaining residue was purified by
silica gel chromatography eluting with EtOAc/hexane (0-100%) to
give tert-butyl
((S)-1-(3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamo-
yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (62 mg, 89.0%)
as a white powder. (MS (M+H).sup.+=529.3.
[1112] Step 27-2, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide: to a DCM (1.0 mL)
solution of tert-butyl
((S)-1-(3-(3,5-difluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl)carbamo-
yl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (62 mg, 1.0 Eq,
0.12 mmol) was added TFA (0.40 mL, 44 Eq, 5.19 mmol). The resulting
mixture was stirred at ambient temperature for 1 hour. The reaction
crude was concentrated, and the remaining residue was purified by
C18 reverse phase chromatography eluting with MeCN (0.1% TFA)/water
(0.1% TFA) (5-35%). Pure fractions were combined, concentrated,
neutralized with saturated NaHCO.sub.3 (3 mL), added solid NaCl (5
g), and extracted with DCM (2.times.20 mL). Organic layer were
combined, dried with Na.sub.2SO.sub.4, filtered and concentrated
with 1.0 M HCl in ethyl acetate (0.2 mL) to give the HCl salt of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-5-(3,5-difluorophenyl)-N-[(2S)-1-
,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide (28 mg, 48%) as a
white solid. MS (M+H).sup.+=429.3.
Example 28.
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-N-(4,4-difluoro
cyclohexyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide (Compound
1-281)
##STR00794##
[1114] Step 28-1, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate: to an ACN (10 mL) solution of ethyl
4,6-dichloronicotinate (1.0 g, 1 Eq, 4.5 mmol) and tert-butyl
(S)-(3-methylpyrrolidin-3-yl)carbamate (920 mg, 1.0 Eq, 4.59 mmol)
was added DIEA (2.0 g, 2.7 mL, 3.4 Eq, 15 mmol) drop-wise at
0.degree. C. The resulting mixture was stirred at 25.degree. C. for
16 hours. The reaction crude was filtered and the filtrate was
concentrated under vacuum to afford the crude title compound (1.5
g, 3.9 mmol, 86%) as a white solid. This material was used for next
step without further purification. MS (M+H).sup.+=384.2.
[1115] Step 28-2, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pylnicotinate: to a THF (5 mL) solution of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-chloroni-
cotinate (500 mg, 1 Eq, 1.30 mmol) was added zinc(II) bromide (150
mg, 0.511 Eq, 666 .mu.mol), tri-tert-butylphosphane (60 mg, 0.23
Eq, 0.30 mmol) and Pd(OAc).sub.2 (30 mg, 0.10 Eq, 0.13 mmol) under
atmospheric nitrogen. Cyclopropylmagnesium bromide (1.0 M, 6 mL, 5
Eq, 6 mmol) was added at ambient temperature drop-wise. The
resulting mixture was stirred at the same temperature for 3 hours.
The reaction crude was quenched with saturated NH.sub.4Cl and
extracted with ethyl acetate (3.times.40 mL). The organic layers
were combined, washed with brine, dried and concentrated under
vacuum. The remaining residue was purified by silica gel
chromatography eluting with ethyl acetate/petroleum ether (1/3) to
afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pylnicotinate (230 mg, 591 .mu.mol, 45.3%) as a yellow solid. MS
(M+H).sup.+=390.1.
[1116] Step 28-3, preparation of ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
cyclopropylnicotinate: ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pylnicotinate (230 mg, 1 Eq, 591 .mu.mol) was combined with AcOH (6
mL) and DCM (1.2 mL) followed by the addition of
1,3,5-tribromo-1,3,5-triazinane-2,4,6-trione (320 mg, 1.48 Eq, 875
.mu.mol) 0.degree. C. portion-wise. The resulting mixture was
stirred at the same temperature for 20 min. The reaction crude was
quenched with saturated NaHSO.sub.3 (10 mL) and extracted with
ethyl acetate (3.times.40 mL). The organic layers were combined,
washed with saturated NaHCO.sub.3and brine, dried and concentrated
under vacuum. The remaining residue was purified by silica gel
chromatography eluting with ethyl acetate/petroleum ether (1/3) to
afford ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6--
cyclopropylnicotinate (130 mg, 278 .mu.mol, 47.0%) as a yellow
solid. MS (M+H).sup.+=468.1, 470.1.
[1117] Step 28-4, preparation of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pyl-5-(3,5-difluorophenyl)nicotinate: to a Toluene (2 mL) solution
of ethyl
(S)-5-bromo-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1--
yl)-6-cyclopropylnicotinate (120 mg, 1 Eq, 256 .mu.mol) was added
(3,5-difluorophenyl) boronic acid (80 mg, 2.0 Eq, 0.51 mmol),
K.sub.3PO.sub.4 (160 mg, 2.94 Eq, 754 .mu.mol), Pd(DTBPF)Cl.sub.2
(18 mg, 0.11 Eq, 28 .mu.mol) and water (0.2 mL) under atmospheric
nitrogen. The resulting mixture was stirred at 80.degree. C. for 1
hour. The reaction mixture was concentrated and the remaining
residue was purified by silica gel chromatography eluting with
ethyl acetate/petroleum ether (1:3) to afford ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pyl-5-(3,5-difluorophenyl)nicotinate (103 mg, 205 .mu.mol, 80.2%)
as a light yellow solid. MS (M+H).sup.+=502.2.
[1118] Step 28-5, preparation of
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pyl-5-(3,5-difluorophenyl)nicotinic acid: to a MeOH (5 mL) solution
of ethyl
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cy-
clopropyl-5-(3,5-difluorophenyl) nicotinate (103 mg, 1 Eq, 205
.mu.mol) was added NaOH (80 mg, 9.7 Eq, 2.0 mmol) and water (1 mL).
The resulting mixture was stirred at 70.degree. C. for 4 hours. The
reaction solution was concentrated under vacuum and diluted with
water. Saturated NaHSO.sub.4 was added until pH=4-5. The resulting
mixture was extracted with DCM (3.times.40 mL). Organic layers were
combined, washed with brine, dried and concentrated under vacuum to
afford crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pyl-5-(3,5-difluorophenyl)nicotinic acid (80 mg, 0.17 mmol, 82.0%)
as a yellow solid. This material was used in next step without
further purification. MS (M+H).sup.+=474.2.
[1119] Step 28-6, preparation of tert-butyl
(S)-(1-(2-cyclopropyl-5-((4,4-difluorocyclohexyl)
carbamoyl)-3-(3,5-difluorophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)ca-
rbamate: to DMF (2 mL) solution of crude
(S)-4-(3-((tert-butoxycarbonyl)amino)-3-methylpyrrolidin-1-yl)-6-cyclopro-
pyl-5-(3,5-difluorophenyl) nicotinic acid (20 mg, 1 Eq, 42 .mu.mol)
was added DIEA (2.0 g, 2.7 mL, 3.4 Eq, 15 mmol) and HATU (20 mg,
1.2 Eq, 53 .mu.mol). The resulting mixture was stirred at ambient
temperature for 10 min followed by the addition of
4,4-difluorocyclohexan-1-amine (20 mg, 3.5 Eq, 0.15 mmol). The
reaction mixture was stirred at the same temperature for 1 hour.
The reaction crude (5 mL) was purified by Prep-HPLC using the
following conditions: Column, SunFine prep OBD 19*150 mm 5 um C-01;
mobile phase, water (0.05% FA) and ACN (27% ACN up to 47% in 7
min); Detector 254 & 220 nm; flow rate, 20 mL/min. This
resulted in tert-butyl
(S)-(1-(2-cyclopropyl-5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluo-
rophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (11 mg, 19
.mu.mol, 44%) as a white solid. MS (M+H).sup.+=591.1.
[1120] Step 28-7, preparation of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-N-(4,4-difluoro
cyclohexyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide: to a DCM
(3 mL) solution of tert-butyl
(S)-(1-(2-cyclopropyl-5-((4,4-difluorocyclohexyl)carbamoyl)-3-(3,5-difluo-
rophenyl)pyridin-4-yl)-3-methylpyrrolidin-3-yl)carbamate (12 mg, 1
Eq, 20 .mu.mol) was added TFA (1 mL). The resulting mixture was
stirred at ambient temperature for 1 hour. The reaction solution
was concentrated and the remaining residue was freeze-dried with
water and ACN to afford the TFA salt of
4-[(3S)-3-amino-3-methylpyrrolidin-1-yl]-6-cyclopropyl-N-(4,4-difluoro
cyclohexyl)-5-(3,5-difluorophenyl)pyridine-3-carboxamide (10.1 mg,
14.1 .mu.mol, 69%) as a light yellow solid. MS
(M+H).sup.+=491.2.
[1121] The following compounds were prepared similarly to Example
28 with appropriate substituting reagents and substrates at
different steps and they may require additional functional group
modifications via well-known chemistry with appropriate reagents.
Different salts, such as HCl or formic acid or TFA salt, maybe
obtained.
TABLE-US-00026 Compound no. MS (M + H).sup.+ 1-290 469.2
Example A-1: Parenteral Pharmaceutical Composition
[1122] To prepare a parenteral pharmaceutical composition suitable
for administration by injection (subcutaneous, intravenous), 1-100
mg of a water-soluble salt of a compound Formula (I), or a
pharmaceutically acceptable salt or solvate thereof, is dissolved
in sterile water and then mixed with 10 mL of 0.9% sterile saline.
A suitable buffer is optionally added as well as optional acid or
base to adjust the pH. The mixture is incorporated into a dosage
unit form suitable for administration by injection
Example A-2: Oral Solution
[1123] To prepare a pharmaceutical composition for oral delivery, a
sufficient amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, is added to water (with
optional solubilizer(s), optional buffer(s) and taste masking
excipients) to provide a 20 mg/mL solution.
Example A-3: Oral Tablet
[1124] A tablet is prepared by mixing 20-50% by weight of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by
weight of low-substituted hydroxypropyl cellulose, and 1-10% by
weight of magnesium stearate or other appropriate excipients.
Tablets are prepared by direct compression. The total weight of the
compressed tablets is maintained at 100-500 mg.
Example A-4: Oral Capsule
[1125] To prepare a pharmaceutical composition for oral delivery,
10-500 mg of a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, is mixed with starch or other suitable
powder blend. The mixture is incorporated into an oral dosage unit
such as a hard gelatin capsule, which is suitable for oral
administration.
[1126] In another embodiment, 10-500 mg of a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, is placed into
Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin)
and the capsule is closed.
Example B-1: SSTR Assays
Membrane Preparation:
[1127] Crude membrane fractions are prepared from Chinese hamster
ovary (CHO) cells stably expressing one of the five human or rodent
somatostatin receptor subtypes. The cells are grown to 85-100%
confluence on standard tissue culture dishes in DM-MEM growth media
(Gibco) with following additives: 10% fetal bovine serum (Gibco),
100 U/mL penicillin (Gibco), 100 ug/mL streptomycin (Gibco), 10 mM
HEPES (Gibco), 0.5 mg/mL G-418 (Gibco). To prepare membranes, cells
are washed once with 1.times. Dulbecco's phosphate buffered saline
(Gibco) containing 10 mM HEPES (Gibco) then once with sodium free
binding buffer (50 mM Tris Base, 5 mM MgCl.sub.2-6H.sub.2O and 1 mM
EGTA adjusted to pH 7.8). The cells are then scraped into binding
buffer containing a protease inhibitor cocktail (100 ug/mL
pepstatin A (Sigma), 50 ug/mL leupeptin (Sigma), 25 ug/mL aprotinin
(Sigma) and 10 mg/mL Bacitracin (USB Corporation)). The cells are
centrifuged at 43,500.times.g, homogenized, and the resulting
membranes are collected by centrifugation at 67,000.times.g. The
membranes are then resuspended in binding buffer containing the
protease inhibitor cocktail using a glass dounce homogenizer.
Functional Assays
[1128] General overview: All five SSTR subtypes are Gi coupled
G-protein coupled receptors (GPCRs) that lead to decreases in
intracellular cyclic AMP (cAMP) when activated by an agonist.
Therefore, measurement of intracellular cAMP levels can be used to
assess whether compounds of the invention are agonists of SSTR
subtypes (John Kelly, Troy Stevens, W. Joseph Thompson, and Roland
Seifert, Current Protocols in Pharmacology, 2005, 2.2.1-2.2). One
example of an intracellular cAMP assay is described below.
cAMP Assay Protocol for SST2R:
[1129] Four days prior to the assay, 5,000 Chinese hamster ovary
cells (CHO-K1, ATCC #CCL-61) stably expressing the human
somatostatin receptor subtype 2 are plated in each well of a
96-well tissue culture-treated plate in Ham's F12 growth media
(ThermoFisher #10-080-CM) supplemented with 10% donor bovine serum
(Gemini Bio-Products #100-506), 100 U/mL penicillin; 100 ug/mL
streptomycin; 2 mM L-glutamine (Gemini Bio-Products #400-110) and
0.2 mg/mL hygromycin B (GoldBio #31282-04-9). The cells are
cultured at 37.degree. C., 5% CO.sub.2 and 95% humidity. On the day
of the assay, the media is aspirated and the cells are treated with
50 .mu.L of 1.6 .mu.M NKH477 (Sigma #N3290) plus various dilutions
of compounds of the invention in assay buffer [1.times. Hank's
Balanced Salt Solution (ThermoFisher #SH3058802), 0.5 mM HEPES pH
7.4, 0.1% bovine serum albumin, 0.2 mM 3-Isobutyl-1-methylxanthine
(IBMX, VWR #200002-790)]. The cells are incubated for 20 minutes at
37.degree. C. (the final concentration of the compounds of the
invention are typically 0-10,000 nM). The cells are treated with 50
.mu.L of lysis buffer (HRTF cAMP kit, Cisbio). The lysate is
transferred to 384-well plates and cAMP detection and visualization
antibodies are added and incubated for 1-24 hours at room
temperature. The time-resolved fluorescent signal is read with a
Tecan M1000Pro multiplate reader. The intracellular cAMP
concentrations are calculated by regression to a standard curve and
are plotted vs. the concentration of the compounds of the invention
and the EC.sub.50 of the compounds are calculated using standard
methods. All data manipulations are in GraphPad Prism v6 or v7.
cAMP Assay Protocol for SST5R:
[1130] Four days prior to the assay, 2,000 Chinese hamster ovary
cells (CHO-K1, ATCC #CCL-61) stably expressing the human
somatostatin receptor subtype 5 are plated in each well of a
96-well tissue culture-treated plate in Ham's F12 growth media
(ThermoFisher #10-080-CM) supplemented with 10% donor bovine serum
(Gemini Bio-Products #100-506), 100 U/mL penicillin; 100 .mu.g/mL
streptomycin; 2 mM L-glutamine (Gemini Bio-Products #400-110) and
0.25 mg/mL G418 Sulfate (GoldBio #108321-42-2). The cells are
cultured at 37.degree. C., 5% CO.sub.2 and 95% humidity. On the day
of the assay, the media is aspirated and the cells are treated with
50 .mu.L of 1.6 .mu.M NKH477 (Sigma #N3290) plus various dilutions
of compounds of the invention in assay buffer [1.times. Hank's
Balanced Salt Solution (ThermoFisher #SH3058802), 0.5 mM HEPES pH
7.4, 0.1% bovine serum albumin, 0.2 mM 3-Isobutyl-1-methylxanthine
(IBMX, VWR #200002-790)]. The cells are incubated for 20 minutes at
37.degree. C. (the final concentration of the compounds of the
invention are typically 0-10,000 nM). The cells are treated with 50
.mu.L of lysis buffer (HRTF cAMP kit, Cisbio) for 30 minutes and
then the lysate is diluted to 250 .mu.L with assay buffer. The
lysate is transferred to 384-well plates and cAMP detection and
visualization antibodies are added and incubated for 1-24 hours at
room temperature. The time-resolved fluorescent signal is read with
a Tecan M1000Pro multiplate reader. The intracellular cAMP
concentrations are calculated by regression to a standard curve and
are plotted vs. the concentration of the compounds of the invention
and the EC.sub.50 of the compounds are calculated using standard
methods. All data manipulations are in GraphPad Prism v6 or v7.
[1131] Illustrative biological activity of compounds is
demonstrated in the following Tables, by evaluating the inhibition
of cAMP activities via human SST receptors.
[1132] Table A demonstrates illustrative biological activity of
compounds by evaluating the inhibition of cAMP activities via human
SST5 receptor, where a means EC.sub.50 is <10 nM; b means
EC.sub.50 is between 10 to 100 nM; c means EC.sub.50 is between 100
to 1000 nM; d means EC.sub.50 is >1000 nM.
TABLE-US-00027 TABLE A Representative SST5 Activity Compd No. SST5
potency 1-1 a 1-2 b 1-3 a 1-4 a 1-5 a 1-6 a 1-7 c 1-8 c 1-9 c 1-10
b 1-11 a 1-12 a 1-13 a 1-14 a 1-15 a 1-16 a 1-17 a 1-18 b 1-19 a
1-20 a 1-21 a 1-22 a 1-23 b 1-24 a 1-25 a 1-26 a 1-27 a 1-28 b 1-29
b 1-30 a 1-31 a 1-32 a 1-33 a 1-34 a 1-35 a 1-36 b 1-37 b 1-38 a
1-39 c 1-40 b 1-41 a 1-42 a 1-43 a 1-44 a 1-45 a 1-46 a 1-47 a 1-48
a 1-49 a 1-50 a 1-51 a 1-52 a 1-53 a 1-54 a 1-55 a 1-56 a 1-57 a
1-58 a 1-59 a 1-60 a 1-61 a 1-62 a 1-63 b 1-64 a 1-65 a 1-66 a 1-67
a 1-68 a 1-69 a 1-70 a 1-71 a 1-72 a 1-73 a 1-74 a 1-75 c 1-76 a
1-77 a 1-78 a 1-79 a 1-80 c 1-81 a 1-82 a 1-83 a 1-84 a 1-85 a 1-86
a 1-87 a 1-88 a 1-89 a 1-90 a 1-91 a 1-92 a 1-93 a 1-94 a 1-95 a
1-96 a 1-97 a 1-98 a 1-99 d 1-100 a 1-101 a 1-102 b 1-103 a 1-104 a
1-105 b 1-106 b 1-107 b 1-108 a 1-109 c 1-110 a 1-111 c 1-112 a
1-113 a 1-114 a 1-115 a 1-116 a 1-117 c 1-118 a 1-119 c 1-120 a
1-121 a 1-122 a 1-123 a 1-124 a 1-125 a 1-126 a 1-127 a 1-128 a
1-129 a 1-130 a 1-131 a 1-132 a 1-133 c 1-134 a 1-135 a 1-136 b
1-137 a 1-138 a 1-139 a 1-140 a 1-141 a 1-142 a 1-143 a 1-144 a
1-145 a 1-146 a 1-147 a 1-148 a 1-149 a 1-150 a 1-151 a 1-152 a
1-153 a 1-154 a 1-155 d 1-156 b 1-157 a 1-158 a 1-159 a 1-160 a
1-161 a 1-162 a 1-163 a 1-164 a 1-165 a 1-166 a 1-167 a 1-168 a
1-169 a 1-170 a 1-171 a 1-172 a 1-173 a 1-174 a 1-175 b 1-176 a
1-177 a 1-178 a 1-179 a 1-180 a 1-181 a 1-182 a 1-183 a 1-184 a
1-185 b 1-186 a 1-187 a 1-188 a 1-189 a 1-190 a 1-191 a 1-192 a
1-193 c 1-194 a 1-195 a 1-196 a 1-197 a 1-198 a 1-199 a 1-200 a
1-201 a 1-202 a 1-203 a 1-204 d 1-205 a 1-209 a 1-210 a 1-211 a
1-212 a 1-213 a 1-214 a 1-215 a 1-216 a 1-217 a 1-218 c 1-219 a
1-222 a 1-223 b 1-224 b 1-225 a 1-226 a 1-227 c 1-228 a 1-229 a
1-230 a 1-231 a 1-232 a 1-233 a 1-234 a 1-235 d 1-236 d 1-237 d
1-238 a 1-239 a 1-240 a 1-241 b 1-242 a 1-243 a 1-244 a 1-245 a
1-246 a 1-247 a 1-259 a 1-260 a 1-261 a
1-262 a 1-263 a 1-264 a 1-265 a 1-266 a 1-267 a 1-268 a 1-269 a
1-272 a 1-273 a 1-274 d 1-275 a 1-276 a 1-277 a 1-278 a 1-279 a
1-280 a 1-281 a 1-282 a 1-283 a 1-284 a 1-285 a 1-286 a 1-287 a
1-288 a 1-289 a 1-290 a 1-206 a 1-208 a 1-248 a 1-249 a 1-250 a
1-251 a 1-252 a 1-253 a 1-254 a 1-255 a 1-256 a 1-257 a 1-258 a
1-270 a 1-271 a 1-220 a 1-221 b 2-1 b 2-2 b 2-3 b 2-4 a 2-5 c 2-6 a
2-7 a 2-8 b 2-9 c 2-10 a 2-11 a 2-12 b 2-13 a 2-14 a 2-15 a 2-16 a
2-17 b 2-18 a 2-19 a 2-20 a 2-21 b 2-22 b 2-23 b 2-24 a 2-25 b 2-26
a 2-27 a 2-28 b 2-29 a 2-30 a 2-31 a 2-32 a 2-33 a 2-34 b 2-35 a
2-36 a 2-37 a 2-38 a 2-39 b 2-40 a 2-41 a 2-42 a 2-43 a 2-44 b 2-45
a 3-1 b 3-2 a 3-3 c 3-4 a 3-5 b 3-6 a 3-7 b 3-8 b 4-1 a 4-2 b 4-3 a
4-4 b 4-5 d
[1133] Table B demonstrates illustrative biological selectivity of
exemplary compounds for the SST5 receptor over SST2 receptor, by
evaluating the inhibition of cAMP activities via human SST5
receptor and human SST2 receptor, where a means EC.sub.50 is <10
nM; b means EC.sub.50 is between 10 to 100 nM; c means EC.sub.50 is
between 100 to 1000 nM; d means EC.sub.50 is >1000 nM; +=10 to
99, ++=100 to 499, +++=>500.
TABLE-US-00028 TABLE B Illustrative Selectivity Data Demonstrating
Preference for SST5 vs SST2 Fold SST5 SST2 selectivity for Compd
No. potency potency SST5 vs SST2 1-1 a b ++ 1-2 b a - 1-3 a c + 1-4
a c ++ 1-5 a c +++ 1-6 a b ++ 1-10 b d ++ 1-11 a d +++ 1-12 a c +++
1-13 a c +++ 1-16 a c +++ 1-17 a c ++ 1-19 a c ++ 1-20 a c +++ 1-21
a b ++ 1-22 a c ++ 1-24 a b +++ 1-25 a c +++ 1-30 a c ++ 1-31 a c
++ 1-34 a c ++ 1-35 a c ++ 1-41 a b ++ 1-44 a c ++ 1-47 a c +++
1-48 a c +++ 1-49 a c +++ 1-51 a c +++ 1-54 a c ++ 1-57 a c ++ 1-58
a c +++ 1-61 a d +++ 1-64 a d +++ 1-66 a d +++ 1-67 a d +++ 1-68 a
d +++ 1-69 a c +++ 1-70 a d +++ 1-71 a c +++ 1-72 a c +++ 1-73 a d
+++ 1-74 a d +++ 1-76 a d +++ 1-77 a b +++ 1-78 a b +++ 1-79 a c
+++ 1-81 a c +++ 1-85 a c +++ 1-86 a c +++ 1-87 a c +++ 1-90 a c
+++ 1-91 a c +++ 1-92 a c +++ 1-93 a b +++ 1-94 a c ++ 1-96 a c ++
1-98 a c ++ 1-100 a d +++ 1-101 a d +++ 1-103 a d +++ 1-104 a d +++
1-108 a d +++ 1-110 a d +++ 1-112 a c +++ 1-113 a d +++ 1-114 a d
+++ 1-115 a d +++ 1-116 a d +++ 1-118 a d +++ 1-120 a b +++ 1-121 a
d +++ 1-122 a c +++ 1-123 a c +++ 1-124 a c +++ 1-125 a b +++ 1-126
a d +++ 1-127 a c +++ 1-128 a c +++ 1-129 a c +++ 1-130 a c +++
1-132 a d +++ 1-135 a c +++ 1-137 a c +++ 1-153 a c +++ 1-154 a d
+++ 1-155 d +++ 1-157 a d +++ 1-158 a d +++ 1-159 a d +++ 1-160 a c
+++ 1-161 a d ++ 1-162 a d +++ 1-163 a c ++ 1-164 a c +++ 1-165 a c
+++ 1-166 a d +++ 1-167 a d +++ 1-168 a c +++ 1-169 a c +++ 1-170 a
c +++ 1-171 a b +++ 1-172 a c +++ 1-173 a c ++ 1-174 a c +++ 1-176
a c +++ 1-177 a b +++ 1-178 a b +++ 1-179 a c +++ 1-180 a b +++
1-181 a c +++ 1-182 a d +++ 1-183 a d +++ 1-184 a c +++ 1-186 a c
+++ 1-187 a d +++ 1-188 a c +++ 1-192 a b ++ 1-195 a b ++ 1-196 a d
+++ 1-197 a c +++ 1-198 a b ++ 1-199 a c +++ 1-200 a c +++ 1-201 a
d +++ 1-202 a d +++ 1-209 a +++ 1-210 a b +++ 1-212 a c +++ 1-213 a
c +++ 1-214 a d +++ 1-215 a c +++ 1-216 a d +++ 1-217 a c +++ 1-226
a c ++ 1-228 a b +++ 1-229 a b +++ 1-230 a c ++ 1-231 a c +++ 1-232
a d +++ 1-233 a d +++ 1-234 a c +++ 1-238 a c +++ 1-239 a d +++
1-240 a c +++ 1-241 b 1-242 a d +++ 1-244 a c +++ 1-245 a d +++
1-246 a c +++ 1-247 a d +++ 1-259 a b +++ 1-260 a c +++ 1-261 a c
+++ 1-262 a c +++ 1-263 a d +++ 1-264 a d +++ 1-265 a d +++ 1-266 a
d +++ 1-267 a c +++ 1-268 a d +++ 1-269 a c +++ 1-272 a c +++ 1-273
a c +++ 1-275 a c +++ 1-276 a c ++ 1-277 a d +++ 1-278 a d +++
1-279 a c +++ 1-280 a c +++ 1-282 a c +++ 1-283 a c +++ 1-284 a c
+++ 1-285 a c +++ 1-286 a c +++ 1-287 a b +++ 1-288 a c +++ 1-289 a
c +++ 1-206 a d +++ 1-208 a c +++ 1-248 a d +++ 1-249 a c +++ 1-250
a d +++ 1-251 a d +++ 1-252 a c +++ 1-253 a c +++ 1-254 a d +++
1-255 a d +++ 1-256 a d +++ 1-257 a d +++ 1-258 a d +++ 1-270 a d
+++ 1-271 a d +++ 2-7 a c ++ 2-11 a b + 2-15 a c ++ 2-26 a c +++
2-29 a b + 2-30 a b + 2-35 a c ++ 2-36 a c +++ 2-37 a c ++ 2-38 a c
+ 2-41 a c + 2-42 a c ++ 2-43 a b + 2-45 a c ++ 3-2 a d +++ 3-6 a d
+++ 4-1 a d +++ 4-(3-(aminomethyl)pyrrolidin- a a 0.084
1-yl)-N,5-bis(3,5- dimethylphenyl)nicotinamide
4-(4-aminopiperidin-1-yl)- d a 0.000096 N,5-bis(3,5-
dimethylphenyl)nicotinamide N-(4-(3-(aminomethyl)pyrrolidin- d a
0.0055 1-yl)-5-(3,5- dimethylphenyl)pyridin-3-yl)-3-
chloro-4-fluorobenzamide
Example B-2: Liver Microsomal Stability Assay Protocol
[1134] The in vitro stabilities of compounds of interest were
determined for various species using pooled male and female human,
pooled male Sprague-Dawley rat, pooled male Cynomolgus monkey, and
pooled male Beagle dog liver microsomes at microsomal protein
concentrations of 0.5 mg/mL. Incubations were carried out in a
potassium phosphate buffer (50 mM). The NADPH-generating system was
composed of NADP+ (1 mM), magnesium chloride (3 mM), EDTA (1 mM),
glucose-6-phosphate (5 mM) and glucose-6-phosphate dehydrogenase (1
Unit/mL) for all experiments. Compounds of interest in
DMSO/acetonitrile were added to achieve a final incubation
concentration of 1 .mu.M (final DMSO content was 0.1% v/v and final
acetonitrile content was 0.9%). The final incubation volume was 400
.mu.L. Incubations were conducted at 37.degree. C. for 0, 5, 10,
20, 40 and 60 minutes in a shaking water bath and terminated by
removing 50 .mu.L of incubation mixture and adding to 100 .mu.L of
ice cold acetonitrile containing internal standard. Following
precipitation by centrifugation at 3500 rpm and 4.degree. C. for 30
minutes, compounds of interest and internal standard were analyzed
in the resultant supernatant using a multiple reaction monitoring
(MRM) LC-MS/MS method. MS conditions were optimized for each
analyte. Depletion rates of compounds of interest were measured and
half-life, scaled intrinsic clearance, and predicted scaled
systemic clearance calculations were made using this data.
Example B-3: Genetic Models of Hyperinsulinism in Rodents
[1135] Representative assays evaluating the effect of a selective
somatostatin subtype (sst5) agonist described herein in genetic
models of hyperinsulinism in rodents, specifically the SUR1.sup.-/-
mouse model, are described. The SUR1.sup.-/- mouse reproduces the
key pathophysiological features of K.sub.ATP congential
hyperinsulinism (HI), the most common and severe genetic form of
hyperinsulinism. SUR1.sup.-/- mice are both significantly more
hypoglycemic when fasted and significantly more hyperglycemic when
glucose-loaded compared with control wild-type. Evaluation of the
effect of oral administration of a somatostatin subtype (sst5)
agonist described herein on plasma glucose levels after a fast is
described below.
In Vivo Experiments:
[1136] SUR1.sup.-/- mice and wild type mice are administered a
somatostatin subtype (sst5) agonist described herein at a dose of
30 mg/Kg/day for 1 week. Fasting plasma glucose, insulin, and
betahydroxybutyrate concentrations are measured after a 16 hr fast
at baseline and after 1 week of treatment. Glucose and an insulin
tolerance tests are performed during the treatment period.
[1137] Sample size: Average fasting plasma glucose levels in
SUR1.sup.-/- mice are 59.4+/-5.0 mg/dL. With 5 mice per group there
is greater than 90% power to detect a difference of 20% (equivalent
to bringing the levels to normal range) on fasting plasma glucose
levels in treated versus control-treated SUR1.sup.-/- mice (using
alpha 0.05).
[1138] Treatment groups: (1) a compound described herein; (2)
selective somatostatin 2 agonist; and (3) Placebo.
[1139] Genotype groups: (1) SUR1.sup.-/- mice; and (2) Wild type
mice
[1140] Experimental Procedures:
[1141] Fasting Evaluation: Fasting plasma glucose are measured
after a 16 hour fast. Plasma glucose and betahydroxybutyrate levels
are checked by a hand held glucose meter (Nova Stat Strip glucose
meters) in blood obtained from a tail nick (only one nick will be
necessary) and 15 microliters of blood are collected to measure
insulin levels.
[1142] Intraperitoneal glucose tolerance test: After an overnight
fast, mice are given an i.p. dose of glucose (2 g/kg). Plasma
glucose and insulin concentrations are measured at baseline and
every 30 min for 2 hrs. Fifteen microliters of blood/time point is
obtained and measured for insulin levels.
[1143] Insulin tolerance test: After a 6 hr fast, mice are given an
i.p. injection of insulin (1 unit/kg). Glucose concentration is
measured at baseline and every 10 min for 30 minutes or until the
mice reach a hypoglycemic state, then every 30 min for 2 hrs.
In Vitro Experiments:
[1144] The direct effects of a somatostatin subtype (sst5) agonist
described herein or selective somatostatin 2 agonist on insulin
secretion are tested in isolated pancreatic islets from wild type
and SUR1.sup.-/- mice. The direct effects of the compounds are also
tested in islets isolated from patients with K.sub.ATPHI who
undergo pancreatectomy and those from healthy human volunteers.
[1145] Batch incubation: 5 islets for each well with 4 replicates
of each condition in 96-well plate format are used for the study.
Islets are exposed to 4 concentrations of glucose (0, 5, 10 and 25
mM) or mixture of amino acids (0, 2, 4 and 10 mM) in the absence or
presents of 4 concentrations of 2 compounds (a somatostatin subtype
(sst5) agonist described herein, somatostatin 2 agonist). The
effects of compounds and the effective doses on insulin secretion
are obtained after those experiments.
[1146] Cytosolic calcium measurements: Cytosolic calcium
([Ca.sup.2+].sub.i) dynamics are assessed using Fura-2 as calcium
indicator; islets isolated from wild type or SUR1.sup.-/- mice are
exposed to glucose and amino acids. The effects of the compounds on
[Ca.sup.2+].sub.i dynamics are directly evaluated.
[1147] Islets perifusion: After batch incubations and calcium
measurements, the effective concentration of compounds are
determined. The effects of those compounds with effective dose on
insulin secretion dynamics are evaluated in perifused islets.
[1148] K.sub.ATPHI human islets: Compounds are also tested with
K.sub.ATPHI human islets. Islets are isolated from surgical
specimens from patients with K.sub.ATPHI who underwent
pancreatectomy. K.sub.ATPHI are perifused in response to amino acid
and glucose stimulation in the absence or presence of the
compounds. [Ca.sup.2+].sub.i dynamics are also tested.
[1149] The examples and embodiments described herein are for
illustrative purposes only and various modifications or changes
suggested to persons skilled in the art are to be included within
the spirit and purview of this application and scope of the
appended claims.
* * * * *