INHIBITORS OF HUMAN ATGL
20220289698 · 2022-09-15
Assignee
Inventors
- Gernot GRABNER (Graz, AT)
- Rudolf ZECHNER (Graz, AT)
- Robert Zimmermann (Graz, AT)
- Rolf Breinbauer (Graz, AT)
- Anna MIGGLAUTSCH (Graz, AT)
- Nikolaus GUTTENBERGER (Graz, AT)
Cpc classification
C07D409/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D277/06
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07D401/10
CHEMISTRY; METALLURGY
C07D409/10
CHEMISTRY; METALLURGY
C07D213/04
CHEMISTRY; METALLURGY
C07D277/56
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
International classification
C07D277/56
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D409/10
CHEMISTRY; METALLURGY
C07D409/12
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
Abstract
The present invention relates to novel inhibitors of adipose triglyceride lipase (ATGL) having an improved inhibitory activity against human ATGL (hATGL) as well as pharmaceutical compositions comprising these inhibitors, and their therapeutic use, particularly in the treatment or prevention of a lipid metabolism disorder, including, e.g., obesity, non-alcoholic fatty liver disease, type 2 diabetes, insulin resistance, glucose intolerance, hypertriglyceridemia, metabolic syndrome, cardiac and skeletal muscle steatosis, congenital generalized lipodystrophy, familial partial lipodystrophy, acquired lipodystrophy syndrome, atherosclerosis, or heart failure.
Claims
1. A compound of the following formula (I) ##STR00322## or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a disease or disorder selected from a lipid metabolism disorder, obesity, non-alcoholic fatty liver disease, type 2 diabetes, insulin resistance, glucose intolerance, hypertriglyceridemia, metabolic syndrome, cardiac and skeletal muscle steatosis, congenital generalized lipodystrophy, familial partial lipodystrophy, acquired lipodystrophy syndrome, atherosclerosis, and heart failure; wherein: A is —CH═C(R.sup.A1)—CH═ or —S—C(R.sup.A2)═; L is selected from a covalent bond, C.sub.1-5 alkylene, C.sub.2-5 alkenylene, and C.sub.2-5 alkynylene, wherein one —CH.sub.2— unit comprised in said C.sub.1-5 alkylene, said C.sub.2-5 alkenylene or said C.sub.2-5 alkynylene is optionally replaced by —O—; R.sup.1 is selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, carbocyclyl, and heterocyclyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups R.sup.Alk, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; R.sup.2 is selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, —(C.sub.0-4 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SH, —(C.sub.0-4 alkylene)-S(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH.sub.2, —(C.sub.0-4 alkylene)-NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —(C.sub.0-4 alkylene)-O—(C.sub.1-5 haloalkyl), —(C.sub.0-4 alkylene)-CN, —(C.sub.0-4 alkylene)-CHO, —(C.sub.0-4 alkylene)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-COOH, —(C.sub.0-4 alkylene)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH.sub.2, —(C.sub.0-4 alkylene)-CO—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—NH—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—N(C.sub.1-5 alkyl)-(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—NH.sub.2, —(C.sub.0-4 alkylene)-SO.sub.2—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein said C.sub.1-10 alkyl, said C.sub.2-10 alkenyl, said C.sub.2-10 alkynyl, each alkyl moiety in any of the aforementioned groups, and each alkylene moiety in any of the aforementioned groups are each optionally substituted with one or more groups R.sup.Alk, and wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; R.sup.A1 and R.sup.A2 are each independently selected from hydrogen, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —(C.sub.0-4 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SH, —(C.sub.0-4 alkylene)-S(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH.sub.2, —(C.sub.0-4 alkylene)-NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —(C.sub.0-4 alkylene)-O—(C.sub.1-5 haloalkyl), —(C.sub.0-4 alkylene)-CN, —(C.sub.0-4 alkylene)-CHO, —(C.sub.0-4 alkylene)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-COOH, —(C.sub.0-4 alkylene)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH.sub.2, —(C.sub.0-4 alkylene)-CO—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—NH—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—N(C.sub.1-5 alkyl)-(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—NH.sub.2, —(C.sub.0-4 alkylene)-SO.sub.2—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; each R.sup.Alk is independently selected from —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-O, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1, haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —CO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; each R.sup.Cyc is independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —CO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), and —SO—(C.sub.1-5 alkyl); each L.sup.X is independently selected from a covalent bond, C.sub.1-5 alkylene, C.sub.2-5 alkenylene, and C.sub.2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-5 haloalkyl, —CN, —OH, —O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), and —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), and further wherein one or more —CH.sub.2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C.sub.1-5 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; and each R.sup.X is independently selected from hydrogen, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), and —SO—(C.sub.1-5 alkyl).
2. The compound for use according to claim 1, wherein A is —CH═C(R.sup.A1)—C═, and said compound has the following structure: ##STR00323##
3. The compound for use according to claim 1, wherein A is —S—C(R.sup.A2)═, and said compound has the following structure: ##STR00324##
4. The compound for use according to any one of claims 1 to 3, wherein L is a covalent bond.
5. The compound for use according to any one of claims 1 to 4, wherein R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, and heterocycloalkyl.
6. The compound for use according to any one of claims 1 to 5, wherein R.sup.1 is selected from ethyl, isopropyl, —CH.sub.2—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—C≡CH, and cyclopropyl.
7. The compound for use according to any one of claims 1 to 6, wherein R.sup.1 is ethyl or isopropyl.
8. The compound for use according to any one of claims 1 to 7, wherein R.sup.2 is selected from C.sub.1-10 alkyl, —O(C.sub.1-10 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-10 alkyl), —O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —O(C.sub.2-4 alkenyl), —S(C.sub.1-5 alkyl), —COO—(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O—(C.sub.1-5 haloalkyl), -L.sup.X-aryl, -L.sup.X-cycloalkyl, -L.sup.X-heteroaryl, and -L.sup.X-heterocycloalkyl, wherein the aryl moiety in said -L.sup.X-aryl, the cycloalkyl moiety in said -L.sup.X-cycloalkyl, the heteroaryl moiety in said -L.sup.X-heteroaryl, and the heterocycloalkyl moiety in said -L.sup.X-heterocycloalkyl are each optionally substituted with one or more groups R.sup.Cyc.
9. The compound for use according to any one of claims 1 to 8, wherein R.sup.2 is selected from —CH.sub.2CH.sub.3, —(CH.sub.2).sub.2CH.sub.3, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3, —O—CH.sub.2CH.sub.3, —O—(CH.sub.2).sub.2CH.sub.3, —O—(CH.sub.2).sub.3CH.sub.3, —O—(CH.sub.2).sub.4CH.sub.3, —O—(CH.sub.2).sub.5CH.sub.3, —O—(CH.sub.2).sub.6CH.sub.3, —CH.sub.2—O—CH.sub.3, and —CH(—CH.sub.3)—O—CH.sub.3, preferably wherein R.sup.2 is —O—CH.sub.2CH.sub.3.
10. The compound for use according to any one of claims 1 to 9, wherein R.sup.A1 and R.sup.A2 are each independently selected from hydrogen, —CH.sub.3, —OCH.sub.3, —CO—CH.sub.3, and —I.
11. The compound for use according to any one of claims 1 to 10, wherein R.sup.A1 and R.sup.A2 are each hydrogen.
12. The compound for use according to claim 1, wherein said compound is any one of the following compounds, or a pharmaceutically acceptable salt or solvate thereof: ##STR00325## ##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332## ##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352## ##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## ##STR00378## ##STR00379## ##STR00380## ##STR00381##
13. A compound of the following formula ##STR00382## or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a covalent bond, C.sub.1-5 alkylene, C.sub.2-5 alkenylene, and C.sub.2-5 alkynylene, wherein one —CH.sub.2— unit comprised in said C.sub.1-5 alkylene, said C.sub.2-5 alkenylene or said C.sub.2-5 alkynylene is optionally replaced by —O—; R.sup.1 is selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, carbocyclyl, and heterocyclyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups R.sup.Alk, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; R.sup.2 is selected from hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, —(C.sub.0-4 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SH, —(C.sub.0-4 alkylene)-S(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH.sub.2, —(C.sub.0-4 alkylene)-NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —(C.sub.0-4 alkylene)-O—(C.sub.1-5 haloalkyl), —(C.sub.0-4 alkylene)-CN, —(C.sub.0-4 alkylene)-CHO, —(C.sub.0-4 alkylene)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-COOH, —(C.sub.0-4 alkylene)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH.sub.2, —(C.sub.0-4 alkylene)-CO—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—NH—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—N(C.sub.1-5 alkyl)-(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—NH.sub.2, —(C.sub.0-4 alkylene)-SO.sub.2—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.XR.sup.X, wherein said C.sub.1-10 alkyl, said C.sub.2-10 alkenyl, said C.sub.2-10 alkynyl, each alkyl moiety in any of the aforementioned groups, and each alkylene moiety in any of the aforementioned groups are each optionally substituted with one or more groups R.sup.Alk, and wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; R.sup.A1 is selected from hydrogen, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —(C.sub.0-4 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SH, —(C.sub.0-4 alkylene)-S(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH.sub.2, —(C.sub.0-4 alkylene)-NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —(C.sub.0-4 alkylene)-O—(C.sub.1-5 haloalkyl), —(C.sub.0-4 alkylene)-CN, —(C.sub.0-4 alkylene)-CHO, —(C.sub.0-4 alkylene)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-COOH, —(C.sub.0-4 alkylene)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH.sub.2, —(C.sub.0-4 alkylene)-CO—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—NH—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—N(C.sub.1-5 alkyl)-(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—NH.sub.2, —(C.sub.0-4 alkylene)-SO.sub.2—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; each R.sup.Alk is independently selected from —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; each R.sup.Cyc is independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —C(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), and —SO—(C.sub.1-5 alkyl); each L.sup.X is independently selected from a covalent bond, C.sub.1-5 alkylene, C.sub.2-5 alkenylene, and C.sub.2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-5 haloalkyl, —ON, —OH, —O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), and —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), and further wherein one or more —CH.sub.2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C.sub.1-5 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; and each R.sup.X is independently selected from hydrogen, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(CO.sub.1-5 alkyl), and —SO—(C.sub.1-5 alkyl); and further wherein the following compounds are excluded: ethyl 6-(4-methoxyphenyl)-2-pyridinecarboxylate; ethyl 6-(4-hydroxyphenyl)-2-pyridinecarboxylate; and ethyl 6-(4-{[(3-fluorophenyl)methyl]oxy}phenyl)-2-pyridinecarboxylate.
14. The compound of claim 13, wherein L is a covalent bond.
15. The compound of claim 13 or 14, wherein R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, and heterocycloalkyl.
16. The compound of any one of claims 13 to 15, wherein R.sup.1 is selected from ethyl, isopropyl, —CH.sub.2—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—C≡CH, and cyclopropyl.
17. The compound of any one of claims 13 to 16, wherein R.sup.1 is ethyl or isopropyl.
18. The compound of any one of claims 13 to 17, wherein R.sup.2 is selected from C.sub.1-10 alkyl, —O(C.sub.1-10 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-10 alkyl), —O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —O(C.sub.2-4 alkenyl), —S(C.sub.1-5 alkyl), —COO—(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O—(C.sub.1-5 haloalkyl), -L.sup.X-aryl, -L.sup.X-cycloalkyl, -L.sup.X-heteroaryl, and -L.sup.X-heterocycloalkyl, wherein the aryl moiety in said -L.sup.X-aryl, the cycloalkyl moiety in said -L.sup.X-cycloalkyl, the heteroaryl moiety in said -L.sup.X-heteroaryl, and the heterocycloalkyl moiety in said -L.sup.X-heterocycloalkyl are each optionally substituted with one or more groups R.sup.Cyc.
19. The compound of any one of claims 13 to 18, wherein R.sup.2 is selected from —CH.sub.2CH.sub.3, —(CH.sub.2).sub.2CH.sub.3, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3, —O—CH.sub.2CH.sub.3, —O—(CH.sub.2).sub.2CH.sub.3, —O—(CH.sub.2).sub.3CH.sub.3, —O—(CH.sub.2).sub.4CH.sub.3, —O—(CH.sub.2).sub.5CH.sub.3, —O—(CH.sub.2).sub.6CH.sub.3, —CH.sub.2—O—CH.sub.3, and —CH(—CH.sub.3)—O—CH.sub.3, preferably wherein R.sup.2 is —O—CH.sub.2CH.sub.3.
20. The compound of any one of claims 13 to 19, wherein R.sup.A1 is selected from hydrogen, —CH.sub.3, —OCH.sub.3, —CO—CH.sub.3, and —I.
21. The compound of any one of claims 13 to 20, wherein R.sup.A1 is hydrogen.
22. The compound of claim 13, wherein said compound is any one of the following compounds, or a pharmaceutically acceptable salt or solvate thereof: ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402##
23. A compound of the following formula ##STR00403## or a pharmaceutically acceptable salt or solvate thereof, wherein: L is selected from a covalent bond, C.sub.1-5 alkylene, C.sub.2-5 alkenylene, and C.sub.2-5 alkynylene, wherein one —CH.sub.2— unit comprised in said C.sub.1-5 alkylene, said C.sub.2-5 alkenylene or said C.sub.2-5 alkynylene is optionally replaced by —O—; R.sup.1 is selected from C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, carbocyclyl, and heterocyclyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups R.sup.Alk, and wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; R.sup.2 is selected from hydrogen, C.sub.1-10 alkyl, —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —O(C.sub.2-4 alkenyl), —(C.sub.0-4 alkylene)-S(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —(C.sub.0-4 alkylene)-O—(C.sub.1-5 fluoroalkyl), -L.sup.X-aryl, -L.sup.X-heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the aryl moiety in said -L.sup.X-aryl, the heteroaryl moiety in said -L.sup.X-heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups R.sup.Cyc; R.sup.A2 is selected from hydrogen, C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —(C.sub.0-4 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-OH, —(C.sub.0-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SH, —(C.sub.0-4 alkylene)-S(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH.sub.2, —(C.sub.0-4 alkylene)-NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —(C.sub.0-4 alkylene)-O—(C.sub.1-5 haloalkyl), —(C.sub.0-4 alkylene)-CN, —(C.sub.0-4 alkylene)-CHO, —(C.sub.0-4 alkylene)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-COOH, —(C.sub.0-4 alkylene)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH.sub.2, —(C.sub.0-4 alkylene)-CO—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—NH—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-CO—O—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—NH—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-O—CO—N(C.sub.1-5 alkyl)-(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—NH.sub.2, —(C.sub.0-4 alkylene)-SO.sub.2—NH(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-NH—SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO.sub.2—(C.sub.1-5 alkyl), —(C.sub.0-4 alkylene)-SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.XR.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; each R.sup.Alk is independently selected from —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups R.sup.Cyc; each R.sup.Cyc is independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), -L.sup.X-carbocyclyl, -L.sup.X-heterocyclyl, and -L.sup.X-R.sup.X, wherein the carbocyclyl moiety in said -L.sup.X-carbocyclyl and the heterocyclyl moiety in said -L.sup.X-heterocyclyl are each optionally substituted with one or more groups independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —O(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), and —SO—(C.sub.1-5 alkyl); each L.sup.X is independently selected from a covalent bond, C.sub.1-5 alkylene, C.sub.2-5 alkenylene, and C.sub.2-5 alkynylene, wherein said alkylene, said alkenylene and said alkynylene are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-5 haloalkyl, —CN, —OH, —O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), and —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), and further wherein one or more —CH.sub.2— units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from —O—, —NH—, —N(C.sub.1-5 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; and each R.sup.X is independently selected from hydrogen, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —N—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), —SO—(C.sub.1-5 alkyl), carbocyclyl, and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups independently selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, —OH, —O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-OH, —(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —SH, —S(C.sub.1-5 alkyl), —NH.sub.2, —NH(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O(C.sub.1-5 haloalkyl), —CN, —CHO, —CO(C.sub.1-5 alkyl), —COOH, —COO(C.sub.1-5 alkyl), —O—CO(C.sub.1-5 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—CO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-CO(C.sub.1-5 alkyl), —NH—COO(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-COO(C.sub.1-5 alkyl), —O—CO—NH(C.sub.1-5 alkyl), —O—CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-5 alkyl), —SO.sub.2—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —NH—SO.sub.2—(C.sub.1-5 alkyl), —N(C.sub.1-5 alkyl)-SO.sub.2—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), and —SO—(C.sub.1-5 alkyl); and further wherein the following compounds are excluded: methyl 2-phenylthiazole-4-carboxylate; methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate; dimethyl 2,2′-[oxybis(4,1-phenylene)]bis(thiazole-4-carboxylate); dimethyl 2,2′-(1,4-phenylene)dithiazole-4-carboxylate; ethyl 2-phenyl-5-chloro-thiazole-4-carboxylate; ethyl 2-(4-methoxyphenyl)-5-chloro-thiazole-4-carboxylate; ethyl 2-(phenylethynyl)-5-chloro-thiazole-4-carboxylate; ethyl 2-phenyl-5-phenyl-thiazole-4-carboxylate; ethyl 2-phenyl-5-vinyl-thiazole-4-carboxylate; ethyl 2-phenyl-5-(2-pyridyl)-thiazole-4-carboxylate; ethyl 2-phenyl-5-(phenylethynyl)-thiazole-4-carboxylate; ethyl 2-(4-methoxyphenyl)-5-phenyl-thiazole-4-carboxylate; 2-phenyl-4-carbethoxythiazole; 2-(4′-methoxyphenyl)-4-carbethoxythiazole; 2-(4′-methylphenyl)-4-carbethoxythiazole; 2-(4′-carbomethoxyphenyl)-4-carbethoxythiazole; 2-(4′-chlorophenyl)-4-carbethoxythiazole; 2-benzyl-4-carbethoxythiazole; and 2-(2′-phenylethyl)-4-carbethoxythiazole.
24. The compound of claim 23, wherein L is a covalent bond.
25. The compound of claim 23 or 24, wherein R.sup.1 is selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, cycloalkyl, and heterocycloalkyl.
26. The compound of any one of claims 23 to 25, wherein R.sup.1 is selected from ethyl, isopropyl, —CH.sub.2—CH═CH.sub.2, —CH.sub.2—C(CH.sub.3)═CH.sub.2, —CH(CH.sub.3)—C≡CH, and cyclopropyl.
27. The compound of any one of claims 23 to 26, wherein R.sup.1 is ethyl or isopropyl.
28. The compound of any one of claims 23 to 27, wherein R.sup.2 is selected from C.sub.1-10 alkyl, —O(C.sub.1-10 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-10 alkyl), —O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-10 alkylene)-O(C.sub.1-5 alkyl), —O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —(C.sub.1-4 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkylene)-O(C.sub.1-5 alkyl), —O(C.sub.2-4 alkenyl), —S(C.sub.1-5 alkyl), —CO—(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)(C.sub.1-5 alkyl), —CO—N(C.sub.1-5 alkyl)-O—(C.sub.1-5 alkyl), —SO.sub.2—(C.sub.1-5 alkyl), halogen, C.sub.1-5 haloalkyl, —O—(C.sub.1-5 fluoroalkyl), -L.sup.X-aryl, -L.sup.X-heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the aryl moiety in said -L.sup.X-aryl, the heteroaryl moiety in said -L.sup.X-heteroaryl, said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups R.sup.Cyc.
29. The compound of any one of claims 23 to 28, wherein R.sup.2 is selected from —CH.sub.2CH.sub.3, —(CH.sub.2).sub.2CH.sub.3, —(CH.sub.2).sub.3CH.sub.3, —(CH.sub.2).sub.4CH.sub.3, —(CH.sub.2).sub.5CH.sub.3, —(CH.sub.2).sub.6CH.sub.3, —O—CH.sub.2CH.sub.3, —O—(CH.sub.2).sub.2CH.sub.3, —O—(CH.sub.2).sub.3CH.sub.3, —O—(CH.sub.2).sub.4CH.sub.3, —O—(CH.sub.2).sub.5CH.sub.3, —O—(CH.sub.2).sub.6CH.sub.3, —CH.sub.2—O—CH.sub.3, and —CH(—CH.sub.3)—O—CH.sub.3, preferably wherein R.sup.2 is —O—CH.sub.2CH.sub.3.
30. The compound of any one of claims 23 to 29, wherein R.sup.A2 is selected from hydrogen, —CH.sub.3, —OCH.sub.3, —CO—CH.sub.3, and —I.
31. The compound of any one of claims 23 to 30, wherein R.sup.A2 is hydrogen.
32. The compound of claim 23, wherein said compound is any one of the following compounds, or a pharmaceutically acceptable salt or solvate thereof: ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417## ##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422## ##STR00423## ##STR00424## ##STR00425## ##STR00426##
33. A pharmaceutical composition comprising a compound as defined in any one of claims 13 to 32 and a pharmaceutically acceptable excipient.
34. The compound of any one of claims 13 to 32 or the pharmaceutical composition of claim 33 for use in treating or preventing an ATGL-mediated disease or disorder.
35. The compound of any one of claims 13 to 32 or the pharmaceutical composition of claim 33 for use in treating or preventing a disease or disorder selected from a lipid metabolism disorder, obesity, non-alcoholic fatty liver disease, type 2 diabetes, insulin resistance, glucose intolerance, hypertriglyceridemia, metabolic syndrome, cardiac and skeletal muscle steatosis, congenital generalized lipodystrophy, familial partial lipodystrophy, acquired lipodystrophy syndrome, atherosclerosis, and heart failure.
36. In vitro use of a compound as defined in any one of claims 1 to 32 as an ATGL inhibitor.
Description
[0209] The invention is also described by the following illustrative figures. The appended figures show:
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[0211]
[0212]
[0213]
[0214]
[0215]
[0216]
[0217]
[0218]
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[0220]
[0221] The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
EXAMPLES
[0222] Various compounds described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.
Examples 1 to 97
[0223] General Information
[0224] Reactions were carried out under air, unless indicated otherwise. For inert reactions, standard Schlenk techniques under an inert atmosphere of N.sub.2 or Ar and anhydrous solvents were used. Specific rotation was measured at 20° C. with a wavelength of 589 nm with a Perkin Elmer Polarimeter 341. The described nuclear resonance spectra were acquired with the following instruments: Bruker AVANCE III with Autosampler: 300.36 MHz .sup.1H-NMR, 75.53 MHz .sup.13C-NMR; Varian Unity Inova: 499.91 MHz .sup.1H-NMR, 125.69 MHz .sup.13C-NMR, 470.35 MHz .sup.19F-NMR. Chemical shifts δ [ppm] are referenced to residual protonated solvent signals as internal standard: CDCl.sub.3: δ=7.26 ppm (.sup.1H), 77.16 ppm (.sup.13C), DMSO-d.sub.6: δ=2.50 ppm (.sup.1H), 39.52 ppm (.sup.13C), and MeOD-d.sub.4: δ=3.31 ppm (.sup.1H), 49.00 ppm (.sup.13C). Signal multiplicities are abbreviated as bs (broad singlet), d (dublet), dd (doublet of doublet), dq (doublet of quadruplet), dt (doublet of triplet), hept (heptett), m (multiplet), s (singlet), t (triplet), and q (quadruplet). The deuterated solvent, the chemical shifts δ in ppm (parts per million), and the coupling constants J in Hertz (Hz) are given. Deuterated solvents for nuclear resonance spectroscopy were purchased from Euriso Top® (CDCl.sub.3, MeOD-d.sub.4) and Aldrich® (DMSO-d.sub.6). Data analysis was performed using the software “MestreNova”. An automatic phase correction as well as an automated baseline correction (Whittaker Smoother) were performed for several spectra. Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates and spots were visualized by UV-light (A=254 and/or 366 nm), or by treatment with KMnO.sub.4 solution (3.0 g KMnO.sub.4 and 20.0 g K.sub.2CO.sub.3 dissolved in 300 mL of a 5% NaOH solution). Column chromatography was performed using silica gel 60 Å (0.04-0.063 mm particle size) from Macherey-Nagel. High Resolution Mass Spectrometry (HRMS): TOF MS EI was performed on a Waters GCT premier micromass with an Electron Impact Ionization (EI)-source (70 eV) and samples were injected via direct insertion (DI). Melting points were determined on a Mel Temp® melting point apparatus (Electrothermal). Purifications via preparative HPLC were performed on a Dionex UltiMate 3000. The separation was carried out using a C-18 reversed-phase column of the type “Nucleodur®100-5” by Macherey-Nagel at 30° C., and detection was accomplished at a wavelength of A=210 nm. Three different methods were used: “method A”: 0-3 min 98% of a 0.01% aqueous formic acid solution and 2% CH.sub.3CN, 3-15 min linear to 100% CH.sub.3CN, 15-18 min 100% CH.sub.3CN with a flow of 15 mLmin.sup.−1; “method B”: 0-3 min 98% of H.sub.2O and 2% CH.sub.3CN, 3-15 min linear to 100% CH.sub.3CN, 15-18 min 100% CH.sub.3CN with a flow of 15 mLmin.sup.−1; “method C”: 0-2 min 90% of H.sub.2O and 10% CH.sub.3CN, 2-12 min linear to 100% CH.sub.3CN, 12-14 min 100% CH.sub.3CN with a flow of 15 mLmin.sup.1. High pressure hydrogenation experiments were performed using the H-Cube™ continuous hydrogenation unit (HC-2.SS) from Thales Nanotechnology Inc. running with a Knauer Smartline pump 100 and equipped with a 10 mL ceramic pump head. As hydrogenation catalyst 10% Pd/C catalyst cartridges were used (Thales Nanotechnology inc., THS01111, 10% Pd/C CatCart™). Chemicals were purchased mainly from the companies ABCR, ACROS Organics, Alfa Aesar, Sigma Aldrich or TCI and were used without further purification, unless stated otherwise. For inert reactions, solvents were stored under an argon atmosphere, and stored over molecular sieves (4 Å molecular sieves were used for CH.sub.2Cl.sub.2, 1,4-dioxane, DME, DMF, DMSO, Et.sub.3N, pyridine, and THF. 3 Å molecular sieves were used for ACN and EtOH). The following solvents were additionally dried and distilled under an argon atmosphere: CH.sub.2Cl.sub.2(CaH.sub.2), Et.sub.3N (Na), EtOH (Na), THF (CaH.sub.2). ACN for inert reactions was passed through an aluminium oxide column (solvent purification system: Puresolv™ from Innovative Technology Inc.) under inert conditions.
[0225] General Procedures Equivalents of reagents and catalysts may vary by +/−5% or +/−1 mol % compared to the given values.
[0226] General Procedure Suzuki Coupling SC1
[0227] A Schienk tube was dried under vacuum and charged with 1.0 eq halogenated substrate, 1.1 eq boronic acid, 5 mol % PdCl.sub.2(dppf), 2.1 eq CsF, and anhydrous DME (˜5 mL/100 mg halogenated substrate). The mixture was degassed via three cycles of vacuum/inert gas and was stirred at 80° C. (oil-bath) overnight, after which time the reaction mixture was cooled to rt and optionally filtered through a pad of silica gel or cotton. Subsequently, the solvent was removed under reduced pressure and final purification via column chromatography yielded the pure product. Reaction control was performed via TLC analysis and/or GC-MS analysis.
[0228] General Procedure Suzuki Coupling SC2
[0229] A Schlenk tube was dried under vacuum and charged with 1.0 eq halogenated substrate, 1.1 eq boronic acid, 5 mol % PdCl.sub.2(dppf), 2.1 eq CsF, and anhydrous DME (˜5 mL/100 mg halogenated substrate). The mixture was degassed by three cycles of vacuum/inert gas and was stirred at 80° C. (oil-bath) overnight, after which time additional 0.3 eq boronic acid and 3 mol % PdCl.sub.2(dppf) were added. Subsequently, the reaction mixture was stirred at 80° C. (oil-bath) overnight and was then cooled to rt and optionally filtered through a pad of silica gel or cotton. After solvent removal under reduced pressure, the crude product was purified via column chromatography. Reaction control was performed via TLC analysis and/or GC-MS analysis.
[0230] General Procedure Suzuki Coupling SC3
[0231] A Schlenk tube was dried under vacuum and charged with 1.0 eq halogenated substrate, 1.0 eq boronic acid, 5 mol % PdCl.sub.2(dppf), 2.1 eq CsF, and anhydrous DME (˜5 mL/100 mg halogenated substrate). The mixture was degassed via three cycles of vacuum/inert gas and was stirred at 80° C. (oil-bath) overnight, after which time the reaction mixture was cooled to rt and optionally filtered through a pad of silica gel or cotton. Subsequently, the solvent was removed under reduced pressure and final purification via column chromatography yielded the pure product. Reaction control was performed via TLC analysis and/or GC-MS analysis.
[0232] General Procedure Esterification ES1
[0233] A Schienk tube was dried under vacuum and charged with 1.0 eq of the carboxylic acid substrate, anhydrous THF (˜2 mL/100 mg carboxylic acid substrate), and 1.5 eq of the corresponding alcohol. Subsequently, 1.1 eq EDC*HCl and 0.15 eq DMAP were added at 0° C. (ice-bath) and the mixture was stirred at rt overnight. Subsequently, the mixture was filtered when necessary and the solvent was removed under reduced pressure and final purification via column chromatography yielded the pure product. Reaction control was performed via TLC analysis and/or GC-MS analysis.
[0234] General Procedure Esterification ES2
[0235] A Schienk tube was dried under vacuum and charged with 1.0 eq of the carboxylic acid substrate, anhydrous CH.sub.2Cl.sub.2, 3.0 eq EDC*HCl, 0.3 eq DMAP, and 3.1 eq of the corresponding alcohol. The mixture was stirred at rt overnight or over the weekend, the solvent was removed under reduced pressure, and final purification via column chromatography yielded the pure product. Reaction control was performed via TLC analysis.
[0236] General Procedure Esterification ES3
[0237] A Schlenk tube was dried under vacuum and charged with 1.0 eq of the carboxylic acid substrate, anhydrous THF (˜2 mL/100 mg carboxylic acid substrate), and 1.0 eq of the corresponding alcohol. Subsequently, 1.0 eq EDC*HCl and 0.1 eq DMAP were added at 0° C. (ice-bath) and the mixture was stirred at rt overnight. Subsequently, the mixture was filtered when necessary and the solvent was removed under reduced pressure and final purification via column chromatography yielded the pure product. Reaction control was performed via TLC analysis and/or GC-MS analysis.
[0238] General Procedure Saponification SA1
[0239] A Schlenk tube was charged with the ester substrate and ˜10-20 mL MeOH/mmol substrate. Subsequently, 2.0-2.1 eq of a 2 M aqueous NaOH solution were added and the mixture was stirred overnight at 80-100° C. (oil-bath). The solvent was removed under reduced pressure and H.sub.2O was added. The aqueous layer was optionally washed with CH.sub.2Cl.sub.2. Using 37m % HCl, the aqueous layer was acidified to pH=1 and extracted several times with EtOAc. Subsequently, the combined organic layers were dried over Na.sub.2SO.sub.4 or MgSO.sub.4, filtered, and the solvent was removed under reduced pressure to give the pure product. Reaction control was performed via TLC analysis.
[0240] General Procedure Saponification SA2
[0241] A Schlenk tube was charged with the ester substrate and ˜7 mL MeOH/mmol substrate. Subsequently, 1.55 eq of a 2 M aqueous NaOH solution were added and the mixture was stirred overnight at 80° C. (oil-bath). The solvent was removed under reduced pressure and H.sub.2O was added. The aqueous layer was acidified to pH=1 with 37 m % HCl and extracted several times with EtOAc. Subsequently, the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure to give the pure product. Reaction control was performed via TLC analysis.
[0242] Experimental Procedures
Example 1: NG-442
[0243] ##STR00049##
[0244] The coupling of methyl 6-bromopyridine-2-carboxylate with 4-ethoxyphenylboronic acid was performed following the general procedure SC1 with the modification that 1.0 g of the bromine substrate were dissolved in 25 mL DME.
[0245] Yield=1.086 g yellowish solid (4.22 mmol, 91%).
[0246] R.sub.f=0.34 (cyclohexane/EtOAc=4+1; UV).
[0247] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.08-7.90 (m, 3H), 7.89-7.75 (m, 2H), 6.98 (d, J=8.6 Hz, 2H), 4.17-3.90 (m, 5H), 1.52-1.32 (t, J=6.87 Hz, 3H).
[0248] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=166.2, 160.4, 157.5, 148.0, 137.7, 131.0, 128.6, 123.0, 122.7, 114.9, 63.7, 52.9, 14.9.
[0249] HRMS (EI-MS) for C.sub.15H.sub.15NO.sub.3: calcd=257.1052, found=257.1050, Δm=0.8 ppm.
[0250] m.p.=102-104° C.
Reference Compound NG-482 (Also Referred to as NG-384, NG-444 and TSch-42)
[0251] ##STR00050##
[0252] The saponification of NG-442 was performed following the general procedure SA1.
[0253] Yield=470.8 mg slightly yellowish solid (1.935 mmol, 96%)
[0254] R.sub.f=0.57 (CH.sub.2Cl.sub.2/MeOH=9+1+some drops HOAc; UV).
[0255] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.18-7.85 (m, 5H), 7.04 (d, J=8.8 Hz, 2H), 4.12 (q, J=7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Example 2: NG-385
[0256] ##STR00051##
[0257] The esterification of NG-384 (see NG-482) with 1-butanol was performed following the general procedure ES3.
[0258] Yield=81.8 mg colorless solid (0.273 mmol, 65%).
[0259] R.sub.f=0.40 (cyclohexane/EtOAc=10+1; UV, KMnO.sub.4).
[0260] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.14-7.89 (m, 3H), 7.83 (d, J=4.2 Hz, 2H), 6.99 (d, J=8.5 Hz, 2H), 4.42 (t, J=6.7 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 1.94-1.69 (m, 2H), 1.60-1.35 (m, 5H), 1.00 (t, J=7.3 Hz, 3H). Minor grease and solvent impurities.
[0261] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.7, 160.4, 157.4, 148.3, 137.7, 131.0, 128.6, 122.7, 122.6, 114.8, 65.7, 63.7, 30.8, 19.4, 14.9, 13.9.
[0262] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1521.
[0263] m.p.=78-81° C.
Example 3: NG-386
[0264] ##STR00052##
[0265] The esterification of NG-384 (see NG-482) with 3-methoxy-1-propanol was performed following the general procedure ES3.
[0266] Yield=85.0 mg slightly yellow solid (0.270 mmol, 64%).
[0267] R.sub.f=0.09 (cyclohexane/EtOAc=10+1; UV, KMnO.sub.4).
[0268] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.08-7.91 (m, 3H), 7.84 (d, J=4.2 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.51 (t, J=6.5 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 3.57 (t, J=6.2 Hz, 2H), 3.37 (s, 3H), 2.11 (p, J=6.3 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).
[0269] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 160.4, 157.4, 148.1, 137.7, 130.9, 128.6, 122.8, 122.7, 114.8, 69.4, 63.7, 63.1, 58.9, 29.2, 14.9.
[0270] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.4: calcd=315.1471, found=315.1468, Δm=1.0 ppm.
[0271] m.p.=36-38° C.
Example 4: NG-387
[0272] ##STR00053##
[0273] The esterification of NG-384 (see NG-482) with 2,2-dimethyl-1-propanol was performed following the general procedure ES1 with the modification that 1.4 eq of the alcohol were used Yield=85.4 mg yellow solid (0.272 mmol, 73%).
[0274] R.sub.f=0.18 (cyclohexane/EtOAc=15+1; KMnO.sub.4).
[0275] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.06 (d, J=8.7 Hz, 2H), 8.00-7.91 (m, 1H), 7.89-7.79 (m, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.24-4.02 (m, 4H), 1.44 (t, J=7.0 Hz, 3H), 1.08 (s, 9H). Grease impurities.
[0276] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.5, 160.4, 157.3, 148.3, 137.6, 131.0, 128.6, 122.5, 114.8, 74.9, 63.7, 31.9, 26.7, 14.9. 1 carbon signal is missing maybe due to overlap.
[0277] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.3: calcd=313.1678, found=313.1671, Δm=2.2 ppm.
[0278] m.p.=89-92° C.
Intermediate NG-388
[0279] ##STR00054##
[0280] The synthesis is based on the literature (Angew. Chem. Int. Ed. 2011, 50, 3730-3733).
[0281] A Schienk tube was dried under vacuum and was charged with 320 mg (8.00 mmol) of a 60 m % NaH dispersion in mineral oil and 15 mL anhydrous THF. Subsequently, 475 μL (6.57 mmol) of 1,3-propanediol were added over the course of 10 min and the mixture is further stirred for 30 min at rt, after which time 1.27 g (6.57 mmol) TIPS-Cl were added. The mixture stirred at rt overnight, after which time 20 mL H.sub.2O were added and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (1×20 mL), dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure and 1.57 g (<6.75 mmol, <100%) of NG-388 were isolated as colorless oil (technical purity).
[0282] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=3.93 (t, J=5.5 Hz, 2H), 3.83 (t, J=5.3 Hz, 2H), 2.27 (s, 1.6H), 1.91-1.73 (m, 2H), 1.18-0.95 (m, 28H—should be 21H).
Example 5: NG-390
[0283] ##STR00055##
[0284] A Schlenk tube was dried under vacuum and charged with 101.4 mg (417 μmol) NG-384 (see NG-482), 2 mL anhydrous THF, and 89.8 mg (468 μmol) EDC*HCl. Subsequently, 167.7 mg (721 μmol) NG-388 and 4.6 mg (37.7 μmol) DMAP were added at 0° C. (ice-bath) and the mixture was stirred at rt overnight. Subsequently, the mixture was filtered and the solvent was removed under reduced pressure and purification via column chromatography yielded a colorless oil that was dissolved in 20 mL THF. Subsequently, TBAF*3H.sub.2O were added and the colorless solution was stirred at rt overnight, after which time the solvent was removed under reduced pressure. The crude product was purified via two consecutive column chromatographies (cyclohexane/EtOAc=1+1; cyclohexane/EtOAc=3+2) and 33 mg (0.1095 mmol, 26% over two steps) of NG-390 were isolated as colorless solid.
[0285] R.sub.f=0.18 (cyclohexane/EtOAc=3+2; KMnO.sub.4).
[0286] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.91 (dd, J=41.2 Hz, 5.9 Hz, 5H), 6.99 (d, J=8.2 Hz, 2H), 4.57 (t, J=5.5 Hz, 2H), 4.09 (dd, J=13.5 Hz, 6.6 Hz, 2H), 3.93-3.74 (m, 2H), 2.83 (s, 1H), 2.17-1.96 (m, 2H), 1.43 (t, J=6.8 Hz, 3H). Minor grease impurities.
[0287] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.7, 160.5, 157.5, 147.7, 137.8, 130.7, 128.6, 123.2, 122.7, 114.9, 64.2, 63.7, 60.6, 31.7, 14.9.
[0288] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.4: calcd=301.1314, found=301.11313, Δm=0.3 ppm.
[0289] m.p.=61-63° C.
Example 6: NG-399
[0290] ##STR00056##
[0291] The esterification of NG-384 (see NG-482) with 2-propanol was performed following the general procedure ES1.
[0292] Yield=21.3 mg slightly yellow solid (0.0747 mmol, 52%).
[0293] R.sub.f=0.21 (cyclohexane/EtOAc=10+1; KMnO.sub.4).
[0294] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.6 Hz, 2H), 7.98-7.90 (m, 1H), 7.83 (d, J=4.2 Hz, 2H), 6.99 (d, J=8.6 Hz, 1H), 5.44-5.23 (m, 1H), 4.09 (q, J=6.9 Hz, 2H), 1.55-1.30 (m, 9H).
[0295] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.0, 160.4, 157.3, 148.5, 137.7, 130.9, 128.7, 122.7, 122.6, 114.8, 69.5, 63.7, 22.0, 14.9.
[0296] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.3: calcd=285.1365, found=285.1361, Δm=1.4 ppm.
[0297] m.p.=96-98° C.
Example 7: NG-400
[0298] ##STR00057##
[0299] The esterification of NG-384 (see NG-482) with 1-hexanol was performed following the general procedure ES1 with the modification that 0.1 eq DMAP were used. An additional column chromatography was performed for purification.
[0300] Yield=26.0 mg colorless solid (0.0794 mmol, 54%).
[0301] R.sub.f=0.19 (cyclohexane/EtOAc=15+1; KMnO.sub.4).
[0302] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.17-7.76 (m, 5H), 6.98 (d, J=8.7 Hz, 2H), 4.40 (t, J=6.8 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 1.92-1.72 (m, 2H), 1.55-1.28 (m, 9H), 1.00-0.82 (m, 3H).
[0303] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ 165.7, 160.4, 157.4, 148.3, 137.6, 131.0, 128.6, 122.6 (2×), 114.8, 66.0, 63.7, 31.6, 28.8, 25.8, 22.7, 14.9, 14.1.
[0304] HRMS (EI-MS) for C.sub.20H.sub.25NO.sub.3: calcd=327.1834, found=327.1821, Δm=4.0 ppm.
[0305] m.p.=48-51° C.
Example 8: NG-402
[0306] ##STR00058##
[0307] The coupling of ethyl-6-bromopicolinate with 4-(2-methoxyethoxy)benzeneboronic acid was performed following the general procedure SC3 with the modification that 2.33 eq CsF were used.
[0308] Yield=96.9 mg colorless solid (0.322 mmol, 63%).
[0309] R.sub.f=0.12 (cyclohexane/EtOAc=5+1; KMnO.sub.4).
[0310] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.14-7.92 (m, 3H), 7.83 (d, J=4.6 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 4.48 (q, J=7.1 Hz, 2H), 4.28-4.09 (m, 2H), 3.85-3.69 (m, 2H), 3.45 (s, 3H), 1.45 (t, J=7.1 Hz, 3H).
[0311] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.7, 160.2, 157.3, 148.3, 137.67, 131.4. 128.6, 122.8, 122.7, 115.0, 71.1, 67.5, 61.9, 59.4, 14.4.
[0312] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.4: calcd=301.11314, found=301.1329, Δm=5.0 ppm.
[0313] m.p.=89-94° C.
Reference Compound NG-403
[0314] ##STR00059##
[0315] The coupling of ethyl-6-bromopicoinate with 4-ethoxy-3,5-dimethylphenylboronic acid was performed following the general procedure SC3.
[0316] Yield=118.8 mg slightly yellow oil (0.397 mmol, 82%).
[0317] R.sub.f=0.20 (cyclohexane/EtOAc=10+1; KMnO.sub.4).
[0318] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.03-7.95 (m, 1H), 7.92-7.78 (m, 1H), 7.70 (s, 1H), 4.49 (q, J=7.1 Hz, 2H), 3.88 (q, J=7.0 Hz, 2H), 2.36 (s, 6H), 1.45 (2×t, J=7.0 Hz, 7.3 Hz, 6H).
[0319] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.5, 157.8, 148.2, 137.7, 133.7, 131.6, 127.9, 123.5, 122.9, 68.1, 62.0, 16.6, 15.9, 14.4. 1 carbon signal is missing maybe due to overlap.
[0320] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1535, Δm=4.7 ppm.
Reference Compound NG-408
[0321] ##STR00060##
[0322] The coupling of ethyl 2-bromo-5-pyridinecarboxylate with 4-ethoxyphenylboronic acid was performed following the general procedure SC3.
[0323] Yield=69.9 mg colorless solid (0.258 mmol, 57%).
[0324] R.sub.f=0.23 (cyclohexane/EtOAc=10+1; UV, KMnO.sub.4).
[0325] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=9.23 (d, J=1.3 Hz, 1H), 8.30 (dd, J=8.3 Hz, 2.0 Hz, 1H), 8.02 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.3 Hz, 1H), 7.00 (d, J=8.7 Hz, 2H), 4.42 (q, J=7.1 Hz, 2H), 4.10 (q, J=6.9 Hz, 2H), 1.55-1.25 (m, 6H).
[0326] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 160.9, 160.5, 150.9, 137.9, 130.7, 128.9, 123.9, 119.0, 115.0, 63.8, 61.4, 14.9, 14.4.
[0327] HRMS (EI-MS) for C.sub.16H.sub.17NO.sub.3: calcd=271.1208, found=271.1206, Δm=0.7 ppm.
[0328] m.p.=106-108° C.
Example 9: NG-409
[0329] ##STR00061##
[0330] The coupling of ethyl-6-bromopicolinate with 4-(benzyloxy)phenylboronic acid was performed following the general procedure SC1 with the modification that 0.96 eq boronic acid and 1.99 eq CsF were used, degassing was omitted, and that after stirring overnight at 80° C. (oil-bath) additional 0.45 eq boronic acid were added. The mixture was stirred another 3 d at 80° C.
[0331] Yield=134.5 mg yellow solid (0.403 mmol, 79%).
[0332] R.sub.f=0.31 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4).
[0333] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.15-7.29 (m, 10H), 7.08 (d, J=8.7 Hz, 2H), 5.14 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).
[0334] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.7, 160.2, 157.4, 148.4, 137.6, 136.9, 131.5, 128.8, 128.7, 128.2, 127.6, 122.8, 122.7, 115.3, 70.2, 61.9, 14.5.
[0335] HRMS (EI-MS) for C.sub.21H.sub.19NO.sub.3: calcd=333.1365, found=333.1374, Δm=2.7 ppm.
[0336] m.p.=143-145° C.
Intermediate NG-412
[0337] ##STR00062##
[0338] The compound is known in the literature (Synth. Commun. 2014, 44, 2121-2127). The esterification of 6-bromopyridine-2-carboxylic acid with 2-propanol was performed following the general procedure ES1 with the modification that 0.1 eq DMAP and 50 mL anhydrous THF were used for 1.49 g 6-bromopyridine-2-carboxylic acid.
[0339] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.03 (dd, J=6.7 Hz, 1.5 Hz, 1H), 7.82-7.59 (m, 2H), 5.37-5.17 (m, 1H), 1.40 (d, J=6.3 Hz, 6H).
[0340] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=163.4, 149.6, 142.4, 139.1, 131.7, 124.0, 70.2, 21.9.
[0341] Yield=840 mg colorless solid (3.44 mmol, 47%).
[0342] R.sub.f=0.24 (cyclohexane/EtOAc=10+1; KMnO.sub.4).
[0343] m.p.=78-80° C.
Example 10: NG-415
[0344] ##STR00063##
[0345] The coupling of NG-412 (isopropyl 6-bromopicolinate) with 4-hydroxyphenylboronic acid was performed following the general procedure SC2 with the modification that 1.0 eq boronic acid were used.
[0346] Yield=294.9 mg yellow solid (1.15 mmol, 56%).
[0347] R.sub.f=0.26 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0348] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.12-7.68 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 5.45-5.25 (m, 1H), 1.42 (d, J=6.1 Hz, 6H).
[0349] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.4, 157.9, 148.1, 137.8, 130.6, 128.9, 123.2, 122.6, 116.1, 69.9, 22.0.
[0350] HRMS (EI-MS) for C.sub.15H.sub.15NO.sub.3: calcd=257.1052, found=257.1062, Δm=3.9 ppm.
[0351] m.p.=154-157° C.
Example 11: NG-416
[0352] ##STR00064##
[0353] The coupling of NG-412 (isopropyl 6-bromopicolinate) with [4-(2-methoxyethoxy)phenyl]boronic acid was performed following the general procedure SC3.
[0354] Yield=121.8 mg yellowish solid (0.386 mmol, 87%).
[0355] R.sub.f=0.27 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0356] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.19-7.71 (m, 5H), 7.02 (d, J=8.7 Hz, 2H), 5.43-5.21 (m, 1H), 4.28-4.05 (m, 2H), 3.88-3.67 (m, 2H), 3.47 (s, 3H), 1.43 (d, J=6.2 Hz, 6H). Minor solvent impurities.
[0357] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 160.2, 157.3, 148.7, 137.6, 131.5, 128.6, 122.6 (2×), 115.0, 71.1, 69.5, 67.5, 59.4, 22.0.
[0358] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.4: calcd=315.1471, found=315.1490, Δm=6.0 ppm.
[0359] m.p.=75-77° C.
Example 12: NG-417
[0360] ##STR00065##
[0361] The coupling of NG-412 (isopropyl 6-bromopicolinate) with 4-(hydroxymethyl)phenylboronic acid was performed following the general procedure SC1 with the modification that 1.0 eq boronic acid were used and that the reaction mixture was stirred 4 times overnight.
[0362] Yield=63.7 mg slightly orange solid (0.235 mmol, 38%).
[0363] R.sub.f=0.18 (cyclohexane/EtOAc=2+1; UV, KMnO.sub.4).
[0364] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.20-7.80 (m, 5H), 7.45 (d, J=6.6 Hz, 2H), 5.44-5.23 (m, 1H), 4.74 (s, 2H), 2.65 (s, 1H), 1.44 (d, J=6.1 Hz, 6H). Minor solvent impurities.
[0365] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.8, 157.3, 148.5, 142.6, 138.1, 137.5, 127.6, 127.4, 123.6, 123.4, 69.7, 65.0, 22.0.
[0366] HRMS (EI-MS) for C.sub.16H.sub.17NO.sub.3: calcd=271.1208, found=271.1215, Δm=2.6 ppm.
[0367] m.p.=129-131° C.
Example 13: NG-418
[0368] ##STR00066##
[0369] A Schlenk tube was dried under vacuum an was a with 80.0 mg (311 μmol) NG-415, 1 mL anhydrous DMF, and 15.6 mg (390 μmol) of a 60 m % NaH dispersion in mineral oil. The mixture was stirred for 15 min at rt and 30 μL 395 μmol) chloromethyl methyl ether were added. The mixture was stirred 45 min at rt and overnight at 100° C. (oil-bath), until which time TLC indicated all starting material to be consumed. The mixture was poured into 5 mL of a saturated aqueous NH.sub.4Cl solution and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=3+1) and 53.1 mg (0.176 mmol, 57%) of NG-418 were isolated as cloudy, colorless oil.
[0370] R.sub.f=0.31 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0371] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.16-7.90 (m, 3H), 7.83 (d, J=4.1 Hz, 2H), 7.14 (d, J=8.6 Hz, 2H), 5.40-5.27 (m, 1H), 5.23 (s, 2H), 3.50 (s, 3H), 1.43 (d, J=6.2 Hz, 6H).
[0372] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.0, 158.6, 157.2, 148.6, 137.7, 132.3, 128.7, 122.8 (2× according to HSQC), 116.5, 94.5, 69.5, 56.2, 22.0.
[0373] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.4: calcd=301.1314, found=301.1319, Δm=1.7 ppm.
Example 14: NG-423
[0374] ##STR00067##
[0375] The coupling of ethyl 6-chloro-4-methylpyridine-2-carboxylate with 4-ethoxyphenylboronic acid was performed following the general procedure SC1 with the modification that 2.2 eq CsF were used and that the reaction mixture was stirred 4 times overnight. An additional crystallization was performed for purification.
[0376] Yield=52.7 mg colorless crystals (0.185 mmol, 37%).
[0377] R.sub.f=0.50 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0378] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.00 (d, J=8.6 Hz, 2H), 7.82 (s, 1H), 7.65 (s, 1H), 6.98 (d, J=8.6 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 2.46 (s, 3H), 1.45 (2×t, 6H).
[0379] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.8, 160.4, 157.3, 149.1, 148.0, 130.9, 128.7, 123.8, 123.8, 114.8, 63.7, 61.9, 21.4, 14.9, 14.5.
[0380] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.3: calcd=285.1365, found=285.1375, Δm=3.9 ppm.
[0381] m.p.=90-91° C.
Example 15: NG-427
[0382] ##STR00068##
[0383] A Schienk tube was dried under vacuum and was charged with 60.7 mg (236 μmol) NG-415, 1 mL anhydrous DMF, and 14.5 mg (363 μmol) of a 60 m % NaH dispersion in mineral oil. The mixture was stirred for 15 min at rt and 50 μL (371 μmol) 2-(2-methoxyethoxy)ethyl bromide were added. The mixture was stirred 80 min at rt and overnight at 100° C. (oil-bath), until which time TLC indicated all starting material to be consumed. The mixture was poured into 5 mL of a saturated aqueous NH.sub.4Cl solution and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=2+1) and 47.2 mg (0.131 mmol, 56%) of NG-427 were isolated as colorless solid.
[0384] R.sub.f=0.20 (cyclohexane/EtOAc=2+1; KMnO.sub.4).
[0385] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.6 Hz, 2H), 7.99-7.89 (m, 1H), 7.82 (d, J=4.1 Hz, 2H), 7.01 (d, J=8.6 Hz, 2H), 5.43-5.23 (m, 1H), 4.29-4.11 (m, 2H), 3.97-3.83 (m, 2H), 3.79-3.68 (m, 2H), 3.65-3.53 (m, 2H), 3.39 (s, 3H), 1.43 (d, J=6.2 Hz, 6H).
[0386] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.0, 160.2, 157.2, 148.6, 137.6, 131.3, 128.6, 122.6, 115.0, 72.1, 70.9, 69.9, 69.5, 67.6, 59.2, 22.0. 1 carbon signal is missing maybe due to overlap.
[0387] HRMS (EI-MS) for C.sub.20H.sub.25NO.sub.5: calcd=359.1733, found=359.1738, Δm=1.4 ppm.
[0388] m.p.=45-46° C.
Example 16: NG-428
[0389] ##STR00069##
[0390] A Schlenk tube was dried under vacuum and was charged with 64.5 mg (261 μmol) NG-415, 1 mL anhydrous DMF, and 17.1 mg (428 μmol) of a 60 m % NaH dispersion in mineral oil. The mixture was stirred for 15 min at rt and 50 μL (444 μmol) 2-bromoethyl ethyl ether were added. The mixture was stirred 80 min at rt and overnight at 100° C. (oil-bath), until which time TLC indicated all starting material to be consumed. The mixture was poured into 5 mL of a saturated aqueous NH.sub.4Cl solution and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=4+1) and 43.7 mg (0.133 mmol, 53%) of NG-428 were isolated as colorless solid.
[0391] R.sub.f=0.26 (cyclohexane/EtOAc=4+1; KMnO.sub.4).
[0392] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.7 Hz, 2H), 7.99-7.89 (m, 1H), 7.83 (d, J=4.1 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 5.44-5.22 (m, 1H), 4.32-4.09 (m, 2H), 3.90-3.73 (m, 2H), 3.62 (q, J=7.0 Hz, 2H), 1.43 (d, J=6.2 Hz, 6H), 1.26 (t, J=7.0 Hz, 3H).
[0393] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 160.3, 157.3, 148.6, 137.6, 131.3, 128.6, 122.6, 115.0, 69.5, 69.0, 67.7, 67.0, 22.0, 15.3. 1 carbon signal missing maybe due to overlap.
[0394] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.4: calcd=329.1627, found=329.1659, Δm=9.7 ppm.
[0395] m.p.=46-47° C.
Example 17: NG-432
[0396] ##STR00070##
[0397] The coupling of isopropyl 6-bromopicolinate with 4-(dimethylamino)benzeneboronic acid was performed following the general procedure SC1 with the modification that 2.34 eq CsF were used.
[0398] Yield=26.5 mg colorless solid (0.0932 mmol, 32%).
[0399] R.sub.f=0.31 (cyclohexane/EtOAc=5+1; KMnO.sub.4).
[0400] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.15-7.68 (m, 5H), 6.84 (d, J=5.8 Hz, 2H), 5.40-5.22 (m, 1H), 3.03 (s, 6H), 1.43 (d, J=6.2 Hz, 6H).
[0401] .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=165.3, 157.6, 148.5, 137.3, 128.2, 121.9 (2×), 112.8, 69.3, 40.8, 22.1. 2 carbon signals are missing maybe due to overlap.
[0402] HRMS (EI-MS) for C.sub.17H.sub.20N.sub.2O.sub.2: calcd=284.1525, found=284.1526, Δm=0.4 ppm.
[0403] m.p.=134-140° C.
Example 18: NG-433
[0404] ##STR00071##
[0405] The coupling of isopropyl 6-bromopicolinate with 4-(ethanesulfonyl)benzeneboronic acid was performed following the general procedure SC1.
[0406] Yield=99.4 mg colorless solid (0.298 mmol, 72%).
[0407] R.sub.f=0.42 (cyclohexane/EtOAc=1+1; UV, KMnO.sub.4).
[0408] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.27 (d, J=8.2 Hz, 2H), 8.16-7.85 (m, 5H), 5.41-5.26 (m, 1H), 3.14 (q, J=7.3 Hz, 2H), 1.44 (d, J=6.2 Hz, 6H), 1.28 (t, J=7.4 Hz, 3H). Minor solvent impurities.
[0409] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.6, 155.6, 149.2, 143.7, 139.0, 138.2, 128.9, 128.2, 124.5, 124.0, 69.9, 50.8, 22.0, 7.6.
[0410] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.4S: calcd=333.1035, found=333.1042, Δm=2.1 ppm.
[0411] m.p.=126-129° C.
Example 19: NG-434
[0412] ##STR00072##
[0413] The coupling of isopropyl 6-bromopicolinate with 4-(methoxymethyl)benzeneboronic acid was performed following the general procedure SC1.
[0414] Yield=93.1 mg colorless solid (0.326 mmol, 79%).
[0415] R.sub.f=0.34 (cyclohexane/EtOAc=4+1; UV, KMnO.sub.4).
[0416] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.19-7.78 (m, 5H), 7.45 (d, J=8.0 Hz, 2H), 5.32 (dd, J=12.4 Hz, 6.2 Hz, 1H), 4.52 (s, 2H), 3.40 (s, 3H), 1.43 (d, J=6.2 Hz, 6H).
[0417] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.0, 157.4, 148.8, 139.7, 138.0, 137.7, 128.2, 127.4, 123.3, 74.4, 69.5, 58.2, 22.0. 1 carbon signal is missing maybe due to overlap.
[0418] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.3: calcd=285.135, found=285.1375, Δm=3.9 ppm.
[0419] m.p.=55-58° C.
Intermediate NG-435
[0420] ##STR00073##
[0421] This compound is known in the literature and was prepared analogously (Eur. J. Org. Chem. 2014, 2942-2955).
[0422] A Schlenk tube was dried under vacuum and was charged with 1.44 g (6.06 mmol) 2,6-dibromopyridine, 1.01 g (6.06 mmol) 4-ethoxyphenylboronic acid, 5.13 g (48.4 mmol) Na.sub.2CO.sub.3, 224.4 mg (3.01 mmol) KCl, 99.0 mg (0.377 mmol) PPh.sub.3, and 211.7 mg (0.183 mmol) Pd(PPh.sub.3).sub.4. Subsequently, a previously degassed solution of 40 mL toluene, 10 mL EtOH, and 20 mL H.sub.2O were added and the mixture was stirred at rt for 5 d, after which time 50 mL H.sub.2O were added and the aqueous layer was extracted with EtOAc (1×50 ml+2×30 mL). The combined organic layers were washed with H.sub.2O (1×50 mL) and the aqueous layer was back-extracted with EtOAc (2×50 mL). All organic layers were combined, dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=3+1) and 1.39 g of impure NG-435 were isolated as yellow solid.
Reference Compound NG-437
[0423] ##STR00074##
[0424] The procedure is based on the synthesis of a similar substrate (Bioorg. Med. Chem. 2004, 12, 5909-5915).
[0425] Caution: CuCN and NaCN are extremely toxic. Do not acidify as this would lead to the formation of toxic gaseous HCN!
[0426] A Schlenk tube was dried under vacuum and was charged with 302 mg (1.09 mmol) crude NG-435, 3 mL anhydrous DMF, 81.9 mg (0.914 mmol) CuCN, 49.4 mg (1.01 mmol) NaCN, and the mixture was stirred at 160° C. (oil-bath) overnight. To the mixture were added 8 mL H.sub.2O and the aqueous layer was extracted with EtOAc (1×15 mL, 2×8 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=4+1) and 161 mg (0.719 mmol, 55% calc. over 2 steps) of NG-437 were isolated as colorless powder.
[0427] R.sub.f=0.31 (cyclohexane/EtOAc=4+1; UV, KMnO.sub.4).
[0428] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.13-7.72 (m, 4H), 7.54 (d, J=6.8 Hz, 1H), 6.99 (d, J=8.5 Hz, 2H), 4.10 (q, J=6.7 Hz, 2H), 1.45 (t, J=6.8 Hz, 3H).
[0429] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=160.9, 158.7, 137.6, 133.8, 129.7, 128.6, 125.9, 122.7, 117.7, 115.0, 63.8, 14.9.
[0430] HRMS (EI-MS) for C.sub.14H.sub.12N.sub.2O: calcd=224.0950, found=224.0949, Δm=0.5 ppm.
[0431] m.p.=109-111° C.
Example 20: NG-441
[0432] ##STR00075##
[0433] The saponification of NG-423 was performed following the general procedure SA1. The esterification with 2-propanol was performed following the general procedure ES2 with the modification that 0.27 eq DMAP were used.
[0434] Yield=15.0 mg colorless solid (0.0501 mmol, 47% calc. over 2 steps).
[0435] R.sub.f=0.38 (cyclohexane/EtOAc=5+1; KMnO.sub.4).
[0436] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.02 (d, J=8.7 Hz, 2H), 7.78 (s, 1H), 7.64 (s, 1H), 6.97 (d, J=8.7 Hz, 2H), 5.45-5.20 (m, 1H), 4.09 (q, J=6.9 Hz, 2H), 2.46 (s, 3H), 1.50-1.32 (m, 9H).
[0437] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.3, 160.3, 157.3, 148.8, 148.5, 131.2, 128.6, 123.7, 123.4, 114.7, 69.4, 63.7, 22.1, 21.4, 14.9.
[0438] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1521.
[0439] m.p.=85-88° C.
Example 21: NG-445
[0440] ##STR00076##
[0441] The esterification of NG-444 (see NG-482) with cyclopropanol was performed following the general procedure ES2.
[0442] Yield=28.5 mg colorless powder (0.101 mmol, 24%).
[0443] R.sub.f=0.34 (cyclohexane/EtOAc=3+1; UV).
[0444] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.16-7.76 (m, 5H), 6.98 (d, J=8.6 Hz, 2H), 4.48-4.36 (m, 1H), 4.09 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H), 1.02-0.75 (m, 5H).
[0445] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=166.6, 160.4, 157.4, 147.9, 137.6, 131.0, 128.6, 122.8, 122.7, 114.8, 63.7, 50.3, 14.9, 5.5.
[0446] HRMS (EI-MS) for C.sub.17H.sub.17NO.sub.3: calcd=283.1208, found=283.1218, Δm=3.5 ppm.
[0447] m.p.=114-115° C.
Example 22: NG-447
[0448] ##STR00077##
[0449] A Schienk tube was dried under vacuum and was charged with 111.0 mg (0.456 mmol) NG-444 (see NG-482), 2 mL anhydrous DMSO, 94.5 mg (0.684 mmol) K.sub.2CO.sub.3, and 71 μL (0.598 mmol) benzyl bromide. The mixture was stirred at rt for 2 h, until which time TLC indicated all starting material to be consumed. Subsequently, 5 mL H.sub.2O were added to the mixture and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure.
[0450] The crude product was purified via column chromatography (cyclohexane/EtOAc=5+1) and 115.7 mg (0.347 mmol, 76%) of NG-447 were isolated as colorless solid.
[0451] R.sub.f=0.33 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4).
[0452] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.16-7.71 (m, 5H), 7.64-7.28 (m, 5H), 6.99 (d, J=8.7 Hz, 2H), 5.47 (s, 2H), 4.10 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).
[0453] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ 165.4, 160.4, 157.5, 148.0, 137.6, 136.1, 131.0, 128.7, 128.6, 128.4 (2×), 122.9, 122.8, 114.9, 67.4, 63.7, 14.9.
[0454] HRMS (EI-MS) for C.sub.21H.sub.19NO.sub.3: calcd=333.1365, found=333.1377, Δm=3.6 ppm.
[0455] m.p.=80-81° C.
Example 23: NG-451
[0456] ##STR00078##
[0457] A screw-cap vial was charged with 54.3 mg (0.211 mmol) NG-415, 2 mL CH.sub.2Cl.sub.2, 20 μL (0.253 mmol) pyridine, and 24 μL (0.253 mmol) acetic anhydride. The mixture was stirred at rt for 260 min, until which time TLC indicated all starting material to be consumed. Subsequently, 2 mL H.sub.2 were added to the mixture and the organic layer was separated after extraction. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3×2 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=4+1) and 43.8 mg (0.146 mmol, 69%) of NG-451 were isolated as slightly yellow solid.
[0458] R.sub.f=0.29 (cyclohexane/EtOAc=4+1; UV, KMnO.sub.4).
[0459] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.24-7.76 (m, 5H), 7.20 (d, J=8.3 Hz, 2H), 5.44-5.19 (m, 1H), 2.29 (s, 3H), 1.42 (d, J=6.2 Hz, 6H).
[0460] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=169.3, 164.9, 156.7, 151.9, 148.8, 137.7, 136.3, 128.5, 123.3, 123.1, 122.0, 69.5, 22.0, 21.2.
[0461] HRMS (EI-MS) for C.sub.17H.sub.17NO.sub.4: calcd=299.1158, found=299.1163, Δm=1.7 ppm.
[0462] m.p.=71-75° C.
Example 24: NG-460
[0463] ##STR00079##
[0464] The coupling of isopropyl 6-bromopicolinate with phenylboronic acid was performed following the general procedure SC1 with the modification that following stirring at 80° C. (oil-bath) overnight, additional 1.45 eq boronic acid and 4.9 mol % PdCl.sub.2(dppf) were added and the mixture was stirred overnight at 80° C.
[0465] Yield=65.0 mg slightly yellow, cloudy oil (0.269 mmol, 63%).
[0466] R.sub.f=0.54 (cyclohexane/EtOAc=4+1; UV, KMnO.sub.4).
[0467] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.16-7.83 (m, 5H), 7.62-7.34 (m, 4H), 5.42-5.25 (m, 1H), 1.44 (d, J=6.2 Hz, 6H).
[0468] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ=165.0, 157.6, 148.8, 138.6, 137.8, 129.6, 128.9, 127.4, 123.4, 123.3, 69.6, 22.0.
[0469] HRMS (EI-MS) for C.sub.15H.sub.15NO.sub.2: calcd=241.1103, found=241.1104, Δm=0.4 ppm.
Reference Compound NG-461
[0470] ##STR00080##
[0471] The coupling of methyl 6-bromo-3-hydroxypicolinate with 4-ethoxyphenylboronic acid was performed following the general procedure SC1.
[0472] Yield=65.2 mg colorless solid (0.239 mmol, 54%).
[0473] R.sub.f=0.39 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4).
[0474] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.84 (dd, J=19.0 Hz, 8.8 Hz, 3H), 7.44 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 4.19-3.95 (m, 6H), 1.44 (t, J=7.0 Hz, 3H).
[0475] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=170.1, 159.9, 157.6, 149.5, 130.7, 129.0, 128.1, 127.5, 126.6, 114.9, 63.7, 53.2, 14.9.
[0476] HRMS (EI-MS) for C.sub.15H.sub.15NO.sub.4: calcd=273.1001, found=273.1010, Δm=3.3 ppm.
[0477] m.p.=114-116° C.
Reference Compound NG-462
[0478] ##STR00081##
[0479] The coupling of methyl 6-bromo-4-methoxypicolinate with 4-ethoxyphenylboronic acid was performed following the general procedure SC1 with the modification that 1.37 eq boronic acid and 2.62 eq CsF were used.
[0480] Yield=96.2 mg colorless solid (0.335 mmol, 80%).
[0481] R.sub.f=0.22 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0482] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.88 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.6 Hz, 2H), 4.15-3.85 (m, 8H), 1.43 (t, J=6.9 Hz, 3H).
[0483] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.9, 159.9, 153.7, 149.2, 138.9, 130.7, 128.2, 123.1, 121.2, 114.9, 63.8, 56.5, 52.8, 15.0.
[0484] HRMS (EI-MS) for C.sub.16H.sub.17NO.sub.4: calcd=287.1158, found=287.1159, Δm=0.3 ppm.
[0485] m.p.=114-116° C.
Intermediate NG-465
[0486] ##STR00082##
[0487] The esterification of 6-chloro-3-methylpicolinic acid with 2-propanol was performed following the general procedure ES2.
[0488] Yield=333.8 mg slightly yellow solid (1.56 mmol, 53%).
[0489] R.sub.f=0.27 (cyclohexane/EtOAc=10+1; KMnO.sub.4).
[0490] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.53 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 5.38-5.18 (m, 1H), 2.48 (s, 3H), 1.40 (d, J=6.3 Hz, 6H).
[0491] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 148.9, 148.5, 142.3, 132.7, 126.3, 70.0, 21.9, 19.0.
[0492] HRMS (EI-MS) for C.sub.10H.sub.12ClNO.sub.2: calcd=213.0557, found=213.0556, Δm=0.5 ppm.
[0493] m.p.=31-33° C.
Example 25: NG-466
[0494] ##STR00083##
[0495] The coupling of isopropyl 6-bromopicolinate with 4-fluorophenylboronic acid was performed following the general procedure SC1.
[0496] Yield=103.1 mg cloudy, colorless oil (0.398 mmol, 97%).
[0497] R.sub.f=0.40 (cyclohexane/EtOAc=5+1; UV).
[0498] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.19-7.77 (m, 5H), 7.16 (t, J=8.6 Hz, 2H), 5.42-5.23 (m, 1H), 1.44 (d, J=6.2 Hz, 6H).
[0499] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 164.9, 162.3, 156.6, 148.8, 137.8, 134.8, 129.3, 129.2, 123.2, 123.0, 116.0, 115.7, 69.6, 22.0.
[0500] HRMS (EI-MS) for C.sub.15H.sub.14FNO.sub.2: calcd=259.1009, found=259.1005, Δm=1.5 ppm.
Reference Compound NG-469
[0501] ##STR00084##
[0502] The coupling of NG-465 with 4-ethoxyphenylboronic acid was performed following the general procedure SC1 with the modification that after stirring overnight at 80° C. (oil-bath), additional 0.52 eq boronic acid and 1 mol % PdCl.sub.2(dppf) were added and the mixture was stirred at 80° C. for additional 66 h.
[0503] Yield=93.7 mg clear, slightly yellowish oil (0.313 mmol, 63%).
[0504] R.sub.f=0.50 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0505] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.00 (d, J=8.7 Hz, 2H), 7.67 (q, J=8.2 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 5.45-5.24 (m, 1H), 4.09 (q, J=6.9 Hz, 2H), 2.50 (s, 3H), 1.52-1.31 (m, 9H).
[0506] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.9, 160.5, 154.1, 148.2, 141.1, 131.1, 129.8, 128.7, 121.8, 114.9, 69.8, 63.7, 22.1, 18.9, 14.9.
[0507] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1518, Δm=1.0 ppm.
Example 26: NG-470
[0508] ##STR00085##
[0509] The coupling of methyl 6-chloro-4-methoxypicolinate with 4-ethoxyphenylboronic acid was performed following the general procedure SC1.
[0510] Yield=91.0 mg colorless solid (0.317 mmol, 64%).
[0511] R.sub.f=0.36 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0512] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.96 (d, J=8.7 Hz, 2H), 7.56 (d, J=2.1 Hz, 1H), 7.31 (d, J=2.1 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 4.16-3.86 (m, 8H), 1.44 (t, J=7.0 Hz, 3H).
[0513] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.6, 165.9, 160.6, 159.0, 149.3, 130.6, 128.9, 114.8, 109.2 (2×), 63.7, 56.0, 53.1, 14.9.
[0514] HRMS (EI-MS) for C.sub.16H.sub.17NO.sub.4: calcd=287.1158, found=287.1162, Δm=1.4 ppm.
[0515] m.p.=94-103° C.
Intermediate NG-473
[0516] ##STR00086##
[0517] This compound is known in the literature known and was prepared analogously (By Collantes, Elizabeth Martha and Schwarz, Jacob Bradley From U.S. Pat. Appl. Publ., 20090197859, 6 Aug. 2009).
[0518] A round-bottom flask was charged with 1.098 g (5.44 mmol) 6-bromopyridine-2-carboxylic acid, 27.5 mL t-BuOH, and 3.8 mL pyridine. Subsequently, 2.11 g (11.1 mmol) TsCl were added at 0° C. (ice-bath) and the mixture was stirred overnight at rt, until which time TLC indicated all starting material to be consumed. To the mixture were poured 40 mL of a saturated aqueous NaHCO.sub.3 solution and the mixture was stirred for 30 min at rt, after which time ˜½ solvent was removed under reduced pressure and the mixture was filtered. The filter residue was washed with H.sub.2O, dried at 60° C. (oil-bath) under oil-pump vacuum, and 1.19 g (4.61 mmol, 85%) of NG-473 were isolated as colorless powder.
[0519] R.sub.f=0.55 (CH.sub.2Cl.sub.2/MeOH=9+2+drops HOAc; UV).
[0520] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.97 (dd, J=6.7 Hz, 1.3 Hz, 1H), 7.70-7.51 (m, 2H), 1.61 (s, 9H).
##STR00087##
Example 27: NG-474
[0521] The coupling of isopropyl 6-bromopicolinate with 4-propoxyphenylboronic acid was performed following the general procedure SC1 with the modification that 8 mol % PdCl.sub.2(dppf) were used.
[0522] Yield=93.0 mg colorless solid (0.311 mmol, 70%).
[0523] R.sub.f=0.43 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4)
[0524] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.15-7.75 (m, 5H), 7.00 (d, J=8.7 Hz, 2H), 5.42-5.22 (m, 1H), 3.98 (t, J=6.6 Hz, 2H), 1.84 (dd, J=14.0 Hz, 7.0 Hz, 2H), 1.43 (t, J=7.7 Hz, 6H), 1.06 (t, J=7.4 Hz, 3H).
[0525] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.7, 160.8, 157.2, 148.3, 138.0, 130.4, 128.8, 122.9, 122.6, 114.9, 69.8, 69.7, 22.7, 22.0, 10.6.
[0526] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1526, Δm=1.7 ppm.
[0527] m.p.=90-93° C.
Reference Compound NG-477
[0528] ##STR00088##
[0529] A screw-cap vial was charged with 46.1 mg (0.169 mmol) NG-461, 1 mL CH.sub.2Cl.sub.2, 16 μL (0.158 mmol) pyridine, and 19 μL (0.201 mmol) acetic anhydride and the mixture was stirred at rt. The mixture was stirred at rt for 100 min and additional 5 μL (0.0493 mmol) pyridine were added. After additional 95 min of stirring at rt, additional 10 μL (0.0986 mmol) pyridine and 10 μL (0.106 mmol) acetic acid were added. The mixture was stirred overnight, 2 mL H.sub.2O were added to the mixture and the organic layer was separated after extraction. The aqueous layer was extracted with CH.sub.2Cl.sub.2 (2×2 mL). The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=3+1) and 37.2 mg (0.118 mmol, 70%) of NG-477 were isolated as colorless solid.
[0530] R.sub.f=0.28 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4)
[0531] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.94 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.6 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 3.97 (s, 3H), 2.38 (s, 3H), 1.44 (t, J=6.9 Hz, 3H).
[0532] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=169.4, 164.5, 160.4, 154.8, 146.1, 140.6, 133.1, 130.3, 128.7, 123.7, 114.9, 63.7, 52.9, 21.0, 14.9.
[0533] HRMS (EI-MS) for C.sub.17H.sub.17NO.sub.5: calcd=315.1107, found=315.1120, Δm=4.1 ppm.
[0534] m.p.=120-123° C.
Example 28: NG-480
[0535] ##STR00089##
[0536] The coupling of NG-473 with 4-ethoxyphenylboronic acid was performed following the general procedure SC1.
[0537] Yield=89.1 mg colorless solid (0.298 mmol, 75%).
[0538] R.sub.f=0.33 (cyclohexane/EtOAc=7+1; UV).
[0539] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.20-7.76 (m, 5H), 6.98 (d, J=8.6 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 1.64 (s, 9H), 1.44 (t, J=6.9 Hz, 3H).
[0540] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.2, 160.5, 157.1, 149.0, 137.8, 130.7, 128.7, 122.5 (2×), 114.8, 82.3, 63.7, 28.3, 14.9.
[0541] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1532, Δm=3.7 ppm.
[0542] m.p.=69-73° C.
Reference Compound NG-481
[0543] ##STR00090##
[0544] The coupling of isopropyl 6-bromopicolinate was performed following the general procedure SC1.
[0545] Yield=115.0 mg colorless solid (0.371 mmol, 88%).
[0546] R.sub.f=0.30 (cyclohexane/EtOAc=7+1; UV).
[0547] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.20 (d, J=1.8 Hz, 1H), 8.11-7.79 (m, 4H), 7.55 (d, J=8.4 Hz, 1H), 5.34 (dt, J=12.4 Hz, 6.2 Hz, 1H), 1.44 (d, J=6.2 Hz, 6H). Minor solvent impurities.
[0548] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.7, 155.2, 149.1, 138.5, 138.1, 133.8, 133.3, 130.9, 129.2, 126.4, 124.0, 123.2, 69.8, 22.0.
[0549] HRMS (EI-MS) for C.sub.15H.sub.13Cl.sub.2NO.sub.2: calcd=309.0323, found=309.0326, Δm=1.0 ppm.
[0550] m.p.=74-76° C.
Example 29: NG-487
[0551] ##STR00091##
[0552] The coupling of isopropyl 6-bromopicolinate with 4-ethoxyphenylboronic acid was performed following the general procedure SC1 with the modification that 2.22 eq CsF were used.
[0553] Yield=103.9 mg colorless oil (0.332 mmol, 80%).
[0554] R.sub.f=0.22 (cyclohexane/EtOAc=7+1; UV, KMnO.sub.4).
[0555] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.28-7.82 (m, 7H), 5.46-5.21 (m, 1H), 4.41 (q, J=7.1 Hz, 2H), 1.43 (dd, J=9.6 Hz, 6.8 Hz, 9H).
[0556] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=166.5, 164.8, 156.5, 149.1, 142.6, 137.9, 131.3, 130.2, 127.2, 124.0, 123.8, 69.7, 61.3, 22.0, 14.5.
[0557] HRMS (EI-MS) for C.sub.18H.sub.19NO.sub.4: calcd=313.1314, found=313.1324, Δm=1.4 ppm.
[0558] m.p.=56-62° C.
Example 30: NG-488
[0559] ##STR00092##
[0560] The esterification of NG-482 with butan-2-ol was performed following the general procedure ES2.
[0561] Yield=14.6 mg colorless solid (0.0488 mmol, 12%).
[0562] R.sub.f=0.28 (cyclohexane/EtOAc=7+1; UV).
[0563] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.05 (d, J=8.7 Hz, 2H), 7.93 (dd, J=8.8 Hz, 4.1 Hz, 1H), 7.82 (d, J=3.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.26-5.08 (m, 1H), 4.10 (q, J=6.9 Hz, 2H), 1.94-1.63 (m, 2H), 1.52-1.32 (m, 6H), 1.02 (t, J=7.4 Hz, 3H).
[0564] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.2, 160.4, 157.3, 148.7, 137.5, 131.1, 128.6, 122.5 (2 carbon atoms according to HSQC), 114.8, 63.7, 29.1, 19.6, 14.9, 9.9.
[0565] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1529, Δm=2.7 ppm.
[0566] m.p.=49-51° C.
Example 31: NG-489
[0567] ##STR00093##
[0568] The esterification of NG-482 with n-propanol was performed following the general procedure ES2.
[0569] Yield=16.6 mg colorless solid (0.0582 mmol, 13%).
[0570] R.sub.f=0.25 (cyclohexane/EtOAc=7+1; UV).
[0571] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.03 (d, J=8.7 Hz, 2H), 7.97 (t, J=4.3 Hz, 1H), 7.83 (d, J=4.3 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.38 (t, J=6.8 Hz, 2H), 4.10 (q, J=6.9 Hz, 2H), 1.85 (dt, J=14.3 Hz, 7.1 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H), 1.06 (t, J=7.4 Hz, 3H).
[0572] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.7, 160.4, 157.3, 148.3, 137.6, 131.0, 122.7, 122.6, 114.9, 67.4, 63.7, 22.2, 14.9, 10.6.
[0573] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.3: calcd 285.1365, found=285.1377, Δm=4.2 ppm.
[0574] m.p.=80-84° C.
Example 32: NG-490
[0575] ##STR00094##
[0576] The procedure is based on the synthesis of a similar substrate (Angew. Chem. Int. Ed. 2014, 53, 10536-10540)
[0577] A Schienk tube was dried under vacuum and was charged with 98.7 mg (0.406 mmol) NG-482, 2 mL anhydrous DMF, 55.2 mg (0.657 mmol) NaHCO.sub.3, and 53 μL (0.613 mmol) allyl bromide. The mixture was stirred at 50° C. (oil-bath) overnight, until which time TLC indicated all starting material to be consumed. To the mixture were added 10 mL H.sub.2O and the mixture was extracted with CH.sub.2Cl.sub.2 (4×10 mL. The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=7+1) and 102.9 mg (0.363 mmol, 90%) of NG-490 were isolated as colorless solid.
[0578] R.sub.f=0.27 (cyclohexane/EtOAc=7+1; UV, KMnO.sub.4).
[0579] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.19-7.91 (m, 3H), 7.84 (d, J=4.2 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 6.21-5.98 (m, 1H), 5.48 (dd, J=1.2 Hz, J=17.2 Hz, 1H), 5.33 (dd, J=1.0 Hz, J=10.4 Hz, 1H), 4.92 (d, J=5.6 Hz, 2H), 4.10 (q, J=6.9 Hz, 2H).
[0580] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.3, 160.45, 157.5, 148.0, 137.7, 132.2, 130.9, 128.7, 122.9, 122.8, 118.8, 114.9, 66.4, 63.7, 14.9.
[0581] HRMS (EI-MS) for C.sub.17H.sub.17NO.sub.3: calcd=283.1208, found=283.1197, Δm=3.9 ppm.
[0582] m.p.=65-70° C.
Example 33: NG-494
[0583] ##STR00095##
[0584] A Schienk tube was dried under vacuum and was charged with 52.8 mg (0.382 mmol) 4-ethoxyphenol, 116.0 mg (0.475 mmol) isopropyl 6-bromopicolinate, 7.0 mg (36.8 μmol) CuI, 9.8 mg (79.6 μmol) picolinic acid, 166.9 mg (0.786 mmol) K.sub.3PO.sub.4, and 1.0 mL anhydrous DMSO. The mixture was stirred at 90° C. (oil-bath) overnight. Subsequently, 4 mL H.sub.2O were added to the mixture and the mixture was extracted with EtOAc (4×4 mL). The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via preparative-HPLC (method A) and 38.6 mg (0.128 mmol, 34%) of NG-494 were isolated as colorless oil.
[0585] R.sub.f=0.45 (cyclohexane/EtOAc=5+1; UV).
[0586] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.88-7.63 (m, 2H), 7.11 (d, J=8.9 Hz, 2H), 6.96-6.82 (m, 3H), 5.36-5.16 (m, 1H), 4.03 (q, J=6.9 Hz, 2H), 1.50-1.25 (m, 10H).
[0587] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.4, 164.1, 156.3, 147.3, 140.1, 122.2, 119.7, 115.6, 113.7, 69.6, 64.0, 22.0, 15.0. 1 carbon signal is missing maybe due to overlap.
[0588] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.4: calcd=301.1314, found=301.1327, Δm=4.3 ppm.
Example 34: NG-495
[0589] ##STR00096##
[0590] A Schienk tube was dried under vacuum and was charged with 52.1 mg (0.554 mmol) phenol, 160.8 mg (0.659 mmol) isopropyl 6-bromopicolinate, 10.8 mg (56.7 μmol) CuI, 16.9 mg (137 μmol) picolinic acid, 236.4 mg (1.11 mmol) K.sub.3PO.sub.4, and 1 mL anhydrous DMSO. The mixture was stirred at 90° C. (oil-bath) overnight. Subsequently, 4 mL H.sub.2O were added to the mixture and the mixture was extracted with EtOAc (4×4 mL). The combined organic layers were dried over MgSO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via preparative-HPLC (method A) and 43.0 mg (0.167 mmol, 30%) of NG-495 were isolated as colorless oil.
[0591] R.sub.f=0.55 (cyclohexane/EtOAc=5+1; UV).
[0592] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.89-7.70 (m, 2H), 7.40 (t, J=7.8 Hz, 2H), 7.25-7.10 (m, 3H), 6.93 (d, J=7.9 Hz, 1H), 5.36-5.15 (m, 1H), 1.38 (d, J=6.2 Hz, 6H).
[0593] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.3, 163.5, 154.1, 147.3, 140.2, 129.9, 125.0, 121.0, 120.0, 114.4, 69.6, 21.9.
[0594] HRMS (EI-MS) for C.sub.15H.sub.15NO.sub.3: calcd=257.1052, found=257.1059, Δm=2.7 ppm.
Example 35: NG-497
[0595] ##STR00097##
[0596] A Schlenk tube was charged with 75.0 mg (0.261 mmol) NG-470 and 1.5 mL MeOH. Subsequently, 183 μL of a 2 M aqueous NaOH (0.366 mmol) were added and the mixture was stirred overnight at 80° C. (oil-bath), after which time TLC analysis indicated all starting material to be consumed. The solvent was removed under reduced pressure and 5 mL H.sub.2O were added. Using 37m % HCl, the aqueous layer was acidified to pH=1 and was extracted with EtOAc (5×5 mL). Subsequently, the combined organic layers were dried over MgSO.sub.4, filtered, and the solvent was removed under reduced pressure and 45.8 mg of a gum-like substance were isolated.
[0597] In a round-bottom flask, equipped with an Ar-inlet were placed 36.5 mg of the crude gum-like substance, 1 mL anhydrous CH.sub.2Cl.sub.2, 76.8 mg (0.401 mmol) EDC*HCl, 5.1 mg (41.7 μmol) DMAP, and 32.9 μL (0.427 mmol) i-PrOH. The mixture was stirred at rt overnight, until which time TLC indicated all starting material to be consumed. The solvent was removed under reduced pressure and the crude product was purified via column chromatography (cyclohexane/EtOAc=5+1) and 22.3 mg (0.0707 mmol, 34% calc. over 2 steps) of NG-497 were isolated as colorless solid.
[0598] R.sub.f=0.29 (cyclohexane/EtOAc=5+1; UV).
[0599] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.00 (d, J=8.6 Hz, 2H), 7.58-7.45 (m, 1H), 7.35-7.25 (m, 1H), 6.97 (d, J=8.6 Hz, 2H), 5.42-5.20 (m, 1H), 4.09 (q, J=6.9 Hz, 2H), 3.96 (s, 3H), 1.54-1.28 (m, 9H).
[0600] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.4, 164.8, 160.5, 158.8, 149.9, 130.7, 128.8, 114.7, 109.1, 108.5, 69.8, 63.7, 55.8, 22.0, 14.9.
[0601] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.4: calcd=315.1471, found=315.1475, Δm=1.3 ppm.
[0602] m.p.=79-81° C.
Reference Compound NG-500
[0603] ##STR00098##
[0604] The coupling of isopropyl 6-bromopicolinate was performed following the general procedure SC1.
[0605] Yield=102.1 mg brown oil (0.368 mmol, 94%).
[0606] R.sub.f=0.52 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4).
[0607] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.32-7.54 (m, 4H), 7.13-6.78 (m, 2H), 5.45-5.16 (m, 1H), 1.38 (m, 6H).
[0608] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3) δ 165.6-165.1 (m), 164.7, 152.7, 148.9, 139.1, 137.6, 132.9 (dd, J=9.7 Hz, 4.3 Hz), 131.6, 127.2 (d, J=10.5 Hz), 124.0, 123.6, 112.4 (d, J=3.6 Hz), 112.1 (d, J=3.6 Hz), 104.8, 104.4), 104.1, 70.2, 69.7, 22.0, 21.9.
[0609] HRMS (EI-MS) for C.sub.15H.sub.13F2NO.sub.2: calcd=277.0914, found=277.0905, Δm=3.2 ppm.
Example 36: NG-510
[0610] ##STR00099##
[0611] The coupling of isopropyl 6-bromopicolinate with 4-(2-tetrahydropyranyloxy)benzeneboronic acid was performed following the general procedure SC1.
[0612] Yield=150.5 mg colorless solid (0.441 mmol, 91%).
[0613] R.sub.f=0.24 (cyclohexane/EtOAc=7+1; UV).
[0614] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.11-7.73 (m, 5H), 7.14 (d, J=8.7 Hz, 1.1H), 6.96 (d, J=8.5 Hz, 0.8H), 5.55-5.45 (m, 0.6H), 5.40-5.25 (m, 1H), 5.00-4.80 (m, 0.3H), 4.10-3.80 (m, 1H), 3.69-3.36 (m, 1H), 2.11-1.50 (m, 6H), 1.43 (d, J=6.2 Hz, 6H).
[0615] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3, major conformer): 6=165.2, 158.1, 157.4, 148.6, 137.6, 132.0, 128.6, 122.8, 122.7, 116.7, 96.4, 69.5, 62.2, 30.4, 25.3, 22.0, 18.8. The occurrence of “double-peaks” hints at the occurrence of both diastereomers. According to .sup.1H-NMR conformer ratio is 0.58:0.42.
[0616] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3, minor conformer): 6=165.0, 158.4, 157.6, 148.0, 138.0, 130.3, 128.9, 123.1, 122.6, 116.1, 94.8, 69.9, 63.1, 30.8, 25.6, 22.0, 19.9.
[0617] HRMS (EI-MS) for C.sub.20H.sub.23NO.sub.4: calcd=341.1627, found=341.1628, Δm=0.3 ppm.
[0618] m.p.=105-107° C.
Example 37: NG-512
[0619] ##STR00100##
[0620] The coupling of isopropyl 6-bromopicolinate with 4-(trifluoromethoxy)phenylboronic acid was performed following the general procedure SC1.
[0621] Yield=126 mg colorless solid (0.387 mmol, 93%)
[0622] R.sub.f=0.34 (cyclohexane/EtOAc=7+1; UV).
[0623] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=8.17-8.08 (m, 2H), 8.03 (dd, J=7.1 Hz, 1.3 Hz, 1H), 7.93-7.84 (m, 2H), 7.32 (d, J=8.3 Hz, 2H), 5.34 (hept, J=6.3 Hz, 1H), 1.44 (d, J=6.3 Hz, 6H).
[0624] .sup.13C-NMR,APT (126 MHz, CDCl.sub.3): δ=164.9, 156.3, 150.4, 149.0, 137.9, 137.3, 128.9, 123.6, 123.2, 122.3, 120.7 (q, J=256.7 Hz), 121.2, 69.7, 22.0.
[0625] HRMS (EI-MS) for C.sub.16H.sub.14F3NO.sub.3: calcd=325.0926, found=325.0936, Δm=3.1 ppm.
[0626] m.p.=43-47° C.
Example 38: NG-513
[0627] ##STR00101##
[0628] The coupling of isopropyl 6-bromopicolinate with 4-(2,2,2-trifluoroethoxy)benzeneboronic acid was performed following the general procedure SC1 with the modification that 2.23 eq CsF were used.
[0629] Yield=116.3 mg slightly yellow solid (0.343 mmol, 84%)
[0630] R.sub.f=0.34 (cyclohexane/EtOAc=5+1; UV).
[0631] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.08 (d, J=8.6 Hz, 2H), 8.04-7.95 (m, 1H), 7.91-7-79 (m, 2H), 7.04 (d, J=8.6 Hz, 2H), 5.45-5.22 (m, 1H), 4.41 (q, J=8.0 Hz, 2H), 1.44 (d, J=6.2 Hz, 6H).
[0632] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.0, 158.6, 156.8, 148.7, 137.8, 133.1, 128.9, 125.3, 123.0, 122.8, 121.6, 115.2, 69.6, 66.0 (q, J=35.7 Hz), 22.0.
[0633] HRMS (EI-MS) for C.sub.17H.sub.16F.sub.3NO.sub.3: calcd=339.1082, found=339.1089, Δm=2.1 ppm.
[0634] m.p.=70-75° C.
Example 39: NG-527
[0635] ##STR00102##
[0636] The coupling of ethyl 6-bromopyridine-2-carboxylate with phenylboronic acid was performed following the general procedure SC1.
[0637] Yield=88.4 mg slightly yellowish solid (0.818 mmol, 93%).
[0638] R.sub.f=0.44 (cyclohexane/EtOAc=5+1; UV).
[0639] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.15-7.95 (m, 3H), 7.95-7.80 (m, 2H), 7.59-7.35 (m, 3H), 4.49 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).
[0640] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 157.7, 148.5, 138.6, 137.7, 129.5, 128.9, 127.3, 123.6, 123.4, 61.9, 14.4.
[0641] HRMS (EI-MS) for C.sub.14H.sub.13NO.sub.2: calcd=227.0946, found=227.0935, Δm=4.8 ppm.
[0642] m.p.=42-46° C.
Example 40: NG-530
[0643] ##STR00103##
[0644] The coupling of methyl 6-chloro-4-methoxypicolinate with 4-(methoxymethyl)benzeneboronic acid was performed following the general procedure SC2 with the modification that 2.22 eq of CsF were used.
[0645] Yield=90.3 mg colorless solid (0.314 mmol, 63%).
[0646] R.sub.f=0.29 (cyclohexane/EtOAc=3+1; UV).
[0647] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.99 (d, J=8.1 Hz, 2H), 7.61 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=2.1 Hz, 1H), 4.51 (s, 2H), 4.06-3.91 (2×s, 6H), 3.39 (s, 3H).
[0648] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.4, 166.2, 159.3, 149.8, 139.7, 138.1, 128.1, 127.4, 110.0, 109.5, 74.4, 58.2, 55.7, 53.0.
[0649] HRMS (EI-MS) for C.sub.15H.sub.17NO.sub.4: calcd=287.1158, found=287.1149, Δm=3.1 ppm.
[0650] m.p.=65-68° C.
Example 41: NG-531
[0651] ##STR00104##
[0652] The coupling of isopropyl 6-bromopicolinate with 4-trifluoromethylphenylboronic acid was performed following the general procedure SC1.
[0653] Yield=75.7 mg colorless crystals (0.245 mmol, 57%).
[0654] R.sub.f=0.39 (cyclohexane/EtOAc=5+1; UV).
[0655] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=8.21 (d, J=8.2 Hz, 2H), 8.07 (dd, J=8.7 Hz, 4.4 Hz, 1H), 7.95-7.91 (m, 2H), 7.74 (d, J=8.2 Hz, 2H), 5.35 (hept, J=6.3 Hz, 1H), 1.45 (d, J=6.3 Hz, 6H).
[0656] .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=164.8, 156.1, 149.2, 141.9, 138.0, 131.4 (q, J=32.4 Hz), 127.6, 125.9 (q, J=3.8 Hz), 124.3 (q, J=272.2 Hz, only 2 signal visible), 124.1, 123.6, 69.7, 22.0.
[0657] HRMS (EI-MS) for C.sub.16H.sub.14F.sub.3NO.sub.2: calcd=309.0977, found=309.0981, Δm=1.3 ppm.
[0658] m.p.=98-99° C.
Example 42: NG-534
[0659] ##STR00105##
[0660] The coupling of isopropyl 6-bromopicolinate with 4-(dimethylcarbamoyl)phenylboronic acid was performed following the general procedure SC1.
[0661] Yield=118.7 mg brown, cloudy oil (0.380 mmol, 90%).
[0662] R.sub.f=0.39 (cyclohexane/EtOAc=1+2; UV).
[0663] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.05-7.91 (m, 3H), 7.90-7.79 (m, 2H), 7.29 (d, J=8.0 Hz, 2H), 5.42-5.24 (m, 1H), 2.64 (t, J=7.5 Hz, 2H), 1.75-1.60 (m, 2H), 1.44 (d, J=6.2 Hz, 6H), 0.95 (t, J=7.3 Hz, 3H).
[0664] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 157.8, 148.7, 144.4, 137.6, 136.2, 129.1, 127.2, 123.1, 123.0, 69.5, 37.9, 24.6, 22.0, 13.9.
[0665] HRMS (EI-MS) for C.sub.18H.sub.20N.sub.2O.sub.3: calcd=312.1474, found=312.1470, Δm=1.3 ppm.
Example 43: NG-536
[0666] ##STR00106##
[0667] The coupling of isopropyl 6-bromopicolinate with 4-propylphenylboronic acid was performed following the general procedure SC1.
[0668] Yield=112.8 mg colorless solid (0.398 mmol, 97%).
[0669] R.sub.f=0.38 (cyclohexane/EtOAc=10+1; UV).
[0670] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.08-7.92 (m, 3H), 7.92-7.79 (m, J=6.3 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 5.42-5.25 (m, 1H), 2.64 (t, J=7.5 Hz, 2H), 1.68 (dd, J=14.8 Hz, 7.6 Hz, 2H), 1.44 (d, J=6.2 Hz, 6H), 0.95 (t, J=7.3 Hz, 3H).
[0671] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 157.8, 148.7, 144.4, 137.6, 136.2, 129.1, 127.2, 123.1, 123.0, 69.5, 37.9, 24.6, 22.0, 13.9.
[0672] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.2: calcd=283.1572, found=283.1572, Δm=0 ppm.
[0673] m.p.=104-107° C.
Example 4: NG-545
[0674] ##STR00107##
[0675] The coupling of ethyl-6-bromopicolinate with 4-octoxyphenylboronic acid was performed following the general procedure SC2 with the modification that KF was used instead of CsF.
[0676] Yield=95.0 mg slightly yellow solid (0.267 mmol, 58%).
[0677] R.sub.f=0.37 (cyclohexane/EtOAc=7+1; UV).
[0678] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.12-7.91 (m, 3H), 7.83 (d, J=4.3 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.48 (q, J=7.1 Hz, 2H), 4.01 (t, J=6.5 Hz, 2H), 1.89-1.71 (m, 2H), 1.57-1.20 (m, 14H), 0.98-0.80 (m, 3H).
[0679] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.7, 160.6, 157.5, 148.3, 137.6, 131.0, 128.6, 122.8, 122.6, 114.9, 68.3, 61.9, 31.9, 29.5, 29.4, 26.2, 22.8, 14.5, 14.2.
[0680] HRMS (EI-MS) for C.sub.22H.sub.29NO.sub.3: calcd=355.2148, found=355.2144, Δm=1.2 ppm.
[0681] m.p.=84-86° C.
Example 45: NG-550
[0682] ##STR00108##
[0683] The coupling of ethyl-6-bromopicolinate with [4-(1-methoxyethyl)phenyl]boronic acid was performed following the general procedure SC1 with the modification that 2.29 eq CsF were used.
[0684] Yield=108.9 mg clear, slightly brown oil (0.382 mmol, 88%).
[0685] R.sub.f=0.31 (cyclohexane/EtOAc=5+1; UV).
[0686] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.13-7.95 (m, 3H), 7.88 (d, J=3.9 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 4.36 (q, J=6.4 Hz, 1H), 3.24 (s, 3H), 1.54-1.36 (m, 6H).
[0687] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 157.7, 148.5, 138.0, 137.8, 127.6, 126.8, 123.6, 123.3, 79.5, 62.0, 56.6, 24.0, 14.4. The occurrence of “double-peaks” hints at the occurrence of both diastereomers.
[0688] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.3: calcd=285.1365, found=285.1355, Δm=3.5 ppm.
Example: NG-556
[0689] ##STR00109##
[0690] The coupling of ethyl-6-bromopicolinate with 4-(1-naphthyl)phenylboronic acid was performed following the general procedure SC1.
[0691] Yield=137.9 mg colorless sticky gum (0.390 mmol, 89%).
[0692] R.sub.f=0.33 (cyclohexane/EtOAc=7+1; UV).
[0693] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.21 (d, J=8.1 Hz, 2H), 8.09 (d, J=7.3 Hz, 1H), 8.04-7.82 (m, 5H), 7.64 (d, J=8.1 Hz, 2H), 7.59-7.40 (m, 4H), 4.52 (q, J=7.1 Hz, 2H), 1.49 (t, J=7.1 Hz, 3H). Minor solvent impurities.
[0694] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 157.6, 148.6, 142.1, 139.8, 137.8, 137.7, 134.0, 131.7, 130.7, 128.5, 128.0, 127.3, 127.0, 126.3, 126.1, 126.0, 125.5, 123.6, 123.5, 62.0, 14.5.
[0695] HRMS (EI-MS) for C.sub.24H.sub.19NO.sub.2: calcd=353.1416, found=353.1420, Δm=1.1 ppm.
Example 47: NG-560
[0696] ##STR00110##
[0697] The coupling of ethyl-6-bromopicolinate with (4-methoxycarbonylmethyl)phenylboronic acid was performed following the general procedure SC1 with the modification that 2.23 eq CsF were used.
[0698] Yield=97.9 mg brown oil (0.327 mmol, 73%).
[0699] R.sub.f=0.26 (cyclohexane/EtOAc=3+1; UV).
[0700] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.18-7.95 (m, 3H), 7.88 (d, J=4.4 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 4.49 (q, J=7.1 Hz, 2H), 3.70, 3.69 (2×s, 5H), 1.46 (t, J=7.1 Hz, 3H).
[0701] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=171.9, 165.6, 157.4, 148.5, 137.8, 137.6, 135.5, 129.9, 127.6, 123.5, 123.4, 62.0, 52.3, 41.1, 14.5.
[0702] HRMS (EI-MS) for C.sub.17H.sub.17NO.sub.4: calcd=299.1158, found=299.1149, Δm=3.0 ppm.
Example 48: NG-561
[0703] ##STR00111##
[0704] The coupling of ethyl-6-bromopicolinate with 4-(2-pyridiyl)phenylboronic acid was performed following the general procedure SC1.
[0705] Yield=46.4 mg slightly yellow solid (0.153 mmol, 34%).
[0706] R.sub.f=0.17 (cyclohexane/EtOAc=3+1; UV).
[0707] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.64 (d, J=4.4 Hz, 1H), 8.21-7.62 (m, 9H), 7.17 (dd, J=8.0 Hz, 3.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H). No referencing could be performed due to overlap.
[0708] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 157.2, 156.9, 149.9, 148.5, 140.3, 139.0, 137.8, 136.9, 127.7, 127.4, 123.6, 123.5. 122.5, 120.8, 62.0, 14.4.
[0709] HRMS (EI-MS) for C.sub.19H.sub.16N.sub.2O.sub.2: calcd=304.1212, found=304.1206, Δm=2.0 ppm.
[0710] m.p.=130-132° C.
Example 49: NG-562
[0711] ##STR00112##
[0712] The coupling of ethyl-6-bromopicolinate with 4-(3-pyridyl)phenylboronic acid was performed following the general procedure SC1.
[0713] Yield=121.5 mg grey solid (0.412 mmol, 93%).
[0714] R.sub.f=0.33 (cyclohexane/EtOAc=2+3; UV).
[0715] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.91 (s, 1H), 8.61 (d, J=3.6 Hz, 1H), 8.20 (d, J=8.2 Hz, 2H), 8.07 (dd, J=6.8 Hz, 1.3 Hz, 1H), 8.00-7.86 (m, 3H), 7.71 (d, J=8.2 Hz, 2H), 7.39 (dd, J=7.8 Hz, 4.8 Hz, 1H), 4.50 (q, J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H).
[0716] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.5, 157.0, 148.9, 148.6, 148.4, 138.9, 138.4, 137.9, 136.1, 134.4, 128.0. 127.6, 123.7, 123.6. 123.5, 62.0, 14.5.
[0717] HRMS (EI-MS) for C.sub.19H.sub.16N.sub.2O.sub.2: calcd=304.1212, found=304.1204, Δm=2.6 ppm.
[0718] m.p.=84-104° C.
Example 50: NG-563
[0719] ##STR00113##
[0720] The coupling of ethyl-6-bromopicolinate with 4-(4-pyridyl)phenylboronic acid was performed following the general procedure SC1.
[0721] Yield=43.0 mg slightly yellow solid (0.327 mmol, 32%).
[0722] R.sub.f=0.24 (cyclohexane/EtOAc=2+3; UV).
[0723] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.75-8.61 (m, 2H), 8.20 (d, J=8.3 Hz, 2H), 8.07 (dd, J=6.8 Hz, 1.7 Hz, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.3 Hz, 2H), 7.63-7.47 (m, 2H), 4.50 (q, J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H).
[0724] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.5, 156.8, 150.4, 148.6, 147.8, 139.2, 139.1, 137.9, 128.0, 127.5, 123.7, 123.6, 121.7, 62.0, 14.4.
[0725] HRMS (EI-MS) for C.sub.19H.sub.16N.sub.2O.sub.2: calcd=304.1212, found=304.1210, Δm=0.7 ppm.
[0726] m.p.=127-131° C.
Example 51: NG-576
[0727] ##STR00114##
[0728] The esterification of 6-bromopyridine-2-carboxylic acid (see also: NG-444/NG-482) with propargyl alcohol was performed following the general procedure ES1.
[0729] Yield=63.4 mg colorless solid (0.225 mmol, 68%).
[0730] R.sub.f=0.31 (cyclohexane/EtOAc=5+1; UV).
[0731] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.15-7.92 (m, 3H), 7.91-7.76 (m, 2H), 6.97 (d, J=8.7 Hz, 2H), 5.00 (d, J=2.2 Hz, 2H), 4.07 (q, J=6.9 Hz, 2H), 2.54 (t, J=2.2 Hz, 1H), 1.42 (t, J=6.9 Hz, 3H).
[0732] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.8, 160.4, 157.5, 147.3, 137.6, 130.8, 128.6, 123.1, 123.0, 114.8, 77.6, 75.4, 63.6, 53.1, 14.9.
[0733] HRMS (EI-MS) for C.sub.17H.sub.15NO.sub.3: calcd=281.1052, found=281.1039, Δm=4.6 ppm.
[0734] m.p.=76-78° C.
Example 52: NG-577
[0735] ##STR00115##
[0736] The esterification of 6-bromopyridine-2-carboxylic acid (see also: NG-444/NG-482) with 4-pentyn-2-ol was performed following the general procedure ES1.
[0737] Yield=54.3 mg colorless oil (0.176 mmol, 53%).
[0738] R.sub.f=0.34 (cyclohexane/EtOAc=5+1; UV).
[0739] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.7 Hz, 2H), 7.95 (dd, J=5.2 Hz, 3.4 Hz, 1H), 7.89-7.80 (m, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.42-5.25 (m, 1H), 4.10 (q, J=6.9 Hz, 2H), 2.81-2.54 (m, 2H), 2.05 (t, J=2.5 Hz, 1H), 1.53 (d, J=6.3 Hz, 3H), 1.44 (t, J=6.9 Hz, 3H).
[0740] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.8, 160.4, 157.5, 148.1, 137.6, 131.0, 128.6, 122.7 (2×), 114.8, 79.8, 70.8, 70.2, 63.7, 25.8, 19.3, 14.9.
[0741] HRMS (EI-MS) for C.sub.19H.sub.19NO.sub.3: calcd=309.1365, found=309.1358, Δm=2.3 ppm.
Intermediate NG-581 (Also Referred to as TSch-39)
[0742] ##STR00116##
[0743] The esterification of 6-chloro-4-methoxypyridine-2-carboxylic acid with isopropanol was performed following the general procedure ES1.
[0744] Yield=555.5 mg colorless solid (2.42 mmol, 60%).
[0745] R.sub.f=0.32 (cyclohexane/EtOAc=5+1; UV).
[0746] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.54 (d, J=1.7 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 5.45-5.10 (m, 1H), 3.91 (s, 3H), 1.40, 1.38 (2 s, 6H).
[0747] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=168.0, 163.6, 152.8, 149.9, 112.4, 111.5, 70.3, 56.2, 21.9.
[0748] HRMS (EI-MS) for C.sub.10H.sub.12ClNO.sub.3: calcd=229.0506, found=229.0500, Δm=2.6 ppm.
[0749] m.p.=62-64° C.
Example 53: NG-582
[0750] ##STR00117##
[0751] The coupling of NG-581 with 4-propylphenylboronic acid was performed following the general procedure SC1.
[0752] Yield=369.7 mg slightly yellowish oil (1.18 mmol, 72%).
[0753] R.sub.f=0.33 (cyclohexane/EtOAc=5+1; UV).
[0754] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.99 (d, J=8.1 Hz, 2H), 7.57 (d, J=2.1 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.30 (d, J=7.7 Hz, 2H), 5.47-5.25 (m, 1H), 3.99 (s, 3H), 2.67 (t, J=7.5 Hz, 2H), 1.70 (dd, J=14.9 Hz, 7.3 Hz, 2H), 1.47 (d, J=6.2 Hz, 6H), 0.98 (t, J=7.3 Hz, 3H).
[0755] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.2, 165.1, 159.4, 150.4, 144.4, 136.3, 129.0, 127.2, 109.3, 109.0, 69.6, 55.6, 37.9, 24.6, 22.0, 13.9.
[0756] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.3: calcd=313.1678, found=313.1673, Δm=1.6 ppm.
Example 54: NG-584
[0757] ##STR00118##
[0758] A Schlenk tube was charged with 328.6 mg (1.05 mmol) NG-582 and 10 mL MeOH. Subsequently, 1.1 mL of a 2 M aqueous NaOH (2.2 mmol) were added and the mixture was stirred overnight at 80° C. (oil-bath), after which time TLC analysis indicated all starting material to be consumed. The solvent was removed under reduced pressure and 25 mL H.sub.2O were added. Using 37m % HCl, the aqueous layer was acidified to pH=1 and was extracted with EtOAc (5×25 mL). Subsequently, the combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure and 109.0 mg of a yellow, sticky oil were isolated. The esterification 39.0 mg of the crude material with 3-butyn-2-ol was performed following the general procedure ES1 with the modification that 1.2 mL THF were used and additional column chromatographies and ACN/hexane extractions were performed for purification.
[0759] Yield=15.9 mg yellow oil (47.2 μmol, 13% over 2 steps).
[0760] R.sub.f=0.21 (cyclohexane/EtOAc=10+1; UV).
[0761] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.96 (d, J=8.1 Hz, 2H), 7.58 (d, J=2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.32-7.18 (m, 2H), 5.82-5.61 (m, 1H), 3.96 (s, 3H), 2.64 (t, J=7.5 Hz, 2H), 2.51 (d, J=2.0 Hz, 1H), 1.77-1.59 (m, 5H), 0.95 (t, J=7.3 Hz, 3H).
[0762] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.3, 164.4, 159.5, 149.3, 144.6, 136.0, 129.0, 127.3, 109.7, 109.5, 82.1, 73.6, 61.7, 55.8, 37.9, 24.6, 21.4, 13.9.
[0763] HRMS (EI-MS) for C.sub.20H.sub.21NO.sub.3: calcd=323.1521, found=323.1503, Δm=5.6 ppm.
Reference Compound NG-587
[0764] ##STR00119##
[0765] The coupling of isopropyl 6-bromopicolinate with 2-fluoro-4-(trifluoromethyl)phenylboronic acid was performed following the general procedure SC1.
[0766] Yield=111.2 mg colorless solid (0.340 mmol, 82%).
[0767] R.sub.f=0.28 (cyclohexane/EtOAc=10+1; UV).
[0768] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=8.31 (t, J=7.9 Hz, 1H), 8.09 (d, J=7.7 Hz, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.92 (t, J=7.8 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.44 (d, J=11.0 Hz, 1H), 5.35 (hept, J=6.3 Hz, 1H), 1.44 (d, J=6.3 Hz, 6H).
[0769] .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=164.4, 161.2, 159.2, 151.9 (d, J=2.5 Hz), 149.1, 137.5, 132.8 (dq, J=8.3 Hz, J=33.4 Hz), 132.4 (d, J=3.3 Hz) 130.0 (d, J=11.4 Hz), 127.4 (d, J=10.4 Hz), 124.2, 123.2 (dq, J=2.5 Hz, J=272.8 Hz), 121.5 (q, J=3.8 Hz), 113.7 (dq, J=26.5 Hz, 3.8 Hz), 69.6, 21.9
[0770] HRMS (EI-MS) for C.sub.16H.sub.13F.sub.4NO.sub.2: calcd=327.0883, found=327.0883, Δm=0 ppm.
[0771] m.p.=96-97° C.
Example 55: NG-590
[0772] ##STR00120##
[0773] The coupling of isopropyl 6-bromopicolinate with 4-ethylphenylboronic acid was performed following the general procedure SC1.
[0774] Yield=99.4 mg colorless solid (0.369 mmol, 89%).
[0775] R.sub.f=0.32 (cyclohexane/EtOAc=10+1; UV).
[0776] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.09-7.92 (m, 3H), 7.91-7.79 (m, 2H), 7.31 (d, J=8.0 Hz, 2H), 5.47-5.22 (m, 1H), 2.71 (q, J=7.5 Hz, 20H), 1.44 (d, J=6.2 Hz, 6H), 1.27 (t, J=7.6 Hz, 3H).
[0777] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 157.7, 148.7, 145.9, 137.6, 136.1, 128.4, 127.3, 123.1, 123.1, 69.5, 28.8, 22.0, 15.6.
[0778] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.2: calcd=269.1416, found=269.1412, Δm=1.5 ppm.
[0779] m.p.=82-84° C.
Example 56: NG-592
[0780] ##STR00121##
[0781] The coupling of NG-581 with 4-(sec-butyl)benzeneboronic acid was performed following the general procedure SC1.
[0782] Yield=75.0 mg slightly brownish oil (0.229 mmol, 79%).
[0783] R.sub.f=0.36 (cyclohexane/EtOAc=7+1; UV).
[0784] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.96 (d, J=8.1 Hz, 2H), 7.54 (d, J=2.1 Hz, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 5.42-5.22 (m, 1H), 3.96 (s, 3H), 2.75-2.55 (m, 1H), 1.7-1.54 (m, 2H), 1.43 (d, J=6.2 Hz, 6H), 1.26 (t, J=7.0 Hz, 3H), 0.83 (t, J=7.4 Hz, 3H).
[0785] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.2, 165.2, 159.5, 150.4, 149.3, 136.6, 127.6, 127.3, 109.3, 109.1, 69.6, 55.7, 41.7, 31.2, 22.0, 22.0, 12.3.
[0786] HRMS (EI-MS) for C.sub.20H.sub.25NO.sub.3: calcd=327.1834, found=327.1832, Δm=0.6 ppm.
Example 57: NG-593
[0787] ##STR00122##
[0788] The coupling of NG-581 with 4-butylphenylboronic acid was performed following the general procedure SC1. An additional preparative-HPLC (method B) was performed for purification.
[0789] Yield=30.8 mg colorless oil (0.0941 mmol, 42%).
[0790] R.sub.f=0.36 (cyclohexane/EtOAc=7+1; UV).
[0791] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.95 (d, J=8.0 Hz, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.27 (d, J=7.9 Hz, 2H), 5.42-5.21 (m, 1H), 3.95 (s, 3H), 2.66 (t, J=7.6 Hz, 2H), 1.70-1.52 (m, 2H), 1.52-1.27 (m, 8H), 0.93 (t, J=7.3 Hz, 3H).
[0792] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.2, 165.1, 159.4, 150.4, 144.6, 136.3, 128.9, 127.2, 109.3, 109.0, 69.6, 55.6, 35.5, 33.6, 22.4, 22.0, 14.1.
[0793] HRMS (EI-MS) for C.sub.20H.sub.25NO.sub.3: calcd=327.1834, found=327.1830, Δm=1.2 ppm.
Example 58: NG-594
[0794] ##STR00123##
[0795] The coupling of isopropyl 6-chloro-4-methoxypicolinate with 4-trifluoromethylphenylboronic acid was performed following the general procedure SC1.
[0796] Yield=48.5 mg colorless solid (0.143 mmol, 53%).
[0797] R.sub.f=0.54 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0798] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=8.16 (d, J=8.1 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.61 (d, J=1.9 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 5.33 (hept, J=6.2 Hz, 1H), 3.98 (s, 3H), 1.44 (d, J=6.3 Hz, 6H).
[0799] .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=167.5, 164.8, 157.7, 150.8, 142.1, 131.4 (q, J=32.5 Hz), 127.7, 125.4 (q, J=3.8 Hz), 124.3 (q, J=272.1), 110.0, 110.0, 69.9, 55.8, 22.0.
[0800] HRMS (EI-MS) for C.sub.17H.sub.16F3NO.sub.3: calcd=339.1082, found=339.1090, Δm=2.4 ppm.
[0801] m.p.=55-56° C.
Example 59: NG-595
[0802] ##STR00124##
[0803] The coupling of TSch39 (see NG-581) with 4-propoxyphenylboronic acid was performed following the general procedure SC1. An additional preparative-HPLC (method B) was performed for purification.
[0804] Yield=37.2 mg colorless solid (0.113 mmol, 46%).
[0805] R.sub.f=0.33 (cyclohexane/EtOAc=5+1; UV).
[0806] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.00 (d, J=8.7 Hz, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 5.45-5.20 (m, 1H), 4.10-3.83 (m, 5H), 1.93-1.73 (m, 2H), 1.43 (d, J=6.2 Hz, 6H), 1.05 (t, J=7.4 Hz, 3H).
[0807] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.2, 165.2, 160.5, 159.0, 150.3, 131.2, 128.6, 114.7, 108.9, 108.4, 69.7, 69.6, 55.6, 22.7, 22.0, 10.6.
[0808] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.4: calcd=329.1627, found=329.1627, Δm=0 ppm.
[0809] m.p.=79-81° C.
Example 60: NG-596
[0810] ##STR00125##
[0811] The coupling of isopropyl 6-bromopicolinate with 4-tert-butylphenylboronic acid was performed following the general procedure SC1.
[0812] Yield=109.6 mg colorless solid (0.369 mmol, 87%).
[0813] R.sub.f=0.44 (cyclohexane/EtOAc=7+1; UV).
[0814] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.13-7.92 (m, 3H), 7.92-7.80 (m, 2H), 7.51 (d, J=8.4 Hz, 2H), 5.44-5.24 (m, 1H), 1.44 (d, J=6.2 Hz, 6H), 1.36 (s, 9H).
[0815] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 157.7, 152.8, 148.8, 137.5, 135.9, 127.1, 125.9, 123.1, 123.0, 69.4, 34.9, 31.4, 22.0.
[0816] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.2: calcd=297.1729, found=297.1730, Δm=0.3 ppm.
[0817] m.p.=104-106° C.
Example 61: NG-597
[0818] ##STR00126##
[0819] The coupling of isopropyl 6-chloro-4-methoxypicolinate with with 4-(methoxymethyl)benzeneboronic acid was performed following the general procedure SC2. An additional preparative-HPLC (method B) was performed for purification.
[0820] Yield=56.1 mg colorless oil (0.178 mmol, 55%).
[0821] R.sub.f=0.25 (cyclohexane/EtOAc=4+1; UV).
[0822] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.03 (d, J=8.1 Hz, 2H), 7.55 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=2.1 Hz, 1H), 5.41-5.22 (m, 6.2 Hz, 1H), 4.51 (s, 2H), 3.95 (s, 3H), 3.39 (s, 3H), 1.43 (d, J=6.2 Hz, 6H).
[0823] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.3, 165.0, 159.0, 139.7, 138.1, 128.0, 127.4, 109.5, 109.3, 74.4, 69.6, 58.2, 55.7, 22.0.
[0824] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.4: calcd=315.1471, found=315.1495, Δm=7.6 ppm.
Example 62: NG-598
[0825] ##STR00127##
[0826] The coupling of isopropyl 6-chloro-4-methoxypicolinate with [4-(1-methoxyethyl)phenyl]boronic acid was performed following the general procedure SC2. An additional preparative-HPLC (method B) was performed for purification.
[0827] Yield=67.0 mg colorless oil (0.203 mmol, 60%).
[0828] R.sub.f=0.31 (cyclohexane/EtOAc=4+1; UV).
[0829] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.02 (d, J=8.1 Hz, 2H), 7.56 (d, J=2.1 Hz, 1H), 7.48-7.30 (m, 3H), 5.42-5.23 (m, 1H), 4.35 (q, J=6.4 Hz, 1H), 3.96 (s, 3H), 3.24 (s, 3H), 1.55-1.35 (m, 9H).
[0830] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.3, 165.1, 159.2, 150.5, 145.1, 138.2, 127.6, 126.7, 109.5, 109.4, 79.5, 69.7, 56.6, 55.7, 24.0, 22.0.
[0831] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.4: calcd=329.1627, found=329.1623, Δm=1.2 ppm.
Example 63: NG-599
[0832] ##STR00128##
[0833] The coupling of isopropyl 6-bromopicolinate with 4-(phenylethynyl)phenylboronic acid pinacol ester was performed following the general procedure SC2. An additional crystallization was performed for purification.
[0834] Yield=102.9 mg colorless crystals (0.301 mmol, 49%, 2 fractions).
[0835] R.sub.f=0.43 (cyclohexane/EtOAc=5+1; UV).
[0836] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.11 (d, J=8.3 Hz, 2H), 8.02 (dd, J=6.5 Hz, 1.9 Hz, 1H), 7.96-7.84 (m, J=6.8 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 7.60-7.50 (m, J=6.2 Hz, 2.8 Hz, 2H), 7.44-7.29 (m, 3H), 5.48-5.23 (m, 1H), 1.45 (d, J=6.2 Hz, 6H).
[0837] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.9, 156.7, 148.9, 138.2, 137.8, 132.2, 131.8, 128.6, 128.5, 127.2, 124.5, 123.5, 123.3, 91.0, 89.4, 69.6, 22.0. 1 carbon signal is missing maybe due to overlap.
[0838] HRMS (EI-MS) for C.sub.23H.sub.19NO.sub.2: calcd=341.1416, found=341.1439, Δm=6.7 ppm.
[0839] m.p.=136-143° C.
Example 64: NG-601
[0840] ##STR00129##
[0841] The coupling of isopropyl 6-bromopicolinate with 4-ethylthiobenzeneboronic acid was performed following the general procedure SC1.
[0842] Yield=107.2 mg slightly yellowish solid (0.356 mmol, 89%).
[0843] R.sub.f=0.43 (cyclohexane/EtOAc=5+1; UV).
[0844] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.13-7.92 (m, 3H), 7.85 (d, J=3.7 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 5.44-5.23 (m, 1H), 3.00 (q, J=7.3 Hz, 2H), 1.55-1.28 (m, 9H).
[0845] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.0, 157.0, 148.8, 138.9, 137.7, 135.9, 128.6, 127.6, 123.2, 122.9, 69.6, 27.3, 22.0, 14.4.
[0846] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.2S: calcd=301.1136, found=301.1133, Δm=1.0 ppm.
[0847] m.p.=93-96° C.
Example 65: NG-602
[0848] ##STR00130##
[0849] The coupling of isopropyl 6-chloro-4-methoxypicolinate was performed following the general procedure SC2. An additional crystallization was performed for purification.
[0850] Yield=32.6 mg colorless solid (0.0936 mmol, 34%).
[0851] R.sub.f=0.33 (cyclohexane/EtOAc=2+3; UV).
[0852] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.91 (s, 1H), 8.61 (d, J=3.4 Hz, 1H), 8.17 (d, J=8.2 Hz, 2H), 7.93 (d, J=7.8 Hz, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.58 (d, J=2.0 Hz, 1H), 7.49-7.31 (m, 2H), 5.46-5.20 (m, J=12.4 Hz, 6.2 Hz, 1H), 3.98 (s, 3H), 1.44 (d, J=6.2 Hz, 6H).
[0853] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.4, 165.0, 158.5, 150.6, 148.8, 148.4, 138.8, 138.5, 136.2, 134.4, 128.0, 127.5, 123.7, 109.6, 109.4, 69.7, 55.7, 22.0.
[0854] HRMS (EI-MS) for C.sub.21H.sub.20N.sub.2O.sub.3: calcd=348.1474, found=348.1463, Δm=3.2 ppm.
[0855] m.p.=118-121° C.
Example 66: NG-605
[0856] ##STR00131##
[0857] The coupling of ethyl 6-bromopicolinate with 4-propylphenylboronic acid was performed following the general procedure SC1. An additional crystallization was performed for purification.
[0858] Yield=218.2 mg colorless solid (0.958 mmol, 68%, 2 fractions).
[0859] R.sub.f=0.26 (cyclohexane/EtOAc=10+1; UV).
[0860] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.10-7.92 (m, 3H), 7.92-7.78 (m, 2H), 7.29 (d, J=8.0 Hz, 2H), 4.48 (q, J=7.1 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 1.80-1.58 (m, 2H), 1.46 (t, J=7.1 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H).
[0861] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.7, 157.9, 148.4, 144.4, 137.6, 136.2, 129.1, 127.2, 123.3, 123.1, 61.9, 37.9, 24.6, 14.5, 13.9.
[0862] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.2: calcd=269.1416, found=269.1412, Δm=1.5 ppm.
[0863] m.p.=68-69° C.
Intermediate NG-607
[0864] ##STR00132##
[0865] The saponification of NG-605 was performed following the general procedure SA2.
[0866] Yield=189.3 mg colorless solid (0.785 mmol, 98%).
[0867] R.sub.f=0.59 (CH.sub.2Cl.sub.2/MeOH/HOAc=90+10+1; UV).
[0868] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.23-8.08 (m, 1H), 8.06-7.82 (m, 4H), 7.34 (d, J=7.9 Hz, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.86-1.57 (m, 2H), 0.98 (t, J=7.3 Hz, 3H).
[0869] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.3, 156.7, 145.9, 145.4, 139.4, 134.6, 129.4, 127.0, 124.7, 121.7, 37.9, 24.5, 13.9.
[0870] HRMS (EI-MS) for C.sub.15H.sub.15NO.sub.2: calcd=241.1103, found=241.1103, Δm=0.0 ppm.
[0871] m.p.=119-121° C.
Example 67: NG-608
[0872] ##STR00133##
[0873] 70.4 mg of NG-599 are dissolved in 4.2 mL MeOH to give a 0.05 M solution. Hydrogenation was performed for 3 h using the H-Cube® (10% Pd/C, full H.sub.2 mode, 0.5 mL/min, closed loop).
[0874] An column chromatography was performed for purification.
[0875] Yield=62.2 mg blue solid (0.180 mmol, 87%).
[0876] R.sub.f=0.26 (cyclohexane/EtOAc=7+1; UV).
[0877] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.17-8.01 (m, 3H), 8.01-7.87 (m, 2H), 7.45-7.32 (m, 4H), 7.32-7.21 (m, 3H), 5.58-5.29 (m, 1H), 3.06 (s, 4H), 1.53 (d, J=6.2 Hz, 6H).
[0878] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 157.6, 148.8, 143.4, 141.7, 137.6, 136.4, 129.1, 128.6, 128.5, 127.3, 126.1, 123.1, 123.1, 69.5, 37.9, 37.8, 22.1.
[0879] HRMS (EI-MS) for C.sub.23H.sub.23NO.sub.2: calcd=345.1729, found=345.1724, Δm=1.4 ppm.
[0880] m.p.=88-89° C.
Example 68: NG-609
[0881] ##STR00134##
[0882] The coupling of isopropyl 6-bromopicolinate with 4-hexylphenylboronic acid was performed following the general procedure SC1. An additional preparative-HPLC (method C) was performed for purification.
[0883] Yield=100.4 mg colorless solid (0.308 mmol, 73%).
[0884] R.sub.f=0.26 (cyclohexane/EtOAc=15+1; UV).
[0885] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.13-7.92 (m, 3H), 7.92-7.73 (m, 2H), 7.29 (d, J=8.0 Hz, 2H), 5.52-5.19 (m, 1H), 2.66 (t, J=7.6 Hz, 2H), 1.76-1.54 (m, 2H), 1.44 (d, J=6.2 Hz, 6H), 1.37-1.20 (m, 6H), 0.89 (t, J=6.2 Hz, 3H).
[0886] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 157.8, 148.8, 144.7, 137.6, 136.1, 129.0, 127.2, 123.1, 123.0, 69.5, 35.9, 31.9, 31.5, 29.1, 22.8, 22.1, 14.2.
[0887] HRMS (EI-MS) for C.sub.21H.sub.27NO.sub.2: calcd=325.2042, found=325.2036, Δm=1.8 ppm.
[0888] m.p.=34-35° C.
Example 69: NG-610
[0889] ##STR00135##
[0890] The coupling of isopropyl 6-bromopicolinate with 4-hexoxyphenylboronic acid was performed following the general procedure SC2.
[0891] Yield=100.3 mg colorless solid (0.294 mmol, 69%).
[0892] R.sub.f=0.28 (cyclohexane/EtOAc=10+1; UV).
[0893] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.7 Hz, 2H), 7.98-7.88 (m, 1H), 7.82 (d, J=3.5 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.49-5.17 (m, 1H), 4.01 (t, J=6.5 Hz, 2H), 1.89-1.74 (m, 2H), 1.57-1.23 (m, 12H), 0.92 (t, J=6.5 Hz, 3H).
[0894] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 160.6, 157.4, 148.6, 137.5, 131.0, 128.6, 122.5, 114.8, 69.4, 68.2, 31.7, 29.3, 25.8, 22.7, 22.0, 14.2. 1 carbon signal is missing maybe due to overlap.
[0895] HRMS (EI-MS) for C.sub.21H.sub.27NO.sub.3: calcd=341.1991, found=341.1988, Δm=0.9 ppm.
[0896] m.p.=68-70° C.
Example 70: NG-613
[0897] ##STR00136##
[0898] The esterification of NG-607 with 3-butyn-2-ol was performed following the general procedure ES1 with the modification that 0.17 eq DMAP were used and the mixture was stirred two times overnight, after which time addition 0.5 eq alcohol, 0.3 eq EDC*HCl, and 0.15 eq DMAP were added and the mixture was then stirred overnight again. For further purification, the product was dissolved in ACN and was washed five times with n-hexane.
[0899] Yield=39.1 mg colorless solid (0.33 mmol, 64%).
[0900] R.sub.f=0.28 (cyclohexane/EtOAc=10+1; UV).
[0901] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.11-7.95 (m, 3H), 7.95-7.82 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 5.92-5.63 (m, 1H), 2.65 (t, J=7.3 Hz, 2H), 2.52 (d, J=2.0 Hz, 1H), 1.78-1.60 (m, 5H), 0.95 (t, J=7.3 Hz, 3H).
[0902] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.4, 157.9, 147.8, 144.5, 137.7, 136.0, 129.1, 127.2, 123.5, 123.4, 82.1, 73.5, 61.6, 38.0, 24.6, 21.4, 13.9.
[0903] HRMS (EI-MS) for C.sub.19H.sub.19NO.sub.2: calcd=293.1416, found=293.1397, Δm=6.5 ppm.
[0904] m.p.=90-92° C.
Example 71: NG-614
[0905] ##STR00137##
[0906] The esterification of NG-607 with (R)-(+)-3-butyn-2-ol was performed following the general procedure ES1 with the modification that the mixture was stirred two times overnight, after which time addition 0.5 eq alcohol, 0.3 eq EDC*HCl, and 0.15 eq DMAP were added and the mixture was then stirred overnight again.
[0907] Yield=47.6 mg colorless solid (0.162 mmol, 78%).
[0908] R.sub.f=0.30 (cyclohexane/EtOAc=10+1; UV).
[0909] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.11-7.95 (m, 3H), 7.94-7.81 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.92-5.62 (m, 1H), 2.65 (t, J=7.8 Hz, 2H), 2.52 (d, J=1.5 Hz, 1H), 1.80-1.55 (m, 5H+H.sub.2O peak), 0.96 (t, J=7.3 Hz, 3H).
[0910] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.4, 157.9, 147.8, 144.5, 137.7, 136.0, 129.1, 127.2, 123.5, 123.4, 82.1, 73.5, 61.6, 38.0, 24.6, 21.4, 13.9.
[0911] HRMS (EI-MS) for C.sub.19H.sub.19NO.sub.2: calcd=293.1416, found=293.1404, Δm=4.1 ppm.
[0912] m.p.=112-113° C.
[0913] [α].sup.20.sub.589=+8.1 (ρ=0.95; CHCl.sub.3)
Example 72: NG-615
[0914] ##STR00138##
[0915] The esterification of NG-607 with (S(−)-3-butyn-2-ol was performed following the general procedure ES1 with the modification that the mixture was stirred two times overnight, after which time addition 0.5 eq alcohol, 0.3 eq EDC*HCl, and 0.15 eq DMAP were added and the mixture was then stirred overnight again. For further purification, the product was dissolved in ACN and was washed five times with n-hexane.
[0916] Yield=35.9 mg colorless solid (0.122 mmol, 59%).
[0917] R.sub.f=0.28 (cyclohexane/EtOAc=10+1; UV).
[0918] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.11-7.94 (m, 3H), 7.94-7.81 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.87-5.65 (m, 1H), 2.65 (t, J=7.4 Hz, 2H), 2.52 (d, J=1.9 Hz, 1H), 1.80-1.58 (m, 5H), 0.96 (t, J=7.3 Hz, 3H).
[0919] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.4, 157.9, 147.8, 144.5, 137.7, 136.0, 129.1, 127.2, 123.5, 123.4, 82.1, 73.5, 61.6, 37.9, 24.6, 21.4, 13.9.
[0920] HRMS (EI-MS) for C.sub.19H.sub.19NO.sub.2: calcd=293.1416, found=293.1407, Δm=3.1 ppm.
[0921] m.p.=112-113° C.
[0922] [α].sup.20.sub.589=+9.6 (ρ=0.63; CHCl.sub.3)
Example 73: NG-616
[0923] ##STR00139##
[0924] The esterification of TSch-42 (see NG-482) with cinnamyl alcohol was performed following the general procedure ES1.
[0925] Yield=117.8 mg colorless solid (0.327 mmol, 78%).
[0926] R.sub.f=0.24 (cyclohexane/EtOAc=7+1; UV).
[0927] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.15-7.95 (m, 3H), 7.85 (d, J=4.1 Hz, 2H), 7.44 (d, J=7.0 Hz, 2H), 7.39-7.21 (m, 3H), 7.00 (d, J=8.7 Hz, 2H), 6.81 (d, J=15.9 Hz, 1H), 6.57-6.40 (dt, J=6.4, 18.8 Hz, 1H), 5.09 (d, J=6.2 Hz, 2H), 4.10 (q, J=6.9 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H).
[0928] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.5, 160.4, 157.5, 148.1, 137.6, 136.4, 134.8, 131.0, 128.7, 128.6, 128.2, 126.8, 123.2, 122.9, 122.8, 114.8, 66.4, 63.7, 14.9.
[0929] HRMS (EI-MS) for C.sub.23H.sub.21NO.sub.3: calcd=359.1521, found=359.1512, Δm=2.5 ppm.
[0930] m.p.=110° C.
Example 74: NG-617
[0931] ##STR00140##
[0932] The esterification of TSch-42 (see NG-482) with 2-phenylethanol was performed following the general procedure ES1. Additional ACN/n-hexane extractions were performed for purification.
[0933] Yield=103.8 mg colorless solid (0.299 mmol, 74%).
[0934] R.sub.f=0.34 (cyclohexane/EtOAc=5+1; UV).
[0935] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.8 Hz, 2H), 7.93 (dd, J=5.6 Hz, 3.0 Hz, 1H), 7.88-7.77 (m, 2H), 7.44-7.29 (m, 4H), 7.29-7.20 (m, 1H), 4.62 (t, J=7.1 Hz, 2H), 4.11 (q, J=6.9 Hz, 2H), 3.15 (t, J=7.1 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H).
[0936] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.6, 160.4, 157.4, 148.1, 138.0, 137.6, 129.3, 128.7, 128.6, 126.8, 122.8, 122.7, 114.8, 66.3, 63.7, 35.3, 14.9.
[0937] HRMS (EI-MS) for C.sub.22H.sub.21NO.sub.3: calcd=347.1521, found=347.1517, Δm=1.2 ppm.
[0938] m.p.=80-82° C.
Example 75: NG-618
[0939] ##STR00141##
[0940] The esterification of TSch-42 (see NG-482) with 1-phenylethanol was performed following the general procedure ES1 with the modification that the mixture was stirred for 91 h, after which time 0.5 eq 1-phenylethanol, 0.3 eq EDC*HCl, and 0.15 eq DMAP were added and the mixture was stirred overnight.
[0941] Yield=87.0 mg colorless oil (0.250 mmol, 61%).
[0942] R.sub.f=0.33 (cyclohexane/EtOAc=5+1; UV).
[0943] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.07 (d, J=8.8 Hz, 2H), 7.97 (dd, J=5.9 Hz, 2.6 Hz, 1H), 7.90-7.76 (m, 2H), 7.52 (d, J=7.1 Hz, 2H), 7.45-7.27 (m, 3H), 7.00 (d, J=8.8 Hz, 2H), 6.30-6.14 (m, 1H), 4.10 (q, J=7.0 Hz, 2H), 1.74 (d, J=6.6 Hz, 3H), 1.45 (t, J=7.0 Hz, 3H).
[0944] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.8, 160.4, 157.4, 148.3, 141.8, 137.5, 131.0, 128.7, 128.6, 128.0, 126.3, 127.7, 126.6, 114.8, 73.8, 63.7, 22.6, 14.9.
[0945] HRMS (EI-MS) for C.sub.22H.sub.21NO.sub.3: calcd=347.1521, found=347.1509, Δm=3.5 ppm.
Example 76: NG-619
[0946] ##STR00142##
[0947] The coupling of isopropyl 6-bromopicolinate with trans-2-phenylvinylboronic acid was performed following the general procedure SC1.
[0948] Yield=210.5 mg slightly yellowish solid (0.787 mmol, 89%).
[0949] R.sub.f=0.38 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4).
[0950] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.85 (d, J=7.6 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.64-7.46 (m, 4H), 7.40-7.14 (m, 4H), 5.39-5.15 (m, 1H), 1.36 (d, J=6.3 Hz, 6H).
[0951] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.9, 156.4, 148.7, 137.4, 136.5, 134.1, 128.9, 128.7, 127.9, 127.4, 124.2, 123.2, 69.6, 22.0.
[0952] HRMS (EI-MS) for C.sub.17H.sub.17NO.sub.2: calcd=267.1259, found=267.1248, Δm=4.1 ppm.
[0953] m.p.=66-71° C.
Example 77: NG-620
[0954] ##STR00143##
[0955] The coupling of isopropyl 6-bromopicolinate with 4-(N,O-dimethylhydroxylaminocarbonyl)phenylboronic acid was performed following the general procedure SC2.
[0956] Yield=99.1 mg yellow oil (0.302 mmol, 69%).
[0957] R.sub.f=0.54 (cyclohexane/EtOAc=1+2; UV).
[0958] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.12 (d, J=8.3 Hz, 2H), 8.04 (dd, J=6.2 Hz, 2.4 Hz, 1H), 7.99-7.86 (m, 2H), 7.80 (d, J=8.2 Hz, 2H), 5.45-5.22 (m, 1H), 3.55 (s, 3H), 3.38 (s, 3H), 1.44 (d, J=6.2 Hz, 6H).
[0959] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=169.6, 164.8, 156.8, 149.0, 140.6, 137.9, 135.0, 128.9, 127.0, 123.8, 123.6, 69.7, 61.3, 33.8, 22.0.
[0960] HRMS (EI-MS) for C.sub.15H.sub.20N.sub.2O.sub.4: calcd=328.1423, found=328.1423, Δm=0 ppm.
Reference Compound NG-622
[0961] ##STR00144##
[0962] The coupling of 2-bromo-6-(trifluoromethyl)pyridine with 4-ethoxyphenylboronic acid was performed following the general procedure SC1.
[0963] Yield=102.4 mg colorless solid (0.383 mmol, 87%).
[0964] R.sub.f=0.46 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4).
[0965] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.02 (d, J=8.8 Hz, 2H), 7.93-7.78 (m, 2H), 7.53 (dd, J=6.1 Hz, 2.2 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H).
[0966] .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=160.7, 157.7, 148.2 (q, J=34.3 Hz), 138.0, 130.4, 128.6, 122.0, 121.8 (q, J=273.7 Hz), 117.8 (q, J=2.8 Hz), 115.0, 63.8, 14.9.
[0967] HRMS (EI-MS) for C.sub.14H.sub.12F.sub.3NO: calcd=267.0871, found=267.0877, Δm=2.2 ppm.
[0968] m.p.=100-101° C.
Example 78: NG-629
[0969] ##STR00145##
[0970] The coupling of methyl-6-bromopicolinate with 4-trifluoromethylphenylboronic acid was performed following the general procedure SC1.
[0971] Yield=541.0 mg colorless solid (1.92 mmol, 84%).
[0972] R.sub.f=0.38 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0973] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.30-8.06 (m, 3H), 8.04-7.86 (m, 2H), 7.74 (d, J=8.2 Hz, 2H), 4.03 (s, 3H).
[0974] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.9, 156.3, 148.5, 141.9, 138.2, 131.7+131.2 (most probably as part of a quartet), 127.7, 125.9 (q, J=3.7 Hz), 124.3, 124.1, 122.4, 53.1.
[0975] HRMS (EI-MS) for C.sub.14H.sub.10F.sub.3NO.sub.2: calcd=281.0664, found=281.0660, Δm=1.4 ppm.
[0976] m.p.=95-96° C.
Reference Compound NG-631
[0977] ##STR00146##
[0978] The coupling of 2-acetyl-6-bromopyridine with 4-ethoxyphenylboronic acid was performed following the general procedure SC1.
[0979] Yield=108.0 mg beige solid (0.448 mmol, 85%).
[0980] R.sub.f=0.55 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0981] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.05 (d, J=8.7 Hz, 2H), 7.97-7.73 (m, 3H), 7.01 (d, J=8.7 Hz, 2H), 4.11 (q, J=6.9 Hz, 2H), 2.81 (s, 3H), 1.46 (t, J=7.0 Hz, 3H).
[0982] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=160.4, 156.3, 153.4, 137.6, 131.0, 128.3, 122.7, 119.1, 114.9, 63.7, 25.9, 14.9.
[0983] HRMS (EI-MS) for C.sub.15H.sub.15NO.sub.2: calcd=241.1103, found=241.1095, Δm=3.3 ppm.
[0984] m.p.=80-86° C.
Example 79: NG-633
[0985] ##STR00147##
[0986] This compound was synthesized using a method described in the literature (J. Org. Chem. 2011, 76, 5320-5334.)
[0987] A Schienk tube was dried under vacuum and charged with 151.3 mg (0.620 mmol) isopropyl 6-bromopicolinate, 74.9 μL (6.3 μmol, 1.1 eq) phenylacetylene, 4.4 mg PdCl.sub.2(PPh.sub.3).sub.2 (6.3 μmol, 1 mol %), 3.5 mg CuI (3.5 mg, 18.4 μmol, 3 mol %), 3.4 mL anhydrous ACN, and 129 μL Et.sub.3N (0.931 mmol, 1.5 eq). The mixture was stirred at 60° C. (oil-bath) overnight, after which time the reaction mixture was cooled to rt and 5 mL H.sub.2O were added. The mixture was extracted with EtOAc (3×5 mL EtOAc) and the combined organic layers were washed with brine (1×5 mL), dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed in vacuo. Final purification via column chromatography yielded the pure product.
[0988] Yield=153.7 mg brown solid (0.579 mmol, 93%).
[0989] R.sub.f=0.52 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[0990] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.02 (d, J=7.7 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.73-7.50 (m, 3H), 7.47-7.27 (m, 3H), 5.54-5.12 (m, 1H), 1.42 (d, J=6.3 Hz, 6H).
[0991] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.3, 149.3, 143.9, 137.1, 132.2, 130.2, 129.3, 128.5, 123.9, 122.2, 90.4, 88.4, 70.0, 21.9.
[0992] HRMS (EI-MS) for C.sub.17H.sub.15NO.sub.2: calcd=265.1103, found=265.1100, Δm=1.1 ppm.
[0993] m.p.=85-86° C.
Example 80: NG-634
[0994] ##STR00148##
[0995] 148.2 mg of NG-619 were dissolved in 11 mL MeOH to give a 0.05 M solution. Hydrogenation was performed for 3.5 h using the H-Cube® (10% Pd/C, full H.sub.2 mode, 0.5 mL/min, closed loop).
[0996] Yield=146.0 mg slightly yellow oil (0.542 mmol, 98%).
[0997] R.sub.f=0.51 (cyclohexane/EtOAc=3+1; UV).
[0998] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.92 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.39-7.09 (m, 6H), 5.45-5.23 (m, 1H), 3.37-3.18 (m, 2H), 3.18-3.00 (m, 2H), 1.44 (d, J=6.2 Hz, 6H).
[0999] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.8, 162.0, 148.2, 141.4, 137.2, 128.7, 128.5, 126.3, 126.1, 122.7, 69.6, 39.9, 35.9, 22.0.
[1000] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.2: calcd=269.1416, found=269.1402, Δm=5.2 ppm.
Example 81: NG-635
[1001] ##STR00149##
[1002] The coupling of ethyl 6-bromopicolinate with 4-trifluoromethylphenylboronic acid was performed following the general procedure SC1. Additional ACN/n-hexane extractions were performed for purification.
[1003] Yield=84.8 mg colorless solid (0.287 mmol, 65%).
[1004] R.sub.f=0.51 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[1005] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=8.19 (d, J=8.2 Hz, 2H), 8.10 (dd, J=5.7 Hz, 3.0 Hz, 1H), 7.97-7.91 (m, 2H), 7.74 (d, J=8.2 Hz, 2H), 4.50 (q, J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H).
[1006] .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=165.3, 156.2, 148.8, 142.0, 138.1, 131.5 (q, J=32.9 Hz), 127.7, 125.9 (q, J=3.7 Hz), 124.3 (q, J=272.3 Hz, only 2 signals visible), 124.2, 123.8, 62.1, 14.5.
[1007] m.p.=110-112° C.
[1008] HRMS (EI-MS) for C.sub.15H.sub.12F.sub.3NO.sub.2: calcd=295.0820, found=295.0829, Δm=3.1 ppm.
Example 82: NG-636
[1009] ##STR00150##
[1010] The procedure is based on the synthesis of a similar substrate (Angew. Chem. Int. Ed. 2014, 53, 10536-10540)
[1011] A Schlenk tube was dried under vacuum and was charged with 84.0 mg (0.314 mmol) NG-632, 1.7 mL anhydrous DMF, 42.4 mg (0.505 mmol) NaHCO.sub.3, and 40.8 μL (0.472 mmol) allyl bromide. The mixture was stirred at 50° C. (oil-bath) overnight, until which time TLC indicated all starting material to be consumed. To the mixture were added 5 mL H.sub.2O and the mixture was extracted with CH.sub.2Cl.sub.2 (4×5 mL). The combined organic layers were washed with brine (1×5 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=3+1) and 68.8 mg (0.224 mmol, 71%) of NG-636 were isolated as colorless solid. Additional ACN/n-hexane extractions were performed for purification.
[1012] R.sub.f=0.50 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[1013] .sup.1H-NMR (500 MHz, CDCl.sub.3): δ=8.19 (d, J=8.1 Hz, 2H), 8.14-8.09 (m, 1H), 7.96-7.92 (m, 2H), 7.74 (d, J=8.2 Hz, 2H), 6.10 (ddt, J=17.1 Hz, 10.5 Hz, 5.7 Hz, 1H), 5.49 (ddd, J=17.2 Hz, 2.9 Hz, 1.5 Hz, 1H), 5.34 (ddd, J=10.4 Hz, 2.5 Hz, 1.2 Hz, 1H), 4.94 (dt, J=5.8 Hz, 1.3 Hz, 2H).
[1014] .sup.13C-NMR (126 MHz, CDCl.sub.3): δ=165.0, 156.2, 148.6, 141.9, 138.1, 132.0, 131.4 (q, J=32.5 Hz), 127.7, 125.9 (q, J=3.8 Hz), 124.3 (q, J=272.1 Hz, only 2 signals visible), 124.3, 123.9, 66.6.
[1015] HRMS (EI-MS) for C.sub.18H.sub.12F.sub.3NO.sub.2: calcd=307.0820, found=307.0811, Δm=3.1 ppm.
[1016] m.p.=79-80° C.
Example 83: NG-637
[1017] ##STR00151##
[1018] The coupling of isopropyl 6-chloro-4-methoxypicolinate with 4-hexoxyphenylboronic acid was performed following the general procedure SC2. An additional column chromatography and preparative-HPLC (method C) was performed for purification.
[1019] Yield=87.9 mg colorless solid (0.237 mmol, 55%).
[1020] R.sub.f=0.57 (cyclohexane/EtOAc=3+1; UV).
[1021] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.00 (d, J=8.8 Hz, 2H), 7.50 (d, J=2.1 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 5.59-5.10 (m, 1H), 4.01 (t, J=6.6 Hz, 2H), 3.95 (s, 3H), 1.91-1.71 (m, 2H), 1.62-1.23 (m, 12H), 0.91 (t, J=6.4 Hz, 3H).
[1022] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=167.2, 165.2, 160.6, 159.0, 150.3, 131.2, 128.6, 114.7, 108.9, 108.4, 69.6, 68.3, 55.6, 31.7, 29.4, 25.9, 22.7, 22.0, 14.2.
[1023] HRMS (EI-MS) for C.sub.22H.sub.29NO.sub.4: calcd=371.2097, found=371.2088, Δm=2.4 ppm.
[1024] m.p.=53-55° C.
Example 84: NG-639
[1025] ##STR00152##
[1026] The coupling of isopropyl 6-bromopicolinate with 4-(1-phenyl-1H-benzimidazol-2-yl)phenylboronic acid was performed following the general procedure SC1.
[1027] Yield=146.8 mg slightly yellow solid (0.339 mmol, 79%).
[1028] R.sub.f=0.44 (cyclohexane/EtOAc=1+1; UV, KMnO.sub.4).
[1029] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.10-7.96 (m, 3H), 7.96-7.79 (m, 3H), 7.69 (d, J=8.3 Hz, 2H), 7.61-7.42 (m, 3H), 7.42-7.21 (m, 5H), 5.51-5.18 (m, 1H), 1.42 (d, J=6.3 Hz, 6H).
[1030] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.8, 156.7, 152.0, 148.9, 143.2, 139.3, 137.8, 137.5, 137.1, 130.1, 130.0, 128.8, 127.6, 127.2, 123.6, 123.2, 120.1, 110.6, 69.6, 22.0. 1 carbon missing maybe due to overlap.
[1031] HRMS (EI-MS) for C.sub.28H.sub.23N.sub.3O.sub.2: calcd=433.1790, found=433.1794, Δm=0.9 ppm.
[1032] m.p.=172-176° C.
Reference Compound NG-640
[1033] ##STR00153##
[1034] The coupling of ethyl 2-(6-bromopyridin-2-yl)acetate with 4-ethoxyphenylboronic acid was performed following the general procedure SC1. An additional crystallization was performed for purification.
[1035] Yield=135.2 mg colorless solid (0.474 mmol, 49%).
[1036] R.sub.f=0.52 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[1037] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.95 (d, J=8.7 Hz, 2H), 7.67 (t, J=7.7 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 4.21 (q, J=7.1 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 3.90 (s, 2H), 1.44 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H).
[1038] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=171.1, 160.0, 156.9, 154.4, 137.2, 131.9, 128.4, 121.3, 118.1, 114.7, 63.7, 61.0, 44.4, 15.0, 14.4.
[1039] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.3: calcd=285.1365, found=285.1360, Δm=1.8 ppm.
[1040] m.p.=90-91° C.
Example 85: NG-642
[1041] ##STR00154##
[1042] The coupling of isopropyl 6-bromopicolinate with 4-pentyloxyphenylboronic acid was performed following the general procedure SC1.
[1043] Yield=130.7 mg slightly yellow solid (0.399 mmol, 96%).
[1044] R.sub.f=0.61 (cyclohexane/EtOAc=3+1; UV).
[1045] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.7 Hz, 2H), 7.98-7.88 (m, 4.0 Hz, 1H), 7.88-7.71 (m, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.56-5.12 (m, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.92-1.71 (m, 2H), 1.44 (d, J=6.2 Hz, 10H), 0.94 (t, J=6.9 Hz, 3H).
[1046] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 160.6, 157.4, 148.6, 137.5, 131.0, 128.6, 122.5, 114.8, 69.4, 68.2, 29.1, 28.3, 22.6, 22.0, 14.2. 1 carbon missing maybe due to overlap.
[1047] HRMS (EI-MS) for C.sub.20H.sub.25NO.sub.3: calcd=327.1834, found=327.1824, Δm=3.1 ppm.
[1048] m.p.=63-65° C.
Example 86: NG-643
[1049] ##STR00155##
[1050] The coupling of isopropyl 6-bromopicolinate with heptoxyphenylboronic acid was performed following the general procedure SC1.
[1051] Yield=153.6 mg slightly yellow solid (0.432 mmol, 99%).
[1052] R.sub.f=0.59 (cyclohexane/EtOAc=3+1; UV).
[1053] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.7 Hz, 2H), 7.98-7.89 (m, 1H), 7.88-7.75 (m, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.51-5.17 (m, 1H), 4.01 (t, J=6.5 Hz, 2H), 1.91-1.69 (m, 2H), 1.56-1.19 (m, 14H), 0.89 (d, J=6.5 Hz, 3H).
[1054] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 160.6, 157.4, 148.6, 137.5, 131.0, 128.6, 122.5, 114.8, 69.4, 68.3, 31.9, 29.4, 29.2, 26.1, 22.7, 22.1, 14.2. 1 carbon missing maybe due to overlap.
[1055] HRMS (EI-MS) for C.sub.22H.sub.29NO.sub.3: calcd=355.2148, found=355.2164, Δm=4.5 ppm.
[1056] m.p.=64-66° C.
Example 87: NG-647
[1057] ##STR00156##
[1058] The coupling of isopropyl 6-bromopicolinate with 4-chlorophenylboronic acid was performed following the general procedure SC1. An additional preparative HPLC (method C) was performed for purification.
[1059] Yield=74.2 mg colorless solid (0.269 mmol, 65%).
[1060] R.sub.f=0.44 (cyclohexane/EtOAc=5+1; UV, KMnO.sub.4).
[1061] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.12-7.96 (m, 3H), 7.95-7.81 (m, 2H), 7.45 (d, J=8.4 Hz, 2H), 5.34 (hept, J=6.2 Hz, 1H), 1.44 (d, J=6.2 Hz, 6H).
[1062] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.9, 156.4, 148.9, 137.9, 137.1, 135.8, 129.1, 128.6, 123.5, 123.1, 69.6, 22.0.
[1063] HRMS (EI-MS) for C.sub.15H.sub.14ClNO.sub.2: calcd=275.0713, found=275.0722, Δm=3.3 ppm.
[1064] m.p.=94-95° C.
Example 88: NG-648
[1065] ##STR00157##
[1066] The coupling of ethyl-6-bromopicolinate with 4-cyonophenylboronic acid was performed following the general procedure SC1. An additional preparative HPLC (method C) was performed for purification.
[1067] Yield=64.2 mg colorless solid (0.255 mmol, 56%).
[1068] R.sub.f=0.30 (cyclohexane/EtOAc=3+1; UV).
[1069] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.19 (d, J=8.3 Hz, 2H), 8.12 (dd, J=6.6 Hz, 1.9 Hz, 1H), 8.04-7.87 (m, 2H), 7.78 (d, J=8.3 Hz, 2H), 4.50 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H).
[1070] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.2, 155.5, 148.9, 142.7, 138.2, 132.8, 127.9, 124.5, 123.9, 118.8, 113.1, 62.2, 14.4.
[1071] HRMS (EI-MS) for C.sub.15H.sub.12N.sub.2O.sub.2: calcd=252.0899, found=252.0900, Δm=0.4 ppm.
[1072] m.p.=108-109° C.
Example 89: NG-652
[1073] ##STR00158##
[1074] The coupling of methyl 6-bromopicolinate with 4-hexyloxyphenylboronic acid was performed following the general procedure SC1.
[1075] Yield=315.2 mg colorless solid (1.01 mmol, 87%).
[1076] R.sub.f=0.56 (cyclohexane/EtOAc=5+1; UV).
[1077] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.13-7.91 (m, 3H), 7.85 (d, J=4.5 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.01 (t, J=5.5 Hz, 5H), 1.92-1.69 (m, 2H), 1.60-1.19 (m, 6H), 0.92 (t, J=6.6 Hz, 3H).
[1078] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=166.3, 160.6, 157.6, 148.0, 137.7, 131.0, 128.6, 123.0, 122.7, 114.9, 68.3, 52.9, 31.7, 29.3, 25.8, 22.7, 14.2.
[1079] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.3: calcd=313.1678, found=313.1672, Δm=1.9 ppm.
[1080] m.p.=68-69° C.
Example 90: NG-658
[1081] ##STR00159##
[1082] The coupling of isopropyl 6-bromopicolinate with 4-(methylthio)benzeneboronic acid was performed following the general procedure SC2. An additional preparative HPLC (method C) was performed for purification.
[1083] Yield=83.4 mg colorless solid (0.290 mmol, 69%).
[1084] R.sub.f=0.57 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[1085] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.14-7.92 (m, 3H), 7.92-7.78 (m, 2H), 7.34 (d, J=8.4 Hz, 2H), 5.33 (hept, J=6.3 Hz, 1H), 2.53 (s, 3H), 1.43 (d, J=6.2 Hz, 6H).
[1086] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.0, 157.0, 148.8, 140.6, 137.7, 135.3, 127.6, 126.5, 123.1, 122.8, 69.5, 22.0, 15.6.
[1087] HRMS (EI-MS) for C.sub.16H.sub.17NO.sub.2S: calcd=287.0980, found=handed in, Δm=xx ppm.
[1088] m.p.=60-61° C.
Example 91: NG-662
[1089] ##STR00160##
[1090] The procedure is based on the literature and was modified (Angew. Chem. Int. Ed. 2012, 51, 9071-9074).
[1091] A Schienk tube was charged with 101.5 mg (0.416 mmol) isopropyl 6-bromopicolinate, 23.2 mg (0.0418 mmol, 10 mol %) Josiphos SL-J009-1, 19.2 mg (0.0186 mmol, 4.5 mol %) Pd.sub.2(dba)-CHCl.sub.3, and 27.1 mg (0.0832 mmol, 20 mol %->mistake: 2 eq should be used) Cs.sub.2CO.sub.3. The mixture was degassed via three cycles of vacuum/argon, after which time 2 mL anhydrous toluene, and 49.8 μL (0.416 mmol, 1.0 eq) 2-phenylethanol were added. The mixture was stirred at 80° C. (oil-bath) for 7 d, after which time the mixture was poured into 5 mL H.sub.2O and 5 mL EtOAc and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine (1×5 mL), dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (cyclohexane/EtOAc=3+1) and an additional preparative-HPLC (method C) was performed for purification. 19.4 mg (0.0680 μmol, 16%) of NG-662 were isolated as clear, yellow oil.
[1092] R.sub.f=0.71 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[1093] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=7.74-7.59 (m, 2H), 7.42-7.14 (m, 5H), 6.89 (dd, J=6.0 Hz, 3.0 Hz, 1H), 5.28 (hept, J=6.2 Hz, 1H), 4.63 (t, J=7.1 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H), 1.40 (d, J=6.2 Hz, 6H).
[1094] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.8, 163.6, 146.2, 139.0, 138.6, 129.3, 128.5, 126.5, 118.5, 115.3, 69.2, 66.9, 35.5, 22.0.
[1095] HRMS (EI-MS) for C.sub.17H.sub.19NO.sub.3: calcd=285.1365, found=285.1364, Δm=0.4 ppm.
Example 92: NG-666
[1096] ##STR00161##
[1097] The coupling of isopropyl 6-bromopicolinate with 4-(4-methoxyphenylethynyl)benzeneboronic acid pinacol ester was performed following the general procedure SC1.
[1098] Yield=45.2 mg colorless solid (0.127 mmol, 30%).
[1099] R.sub.f=0.49 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[1100] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.09 (d, J=8.3 Hz, 2H), 8.01 (dd, J=6.6, 1.8 Hz, 1H), 7.88 (q, J=7.6 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.34 (hept, J=6.2 Hz, 1H), 3.83 (s, 3H), 1.44 (d, J=6.2 Hz, 6H).
[1101] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=164.9, 159.9, 156.8, 148.9, 137.9, 137.8, 133.3, 132.0, 127.1, 124.9, 123.4, 123.2, 115.4, 114.2, 91.1, 88.2, 69.6, 55.5, 22.0.
[1102] HRMS (EI-MS) for C.sub.24H.sub.21NO.sub.3: calcd=371.1521, found=handed in, Δm=xx ppm.
[1103] m.p.=152-155° C.
Example 93: STS-9
[1104] ##STR00162##
[1105] The coupling of ethyl 6-bromopicolinate with 4-(acetoxymethyl)benzeneboronic acid was performed following the general procedure SC1.
[1106] Yield=93.0 mg slightly blue oil (0.311 mmol, 70%).
[1107] R.sub.f=26 (cyclohexane/EtOAc=4+1; UV).
[1108] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.15-7.99 (m, 3H), 7.89 (d, J=4.2 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 5.16 (s, 2H), 4.49 (q, J=7.1 Hz, 2H), 2.12 (s, 3H), 1.45 (t, J=7.1 Hz, 3H).
[1109] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=171.0, 165.6, 157.2, 148.6, 138.6, 137.8, 137.4, 128.7, 127.5, 123.6, 66.0, 62.0, 21.1, 14.4.
[1110] HRMS (EI-MS) for C.sub.17H.sub.17NO.sub.4: calcd=299.1158, found=299.1141, Δm=5.7 ppm.
Example 94: STS-15
[1111] ##STR00163##
[1112] The coupling of isopropyl 6-bromopicolinate with 4-butylphenylboronic acid was performed following the general procedure SC1.
[1113] Yield=98.9 mg slightly yellow solid (0.333 mmol, 80%).
[1114] R.sub.f=0.29 (cyclohexane/EtOAc=10+1; UV).
[1115] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.10-7.91 (m, 3H), 7.91-7.79 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 5.45-5.22 (m, 1H), 2.67 (t, J=7.6 Hz, 2H), 1.62 (dd, J=15.8 Hz, 8.2 Hz, 2H), 1.50-1.26 (m, 8H), 0.94 (t, J=7.3 Hz, 3H).
[1116] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 157.8, 148.7, 144.6, 137.6, 136.1, 129.0, 127.2, 123.1, 123.0, 69.5, 35.6, 33.6, 22.4, 22.0, 14.1.
[1117] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.2: calcd=297.1729, found=297.1730, Δm=0.3 ppm.
[1118] m.p.=51-55° C.
Example 95: STS-18
[1119] ##STR00164##
[1120] The coupling of isopropyl 6-bromopicolinate with 4-isopropylphenylboronic acid was performed following the general procedure SC1. An additional preparative-HPLC (method B) was performed for purification.
[1121] Yield=20.2 mg slightly yellow oil (0.0675 mmol, 16%).
[1122] R.sub.f=0.29 (cyclohexane/EtOAc=7+1; UV).
[1123] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.03 (d, J=8.7 Hz, 2H), 7.93 (dd, J=8.5 Hz, 4.1 Hz, 1H), 7.81 (d, J=3.9 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 5.55-5.14 (m, J=12.4 Hz, 6.2 Hz, 1H), 4.82-4.43 (m, J=12.0 Hz, 6.0 Hz, 1H), 1.40 (dd, J=20.4 Hz, 6.1 Hz, 12H).
[1124] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 159.3, 157.4, 148.6, 137.5, 131.0, 128.6, 122.5, 116.1, 70.1, 69.4, 22.1, 22.0.
[1125] HRMS (EI-MS) for C.sub.18H.sub.21NO.sub.3: calcd=299.1521, found=299.1517, Δm=1.3 ppm.
Example 96: STS-19
[1126] ##STR00165##
[1127] The coupling of isopropyl 6-bromopicolinate with 4-Isobutoxyphenylboronic acid was performed following the general procedure SC1. An additional crystallization was performed for purification.
[1128] Yield=64.1 mg colorless needles (0.205 mmol, 50%).
[1129] R.sub.f=0.25 (cyclohexane/EtOAc=7+1; UV).
[1130] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, J=8.7 Hz, 2H), 7.98-7.89 (m, 1H), 7.89-7.75 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 5.45-5.22 (m, 1H), 3.78 (d, J=6.5 Hz, 2H), 2.23-2.02 (m, 1H), 1.43 (d, J=6.2 Hz, 6H), 1.04 (d, J=6.7 Hz, 6H).
[1131] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=165.1, 160.7, 157.4, 148.6, 137.5, 131.0, 128.6, 122.5, 114.9, 69.4, 28.4, 22.0, 19.4.
[1132] HRMS (EI-MS) for C.sub.19H.sub.23NO.sub.3: calcd=301.1136, found=313.1673, Δm=1.6 ppm.
[1133] m.p.=103-107° C.
Example 97: STS-25
[1134] ##STR00166##
[1135] The coupling of isopropyl 6-bromopicolinate with 4-(isopropoxycarbonyl)phenylboronic acid was performed following the general procedure SC1. An additional column chromatography was performed for purification.
[1136] Yield=91.0 mg colorless oil (0.278 mmol, 60%).
[1137] R.sub.f=0.54 (cyclohexane/EtOAc=3+1; UV, KMnO.sub.4).
[1138] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ=8.26-7.99 (m, 5H), 7.99-7.84 (m, 2H), 5.44-5.20 (m, 2H), 1.42 (2×d).
[1139] .sup.13C-NMR,APT (76 MHz, CDCl.sub.3): δ=166.0, 164.8, 156.5, 149.0, 142.5, 137.9, 131.7, 130.1, 127.2, 123.9, 123.7, 69.7, 68.7, 22.1, 22.0.
[1140] HRMS (EI-MS) for C.sub.16H.sub.16FNO.sub.3: calcd=289.1114, found=327.1459, Δm=3.7 ppm.
Examples 98 to 100
[1141] General Procedures
[1142] Suzuki Coupling Procedure A
[1143] A 20 mL Schlenk tube with magnetic stirring bar was charged with 1.0 eq boronic acid, 2.0 eq potassium carbonate and 5.0 mol-% Pd(PPh.sub.3).sub.4 in a 10:1 (v/v) mixture of toluene/H.sub.2O. The reaction mixture was degassed by evacuation and purging with Ar (repeated three times) and subsequently 1.0 eq ethyl 5-bromo-2-furoate was added via Eppendorf® pipette in an Ar counterstream. The reaction vessel was placed in an oil bath and stirred at 80° C. After 24 h reaction time 3.0 mol-% Pd(PPh.sub.3).sub.4 were added additionally and the temperature was set to 90° C. and 100° C. after 30 h and 46 h, respectively. After 52 h the reaction mixture was cooled to RT and filtered through a pad of Celite®. The filter cake was washed with EtOAc (3×6 mL), the volatiles were removed under reduced pressure and the crude residue was died in oil-pump vacuum. Pure product was obtained via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc 15:1).
[1144] Suzuki Coupling Procedure B
[1145] A predried 20 mL Schlenk tube with magnetic stirring bar was charged with 5 mol-% PdCl.sub.2(dppf), 1.0 eq aryl halide, 1.0 eq boronic acid and 2.1 eq cesium fluoride in anhydrous DME. The reaction mixture was degassed by evacuation and purging with Ar (repeated three times) and placed in an oil bath at 80° C. After stirring for 24-96 h (reaction control via TLC and GC/MS) the reaction mixture was cooled to RT and filtered through a pad of Celite®. The filter cake was washed with an appropriate amount of EtOAc, the volatiles were removed under reduced pressure and the crude residue was died in oil-pump vacuum. Pure product was obtained via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc).
[1146] Suzuki Coupling Procedure C
[1147] A 15-50 mL Schlenk-tube with magnetic stirring bar was evacuated and purged with Ar (repeated three times). The Schlenk-tube was subsequently charged with 5 mol-% Pd(OAc).sub.2, 10 mol-% SPhos, 1.2 eq boronic acid, 1.0 eq aryl halide (if solid) and 5.0 mL 1,4-dioxane. At this point 1.0 eq aryl halide (if liquid) and 1.0 mL of a 3.4 M K.sub.3PO.sub.4 solution (degassed) was added via Eppendorf® pipette in an Ar counterstream. The reaction mixture was degassed by evacuation and purging with Ar (repeated three times) and placed in an oil bath at 60° C. After stirring for 18-22 h (reaction control via TLC and GC/MS) the reaction mixture was cooled to RT, the phases separated and the organic phase filtered through a pad of Celite®. The filter cake was washed with an appropriate amount of EtOAc, the volatiles were removed under reduced pressure and the crude residue was died in oil-pump vacuum. Pure product was obtained via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc).
Example 98: Ethyl 2-(4-(ethylthio)phenyl)thiazole-4-carboxylate (CLF-3-205)
[1148] ##STR00167##
[1149] 4-(Ethylthio)benzeneboronic acid (92.5 mg, 0.508 mmol, 1.2 eq), ethyl 2-bromothiazole-4-carboxylate (100.0 mg, 0.424 mmol, 1.0 eq) and potassium phosphate (726.5 mg, 3.423 mmol, 8.1 eq) in 6.0 mL 1,4-dioxane/H.sub.2O 5:1 (v/v) were reacted in presence of Pd(OAc).sub.2 (4.8 mg, 0.021 mmol, 5 mol-%) and SPhos (17.4 mg, 0.042 mmol, 10 mol-%) for 18 h at 60° C. according to general procedure C. The crude product was purified via flash column chromatography (16 g SiO.sub.2, cyclohexane/EtOAc 10:1 (v/v), column size 13×2 cm) to obtain the pure product as pale yellow solid.
[1150] Yield: 69.9 mg (0.238 mmol, 56%), pale yellow solid.
[1151] C.sub.14H.sub.15NO.sub.2S.sub.2[293.40 g/mol].
[1152] R.sub.f=0.38 (cyclohexane/EtOAc=5:1 (v/v); staining: KMnO.sub.4).
[1153] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.12 (s, 1H, Ar—H), 7.91 (d, J=8.4 Hz, 2H, Ar—H), 7.33 (d, J=8.3 Hz, 2H, Ar—H), 4.44 (q, J=7.1 Hz, 2H, CH.sub.2), 3.01 (q, J=7.3 Hz, 2H, CH.sub.2′), 1.52-1.26 (m, 6H, 2×CH.sub.3).
[1154] .sup.13C NMR (75 MHz, CDCl.sub.3): δ=168.5, 161.6, 148.2, 141.0, 130.0, 127.9, 127.4, 126.8, 61.6, 26.9, 14.5, 14.2.
[1155] HRMS (DI-EI): Calcd. for C.sub.14H.sub.15NO.sub.2S.sub.2: 293.0544; found: 293.0546.
Example 99: Ethyl 2-(4-(methylthio)phenyl)thiazole-4-carboxylate (CLF-3-206)
[1156] ##STR00168##
[1157] 4-(Methylthio)benzeneboronic acid (85.4 mg, 0.508 mmol, 1.2 eq), ethyl 2-bromothiazole-4-carboxylate (100.0 mg, 0.424 mmol, 1.0 eq) and potassium phosphate (726.5 mg, 3.423 mmol, 8.1 eq) in 6.0 mL 1,4-dioxane/H.sub.2O 5:1 (v/v) were reacted in presence of Pd(OAc).sub.2 (4.8 mg, 0.021 mmol, 5 mol-%) and SPhos (17.4 mg, 0.042 mmol, 10 mol-%) for 18 h at 60° C. according to general procedure C. The crude product was purified via flash column chromatography (18 g SiO.sub.2, cyclohexane/EtOAc 10:1 (v/v), column size 13×2 cm) to obtain the pure product as pale yellow solid.
[1158] Yield: 59.0 mg (0.211 mmol, 50%), pale yellow solid.
[1159] C.sub.13H.sub.13NO.sub.2S.sub.2[279.37 g/mol].
[1160] R.sub.f=0.34 (cyclohexane/EtOAc=5:1 (v/v); staining: KMnO.sub.4).
[1161] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.12 (s, 1H, Ar—H), 7.92 (d, J=8.4 Hz, 2H, Ar—H), 7.28 (d, J=8.5 Hz, 2H, Ar—H), 4.44 (q, J=7.1 Hz, 2H, CH.sub.2), 2.52 (s, 3H, CH.sub.3), 1.42 (t, J=7.1 Hz, 3H, CH.sub.3′).
[1162] .sup.13C NMR (75 MHz, CDCl.sub.3): δ=168.6, 161.6, 148.2, 145.5, 129.5, 127.4, 126.7, 126.1, 61.6, 15.3, 14.5.
[1163] HRMS (DI-EI): Calcd. for C.sub.13H.sub.13NO.sub.2S.sub.2: 279.0388; found: 279.0394.
Example 100: Ethyl 2-(4-isopropylthio)phenyl)thiazole-4-carboxylate (CLF-3-213)
[1164] ##STR00169##
[1165] 4-(Isopropylthio)benzeneboronic acid (99.7 mg, 0.508 mmol, 1.2 eq), ethyl 2-bromothiazole-4-carboxylate (100.0 mg, 0.424 mmol, 1.0 eq) and potassium phosphate (726.5 mg, 3.423 mmol, 8.1 eq) in 6.0 mL 1,4-dioxane/H.sub.2O 5:1 (v/v) were reacted in presence of Pd(OAc).sub.2 (4.8 mg, 0.021 mmol, 5 mol-%) and SPhos (17.4 mg, 0.042 mmol, 10 mol-%) for 20 h at 60° C. according to general procedure C. The crude product was purified via flash column chromatography (22 g SiO.sub.2, cyclohexane/EtOAc 15:1 (v/v), column size 14×2 cm) to obtain the pure product as pale yellow wax.
[1166] Yield: 77.9 mg (0.253 mmol, 60%), pale yellow wax.
[1167] C.sub.15H.sub.17NO.sub.2S.sub.2[307.43 g/mol].
[1168] R.sub.f=0.15 (cyclohexane/EtOAc=15:1 (v/v); staining: CAM).
[1169] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.13 (s, 1H, Ar—H), 7.91 (d, J=8.3 Hz, 2H, Ar—H), 7.39 (d, J=8.3 Hz, 2H, Ar—H), 4.44 (q, J=7.1 Hz, 2H, CH.sub.2), 3.60-3.38 (m, 1H, C
[1170] .sup.13C NMR (75 MHz, CDCl.sub.3): δ=168.5, 161.6, 148.2, 140.0, 130.7, 130.5, 127.4, 127.0, 61.6, 37.6, 23.1, 14.5.
[1171] HRMS (DI-EI): Calcd. for C.sub.15H.sub.17NO.sub.2S.sub.2: 307.0701; found: 307.0710.
Examples 101 to 181
[1172] General Procedure A: Suzuki Coupling
[1173] In an inert Schlenk flask equipped with magnetic stirring bar heterocyclic bromide (1.0 eq), boronic acid (0.9 to 1.5 eq) and K.sub.2CO.sub.3 (2.0 eq) were dissolved in degassed toluene abs. (0.1 M). Pd[PPh.sub.3].sub.4 (3 mol %) was added and the reaction mixture was stirred at 80° C. The reaction was monitored via TLC. When full conversion was observed, the reaction mixture was cooled down to RT and filtered through a pad of Celite. The solvent was removed under reduced pressure and the crude product was purified via column chromatography or preparative HPLC, respectively.
[1174] General Procedure B: Fischer-Esterification
[1175] In a round-bottom flask heterocyclic acid (1.0 eq.) was dissolved in the corresponding alcohol (0.1-0.2 M) and H.sub.2SO.sub.4 (3.0 eq.) was added. The reaction mixture was equipped with an air condenser and stirred at reflux until full conversion was detected via TLC. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The residue was taken up in NaHCO.sub.3 sat and extracted with DCM (3×15 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.
[1176] General Procedure C: DCC-Mediated Esterification
[1177] In an inert 10 mL Schienk flask 2-(4-ethoxyphenyl)thiazole acid (1.0 eq) was dissolved in DCM abs. (0.1 M). DCC (1.5 eq.) and DMAP (0.2 eq.) were added successively and the reaction mixture was cooled to 0° C. using an ice bath. The corresponding alcohol (1.5 eq.) was added and the cloudy reaction mixture was stirred at RT until full conversion was observed via TLC. The reaction mixture was filtered through a pad of Celite and the solvent was removed under reduced pressure. The crude product was purified via column chromatography or preparative HPLC, respectively.
[1178] General Procedure D: Ullman-Type Coupling
[1179] In an inert 10 mL Schlenk flask tert-butyl 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq), CuI (0.1 eq) and K.sub.2CO.sub.3 (2.0 eq) were dissolved in anhydrous DMF (0.1 M). The corresponding amine (2.1 eq) was added and the reaction mixture was stirred at 100° C. until full conversion was observed via TLC. The reaction mixture was quenched via the addition of NH4Cl and extracted with EA (3×). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography.
[1180] Preparative HPLC was performed on a Thermo Scientific UltiMate 3000 system. Detection was accomplished with a Dionex UltiMate DAD. The separations were carried out on a Macherey-Nagel 125/21 Nucleodur 100-5C18EC (125×21 mm, 5.0 μm) column. As eluents MeCN and water with 0.05% HCOOH were used. Following methods were used:
[1181] Method A 0.0 min-8.0 min linear increase 40 to 100% MeCN, 8.0-10.0 min 100% MeCN isocratic, 10.0-12.0 min linear decrease 100 to 40% MeCN, 12.0-14.0 min 40% MeCN isocratic, 12 mL/min, 30° C.
[1182] Method B 0.0 min-8.0 min linear increase 60 to 100% MeCN, 8.0-10.0 min 100% MeCN isocratic, 10.0-12.0 min linear decrease 100 to 60% MeCN, 12.0-14.0 min 40% MeCN isocratic, 12 mL/min, 30° C.
[1183] Method C 0.0 min-6.0 min linear increase 40 to 80% MeCN, 6.0-7.0 min linear increase 80 to 100% MeCN, 7.0-9.0 min 100% MeCN isocratic, 9.0-12.0 min linear decrease 100 to 40% MeCN, 12.0-14.0 min 40% MeCN isocratic, 12 mL/min, 30° C.
[1184] Method D 0.0 min-14.0 min 50% MeCN isocratic, 14.0-16.0 min 50 to 100% MeCN 100% linear increase, 16.0-18.0 min 100% MeCN isocratic, 18.0-20.0 min linear decrease 100 to 50% MeCN, 20.0-22.0 min 50% MeCN isocratic, 12 mL/min, 30° C.
[1185] Method E 0.0 min-17.0 min linear increase 2 to 100% MeCN, 17.0-19.0 min 100% MeCN isocratic, 19.0-22.0 min linear decrease 100 to 2% MeCN, 22.0-24.0 min 2% MeCN isocratic, 12 mL/min, 30° C.
[1186] Method F 0.0 min-2.0 min linear increase 3 to 10% MeCN, 2.0 to 4.0 min 10% MeCN isocratic, 4.0-16.0 min linear increase to 95% MeCN, 17.0-21.0 min 100% MeCN isocratic, 21.0-23.0 min 3% MeCN isocratic, 14 mL/min, 30° C.
[1187] Method G 0.0 min-3.0 min 80% MeCN isocratic, 3.0 to 6.0 min linear increase to 100% MeCN, 6.0-8.0 min 100% MeCN isocratic, 8.0-10.0 min linear decrease to 80% MeCN, 10.0-14.0 min 80% MeCN isocratic, 12 mL/min, 30° C.
Example 101: Ethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-50)
[1188] ##STR00170##
[1189] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 805 μmol, 200 mg) was coupled with 4-ethoxyphenylboronic acid (0.9 eq, 724 μmol, 120 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 8:1).
[1190] Yield: 143 mg (516 μmol, 73%) light yellow solid
[1191] C.sub.14H.sub.17NO.sub.3S [277.34]
[1192] m.p.: 90° C.
[1193] R.sub.f: 0.36 (CH/EA 4:1)
[1194] HR-MS [EI, M.sup.+]: calcd. 277.0773, found 277.0771.
[1195] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.0 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H12/16), 6.94 (d, J=8.7 Hz, 2H, H13/15), 4.44 (q, J=7.1 Hz, 2H, H9), 4.08 (q, J=6.9 Hz, 2H, H18), 1.43 (m, 6H, H10/19).
[1196] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.7 (C.sub.q, C6), 161.2 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.7 (2 CH, C12/16), 126.3 (CH, C5), 125.7 (C.sub.q, C11), 114.9 (2 CH, C13/15), 63.8 (CH.sub.2, C9), 61.6 (CH.sub.2, C18), 14.9 (CH.sub.3, C10), 14.5 (CH.sub.3, C19).
Example 102: Ethyl 2-(4-methoxyphenyl)thiazole-4-carboxylate (AM-1-71)
[1197] ##STR00171##
[1198] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 805 μmol, 200 mg) was coupled with 4-methoxyphenylboronic acid (0.9 eq, 724 μmol, 110 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 5:1).
[1199] Yield: 127 mg (516 μmol, 66%) light yellow solid
[1200] C.sub.13H.sub.13NO.sub.3S [263.31]
[1201] m.p.: 100° C.
[1202] R.sub.f: 0.32 (CH/EA 4:1)
[1203] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H, H5), 7.95 (d, J=8.8 Hz, 2H, H12/16), 6.95 (d, J=8.8 Hz, 2H, H13/15), 4.44 (q, J=7.1 Hz, 2H, H9), 3.86 (s, 3H, H18), 1.42 (t, J=7.1 Hz, 3H, H10)
[1204] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.9 (C.sub.q, C2), 161.8 (C.sub.q, C6), 161.7 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.7 (2C, CH, C12/16), 126.4 (CH, C6), 125.9 (C.sub.q, C11), 114.4 (2C, CH, C13/15), 61.6 (CH.sub.2, C9), 55.6 (CH.sub.3, C18), 14.5 (CH.sub.3, C10).
Example 103: Ethyl 2-(4-(dimethylamino)phenyl)thiazole-4-carboxylate (AM-1-74)
[1205] ##STR00172##
[1206] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 805 μmol, 200 mg) was coupled with 4-dimethylaminophenylboronic acid (0.9 eq, 724 μmol, 120 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 4:1) and preparative HPLC (method A).
[1207] Yield: 72 mg (516 μmol, 36%) colorless crystals
[1208] C14H16N2O2S [276.35]
[1209] m.p.: 126° C.
[1210] R.sub.f: 0.30 (CH/EA 4:1)
[1211] HR-MS [EI, M.sup.+]: calcd. 276.0932, found 276.0929.
[1212] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.00 (s, 1H, H5), 7.87 (d, J=8.7 Hz, 2H, H12/16), 6.71 (d, J=8.6 Hz, 2H, H13/15), 4.43 (q, J=7.0 Hz, 2H, H9), 3.03 (s, 6H, H18/19), 1.42 (t, J=7.1 Hz, 3H, H10).
[1213] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.8 (C.sub.q, C2), 161.9 (C.sub.q, C6), 152.0 (C.sub.q, C14), 147.7 (C.sub.q, C4), 128.36 (2C, CH, C12/16) 125.3 (CH, C5), 121.2 (C.sub.q, C11), 111.8 (2C, CH, C13/15), 61.4 (CH.sub.2, C9), 40.4 (2C, CH.sub.3, C18/19), 14.5 (CH.sub.3, C10).
Example 10: Ethyl 2-(4-isobutoxyphenyl)thiazole-4-carboxylate (AM-1-75)
[1214] ##STR00173##
[1215] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 805 μmol, 200 mg) was coupled with 4-isobutoxyphenylboronic acid (0.9 eq, 724 μmol, 140 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 9:1 to 4:1).
[1216] Yield: 172 mg (563 μmol, 78%) light yellow solid
[1217] C.sub.16H.sub.19NO.sub.3S [305.39]
[1218] m.p.: 91° C.
[1219] R.sub.f: 0.47 (CH/EA 4:1)
[1220] HR-MS [EI, M.sup.+]: calcd. 305.1086, found 305.1084.
[1221] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H12/16), 6.95 (d, J=8.8 Hz, 2H, C13/15), 4.44 (q, J=7.1 Hz, 2H, H9), 3.77 (d, J=6.5 Hz, 2H, H18), 2.11 (hept, J=6.6 Hz, 1H, H19), 1.43 (t, J=7.1 Hz, 3H, H10), 1.03 (d, J=8.9 Hz, 6H, H20/21).
[1222] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.7 (C.sub.q, C6), 161.5 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.64 (2C, CH, C12/16), 126.3 (CH, C5), 125.6 (C.sub.q, 11), 114.9 (2C, CH, C13/15), 74.7 (CH.sub.2, C18), 61.6 (CH.sub.2, C9), 28.4 (CH, C19), 19.4 (2C, CH.sub.3, C20/21), 14.5 (CH.sub.3, C10).
Example 105: Ethyl 2-(4-propoxyphenyl)thiazole-4-carboxylate (AM-1-82)
[1223] ##STR00174##
[1224] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 678 μmol, 160 mg) was coupled with 4-propoxyyphenylboronic acid (1.05 eq, 724 μmol, 137 mg). The crude product was purified via preparative HPLC (method A).
[1225] Yield: 109 mg (374 μmol, 55%) colorless crystals
[1226] C.sub.15H.sub.17NO.sub.3S [291.37]
[1227] m.p.: 97° C.
[1228] R.sub.f: 0.36 (CH/EA 4:1)
[1229] HR-MS [EI, M.sup.+]: calcd. 291.0929, found 291.0933.
[1230] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H12/16), 6.94 (d, J=8.8 Hz, 2H, H13/15), 4.44 (q, J=7.1 Hz, 2H, H9), 3.97 (t, J=6.5 Hz, 2H, H18), 1.90-1.76 (m, 2H, H19), 1.42 (t, J=7.1 Hz, 3H, H10), 1.05 (t, J=7.4 Hz, 3H, H20).
[1231] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.7 (C.sub.q, C6), 161.4 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.7 (2C, CH, C12/16), 126.3 (CH, C5), 125.7 (C.sub.q, C11), 114.9 (2C, CH, C13/15), 69.8 (CH.sub.2, C18), 61.6 (CH.sub.2, C9), 22.7 (CH.sub.2, C19), 14.5 (CH.sub.3, C10), 10.6 (CH.sub.3, C20).
Example 106: Ethyl 2-(4-isopropoxyphenyl)thiazole-4-carboxylate (AM-1-93a)
[1232] ##STR00175##
[1233] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 847 μmol, 200 mg) was coupled with 4-isopropoxyphenylboronic acid (0.9 eq, 770 μmol, 139 mg). The crude product was purified column chromatography (65 mL SiO.sub.2, eluent CH/EA/DCM 10:1:1)
[1234] Yield: 164 mg (563 μmol, 73%) light yellow solid
[1235] C.sub.15H.sub.17NO.sub.3S [291.37]
[1236] m.p.: 58° C.
[1237] R.sub.f: 0.36 (CH/EA 4:1)
[1238] HR-MS [EI, M.sup.+]: calcd. 291.0929, found 291.0928.
[1239] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H12/16), 6.93 (d, J=8.6 Hz, 2H, H13/15), 4.62 (m, 1H, H18), 4.44 (q, J=7.1 Hz, 2H, C9), 1.42 (t, J=7.1 Hz, 3H, C10), 1.36 (d, J=6.0 Hz, 6H, C19/20).
[1240] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.7 (C.sub.q, C6), 160.2 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.7 (2C, C12/16), 126.3 (CH, C5), 125.5 (C.sub.q, C11), 116.0 (2C, CH, C13/15), 70.2 (CH, C18), 61.6 (CH.sub.2, C9), 22.1 (2C, CH.sub.3, C19/20), 14.5 (CH.sub.3, C10).
Example 107: Ethyl 2-(4-(trifluoromethoxy)phenyl)thiazole-4-carboxylate (AM-1-93b)
[1241] ##STR00176##
[1242] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 847 μmol, 200 mg) was coupled with 4-trifluoromethoxyphenylboronic acid (0.9 eq, 770 μmol, 160 mg). The crude product was purified column chromatography (65 mL SiO.sub.2, eluent CH/EA/DCM 10:1:1) and preparative HPLC (method A)
[1243] Yield: 56 mg (177 μmol, 23%) colorless solid
[1244] C.sub.13H.sub.10F.sub.3NO.sub.3S [317.28]
[1245] m.p.: 92° C.
[1246] R.sub.f: 0.42 (CH/EA 4:1)
[1247] HR-MS [EI, M.sup.+]: calcd. 291.0929, found 291.0928.
[1248] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.17 (s, 1H, H5), 8.05 (d, J=8.7 Hz, 2H, H12/16), 7.30 (d, J=8.2 Hz, 2H, H13/15), 4.45 (q, J=7.1 Hz, 2H; H9), 1.43 (t, J=7.1 Hz, 3H, H10).
[1249] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 167.3 (C.sub.q, C2), 161.5 (C.sub.q, C6), 151.0 (C.sub.q, C14), 148.5 (C.sub.q, C4), 131.5 (C.sub.q, C11), 128.7 (2C, CH, C12/16), 127.5 (CH, C5), 122.2, 118.8 (d, J=258, CF.sub.3), 121.4 (2C, CH, C13/15), 61.7 (CH.sub.2, C9), 14.5 (CH.sub.3, C10).
Example 108: Ethyl 2-(4-(2,2,2-trifluoroethoxy)phenyl)thiazole-4-carboxylate (AM-1-98)
[1250] ##STR00177##
[1251] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 225 μmol, 53 mg) was coupled with (4-(2,2,2-trifluoroethoxy)phenyl)boronic acid (1.0 eq, 225 μmol, 50 mg). The crude product was purified column chromatography (25 mL SiO.sub.2, eluent CH/EA/DCM 12:1:1 to 8:1:1).
[1252] Yield: 50 mg (151 μmol, 67%) off-white solid
[1253] C.sub.14H.sub.12F.sub.3NO.sub.3S [331.31]
[1254] m.p.: 119° C.
[1255] R.sub.f: 0.15 (CH/EA 4:1)
[1256] HR-MS [EI, M.sup.+]: calcd. 331.0490, found 331.0491.
[1257] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.11 (s, 1H, H5), 7.98 (d, J=8.8 Hz, 2H, H12/16), 7.01 (d, J=8.7 Hz, 2H, H13/15), 4.49-4.35 (m, 4H, H9/18), 1.43 (t, J=7.1 Hz, 3H, H10).
[1258] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.2 (C.sub.q, C2), 161.6 (C.sub.q, C6), 159.2 (C.sub.q, C14), 148.2 (C.sub.q, C4), 128.9 (2C, CH, C12/16), 127.7 (C.sub.q, C11), 126.8 (CH, C5), 115.3 (2C, CH, C13/15), 66.10, 65.63 (d, J=36, CH.sub.2, C18), 61.65 (CH.sub.2, C9), 14.50 (CH.sub.3, C10).
Example 109: Ethyl 2-(4-butoxyphenyl)thiazole-4-carboxylate (AM-2-102a)
[1259] ##STR00178##
[1260] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 847 μmol, 200 mg) was coupled with 4-butoxyphenylboronic acid (1.0 eq, 847 μmol, 164 mg). The crude product was purified column chromatography (60 mL SiO.sub.2, eluent CH/EA/DCM 18:1:1 to 12:1:1).
[1261] Yield: 95 mg (311 μmol, 77%) yellow solid
[1262] C.sub.16H.sub.19NO.sub.3S [305.39]
[1263] m.p.: 64° C.
[1264] R.sub.f: 0.37 (CH/EA 4:1)
[1265] HR-MS [EI, M.sup.+]: calcd. 305.1086, found 305.1087.
[1266] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H12/16), 6.94 (d, J=8.8 Hz, 2H, H13/15), 4.44 (q, J=7.1 Hz, 2H, H9), 4.01 (t, J=6.5 Hz, 2H, H18), 1.85-1.71 (m, 2H, H19), 1.52 (m, 2H, H20), 1.42 (t, J=7.1 Hz, 3H, H10), 0.98 (t, J=7.3 Hz, 3H, H21).
[1267] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.7 (C.sub.q, C6), 161.4 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.7 (2C, CH, C12/16), 126.3 (CH, C5), 125.7 (C.sub.q, C11), 114.9 (2C, CH, C13/15), 68.0 (CH.sub.2, C18), 61.6 (CH.sub.2, C9), 31.4 (CH.sub.2, C19), 19.4 (CH.sub.2, C20), 14.5 (CH.sub.3, C10), 14.0 (CH.sub.3, C21).
Example 110: Ethyl 2-(4-(pentyloxy)phenyl)thiazole-4-carboxylate (AM-2-102b)
[1268] ##STR00179##
[1269] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 847 μmol, 200 mg) was coupled with 4-pentyloxyphenylboronic acid (1.0 eq, 847 μmol, 176 mg). The crude product was purified column chromatography (60 mL SiO.sub.2, eluent CH/EA/DCM 16:1:1 to 10:1:1).
[1270] Yield: 183 mg (311 μmol, 69%) yellow solid
[1271] C.sub.17H.sub.21NO.sub.3S [319.42]
[1272] m.p.: 70° C.
[1273] R.sub.f: 0.42 (CH/EA 4:1)
[1274] HR-MS [EI, M.sup.+]: calcd. 319.1242, found 319.1243.
[1275] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.07 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H12/16), 6.94 (d, J=8.8 Hz, 2H, H13/15), 4.44 (q, J=7.1 Hz, 2H, H9), 4.00 (t, J=6.5 Hz, 2H, H18), 1.81 (m, 2H, H19), 1.42 (m, 7H, H10/20/21), 0.94 (t, J=6.9 Hz, 3H, H22).
[1276] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C5), 161.7 (C.sub.q, C6), 161.4 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.7 (2C, C12/16) 126.3 (CH, C5), 125.7 (C.sub.q, C11), 114.9 (2C, CH, C13/15), 68.4 (CH.sub.2, C18), 61.6 (CH.sub.2, C9), 29.0 (CH.sub.2, C19), 28.3 (CH.sub.2, C20), 22.6 (CH.sub.2, C21), 14.5 (CH.sub.3, C10), 14.13 (CH.sub.3, C22).
Example 111: Ethyl 2-(4-(hexyloxy)phenyl)thiazole-4-carboxylate (AM-2-102c)
[1277] ##STR00180##
[1278] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 847 μmol, 200 mg) was coupled with 4-hexyloxyphenylboronic acid (1.0 eq, 847 μmol, 188 mg). The crude product was purified column chromatography (60 mL SiO.sub.2, eluent CH/EA/DCM 18:1:1 to 12:1:1).
[1279] Yield: 192 mg (311 μmol, 68%) yellow solid
[1280] C.sub.18H.sub.23NO.sub.3S [333.45]
[1281] m.p.: 70° C.
[1282] R.sub.f: 0.40 (CH/EA 4:1)
[1283] HR-MS [EI, M.sup.+]: calcd. 333.1399, found 333.1396.
[1284] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.07 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H12/16), 6.94 (d, J=8.7 Hz, 2H, H13/15), 4.44 (q, J=7.1 Hz, 2H, H9), 4.00 (t, J=6.5 Hz, 2H, H18), 1.85-1.74 (m, 2H, H19), 1.55-1.45 (m, 2H, H20), 1.42 (t, J=7.1 Hz, 3H, H10), 1.39-1.30 (m, 4H, H21/22), 0.92 (t, J=6.6 Hz, 3H, H23).
[1285] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.7 (C.sub.q, C6), 161.4 (C.sub.q, C14), 148.0 (C.sub.q, C4), 128.7, (2C, CH, C12/16), 126.3 (CH, C5), 125.7 (C.sub.q, C11), 114.9 (2C, CH, C13/15), 68.4 (CH.sub.2, C18), 61.6 (CH.sub.2, C9), 31.7 (CH.sub.2, C21), 29.3 (CH.sub.2, C19), 25.8 (CH.sub.2, C20), 22.7 (CH.sub.2, C22), 14.5 (CH.sub.3, C10), 14.2 (CH.sub.3, C23).
Example 112: Ethyl 2-(4-(sec-butoxy)phenyl)thiazole-4-carboxylate (AM-1-103)
[1286] ##STR00181##
[1287] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 773 μmol, 182 mg) was coupled with 4-(sec-butoxy)phenylboronic acid (1.0 eq., 773 μmol, 150 mg). The crude product was purified column chromatography (60 mL SiO.sub.2, eluent CH/EA/DCM 12:1:1)
[1288] Yield: 90 mg (295 μmol, 38%) yellowish oil
[1289] C.sub.16H.sub.19NO.sub.3S [305.39]
[1290] R.sub.f: 0.42 (CH/EA 4:1)
[1291] HR-MS [EI, M.sup.+]: calcd. 305.1086, found 305.1089.
[1292] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ (ppm) 8.46 (s, 1H, H5), 7.88 (d, J=8.5 Hz, 2H, H12/16), 7.04 (d, J=8.5 Hz, 2H, H13/15), 4.48 (td, J=11.4, 5.5 Hz, 1H, H18), 4.32 (q, J=7.0 Hz, 2H, H9), 1.72-1.56 (m, 2H, H19), 1.32 (t, J=7.1 Hz, 3H, H10), 1.25 (d, J=5.9 Hz, 3H, H21), 0.92 (t, J=7.3 Hz, 2H, H20).
[1293] .sup.13C-NMR (75.5 MHz, DMSO-d.sub.6): δ (ppm) 167.7 (C.sub.q, C2), 160.8 (C.sub.q, C6), 159.9 (C.sub.q, C14), 146.7 (C.sub.q, C4), 128.2 (CH, C5), 128.1 (2C, CH, C12/16), 124.8 (C.sub.q, C11), 116.0 (2C, CH, C13/15) 74.4 (CH, C18), 60.8 (CH.sub.2, C9), 28.5 (CH.sub.2, C19), 18.9 (CH.sub.3, C21), 14.2 (CH.sub.3, C10), 9.4 (CH.sub.3, C20).
Example 113: Ethyl 2-(4-(allyloxy)phenyl)thiazole-4-carboxylate (AM-1-109)
[1294] ##STR00182##
[1295] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq, 899 μmol, 212) was coupled with (4-(allyloxy)phenyl)boronic acid (1.0 eq., 899 μmol, 160 mg). The crude product was purified column chromatography (75 mL SiO.sub.2, eluent CH/EA/DCM 12:1:1)
[1296] Yield: 90 mg (411 μmol, 46%) yellowish solid
[1297] C.sub.15H.sub.15NO.sub.3S [289.3490]
R.SUB.f.: 0.38 (CH/EA 4:1)
[1298] m.p.: 58° C.
[1299] HR-MS [EI, M.sup.+]: calcd. 289.0773, found 289.0776.
[1300] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ (ppm) 8.08 (s, 1H, H5), 7.94 (d, J=8.8 Hz, 2H, H12/16), 6.97 (d, J=8.8 Hz, 2H, H13/15), 6.06 (ddd, J=22.4, 10.5, 5.2 Hz, 1H, H19), 5.50-5.23 (m, 2H, H20), 4.59 (d, J=5.2 Hz, 2H, H18), 4.44 (q, J=7.1 Hz, 2H, H9), 1.42 (t, J=7.1 Hz, 3H, H10).
[1301] .sup.13C-NMR (75.5 MHz, DMSO-d): δ (ppm) 168.9 (C.sub.q, C2), 161.7 (C.sub.q, C6), 160.8 (C.sub.q, C14), 148.0 (C.sub.q, C4), 132.9 (CH, C19), 128.7 (2C, CH, C12/16), 126.4 (CH, C5), 126.0 (C.sub.q, C11), 118.2 (CH.sub.2, C20), 115.2 (2C, CH, C13/15), 69.0 (CH.sub.2, C18), 61.6 (CH.sub.2, C9), 14.5 (CH.sub.3, C10).
Intermediate: sec-Butyl 2-bromothiazole-4-carboxylate (AM-2-175a)
[1302] ##STR00183##
[1303] According to General Procedure B, 2-Bromothiazole-4-carboxylic acid (1.0 eq, 481 μmol, 100 mg) was esterified with 2-butanol.
[1304] Yield: 122 mg (462 μmol, 96%) off-white solid
[1305] C.sub.8H.sub.10BrNO.sub.2S [264.14]
[1306] m.p.: 64° C.
[1307] R.sub.f: 0.44 (CH/EA 4:1)
[1308] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, J=12.1 Hz, 1H, H5), 5.18-5.05 (m, 1H, H9), 1.83-1.60 (m, 2H, H10), 1.34 (d, J=6.3 Hz, 3H, H12), 0.95 (t, J=7.4 Hz, 3H, H11).
[1309] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 160.0 (C.sub.q, C6), 147.9 (C.sub.q, C2), 136.8 (C.sub.q, C4), 130.6 (CH, C5), 74.3 (CH, C9), 29.9 (CH.sub.2, C10), 19.6 (CH.sub.3, C12), 9.9 (CH.sub.3, C11).
Intermediate: iso-Butyl 2-bromothiazole-4-carboxylate (AM-2-176)
[1310] ##STR00184##
[1311] According to General Procedure B, 2-bromothiazole-4-carboxylic acid (1.0 eq, 913 μmol, 200 mg) was esterified with isobutanol.
[1312] Yield: 230 mg (871 μmol, 95%) beige solid
[1313] C.sub.8H.sub.10BrNO.sub.2S [264.14]
[1314] R.sub.f: 0.56 (CH/EA 2:1)
[1315] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, J=12.4 Hz, 1H, H5), 4.12 (d, J=6.8 Hz, 2H, H9), 2.20-2.00 (m, 1H, H10), 0.98 (d, J=6.7 Hz, 6H, H11/12).
[1316] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 160.2 (C.sub.q, C6), 147.4 (C.sub.q, C2), 136.9 (C.sub.q, C4), 130.7 (CH, C5), 71.8 (CH.sub.2, C9), 27.9 (CH, C10), 19.2 (2C, CH.sub.3, C11/12).
Example 114: sec-Butyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-2-178a)
[1317] ##STR00185##
[1318] According to general procedure A, AM-2-175a (1.0 eq., 340 μmol, 90 mg) was coupled with 4-ethoxyphenylboronic acid (1.74 eq, 590 μmol, 98 mg). The crude product was purified via column chromatography (40 mL SiO.sub.2, eluent CH/EA 10:1).
[1319] Yield: 68 mg (223 μmol, 66%) orange solid
[1320] C.sub.16H.sub.19NO.sub.3S [305.39]
[1321] m.p.: 54° C.
[1322] R.sub.f: 0.49 (CH/EA 4:1)
[1323] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.03 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H14/18), 6.94 (d, J=8.7 Hz, 2H, H15/17), 5.13 (dd, J=12.5, 6.2 Hz, 1H, H9), 4.08 (q, J=6.9 Hz, 2H, H20), 1.73 (dtd, J=21.0, 13.9, 6.9 Hz, 2H, H10), 1.44 (t, J=6.9 Hz, 3H, H21), 1.36 (d, J=6.2 Hz, 3H, H12), 0.98 (t, J=7.4 Hz, 3H, H11).
[1324] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.8 (C.sub.q, C2), 161.3 (C.sub.q, C6), 161.2 (C.sub.q, C16), 148.4 (C.sub.q, C4), 128.7 (2C, CH, C14/18), 125.9 (CH, C5), 125.8 (C.sub.q, C13) 114.9 (2C, CH, C15/17), 73.6 (CH, C9), 63.8 (CH.sub.2, C20), 29.0 (CH.sub.2, C10), 19.7 (CH.sub.3, C12), 14.9 (CH.sub.3, C21), 9.9 (CH.sub.3, C11).
Example 115: sec-Butyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-2-178b)
[1325] ##STR00186##
[1326] According to general procedure A, AM-2-176 (1.0 eq., 379 μmol, 100 mg) was coupled with 4-ethoxyphenylboronic acid (1.5 eq, 568 μmol, 95 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 10:1).
[1327] Yield: 77 mg (252 μmol, 66%) orange solid
[1328] C.sub.16H.sub.19NO.sub.3S [305.39]
[1329] m.p.: 100° C.
[1330] R.sub.f: 0.49 (CH/EA 4:1)
[1331] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.05 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H14/18), 6.94 (d, J=8.7 Hz, 2H, H15/17), 4.15 (d, J=6.8 Hz, 2H, H9), 4.09 (q, J=7.0 Hz, 2H, H20), 2.11 (tt, J=15.6, 7.9 Hz, 1H, H10), 1.44 (t, J=7.0 Hz, 3H, H21), 1.02 (d, J=6.7 Hz, 6H, H11/12).
[1332] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.9 (C.sub.q, C2), 161.6 (C.sub.q, C6), 161.2 (C.sub.q, C16), 148.0 (C.sub.q, C4), 128.7 (2C, CH, C14/18), 126.1 (CH, C5), 125.8 (C.sub.q, C13), 114.9 (2C, CH, C15/17), 71.4 (CH.sub.2, C9), 63.8 (CH.sub.2, C20), 28.0 (CH, C10), 19.3 (2C, CH.sub.3, C11/12), 14.9 (CH.sub.3, C21).
Reference Compound: 2-(4-Ethoxyphenyl)thiazole-4-carboxylic acid (AM-2-177)
[1333] ##STR00187##
[1334] In a 250 mL round bottom flask ethyl-(4-ethoxyphenyl)thiazole-2-carboxylate (1.0 eq., 2.16 mmol, 600 mg) was dissolved in 50 mL THF/MeOH/H.sub.2O (5:4:1) and LiOH (5.0 eq, 10.8 mmol, 253 mg) was added. The reaction mixture was stirred at RT for 16 h. When full conversion was observed via TLC, the solvent was removed under reduced pressure. The residue was taken up in 50 mL H.sub.2O, acidified to pH 2 and extracted with DCM (2×100 mL). The combined organic phases was washed with Brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude product was used in the next step without further purification.
[1335] Yield: 531 mg (2.13 μmol, 99%) off-white solid
[1336] C.sub.12H.sub.11NO.sub.3S [249.28]
[1337] m.p.: 158° C.
[1338] R.sub.f: 0.06 (CH/EA 2:1)
[1339] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 9.81 (bs, 1H, H8), 8.19 (d, J=14.7 Hz, 1H, H5), 7.92 (d, J=8.7 Hz, 2H, H10/14), 6.96 (d, J=8.7 Hz, 2H, H11/13), 4.10 (q, J=6.9 Hz, 2H, H16), 1.45 (t, J=6.9 Hz, 3H, H17).
[1340] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.3 (C.sub.q, C2), 163.8 (C.sub.q, C6), 161.5 (C.sub.q, C12), 146.7 (C.sub.q, C4), 128.6 (2C, CH, C10/14), 127.4 (CH, C5), 125.2 (C.sub.q, C9), 115.1 (2C, CH, C11/13), 63.9 (CH.sub.2, C16), 14.9 (CH.sub.3, C17).
Example 116: 2,2,2-Trifluoroethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-2-180b)
[1341] ##STR00188##
[1342] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 2,2,2,-trifluoroethanol (1.5 eq, 451 μmol, 32 μL). The crude product was purified via column chromatography (40 mL SiO.sub.2, eluent CH/EA 10:1 to 8:1) and preparative HPLC (method B).
[1343] Yield: 37 mg (112 μmol, 37%) colorless crystals
[1344] C.sub.14H.sub.12F.sub.3NO.sub.3S [331.31]
[1345] m.p.: 136° C.
[1346] R.sub.f: 0.83 (CH/EA 1:1)
[1347] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.18 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H12/16), 6.95 (d, J=8.7 Hz, 2H, H13/15), 4.75 (q, J=8.3 Hz, 2H, H9), 4.09 (q, J=6.9 Hz, 2H, H18), 1.45 (t, J=6.9 Hz, 3H, H19).
[1348] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.5 (C.sub.q, C2), 161.4 (C.sub.q, C6), 159.7 (C.sub.q, C14), 145.7 (C.sub.q, C4), 128.7 (2C, CH, C12/16), 128.2 (CH, C5), 125.4 (C.sub.q, C11), 125.0, 121.3 (d, J=123 Hz, CF.sub.3), 115.0 (2C CH, C13/15), 63.87 (CH.sub.2, C18), 61.2, 60.7 (d, J=61 Hz, CH.sub.2, C9), 14.9 (CH.sub.3, C19).
Example 117: Pentan-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-183b)
[1349] ##STR00189##
[1350] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 2-pentanol (1.5 eq, 451 μmol, 49 μL). The crude product was purified via column chromatography (45 mL SiO.sub.2, eluent CH/EA/DCM 14:1:1).
[1351] Yield: 81 mg (254 μmol, 84%) colorless liquid
[1352] C.sub.17H.sub.21NO.sub.3S [319.42]
[1353] m.p.: 136° C.
[1354] R.sub.f: 0.86 (CH/EA 1:1)
[1355] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.02 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H15/19), 6.94 (d, J=8.7 Hz, 2H, H16/18), 5.21 (dd, J=12.6, 6.2 Hz, 1H, H9), 4.09 (q, J=6.9 Hz, 2H, H21), 1.76-1.54 (m, 2H, H10), 1.44 (t, J=6.9 Hz, 5H, H11/21), 1.36 (d, J=6.2 Hz, 3H, H13), 0.95 (t, J=7.2 Hz, 3H, H12).
[1356] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.8 (C.sub.q, C2), 161.3 (C.sub.q, C6), 161.2 (C.sub.q, C17), 148.4 (C.sub.q, C4), 128.7 (2C, CH, C15/19), 125.9 (CH, C5), 125.8 (C.sub.q, C14), 114.9 (2C, CH, C16/18), 72.2 (CH, C9), 63.8 (CH.sub.2, C21), 38.3 (CH.sub.2, C10), 20.2 (CH.sub.3, C13), 18.9 (CH.sub.2, C11), 14.8 (CH.sub.3, C22), 14.1 (CH.sub.3, C12).
Example 118: tert-Pentyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-190a)
[1357] ##STR00190##
[1358] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with tert-pentanol (1.5 eq, 451 μmol, 49 μL). The crude product was purified via column chromatography (35 mL SiO.sub.2, eluent CH/EA 10:1) and preparative HPLC (method B).
[1359] Yield: 67 mg (210 μmol, 70%) colorless solid
[1360] C.sub.17H.sub.21NO.sub.3S [319.42]
[1361] m.p.: 75° C.
[1362] R.sub.f: 0.84 (CH/EA 1:1)
[1363] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.94 (m, 3H, H5/15/19), 6.93 (d, J=8.7 Hz, 2H, H16/18), 4.08 (q, J=6.9 Hz, 2H, H21), 1.94 (q, J=7.4 Hz, 2H, H10), 1.59 (s, 6H, H12/13), 1.43 (t, J=6.9 Hz, 3H, H22), 0.98 (t, J=7.4 Hz, 3H, H11).
[1364] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.5 (C.sub.q, C2), 161.1 (C.sub.q, 06), 160.6 (C.sub.q, C17), 149.3 (C.sub.q, C4), 128.6 (2C, CH, C15/19), 125.9 (C.sub.q, C14), 125.3 (CH, C5), 114.8 (2C, CH, C16/18), 84.5 (C.sub.q, C9), 63.8 (CH.sub.2, C21), 33.9 (CH.sub.2, C10), 25.8 (2C, CH.sub.3, C12/13), 14.9 (CH.sub.3, C22), 8.5 (CH.sub.3, C11).
Example 119: 3-Methoxypropyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-213b)
[1365] ##STR00191##
[1366] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 3-methoxypropanol (1.5 eq, 451 μmol, 43 μL). The crude product was purified via column chromatography (35 mL SiO.sub.2, eluent CH/EA 10:1) and preparative HPLC (method B).
[1367] Yield: 67 mg (210 μmol, 70%) colorless solid
[1368] C.sub.15H.sub.19NO.sub.4S [321.39]
[1369] m.p.: 58° C.
[1370] R.sub.f: 0.60 (CH/EA 1:1)
[1371] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.07 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H15/19), 6.94 (d, J=8.8 Hz, 2H, H16/18), 4.46 (t, J=6.5 Hz, 2H, H9), 4.09 (q, J=7.0 Hz, 2H, H21), 3.54 (t, J=6.2 Hz, 2H, H11), 3.36 (s, 3H, H13), 2.12-1.98 (m, 2H, H10), 1.44 (t, J=7.0 Hz, 3H, H22).
[1372] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.6 (C.sub.q, C6), 161.2 (C.sub.q, C17), 147.8 (C.sub.q, C4), 128.7 (2C, CH, C15/19), 126.4 (CH, C5), 125.7 (C.sub.q, C14), 114.9 (2C, CH, C16/18), 69.3 (CH.sub.2, C11), 63.8 (CH.sub.2, C21), 62.7 (CH.sub.2, C9), 58.9 (CH.sub.3, C13), 29.2 (CH.sub.2, C10), 14.9 (CH.sub.3, C22).
Example 120: 2-Methylallyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AMU-18)
[1373] ##STR00192##
[1374] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with R-methylallyl alcohol (1.5 eq, 602 μmol, 50 μL). The crude product was purified via column chromatography (90 mL SiO.sub.2, eluent CH/EA 15:1).
[1375] Yield: 55 mg (181 μmol, 45%) colorless solid
[1376] C.sub.16H.sub.17NO.sub.3S [303.38]
[1377] m.p.: 88° C.
[1378] R.sub.f: 0.20 (CH/EA 15:1)
[1379] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H14/18), 6.94 (d, J=8.7 Hz, 2H, H15/17), 5.04 (d, J=30.6 Hz, 2H, H, H11), 4.80 (s, 2H, H9), 4.09 (q, J=6.9 Hz, 2H, H20), 1.84 (s, 3H, H12), 1.44 (t, J=6.9 Hz, 3H, H21).
[1380] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.2 (C.sub.q, C16), 147.6 (C.sub.q, C6), 139.86, 128.67, 126.5 (CH, C5), 125.7 (C.sub.q, C13), 114.9 (2C, CH.sub.2, C15/17), 113.4 (CH.sub.2, C11), 68.4 (CH.sub.2, C9), 63.8 (CH.sub.2, C20), 19.7 (CH.sub.3, C12), 14.9 (CH.sub.3, C21).
Example 121: (E)-but-2-en-1-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AMU-19)
[1381] ##STR00193##
[1382] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with crotyl alcohol (1.5 eq, 602 μmol, 51 μL). The crude product was purified via column chromatography (90 mL SiO.sub.2, eluent CH/EA 15:1).
[1383] Yield: 53 mg (170 μmol, 41%) colorless solid
[1384] C.sub.16H.sub.17NO.sub.3S [303.38]
[1385] m.p.: 73° C.
[1386] R.sub.f: 0.20 (CH/EA 15:1)
[1387] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H14/18), 6.94 (d, J=8.7 Hz, 2H, H15/17), 5.90 (dt, J=21.3, 6.4 Hz, 1H, H10), 5.82-5.63 (m, 1H, H11), 4.80 (d, J=6.4 Hz, 2H, H9), 4.08 (q, J=6.9 Hz, 2H, H20), 1.75 (d, J=6.1 Hz, 3H, H12), 1.44 (t, J=7.0 Hz, 3H, H21).
[1388] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.5 (C.sub.q, C6), 161.2 (C.sub.q, C16), 147.9 (C.sub.q, C4), 132.2 (CH, C10), 128.7 (2C, CH, C14/18), 126.5 (CH, C5), 125.7 (C.sub.q, C13), 125.1 (CH, C11), 114.9 (2C, CH, C15/17), 66.2 (CH.sub.2, C9), 63.8 (CH.sub.2, C20), 18.0 (CH.sub.3, C12), 14.9 (CH.sub.3, C21).
Example 122: Methyl 2-(4-ethoxyphenyl) thiazole-4-carboxylate (NP22c)
[1389] ##STR00194##
[1390] According to general procedure A, methyl 2-bromothiazole-4-carboxylate (1.0 eq., 0.45 mmol, 101 mg) was coupled with 4-ethoxyphenylboronic acid (0.9 eq, 0.47 μmol, 67 mg). The crude product was purified via column chromatography (32 mL SiO.sub.2, eluent CH/EA/DMC 8:1:1).
[1391] Yield: 60 mg (228 μmol, 50%) beige solid
[1392] C.sub.13H.sub.13NO.sub.3S [263.31]
[1393] m.p.: 70° C.
[1394] R.sub.f: 0.33 (CH/EA 4:1)
[1395] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.10 (s, 1H, C5), 7.93 (d, J=8.7 Hz, 2H, C11/15), 6.94 (d, J=8.7 Hz, 2H, C12/14), 4.09 (q, J=6.9 Hz, 2H, C17), 3.97 (s, 3H, C9), 1.44 (t, J=7.0 Hz, 3H, C18).
[1396] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 162.2 (C.sub.q, C6), 161.3 (C.sub.q, C13), 147.6 (C.sub.q, C4), 128.7 (C.sub.q, C10), 126.6 (2C, CH, C11/15), 125.6 (CH, C5), 114.9 (2C, CH, C12/14), 63.8 (CH.sub.2, C17), 52.6 (CH.sub.3, C9), 14.9 (CH.sub.3, C18).
Example 123: Isopropyl 2-(4-ethoxyphenyl) thiazole-4-carboxylate (NP22d)
[1397] ##STR00195##
[1398] According to general procedure A, isopropyl 2-bromothiazole-4-carboxylate (1.0 eq., 0.40 mmol, 100 mg) was coupled with 4-ethoxyphenylboronic acid (0.9 eq, 0.36 mmol, 60 mg). The crude product was purified via column chromatography (26 mL SiO.sub.2, eluent CH/EA/DMC 10:1:1).
[1399] Yield: 50 mg (172 μmol, 43%) yellowish solid
[1400] C.sub.15H.sub.17NO.sub.3S [291.37]
[1401] m.p.: 95° C.
[1402] R.sub.f: 0.38 (CH/EA 4:1)
[1403] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.04 (s, 1H, C5), 7.94 (d, J=8.7 Hz, 2H, C7/11), 6.94 (d, J=8.7 Hz, 2H, C-8/10), 5.38-5.20 (m, 1H, C18), 4.09 (q, J=6.9 Hz, 2H, C-13), 1.42 (m, 9H, C14/19/20).
[1404] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.8 (C.sub.q, C2), 161.2 (C.sub.q, C15), 161.2 (C.sub.q, C9), 148.4 (C.sub.q, C4), 128.7 (2C, CH, C7/11), 126.0 (CH, C5), 125.8 (C.sub.q, C6), 114.9 (2C, CH, C8/10), 69.1 (CH, C18), 63.8 (CH.sub.2, C13), 22.1 (2C, CH.sub.3, C19/20), 14.9 (CH.sub.3, C14) ppm.
Intermediate: Ethyl 2-diazo-3-oxobutanoate (AM-59)
[1405] ##STR00196##
[1406] In an inert 100 mL round bottom flask equipped with Schlenk adapter and magnetic stirring bar 4-acetamidobenzenesulfonylazide (1.1 eq, 6.34 mmol, 1.57 g) was dissolved in 40 mL MeCN abs and cooled to 0° C. Ethyl acetoacetate (1.0 eq., 5.76 mmol, 740 μL) was added via syringe. Et.sub.3N (3.0 eq, 17.3 mmol, 2.4 mL) was slowly added via syringe over 5 minutes. After further 10 minutes, the cooling bath was removed and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the solvent removed under reduced pressure. The solid residue was taken up in Et.sub.2O and triturated. It was filtered and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. It contained 20% sulfonamide.
[1407] Yield: 680 mg (impure, 3.49 mmol, 61%) yellow liquid
[1408] C.sub.6H.sub.8N.sub.2O.sub.3[156.05]
[1409] R.sub.f: 0.39 (CH/EA 4:1)
[1410] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 4.30 (q, J=7.1 Hz, 2H, H9), 2.48 (s, 3H, H1), 1.33 (t, J=7.1 Hz, 3H, H10).
[1411] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 190.4 (C.sub.q, C2), 161.6 (C.sub.q, C6), 61.6 (CH.sub.2, C9), 28.4 (CH.sub.3, C1), 14.5 (CH.sub.3, C10).
Intermediate: Ethyl 2-(4-ethoxy (AM-61)
[1412] ##STR00197##
[1413] In an inert 25 ml two-neck round-bottom-flask equipped with air condenser with gas inlet and bubbler and magnetic stirring bar 4-ethoxybenzamide (1.0 eq, 2.42 mmol, 400 mg) and Rh.sub.2(OAc).sub.4 (2.5 mol %, 58 μmol, 26 mg) were dissolved in 5 mL DCE and heated to reflux. A solution of AM-59 (1.44 eq, 3.48 mmol, 680 mg) in 2.5 mL DCE was added to the reaction mixture over a septum via syringe pump ((187.5 μL/h) under a flow of Ar. When the addition was completed, the reaction mixture was further stirred at reflux for 3 h. When full conversion was observed via TLC, the reaction mixture was cooled down to RT and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (100 mL SiO2, eluent CH/EA 4:1 to 3:1 to 2:1).
[1414] Yield: 443 mg (1.51 mmol, 62%) yellow oil
[1415] C.sub.15H.sub.19NO.sub.5 [293.13]
[1416] R.sub.f: 0.57 (CH/EA 1:1)
[1417] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.80 (d, J=8.7 Hz, 2H, H2/6), 7.20 (d, J=5.2 Hz, 1H, NH), 6.92 (d, J=8.7 Hz, 2H, H3/5), 5.41 (d, J=6.2 Hz, 1H, H11), 4.30 (q, J=7.1 Hz, 2H, H15), 4.08 (q, J=6.9 Hz, 2H, H8), 2.44 (s, 3H, H13), 1.43 (t, J=7.0 Hz, 3H, H9), 1.32 (t, J=7.1 Hz, 3H, H16).
[1418] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 199.0 (C.sub.q, C12), 166.5 (C.sub.q, C14), 166.4 (C.sub.q, C10), 162.3 (C.sub.q, C4), 129.3 (2C, CH, C2/6), 125.2 (C.sub.q, C1), 114.5 (2C, CH, C3/5), 63.8 (CH.sub.2, C8), 63.7 (CH, C11), 62.8 (CH.sub.2, C15), 28.3 (CH.sub.3, C13), 14.8 (CH.sub.3, C9), 14.2 (CH.sub.3, C16).
Example 124: Ethyl 2-(4-ethoxyphenyl)-5-methylthiazole-4-carboxylate (AM-62)
[1419] ##STR00198##
[1420] In an inert 100 mL Schlenk flask Lawesson's reagent (2.0 eq, 2.72 mmol, 1.1 g) and AM-61 (1.0 eq, 1.36 mmol, 400 mg) were dissolved in 10 mL THF abs and heated to reflux. When full conversion was observed via TLC after 3 h, the reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (100 mL SiO.sub.2, eluent CH/EA 9:1).
[1421] Yield: 232 mg (797 μmol, 58%) yellowish solid
[1422] C.sub.15H.sub.17NO.sub.3S [291.09]
[1423] m.p. 78° C.
[1424] R.sub.f: 0.50 (CH/EA 4:1)
[1425] HR-MS [EI, M.sup.+]: calcd. 291.0929, found 291.0920.
[1426] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 7.85 (d, J=8.8 Hz, 2H, H13/17), 6.92 (d, J=8.8 Hz, 2H, H14/16), 4.43 (q, J=7.1 Hz, 2H, H9), 4.08 (q, J=6.9 Hz, 2H, H19), 2.78 (s, 3H, H11), 1.43 (t, J=7.0 Hz, 6H, H10/20).
[1427] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 163.9 (C.sub.q, C2), 162.9 (C.sub.q, C6), 160.9 (C.sub.q, C15), 143.7 (C.sub.q, C4), 142.1 (C.sub.q, C5), 128.3 (C.sub.q, C12), 125.9 (2C, CH, C13/17), 114.8 (2C, CH, C14/16), 63.8 (CH.sub.2, C19), 61.2 (CH.sub.2, C9), 14.9 (CH.sub.3, C20), 14.5 (CH.sub.3, C10), 13.4 (CH.sub.3, C11).
Intermediate: Ethyl 2-bromo-5-chlorothiazole-4-carboxylate (AM-2-135)
[1428] ##STR00199##
[1429] In an inert 100 mL Schlenk flask CuBr.sub.2 (1.2 eq., 11.85 mmol, 2.65 g) was dried in vacuum for 1 h. AM-1-133 (1.0 eq, 9.87 mmol, 2.4 g) was added and dissolved in MeCN abs (70 mL). The reaction mixture was heated to 60° C. .sup.tBuONO (1.5 eq., 14.81 mmol, 2.0 mL) was added dropwise over septum via syringe, upon addition gas evolution was observed. Full conversion was observed via TLC and GC-MS after 30 min and the reaction mixture was cooled down to RT. It was diluted with 100 mL DCM and quenched via addition of 100 mL HCl 1 M. The phases were separated and the aqueous phase was extracted with DCM (2×100 mL). The combined organic phases were washed with Brine (1×100 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via filtration over a pad of silica (eluent DCM/EA 19:1).
[1430] Yield: 2.23 g (8.24 mmol, 84%) brownish solid
[1431] C.sub.6H.sub.5BrClNO.sub.2S [270.53]
[1432] m.p.: 63° C.
[1433] R.sub.f: 0.62 (CH/EA 4:1)
[1434] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 4.43 (q, J=7.1 Hz, 2H, H9), 1.40 (t, J=7.1 Hz, 3H, H10).
[1435] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 159.5 (C.sub.q, C6), 141.6 (C.sub.q, C2), 132.7 (C.sub.q, C5), 62.2 (CH.sub.2, C9), 14.4 (CH.sub.3, C10).
Example 125: Ethyl 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-2-137)
[1436] ##STR00200##
[1437] According to General Procedure A, AM-2-135 (1.0 eq, 1.85 mmol, 500 mg) was coupled with 4-ethoxyphenylboronic acid (1.0 eq., 1.85 mmol, 307 mg). The crude product was purified column chromatography (120 mL SiO.sub.2, eluent CH/EA 12:1).
[1438] Yield: 287 mg (0.92 mmol, 50%) colorless solid
[1439] C.sub.14H.sub.14ClNO.sub.3S [311.78]
[1440] m.p. 91° C.
[1441] R.sub.f: 0.50 (CH/EA 4:1)
[1442] HR-MS [EI, M.sup.+]: calcd. 311.0383, found 311.0380.
[1443] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.81 (d, J=8.7 Hz, 2H, H12/16), 6.93 (d, J=8.7 Hz, 2H, H13/15), 4.45 (q, J=7.1 Hz, 2H, H9), 4.08 (q, J=6.9 Hz, 2H, H18), 1.44 (t, J=7.0 Hz, 6H, H10/19).
[1444] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 164.7 (C.sub.q, C2), 161.5 (C.sub.q, C6), 161.1 (C.sub.q, C14), 141.8 (C.sub.q, C4), 133.0 (C.sub.q, C5), 128.3 (2C, CH, C12/16), 125.2 (C.sub.q, C11), 115.0 (2C, CH, C13/15), 63.9 (CH.sub.2, C18), 61.8 (CH.sub.2, C9), 14.8 (CH.sub.3, C19), 14.4 (CH.sub.3, C10).
Example 126: Ethyl 2-(4-ethoxyphenyl)-5-methoxythiazole-4-carboxylate (AM-2-139)
[1445] ##STR00201##
[1446] In an inert Schienk flask Na (4.3 eq., 2.74 mmol, 63 mg) was dissolved in 7 mL MeOH abs. The solution was cooled down to 0° C. and AM-2-137 (1.0 eq, 641 μmol, 200 mg) was added. The reaction was stirred at RT, and after no conversion was observed after 1 h, it was further stirred at 55° C. After 21 h the reaction was quenched via the addition of water. The aqueous phase was neutralized and extracted with DCM (2×15 mL). The combined organic phase was washed with Brine (1×20 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The flask containing the intermediate product was equipped with Schienk adapter and stirring bar and evacuated and backfilled with N.sub.2 for three times. The intermediate was dissolved in 7 mL EtOH abs and Ti(O.sup.iPr).sub.4 was added via syringe (0.1 eq., 64 μmol, 20 μL). The reaction mixture was stirred at 90° C. overnight. When full conversion was observed via TLC, the reaction was cooled down to RT and quenched via the addition of NH.sub.4Cl sat. It was extracted with EA (3×15 mL). The combined organic phases were washed with NaHCO.sub.3 sat (1×15 mL) and Brine (1×15 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via preparative HPLC (method D).
[1447] Yield: 59 mg (192 μmol, 30%) colorless solid
[1448] C.sub.15H.sub.17NO.sub.4S [307.09]
[1449] m.p. 120° C.
[1450] R.sub.f: 0.36 (CH/EA 4:1)
[1451] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.77 (d, J=8.8 Hz, 2H, H12/16), 6.91 (d, J=8.7 Hz, 2H, H13/15), 4.41 (q, J=7.1 Hz, 2H, H9), 4.13 (s, 3H, H21), 4.07 (q, J=7.0 Hz, 2H, H18), 1.42 (m, 6H, H10/19).
[1452] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.2 (C.sub.q, C2), 161.9 (C.sub.q, C6), 160.7 (C.sub.q, C14), 152.8 (C.sub.q, C4), 127.7 (2C, CH, C12/16), 126.7 (C.sub.q, C5), 126.1 (C.sub.q, C11), 114.8 (2C, CH, C13/15), 64.7 (CH.sub.3, C21), 63.8 (CH.sub.2, C18), 61.0 (CH.sub.2, C9), 14.9 (CH.sub.3, C19), 14.6 (CH.sub.3, C10).
Example 127: Cyclopentyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-2-179)
[1453] ##STR00202##
[1454] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with cyclopentanol (1.5 eq, 602 μmol, 50 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA/DCM 15:1:1).
[1455] Yield: 49 mg (154 μmol, 39%) colorless crystals
[1456] C.sub.17H.sub.19NO.sub.3S [317.40]
[1457] R.sub.f: 0.82 (CH/EA 1:1)
[1458] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.00 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H9/13), 6.94 (d, J=8.7 Hz, 2H, H10/12), 5.52-5.33 (m, 1H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 2.08-1.65 (m, 8H, H19/20/21/22), 1.44 (t, J=6.9 Hz, 3H, H16).
[1459] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.8 (C.sub.q, C2), 161.4 (C.sub.q, C6), 161.2 (C.sub.q, C11), 148.4 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 125.9 (CH, C5), 125.8 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 78.3 (CH, C18), 63.8 (CH.sub.2, C15), 32.9 (2C, CH.sub.2, C19/22), 24.0 (2C, CH.sub.2, C20/21), 14.9 (CH.sub.3, C16).
Example 128: 1,1,1,3,3,3-Hexafluoropropan-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-2-180a)
[1460] ##STR00203##
[1461] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 1,1,1,3,3,3-hexafluoropropan-2-ol (1.5 eq, 451 μmol, 47 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA/DCM 18:1:1) and preparative HPLC (method E).
[1462] Yield: 43 mg (154 μmol, 36%) colorless powder
[1463] C.sub.15H.sub.11F.sub.6NO.sub.3S [399.31]
[1464] m.p.: 113° C.
[1465] R.sub.f: 0.88 (CH/EA 1:1)
[1466] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.28 (s, 1H, H5), 7.95 (d, J=8.7 Hz, 2H, H9/13), 6.96 (d, J=8.6 Hz, 2H, H10/12), 6.04 (q, J=5.9 Hz, 1H, H18), 4.10 (q, J=6.9 Hz, 2H, H15), 1.45 (t, J=6.9 Hz, 3H, H16).
[1467] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 170.0 (C.sub.q, C2), 161.6 (C.sub.q, C11), 157.7 (C.sub.q, C6), 144.1 (C.sub.q, C4), 129.8 (CH, C5), 128.8 (2C, CH, C9/13), 125.2 (C.sub.q, C8), 115.1 (2C, CH, C10/12), 67.1 (CH, C18), 63.9 (CH.sub.2, C15), 14.9 (CH.sub.3, C16).
Example 129: Cyclobutyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-183a)
[1468] ##STR00204##
[1469] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with cyclobutanol (1.5 eq, 451 μmol, 35 μL). The crude product was purified via column chromatography (40 mL SiO.sub.2, eluent CH/EA/DCM 10:1:1) and preparative HPLC (method B).
[1470] Yield: 63 mg (208 μmol, 69%) off-white solid
[1471] C.sub.16H.sub.17NO.sub.3S [303.38]
[1472] m.p.: 115° C.
[1473] R.sub.f: 0.83 (CH/EA 1:1)
[1474] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.07 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H9/13), 6.94 (d, J=8.7 Hz, 2H, H10/12), 5.33-5.15 (m, 1H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 2.56-2.37 (m, 2H, H19/21), 2.36-2.18 (m, 2H, H19/21), 1.86 (dd, J=20.1, 10.0 Hz, 1H, H20), 1.70 (m, 1H, H20), 1.44 (t, J=6.9 Hz, 3H, H16).
[1475] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.9 (C.sub.q, C2), 161.2 (C.sub.q, C11), 161.0 (C.sub.q, C6), 147.9 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 126.3 (CH, C5), 125.7 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 70.0 (CH, C18), 63.8 (CH.sub.2, C15), 30.6 (2C, CH.sub.2, C19/21), 14.9 (CH.sub.2, C16), 13.7 (CH.sub.2, C20).
Example 130: Tetrahydrofuran-3-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-187a)
[1476] ##STR00205##
[1477] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 3-tetrahydrofuranol (1.5 eq, 451 μmol, 36 μL). The crude product was purified via column chromatography (30 mL SiO.sub.2, eluent CH/EA/2.5:1).
[1478] Yield: 74 mg (221 μmol, 77%) colorless solid
[1479] C.sub.16H.sub.17NO.sub.4S [319.38]
[1480] m.p.: 130° C.
[1481] R.sub.f: 0.51 (CH/EA 1:1)
[1482] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.06 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H9/13), 6.94 (d, J=8.7 Hz, 2H, H10/12), 5.57 (d, J=2.3 Hz, 1H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 4.05-3.97 (m, 3H, H20/22), 3.91 (m, 1H, H20), 2.41-2.15 (m, 2H, H19), 1.44 (t, J=6.9 Hz, 3H, H16).
[1483] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 169.1 (C.sub.q, C2), 161.3 (2C, C.sub.q, C6/11), 147.5 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 126.7 (CH, C5), 125.6 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 76.0 (CH, C18), 73.2 (CH.sub.2, C22), 67.3 (CH.sub.2, C20), 63.8 (CH.sub.2, C15), 33.0 (CH.sub.2, C19), 14.9 (CH.sub.3, C16).
Example 131: Pentan-3-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-187b)
[1484] ##STR00206##
[1485] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 3-pentanol (1.5 eq, 451 μmol, 49 μL). The crude product was purified via column chromatography (30 mL SiO.sub.2, eluent CH/EA/10:1).
[1486] Yield: 83 mg (260 μmol, 86%) colorless solid
[1487] C.sub.17H.sub.21NO.sub.3S [319.42]
[1488] m.p.: 55° C.
[1489] R.sub.f: 0.84 (CH/EA 1:1)
[1490] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.03 (s, 1H, H5), 7.95 (d, J=8.7 Hz, 2H, H9/13), 6.94 (d, J=8.7 Hz, 2H, H10/12), 5.10-4.99 (m, 1H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 1.79-1.65 (m, 4H, H19/21), 1.44 (t, J=6.9 Hz, 3H, H16), 0.96 (t, J=7.4 Hz, 6H, H20/21).
[1491] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.8 (C.sub.q, C2), 161.5 (C.sub.q, C11), 161.2 (C.sub.q, C6), 148.3 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 125.8 (C.sub.q, C8), 125.8 (CH, C5), 114.9 (2C, CH, C10/12), 78.0 (CH, 18), 63.8 (CH.sub.2, C15), 26.7 (2C, CH.sub.2, C19/21), 14.9 (CH.sub.3, C16), 9.9 (2C, CH.sub.3, C20/22).
Example 132: Phenyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-188a)
[1492] ##STR00207##
[1493] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with phenol (1.5 eq, 451 μmol, 42 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA/10:1) and preparative HPLC (method B).
[1494] Yield: 66 mg (203 μmol, 67%) colorless solid
[1495] C.sub.18H.sub.15NO.sub.3S [325.38]
[1496] m.p.: 100° C.
[1497] R.sub.f: 0.32 (CH/EA 4:1)
[1498] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ 8.75 (s, 1H, H5), 7.93 (d, J=8.6 Hz, 2H, H9/13), 7.47 (t, J=7.7 Hz, 2H, H20/22), 7.30 (t, J=9.1 Hz, 3H, H19/21/23), 7.05 (d, J=8.7 Hz, 2H, H10/12), 4.09 (q, J=6.9 Hz, 2H, H15), 1.33 (t, J=6.9 Hz, 3H, H16).
[1499] .sup.13C-NMR (75.5 MHz, DMSO-d.sub.6): δ 168.0 (C.sub.q, C2), 160.7 (C.sub.q, C11), 159.2 (C.sub.q, C6), 150.3 (C.sub.q, C18), 145.7 (C.sub.q, C4), 130.2 (CH, C5), 129.6 (2C, CH, C20/22), 128.2 (2C, CH, C9/13), 126.1 (CH, C21), 124.9 (C.sub.q, C8), 121.9 (2C, CH, C19/23), 115.1 (2C, CH, C10/12), 63.5 (CH.sub.2, C15), 14.5 (CH.sub.3, C16).
Example 133: Cyclohexyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-188b)
[1500] ##STR00208##
[1501] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with phenol (1.5 eq, 451 μmol, 48 μL). The crude product was purified via column chromatography (35 mL SiO.sub.2, eluent CH/EA/10:1).
[1502] Yield: 89 mg (269 μmol, 89%) colorless solid
[1503] C.sub.18H.sub.21NO.sub.3S [331.43]
[1504] m.p.: 128° C.
[1505] R.sub.f: 0.38 (CH/EA 4:1)
[1506] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.03 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H9/13), 6.94 (d, J=8.7 Hz, 2H, H10/12), 5.12-4.97 (m, 1H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 1.98 (s, 2H, H19/23), 1.78 (s, 2H, H20/22), 1.60 (m, 3H, H19/21/23), 1.45 (m, 5H, H18/20/22), 1.34-1.22 (m, 1H, H21).
[1507] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.8 (C.sub.q, C2), 161.2 (C.sub.q, C11), 161.0 (C.sub.q, C6), 148.4 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 125.9 (CH, C5), 125.8 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 73.9 (CH, C18), 63.8 (CH.sub.2, C15), 31.8 (2C, CH.sub.2, C19/23), 25.6 (CH.sub.2, C21), 24.0 (2C, CH.sub.2, C20/22), 14.9 (CH.sub.3, C16).
Example 134: (Tetrahydrofuran-2-yl)methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-190b)
[1508] ##STR00209##
[1509] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with tetrahydrofurfurylalcohol (1.5 eq, 451 μmol, 43 μL). The crude product was purified via column chromatography (35 mL SiO.sub.2, eluent CH/EA 2.4:1).
[1510] Yield: 65 mg (195 μmol, 68%) colorless solid
[1511] C.sub.17H.sub.19NO.sub.4S [333.40]
[1512] m.p.: 75° C.
[1513] R.sub.f: 0.56 (CH/EA 1:1)
[1514] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.10 (s, 1H, H5), 7.93 (d, J=8.6 Hz, 2H, H9/13), 6.93 (d, J=8.6 Hz, 2H, H10/12), 4.41 (t, J=7.0 Hz, 1H, H18), 4.36-4.23 (m, 2H, H18/19), 4.08 (q, J=6.9 Hz, 2H, H15)), 3.94 (dd, J=14.6, 6.9 Hz, 1H, H22), 3.83 (dd, J=14.1, 7.3 Hz, 1H, H22), 2.14-1.86 (m, 3H, H10/21), 1.79-1.65 (m, J=10.5, 6.9 Hz, 1H, H20), 1.43 (t, J=6.9 Hz, 3H, H16).
[1515] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.9 (C.sub.q, C2), 161.5 (C.sub.q, C11), 161.2 (C.sub.q, C6), 147.5 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 126.7 (CH, C5), 125.7 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 76.6 (CH.sub.2, C22), 68.6 (CH.sub.2, C18), 67.3 (CH.sub.2, C15), 63.8 (CH.sub.2, C15), 28.3 (CH.sub.2, C20), 25.8 (CH.sub.2, C21), 14.9 (CH.sub.3, C16).
Example 135: 1,3-Difluoropropan-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-210)
[1516] ##STR00210##
[1517] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 297 μmol, 74 mg) was esterified with 1,3-difluoropropan-2-ol (1.5 eq, 445 μmol, 35 μL). The crude product was purified via column chromatography (30 mL SiO.sub.2, eluent CH/EA 6:1).
[1518] Yield: 88 mg (269 μmol, 90%) colorless solid
[1519] C.sub.15H.sub.15F.sub.2NO.sub.3S [327.35]
[1520] m.p.: 120° C.
[1521] R.sub.f: 0.68 (CH/EA 1:1)
[1522] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.15 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H9/13), 6.95 (d, J=8.7 Hz, 2H, H10/12), 5.61-5.35 (m, 1H, H18), 4.83 (d, J=4.4 Hz, 2H, H19), 4.67 (d, J=3.7 Hz, 2H, H21), 4.09 (q, J=6.9 Hz, 2H, H15), 1.44 (t, J=7.0 Hz, 3H, H16).
[1523] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 169.3 (C.sub.q, C2), 161.3 (C.sub.q, C11), 160.5 (C.sub.q, C6), 146.6 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.6 (CH, C5), 125.5 (C.sub.q, C8), 115.0 (2C, CH, C10/12), 81.5 (d, CH.sub.2, C21), 79.2 (d, CH.sub.2, C19), 71.3 (t, CH, C18), 63.9 (CH.sub.2, C15), 14.9 (CH.sub.3, C16).
Example 13 Cyclopropylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-213a)
[1524] ##STR00211##
[1525] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 1,3-difluoropropan-2-ol (1.5 eq, 451 μmol, 37 μL). The crude product was purified via column chromatography (40 mL SiO.sub.2, eluent CH/EA 12:1).
[1526] Yield: 65 mg (214 μmol, 71%) colorless solid
[1527] C.sub.16H.sub.17NO.sub.3S [303.38]
[1528] m.p.: 110° C.
[1529] R.sub.f: 0.81 (CH/EA 1:1)
[1530] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.10 (s, 1H, H5), 7.94 (d, J=8.8 Hz, 2H, H9/13), 6.94 (d, J=8.8 Hz, 2H, H10/12), 4.21 (d, J=7.3 Hz, 2H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 1.44 (t, J=7.0 Hz, 3H, H16), 1.35-1.20 (m, 1H, H19), 0.70-0.52 (m, 2H, H20/21), 0.52-0.29 (m, 2H, H20/21).
[1531] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 169.0 (C.sub.q, C2), 161.8 (C.sub.q, C11), 161.2 (C.sub.q, C6), 148.0 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 126.4 (CH, C5), 125.8 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 70.3 (CH.sub.2, C18), 63.8 (CH.sub.2, C15), 14.9 (CH.sub.3, C16), 10.1 (CH, C19), 3.6 (2C, CH.sub.2, C20/21).
Example 137: 1,1,1-Trifluoro-3-methylbutan-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-220a)
[1532] ##STR00212##
[1533] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 1,1,1,-trifluoro-3-methylbutan-2-ol (1.5 eq, 602 μmol, 75 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 12:1).
[1534] Yield: 93 mg (249 μmol, 62%) colorless solid
[1535] C.sub.17H.sub.18F.sub.3NO.sub.3S [373.39]
[1536] R.sub.f: 0.47 (CH/EA 4:1)
[1537] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.15 (s, 1H, H5), 7.95 (d, J=8.7 Hz, 2H, H9/13), 6.95 (d, J=8.7 Hz, 2H, H10/12), 5.42 (dt, J=14.1, 7.2 Hz, 1H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 2.31 (td, J=13.1, 6.5 Hz, 1H, H19), 1.44 (t, J=6.9 Hz, 3H, H16), 1.10 (d, J=6.5 Hz, 6H, H21/22).
[1538] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 169.4 (C.sub.q, C2), 161.4 (C.sub.q, C11), 159.8 (C.sub.q, C6), 146.2 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.6 (CH, C5), 125.5 (C.sub.q, C8), 115.0 (2C, CH, C10/12), 74.1 (q, CH, C18), 63.9 (CH.sub.2, C15), 28.2 (CH, C19), 19.2 (CH.sub.3, C21), 17.6 (CH.sub.3, C22), 14.9 (CH.sub.3, C16).
Example 138: 3-(Methylamino)propyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate hydrochloride (AM-3-238)
[1539] ##STR00213##
[1540] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 482 μmol, 120 mg) was esterified with tert-butyl (3-hydroxypropylxmethyl)carbamate (1.5 eq, 722 μmol, 102 μL). The crude product was purified via column chromatography (60 mL SiO.sub.2, eluent CH/EA 3:1). An inert Schienk flask was charged with the Boc-protected product and 1.0 mL HCl 4 M in dioxane was added. The reaction was stirred at RT overnight, when a colorless precipitate formed. The precipitate was collected by filtration and washed with EA. No further purification was necessary.
[1541] Yield: 101 mg (283 μmol, 59%) colorless solid
[1542] C.sub.18H.sub.20N.sub.2O.sub.3S*HCl [356.87]
[1543] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ 8.94 (bs, 2H, NH.sub.2), 8.55 (s, 1H, H5), 7.88 (d, J=8.6 Hz, 2H, H9/13), 7.04 (d, J=8.7 Hz, 2H, H10/12), 4.33 (t, J=5.9 Hz, 2H, H18), 4.08 (t, J=6.8 Hz, 2H, H15), 3.01 (s, 2H, H, H20), 2.53 (s, 3H, H22), 2.13-1.98 (m, 2H, H19), 1.32 (t, J=6.9 Hz, 3H, H16).
[1544] .sup.13C-NMR (75.5 MHz, DMSO-d.sub.6): δ 167.7 (C.sub.q, C2), 160.6 (C.sub.q, C11), 160.5 (C.sub.q, C6), 146.5 (C.sub.q, C4), 128.6 (CH, C5), 128.1 (2C, CH, C9/13), 124.9 (C.sub.q, C8), 115.1 (2C, CH, C10/12), 63.4 (CH.sub.2, C15), 62.0 (CH.sub.2, C18), 45.5 (CH.sub.2, C20), 32.4 (CH.sub.3, C22), 24.9 (CH.sub.2, C19), 14.5 (CH.sub.3, C16).
Example 139: (1S,2R)-2-Methylcyclopentyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-239e)
[1545] ##STR00214##
[1546] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with trans-2-methylcyclopentan-2-ol (1.5 eq, 451 μmol, 49 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 7.5:1) and preparative HPLC (method E).
[1547] Yield: 55 mg (166 μmol, 55%) colorless solid
[1548] C.sub.18H.sub.21NO.sub.3S [331.43]
[1549] m.p.: 50° C.
[1550] R.sub.f: 0.84 (CH/EA 1:1)
[1551] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.01 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H9/13), 6.93 (d, J=8.8 Hz, 2H, H10/12), 5.06-4.87 (m, 1H, H18), 4.07 (q, J=6.9 Hz, 2H, H15), 2.29-2.05 (m, 2H, H22, H21), 2.05-1.91 (m, 1H, H19), 1.85-1.64 (m, 3H, H20/21), 1.43 (t, J=7.0 Hz, 3H, H16), 1.27 (dt, J=12.5, 7.6 Hz, 1H, H19), 1.07 (d, J=6.9 Hz, 3H, H23).
[1552] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.8 (C.sub.q, C2), 161.6 (C.sub.q, C11), 161.1 (C.sub.q, C6), 148.3 (C.sub.q, C4), 128.6 (2C, CH, C9/13), 125.9 (CH, C5), 125.8 (C.sub.q, C8), 114.8 (2C, CH, C10/12), 83.8 (CH, C18), 63.8 (CH.sub.2, C15), 40.2 (CH, C11), 32.1 (CH.sub.2, C19), 31.6 (CH.sub.2, C13), 22.7 (CH.sub.2, C20), 18.4 (CH.sub.3, C23), 14.8 (CH.sub.3, C16).
Example 140: 2,3-Dihydro-1H-Inden-1-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-240b)
[1553] ##STR00215##
[1554] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with 2,3-dihydro-1H-inden-1-ol (1.5 eq, 451 μmol, 61 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 9:1).
[1555] Yield: 95 mg (266 μmol, 86%) colorless solid
[1556] C.sub.21H.sub.19NO.sub.3S [365.45]
[1557] m.p.: 90° C.
[1558] R.sub.f: 0.38 (CH/EA 4:1)
[1559] .sup.1H-NMR (300 MHz, CD.sub.3CN): δ 8.12 (s, 1H, H5), 7.84 (d, J=8.8 Hz, 2H, H9/13), 7.47 (d, J=7.3 Hz, 1H, H23), 7.38-7.16 (m, 3H, H24/25/26), 6.96 (d, J=8.8 Hz, 2H, H10/12), 6.39 (dd, J=6.8, 3.6 Hz, 1H, H18), 4.06 (q, J=6.9 Hz, 2H, H15), 3.21-3.05 (m, 1H, H22), 2.98-2.85 (m, 1H, H22), 2.64-2.48 (m, 1H, H21), 2.28-2.14 (m, 1H, H21), 1.35 (t, J=7.0 Hz, 3H, H16).
[1560] .sup.13C-NMR (75.5 MHz, CD.sub.3CN): δ 169.3 (C.sub.q, C2), 162.1 (C.sub.q, C11), 162.1 (C.sub.q, C6), 148.6 (C.sub.q, C4), 145.8 (C.sub.q, C20), 142.0 (C.sub.q, C19), 130.1 (CH, C26), 129.1 (2C, CH, C9/13), 128.2 (CH, C25), 127.67, 126.6 (CH, C23), 126.5 (C.sub.q, C8), 125.9 (CH, C24), 115.9 (2C, CH, C10/12), 80.1 (CH, C18), 64.7 (CH.sub.2, C15), 33.0 (CH.sub.2, C21), 30.8 (CH.sub.2, C22), 15.0 (CH.sub.3, C16).
Example 141: Benzo[d][1,3]dixol-5-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-241a)
[1561] ##STR00216##
[1562] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 321 μmol, 80 mg) was esterified benzo[d][1,3]dioxol-5-ylmethanol (1.5 eq, 481 μmol, 73 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 6:1).
[1563] Yield: 78 mg (203 μmol, 63%) colorless solid
[1564] C.sub.20H.sub.17NO.sub.5S [383.42]
[1565] m.p.: 105° C.
[1566] R.sub.f: 0.78 (CH/EA 1:1)
[1567] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.08 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H9/13), 7.04-6.87 (m, 4H, H10/12/21/24), 6.80 (d, J=7.8 Hz, 1H, H20), 5.97 (s, 2H, H26), 5.31 (s, 2H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 1.44 (t, J=6.9 Hz, 3H, H16).
[1568] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 169.0 (C.sub.q, C2), 161.5 (C.sub.q, C11), 161.2 (C.sub.q, C6), 148.0 (C.sub.q, C23), 147.9 (C.sub.q, C4), 147.6 (C.sub.q, C22), 129.7 (C.sub.q, C19), 128.7 (2C, CH, C9/13), 126.7 (CH, C5), 125.7 (C.sub.q, C8), 122.8 (CH, C24), 114.9 (2C, CH, C10/12), 109.5 (CH, C21), 108.4 (CH, C20), 101.3 (CH.sub.2, C26), 67.1 (CH.sub.2, C18), 63.8 (CH.sub.2, C15), 14.9 (CH.sub.3, C16).
Example 142: 4-Acetoxybenzyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-241b)
[1569] ##STR00217##
[1570] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 321 μmol, 80 mg) was esterified with 4-(hydroxymethyl)phenyl acetate (1.5 eq, 481 μmol, 80 mg). The crude product was purified three times via column chromatography (50 mL SiO.sub.2, eluent CH/EA 5:1, 25 mL SiO.sub.2, eluent toluene/EA 8:1, 20 mL SiO.sub.2, eluent toluene/EA 10:1).
[1571] Yield: 46 mg (116 μmol, 36%) colorless solid
[1572] C.sub.21H.sub.19NO.sub.5S [397.45]
[1573] m.p.: 102° C.
[1574] R.sub.f: 0.71 (CH/EA 1:1)
[1575] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.09 (s, 1H, H5), 7.93 (d, J=8.7 Hz, 2H, H9/13), 7.50 (d, J=8.4 Hz, 2H, H21/23), 7.11 (d, J=8.4 Hz, 2H, H20/24), 6.94 (d, J=8.7 Hz, 2H, H10/12), 5.39 (s, 2H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 2.30 (s, J=14.6 Hz, 3H, H27), 1.44 (t, J=6.9 Hz, 3H, H16).
[1576] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 169.5 (C.sub.q, C2), 169.1 (C.sub.q, C26), 161.4 (C.sub.q, C11), 161.2 (C.sub.q, C6), 150.8 (C.sub.q, C22), 147.5 (C.sub.q, C4), 133.5 (C.sub.q, C19), 130.0 (2C, CH, C21/23), 128.7 (2C, CH, C9/13), 126.8 (CH, C5), 125.7 (C.sub.q, C8), 121.9 (2C, CH, C20/24), 114.9 (2C, CH, C10/12), 66.4 CH.sub.2, C18), 63.8 (CH.sub.2, C15), 21.3 (CH.sub.3, C27), 14.9 (CH.sub.3, C16).
Example 143: 3-Methylbut-2-en-1-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-4-254)
[1577] ##STR00218##
[1578] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 389 μmol, 97 mg) was esterified with prenol (1.5 eq, 584 μmol, 59 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 6:1).
[1579] Yield: 109 mg (343 μmol, 88%) colorless solid
[1580] C.sub.17H.sub.19NO.sub.3S [317.40]
[1581] m.p.: 56° C.
[1582] R.sub.f: 0.39 (CH/EA 4:1)
[1583] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.07 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.49 (t, J=7.1 Hz, 1H), 4.87 (d, J=7.1 Hz, 2H), 4.08 (q, J=6.9 Hz, 2H), 1.78 (s, J=31.7 Hz, 6H), 1.44 (t, J=7.0 Hz, 3H).
[1584] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.9, 161.7, 161.2, 147.99, 139.5, 128.7, 126.3, 125.8, 118.7, 114.9, 63.8, 62.4, 26.0, 18.3, 14.9.
Example 144: 1-(Thiophen-2-yl)ethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-4-287)
[1585] ##STR00219##
[1586] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 1-(thiophen-2-yl)ethan-1-ol (1.5 eq, 602 μmol, 124 mg). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 9:1). The product was dissolved in acetonitrile, washed with pentane and evaporated to dryness.
[1587] Yield: 45 mg (125 μmol, 31%) colorless solid
[1588] C.sub.18H.sub.17NO.sub.3S.sub.2[359.46]
[1589] R.sub.f: 0.36 (CH/EA 4:1)
[1590] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.03 (d, J=16.2 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H), 7.29 (d, J=4.9 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 7.08-6.82 (m, 3H), 6.46 (q, J=6.4 Hz, 1H), 4.08 (q, J=6.9 Hz, 2H), 1.81 (d, J=6.5 Hz, 3H), 1.44 (t, J=6.9 Hz, 3H).
[1591] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.9, 161.2, 160.6, 147.7, 144.2, 128.6, 126.7, 126.6, 125.8, 125.7, 125.5, 114.84, 68.7, 63.8, 22.2, 14.8.
Example 145: 1-Morpholinopropan-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AMU-10)
[1592] ##STR00220##
[1593] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 1-(4-morpholinyl)-2-propanol (1.5 eq, 602 μmol, 86 μL). The crude product was purified via column chromatography (110 mL SiO.sub.2, eluent CH/EA 1:1).
[1594] Yield: 98 mg (261 μmol, 65%) brownish oil
[1595] C.sub.19H.sub.24N.sub.2O.sub.4S [376.15]
[1596] R.sub.f: 0.30 (CH/EA 1:1)
[1597] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.04 (s, 1H), 7.93 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 5.47-5.31 (m, 1H), 4.09 (q, J=6.9 Hz, 2H), 3.67 (t, J=4.5 Hz, 4H), 2.71 (dd, J=13.1, 7.4 Hz, 1H), 2.64-2.42 (m, 5H), 1.49-1.34 (m, 6H).
[1598] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.9, 161.2, 161.1, 148.2, 128.6, 126.1, 125.8, 114.90, 69.3, 67.2, 63.8, 63.5, 54.3, 18.7, 14.9.
Example 146: 1,3-Bis(methylthio)propan-2-yl-2-(4-ethoxyphenyl)thiazole-4-carboxylate (AMU-14)
[1599] ##STR00221##
[1600] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 1,3-bis(methylthio)-2-propanol (1.5 eq, 602 μmol, 96 mg). The crude product was purified via column chromatography (55 mL SiO.sub.2, eluent toluene/EA 30:1).
[1601] Yield: 90 mg (235 μmol, 59%) colorless solid
[1602] C.sub.17H.sub.21NO.sub.3S.sub.3 [383.07]
[1603] m.p.: 63-65° C.
[1604] R.sub.f: 0.28 (toluene/EA 30:1)
[1605] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.08 (s, 1H), 7.93 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 5.58-5.05 (m, 1H), 4.09 (q, J=6.9 Hz, 2H), 3.10-2.77 (m, 4H), 2.23 (s, 6H), 1.44 (t, J=6.9 Hz, 3H).
[1606] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 169.0, 161.3, 161.0, 147.4, 128.6, 126.8, 125.7, 114.93, 73.2, 63.8, 36.9, 16.6, 14.9.
Example 147: Allyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AMU-21)
[1607] ##STR00222##
[1608] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with allylalcohol (1.5 eq, 602 μmol, 41 μL). The crude product was purified via column chromatography (65 mL SiO.sub.2, eluent CH/EA 15:1).
[1609] Yield: 31 mg (107 μmol, 26%) colorless solid
[1610] C.sub.15H.sub.15NO.sub.3S [289.35]
[1611] m.p.: 102° C.
[1612] R.sub.f: 0.21 (CH/EA 15:1)
[1613] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.10 (s, 1H), 7.94 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.13-6.00 (m, J=22.8, 11.0, 5.8 Hz, 1H), 5.37 (dd, J=37.5, 13.7 Hz, 2H), 4.87 (d, J=5.6 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H).
[1614] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): 169.0, 161.3, 161.2, 147.6, 132.1, 128.7, 126.6, 125.7, 119.0, 114.9, 66.1, 63.8, 14.9.
Example 148: But-3-en-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AMU-28)
[1615] ##STR00223##
[1616] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 2-buten-2-ol (1.5 eq, 602 μmol, 50 μL). The crude product was purified via column chromatography (60 mL SiO.sub.2, eluent CH/EA 10:1).
[1617] Yield: 56 mg (185 μmol, 45%) colorless solid
[1618] C.sub.16H.sub.17NO.sub.3S [303.38]
[1619] m.p.: 54° C.
[1620] R.sub.f: 0.19 (CH/EA 10:1)
[1621] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 8.03 (d, J=20.0 Hz, 1H), 7.94 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.10-5.90 (m, J=16.7, 10.5, 5.9 Hz, 1H), 5.71-5.56 (m, 1H), 5.40-5.11 (m, 2H), 4.09 (q, J=6.9 Hz, 2H), 1.52-1.39 (m, J=15.4, 6.8 Hz, 6H).
[1622] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ 168.9, 161.2, 160.9, 148.1, 137.6, 128.7, 126.2, 125.8, 116.5, 114.9, 72.3, 63.8, 20.1, 14.9.
Example 149: Prop-2-yn-1-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AMU-29)
[1623] ##STR00224##
[1624] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with propargyl alcohol (1.5 eq, 602 μmol, 40 μL). The crude product was purified via column chromatography (90 mL SiO.sub.2, eluent CH/EA 10:1).
[1625] Yield: 42 mg (146 μmol, 31%) colorless solid
[1626] C.sub.15H.sub.13NO.sub.3S [287.33]
[1627] m.p.: 83° C.
[1628] R.sub.f: 0.16 (CH/EA 10:1)
[1629] .sup.1H-NMR (300 MHz, Acetone-d.sub.6): δ 8.41 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 4.99 (d, J=2.4 Hz, 2H), 4.23-4.08 (m, 2H), 3.13 (t, J=2.4 Hz, 1H), 1.41 (t, J=7.0 Hz, 3H).
[1630] .sup.13C-NMR (75.5 MHz, Acetone-d.sub.6): δ 169.2, 162.2, 161.0, 147.7, 129.1, 128.69, 126.5, 115.9, 78.8, 76.7, 64.4, 52.9, 15.0.
Example 150: tert-Butyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (TSch-61a)
[1631] ##STR00225##
[1632] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with tert-butanol (1.5 eq, 602 μmol, 56 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 20:1).
[1633] Yield: 81 mg (265 μmol, 67%) colorless solid
[1634] C.sub.16H.sub.19NO.sub.3S [305.39]
[1635] m.p.: 108-111° C.
[1636] R.sub.f: 0.40 (CH/EA 5:1)
[1637] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.95-7.93 (m, 3H), 6.95-6.92 (d, J=8.8 Hz, 2H), 4.14-4.05 (q, J=7.0 Hz, 2H), 1.62 (s, 9H), 1.46-1.42 (t, J=7.0 Hz, 3H).
[1638] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.6, 161.1, 160.8, 149.3, 128.6, 125.9, 125.4, 114.9, 82.1, 63.8, 28.4, 14.9.
Example 151: Cyclopropyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (TSch-61d)
[1639] ##STR00226##
[1640] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with cyclopropanol (1.5 eq, 602 μmol, 38 μL). The crude product was purified via column chromatography (40 mL SiO.sub.2, eluent CH/EA 8:1).
[1641] Yield: 31 mg (107 μmol, 27%) colorless solid
[1642] C.sub.15H.sub.15NO.sub.3S [289.35]
[1643] m.p.: 89-92° C.
[1644] R.sub.f: 0.28 (CH/EA 5:1)
[1645] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.04 (s, 1H), 7.93-7.90 (d, J=8.7 Hz, 2H), 6.94-6.91 (d, J=8.7 Hz, 2H), 4.39-4.34 (m, 1H), 4.11-4.04 (q, J=6.9 Hz, 2H), 1.45-1.40 (t, J=6.9 Hz, 3H), 0.88-0.79 (m, 4H).
[1646] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 162.5, 161.2, 147.5, 128.6, 126.5, 125.6, 114.9, 63.8, 50.0, 14.8, 5.5.
Example 152: Thiophen-2-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (TSch-62a)
[1647] ##STR00227##
[1648] According to General Procedure C, 2-(4-ethoxyphenyl)thiazol 4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 2-thiophenemethanol (1.5 eq, 602 μmol, 57 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 8:1).
[1649] Yield: 90 mg (260 μmol, 65%) yellowish solid
[1650] C.sub.17H.sub.15NO.sub.3S.sub.2 [345.43]
[1651] m.p.: 101-103° C.
[1652] R.sub.f: 0.20 (CH/EA 8:1)
[1653] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, 1H), 7.94-7.91 (d, J=8.7 Hz, 2H), 7.35-7.33 (d, J=5.0 Hz, 1H), 7.21-7.20 (d, J=2.9 Hz, 1H), 7.02-7.00 (dd, .sup.3J (H,H)=4.9 Hz, 1H), 6.95-6.92 (d, J=8.7 Hz, 2H), 5.56 (s, 2H), 4.11-4.05 (q, J=6.9 Hz, 2H), 1.46-1.41 (t, J=7.0 Hz, 3H).
[1654] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 161.2, 161.2, 147.4, 137.7, 128.9, 128.7, 127.2, 127.0, 127.0, 125.6, 114.9, 63.8, 61.3, 14.9.
Example 153: Furan-2-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (TSch-62b)
[1655] ##STR00228##
[1656] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with furfuryl alcohol (1.5 eq, 602 μmol, 52 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 8:1).
[1657] Yield: 98 mg (298 μmol, 75%) yellowish solid
[1658] C.sub.17H.sub.15NO.sub.4S [329.37]
[1659] m.p.: 72-74° C.
[1660] R.sub.f: 0.46 (CH/EA 4:1)
[1661] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, 1H), 7.94-7.91 (d, J=8.8 Hz, 2H), 7.44 (d, J=0.9 Hz, 1H), 6.94-6.91 (d, J=8.8 Hz, 2H), 6.52-6.51 (d, J=3.0 Hz, 1H), 6.39-6.38 (dd, J=4.8 Hz, 1H), 5.35 (s, 2H), 4.11-4.04 (q, J=6.9 Hz, 2H), 1.46-1.41 (t, J=7.0 Hz, 3H).
[1662] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 161.2, 161.2, 149.4, 147.3, 143.5, 128.7, 127.0, 125.6, 114.9, 111.4, 110.8, 63.8, 58.8, 14.9.
Example 154: Isopentyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (TSch-62d)
[1663] ##STR00229##
[1664] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with isopentyl alcohol (1.5 eq, 602 μmol, 65 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 8:1).
[1665] Yield: 112 mg (351 μmol, 88%) colorless solid
[1666] C.sub.17H.sub.21NO.sub.3S [319.42]
[1667] m.p.: 49-52° C.
[1668] R.sub.f: 0.58 (CH/EA 4:1)
[1669] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.05 (s, 1H), 7.95-7.92 (d, J=8.7 Hz, 2H), 6.95-6.92 (d, J=8.7 Hz, 2H), 4.42-4.38 (t, J=6.8 Hz, 2H), 4.13-4.05 (q, J=6.9 Hz, 2H), 1.81-1.74 (m, 1H), 1.72-1.68 (t, J=6.7 Hz, 2H), 1.46-1.42 (t, J=9.3 Hz, 3H), 0.98-0.96 (d, J=6.4 Hz, 6H).
[1670] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.9, 161.7, 161.2, 148.0, 128.7, 126.2, 125.7, 114.9, 64.2, 63.8, 37.5, 25.3, 22.7, 14.9.
Example 155: (E)-Hex-2-en-1-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-8)
[1671] ##STR00230##
[1672] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with trans-2-hexen-1-ol (1.5 eq, 602 μmol, 107 μL). The crude product was purified twice via column chromatography (60 mL SiO.sub.2, eluent CH/EA 8:1 and 15 mL SiO.sub.2, eluent toluene/EA 30:1).
[1673] Yield: 35 mg (106 μmol, 26%) colorless solid
[1674] C.sub.18H.sub.21NO.sub.3S [331.43]
[1675] m.p.: 46-48° C.
[1676] R.sub.f: 0.26 (toluene/EA 30:1)
[1677] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 5.97-5.59 (m, 2H), 5.79-5.62 (m, 1H), 4.82 (d, J=6.4 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 2.06 (dd, J=14.0, 6.8 Hz, 2H), 1.50-1.34 (m, 5H), 0.91 (t, J=7.3 Hz, 3H).
[1678] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 161.5, 161.2, 147.9, 137.2, 128.7, 126.4, 125.7, 123.9, 114.89, 66.3, 63.8, 34.5, 22.2, 14.9, 13.8.
Example 156: Hexyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-9)
[1679] ##STR00231##
[1680] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 609 μmol, 150 mg) was esterified with 1-hexanol (1.5 eq, 903 μmol, 123 μL). The crude product was purified twice via column chromatography (70 mL SiO.sub.2, eluent CH/EA 8:1 and 30 mL SiO.sub.2, eluent toluene/EA 30:1).
[1681] Yield: 52 mg (156 μmol, 26%) colorless solid
[1682] C.sub.18H.sub.23NO.sub.3S [333.45]
[1683] m.p.: 58-61° C.
[1684] R.sub.f: 0.26 (toluene/EA 30:1)
[1685] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.99 (s, J=18.6 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.29 (t, J=6.8 Hz, 2H), 4.02 (q, J=6.9 Hz, 2H), 1.81-1.64 (m, 2H), 1.44-1.21 (m, 9H), 0.92-0.74 (m, J=6.7 Hz, 3H).
[1686] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.9, 161.7, 161.2, 148.0, 128.7, 126.2, 125.8, 114.9, 65.7, 63.8, 31.6, 28.8, 25.8, 22.7, 14.9, 14.1.
Example 157: But-3-yn-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-11)
[1687] ##STR00232##
[1688] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 3-butyn-2-ol (1.5 eq, 602 μmol, 47 μL). The crude product was purified via column chromatography (100 mL SiO.sub.2, eluent CH/EA 8:1).
[1689] Yield: 113 mg (375 μmol, 94%) colorless solid
[1690] C.sub.16H.sub.15NO.sub.3S [301.36]
[1691] m.p.: 86-88° C.
[1692] R.sub.f: 0.41 (CH/EA 4:1)
[1693] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.11 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 5.78-5.65 (m, 1H), 4.07 (q, J=6.9 Hz, 2H), 2.51 (d, J=2.0 Hz, 1H), 1.66 (d, J=6.7 Hz, 3H), 1.42 (t, J=7.0 Hz, 3H).
[1694] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 161.21, 160.3, 147.2, 128.7, 127.0, 125.6, 114.9, 82.0, 73.6, 63.8, 61.2, 21.5, 14.8.
Example 158: Benzyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-12)
[1695] ##STR00233##
[1696] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with benzyl alcohol (1.5 eq, 602 μmol, 62 μL). The crude product was purified via column chromatography (100 mL SiO.sub.2, eluent CH/EA 8:1).
[1697] Yield: 53 mg (156 μmol, 39%) colorless solid
[1698] C.sub.19H.sub.17NO.sub.3S [339.41]
[1699] m.p.: 69-71° C.
[1700] R.sub.f: 0.41 (CH/EA 4:1)
[1701] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.41 (dt, J=14.9, 7.0 Hz, 5H), 6.94 (d, J=8.8 Hz, 2H), 5.42 (s, 2H), 4.09 (q, J=6.9 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).
[1702] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 161.4, 161.2, 147.6, 136.0, 128.7, 128.7, 128.6, 128.5, 126.7, 125.7, 114.9, 67.1, 63.8, 14.9.
Example 159: Pyridin-4-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-17)
[1703] ##STR00234##
[1704] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 4-pyridinmethanol (1.5 eq, 602 μmol, 66 mg). The crude product was purified via column chromatography (75 mL SiO.sub.2, eluent CH/EA 1:1.5).
[1705] Yield: 88 mg (259 μmol, 65%) colorless solid
[1706] C.sub.18H.sub.16N.sub.2O.sub.3S [340.40]
[1707] m.p.: 124-128° C.
[1708] R.sub.f: 0.16 (CH/EA 1:1)
[1709] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.63 (d, J=5.5 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.37 (d, J=5.0 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 5.43 (s, 1H), 4.10 (q, J=6.9 Hz, 1H), 1.45 (t, J=7.0 Hz, 2H).
[1710] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.3, 161.4, 161.1, 150.2, 147.0, 144.9, 128.7, 127.3, 125.5, 122.2, 115.0, 65.0, 63.9, 14.9.
Example 160: Pyridin-3-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-18)
[1711] ##STR00235##
[1712] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 3-pyridinmethanol (1.5 eq, 602 μmol, 58 μL). The crude product was purified via column chromatography (75 mL SiO.sub.2, eluent CH/EA 1:1.5).
[1713] Yield: 101 mg (297 μmol, 74%) colorless solid
[1714] C.sub.18H.sub.16N.sub.2O.sub.3S [340.40]
[1715] m.p.: 100-103° C.
[1716] R.sub.f: 0.16 (CH/EA 1:1)
[1717] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.75 (s, 1H), 8.60 (d, J=3.5 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.83 (d, J=7.8 Hz, 1H), 7.32 (dt, J=13.6, 6.9 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 5.43 (s, 2H), 4.08 (q, J=6.9 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).
[1718] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.2, 161.3, 150.1, 149.9, 147.2, 136.5, 131.6, 128.7, 127.7, 125.6, 123.7, 115.0, 64.5, 63.8, 14.7.
Example 161: Pyridin-2-ylmethyl 2(4-ethoxyphenyl)thiazole-4-carboxylate (LS-21)
[1719] ##STR00236##
[1720] According to General Procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 2-pyridinmethanol (1.5 eq, 602 μmol, 58 μL). The crude product was purified via column chromatography (75 mL SiO.sub.2, eluent CH/EA 1:1).
[1721] Yield: 69 mg (203 μmol, 51%) colorless solid
[1722] C.sub.18H.sub.16N.sub.2O.sub.3S [340.40]
[1723] m.p.: 123-127° C.
[1724] R.sub.f: 0.32 (CH/EA 1:1)
[1725] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.61 (d, J=3.9 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.72 (td, J=7.7, 1.6 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.31-7.17 (m, 1H), 6.94 (d, J=8.8 Hz, 2H), 5.53 (s, 2H), 4.08 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).
[1726] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1, 161.3, 155.9, 149.6, 147.3, 137.0, 128.7, 127.1, 125.6, 123.1, 122.1, 114.9, 67.5, 63.8, 14.9.
Example 162: tert-Butyl 5-chloro-2(4-ethoxyphenyl)thiazole-4-carboxylate (AL-6)
[1727] ##STR00237##
[1728] In a 50 mL round-bottom flask equipped with a magnetic stirring bar 700 mg tert-butyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (2.29 mmol, 1.0 eq.) and 368 mg N-chlorosuccinimide (2.75 mmol, 1.2 eq.) were dissolved in 20 mL MeCN (HPLC-grade). The flask was equipped with a reflux condenser and heated to 80° C. The reaction was monitored via TLC (CH/EA 4:1). After 3 h the conversion was incomplete and did not change during the subsequent 3 h. The reaction was cooled to RT and the solvent was evaporated in vacuo. The crude product was purified via column chromatography (CH/EA 10:1, 110 g SiO.sub.2).
[1729] Yield: 364 mg (1.03 mmol, 47%, white solid)
[1730] C.sub.16H.sub.19NO.sub.3S [339.83]
[1731] m.p.: 97-98° C.
[1732] R.sub.f: 0.26 (CH/EA 12:1)
[1733] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.83 (d, J=9.01 Hz, 2H, H-14/18), 6.94 (d, J=9.01 Hz, 2H, H-15/17), 4.07 (q, 2H, H-20), 1.63 (s, 9H, H-10/11/12), 1.43 (t, 3H, H-21)
[1734] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ (ppm) 164.30 (C.sub.q, C-2), 161.39 (C.sub.q, C-6), 160.12 (C.sub.q, C-16), 143.24 (C.sub.q, C-4), 131.67 (C.sub.q, C-13), 128.25 (CH, C-14/18), 125.32 (C.sub.q, C-5), 114.95 (CH, C-15/17), 82.91 (C.sub.q, C-9), 63.86 (CH.sub.2, C-20), 28.35 (CH.sub.3, C-10/11/12), 14.85 (CH.sub.3, C-21)
Example 163: tert-Butyl 5-bromo-2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-4-272=RE-3)
[1735] ##STR00238##
[1736] In a 250 mL round-bottom flask equipped with a magnetic stirring bar 1.53 g tert-butyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (5.0 mmol, 1.0 eq.) and 1.079 g N-bromosuccinimide (6.06 mmol, 1.2 eq.) were dissolved in 35 mL MeCN (HPLC-grade). The flask was equipped with a reflux condenser and heated to 80° C. When full conversion was observed via TLC (CH/EA 4:1), the reaction was cooled down to RT and the solvent was evaporated in vacuo. The crude product was purified via column chromatography (500 mL SiO.sub.2, eluent CH/EA 8:1).
[1737] Yield: 1.64 g (4.28 mmol, 86%, off-white solid)
[1738] C.sub.16H.sub.18BrNO.sub.3S [384.29]
[1739] m.p.: 112-116° C.
[1740] R.sub.f: 0.58 (CH/EA 4:1)
[1741] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.83 (d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 4.08 (q, J=6.9 Hz, 2H), 1.64 (s, 9H), 1.43 (t, J=6.9 Hz, 3H).
[1742] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ (ppm) 167.6, 161.4, 160.4, 145.7, 128.3, 125.3, 115.0, 113.8, 83.0, 63.9, 28.4, 14.9.
Example 164: Ethyl 5-bromo-2-(4-ethoxyphenyl)thiazole-4-carboxylate (OKO-06)
[1743] ##STR00239##
[1744] In a 100 mL round-bottom flask equipped with a magnetic stirring bar ethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq., 2.0 mmol, 556 mg) and N-bromosuccinimide (1.2 eq., 2.4 mmol, 425 mg) were dissolved in 10 mL MeCN (HPLC-grade). The flask was equipped with a reflux condenser and heated to 80° C. When full conversion was observed via TLC (CH/EA 4:1), the reaction was cooled down to RT and the solvent was evaporated in vacuo. The crude product was purified via column chromatography (500 mL SiO.sub.2, eluent CH/EA 10:1).
[1745] Yield: 178 g (500 μmol, 25%) off-white solid
[1746] C.sub.14H.sub.14BrNO.sub.3S [356.23]
[1747] R.sub.f: 0.46 (CH/EA 4:1)
[1748] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.82 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 4.45 (q, J=7.1 Hz, 2H), 4.08 (q, J=7.0 Hz, 2H), 1.52-1.36 (m, J=7.0, 2.3 Hz, 6H).
[1749] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ (ppm) 168.0, 161.5, 161.4, 144.3, 128.4, 125.2, 115.3, 115.0, 63.98, 61.9, 14.8, 14.4.
Example 165: Ethyl 2-(4-ethoxyphenyl)-5-iodothiazole-4-carboxylate (OKO-31)
[1750] ##STR00240##
[1751] In a 100 mL round-bottom flask equipped with a magnetic stirring bar ethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq., 1.81 mmol, 505 mg) and N-iodosuccinimide (2.1 eq., 3.83 mmol, 808 mg) were dissolved in 20 mL MeCN (HPLC-grade). The flask was equipped with a reflux condenser and heated to 80° C. After 17 h the reaction was cooled down to RT and the solvent was evaporated in vacuo. The crude product was purified via column chromatography (300 mL SiO.sub.2, eluent CH/EA 8:1).
[1752] Yield: 410 g (1.02 mmol, 25%, with impurities) off-white solid
[1753] C.sub.14H.sub.14INO.sub.3S [403.23]
[1754] m.p.: 88° C.
[1755] R.sub.f: 0.46 (CH/EA 4:1)
[1756] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.84 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H), 4.08 (q, J=6.9 Hz, 2H), 1.57-1.33 (m, J=14.8, 7.3 Hz, 6H).
[1757] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ (ppm) 173.1, 161.7, 161.4, 148.6, 128.5, 125.2, 115.0, 77.4, 63.8, 61.9, 14.8, 14.4.
Example 166: tert-Butyl 2-(4-ethoxyphenyl)-5-(pyrrolidin-1-yl)thiazole-4-carboxylate (AL-10)
[1758] ##STR00241##
[1759] According to General Procedure D, 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq, 294 μmol, 100 mg) was coupled with pyrrolidine (2.1 eq, 609 μmol, 43 mg). The crude product was purified via column chromatography (20 g SiO.sub.2, CH/EA 6:1).
[1760] Yield: 91 mg (243 μmol, 83%, white solid)
[1761] C.sub.20H.sub.26N.sub.2O.sub.3S [374.50]
[1762] m.p.: 149-150° C.
[1763] R.sub.f: 0.61 (CH/EA 2:1)
[1764] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.72 (d, J=9.01 Hz, 2H, H-14/18), 6.89 (d, J=9.01 Hz, 2H, H-15/17), 4.04 (q, 2H, H-20), 3.42 (t, 4H, H-23/26), 1.99 (t, 4H, H-24/25), 1.62 (s, 9H, H-10/11/12), 1.42 (t, 3H, H-21)
[1765] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ (ppm) 162.63 (C.sub.q, C-2), 159.81 (C.sub.q, C-6), 159.10 (C.sub.q, C-16), 149.27 (C.sub.q, C-4), 127.24 (C.sub.q, C-13), 126.94 (CH, C-14/18), 124.39 (C.sub.q, C-5), 114.65 (CH, C-15/17), 80.70 (C.sub.q, C-9), 63.67 (CH.sub.2, C-20), 55.40 (CH.sub.2, C-23/26), 28.58 (CH.sub.3, C-10/11/12), 26.37 (CH.sub.2, C-23/26), 14.91 (CH.sub.3, C-21)
Example 167: tert-Butyl 2-(4-ethoxyphenyl)-5-(piperidin-1-yl)thiazole-4-carboxylate (LS-7)
[1766] ##STR00242##
[1767] According to General Procedure D, 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq, 294 μmol, 100 mg) was coupled with piperidine (2.1 eq, 609 μmol, 61 μL). The crude product was purified via column chromatography (100 mL SiO.sub.2, CH/EA 8:1).
[1768] Yield: 27 mg (70 μmol, 24%, white solid)
[1769] C.sub.21H.sub.28N.sub.2O.sub.3S [388.53]
[1770] m.p.: 105-106° C.
[1771] R.sub.f: 0.80 (CH/EA 2:1)
[1772] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.78 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.05 (q, J=6.9 Hz, 2H), 3.21-3.03 (m, 4H), 1.81-1.71 (m, J=4.6 Hz, 4H), 1.63 (s, J=14.6 Hz, 11H), 1.41 (t, J=7.0 Hz, 3H).
[1773] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ (ppm) 162.4, 161.91, 160.2, 154.7, 131.0, 127.6, 126.7, 114.7, 81.2, 63.7, 56.1, 28.6, 25.7, 23.8, 14.9.
Example 168: tert-Butyl 5-(dimethylamino)-2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-14)
[1774] ##STR00243##
[1775] According to General Procedure D, 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq, 221 μmol, 75 mg) was coupled with dimethylamine (2.1 eq, 2.0 M in THF, 232 μL). The crude product was purified via column chromatography (30 ml SiO.sub.2, CH/EA 8:1).
[1776] Yield: 50 mg (144 μmol, 65%, white solid)
[1777] C.sub.18H.sub.24N.sub.2O.sub.3S [348.46]
[1778] m.p.: 93-96° C.
[1779] R.sub.f: 0.29 (CH/EA 8:1)
[1780] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.77 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 4.06 (dd, J=13.9, 6.9 Hz, 2H), 3.01 (s, 6H), 1.63 (s, 9H), 1.42 (t, J=7.0 Hz, 3H).
[1781] .sup.13C-NMR (76 MHz, CDCl.sub.3): δ (ppm) 163.1, 162.0, 160.2, 152.8, 128.7, 127.5, 126.7, 114.7, 81.2, 63.7, 46.8, 28.5, 14.9.
Example 169: tert-Butyl 2-(4-ethoxyphenyl)-5-(1-hydroxyethyl)thiazole-4-carboxylate (RE-09)
[1782] ##STR00244##
[1783] An inert 10 mL Schienk flask equipped with magnetic stirring bar was charged with tert-butyl 5-bromo-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq, 520 μmol, 200 mg) and cooled down to −15° C. using an ice/NaCl bath. iPrMgCl*LiCl (1.3 M in THF, 1.1 eq. 420 μL) was added and the reaction mixture turned dark red immediately. Acetaldehyde (1 M in THF, 1.2 eq., 624 μL) and CuCN*2LiCl (1 M in THF, 1 drop) was added. The reaction was allowed to warm to RT. After 2 h full conversion was observed via TLC (CH/EA 4:1). The reaction was quenched via the addition of HCl (1 M, 4 ml) and extracted with DCM (3×10 mL). The combined organic phase was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 4:1).
[1784] Yield: 132 mg (378 μmol, 73%) white solid
[1785] C.sub.18H.sub.23NO.sub.4S [349.45]
[1786] m.p.: 155-158° C.
[1787] R.sub.f: 0.24 (CH/EA 4:1)
[1788] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.77 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 4.06 (q, J=6.9 Hz, 2H), 3.01 (s, 6H), 1.63 (s, 9H), 1.42 (t, J=7.0 Hz, 3H).
[1789] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 164.6, 162.4, 160.9, 152.8, 142.5, 128.2, 125.8, 114.7, 82.9, 63.8, 63.7, 28.2, 24.2, 14.7.
Example 170: tert-Butyl 2-(4-ethoxyphenyl)-5-(1-hydroxy-2-methylpropyl)thiazole-4-carboxylate (RE-13a)
[1790] ##STR00245##
[1791] According to the synthesis of RE-09, tert-butyl 5-bromo-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq, 520 μmol, 200 mg) was converted to the corresponding Grignard reagent and subsequently treated with isobutyraldehyde (1 M in THF, 1.1 eq., 574 μL). The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 4:1).
[1792] Yield: 154 mg (408 μmol, 79%) orange solid
[1793] C.sub.20H.sub.27NO.sub.4S [377.50]
[1794] m.p.: 116-120° C.
[1795] R.sub.f: 0.20 (CH/EA 4:1)
[1796] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.80 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 5.11 (d, J=6.7 Hz, 1H), 4.01 (dd, J=13.9, 6.9 Hz, 2H), 2.01 (td, J=13.3, 6.7 Hz, 1H), 1.57 (s, 9H), 1.36 (t, J=6.9 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.7 Hz, 3H).
[1797] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 165.2, 162.4, 161.0, 150.8, 142.8, 128.3, 125.9, 114.8, 82.8, 73.21, 63.4, 35.7, 28.4, 19.7, 18.1, 14.9.
Example 171: tert-Butyl 5-acetyl-2-(4-ethoxyphenyl)thiazole-4-carboxylate (RE-10)
[1798] ##STR00246##
[1799] An inert 25 mL round bottom flask equipped with magnetic stirring bar and Schienk adapter was charged with RE-09 (1.0 eq, 213 μM, 75 mg) and dissolved in anhydrous DCM. The reaction mixture was cooled down to 0° C. using and ice bath and Dess Martin-Periodinan (DMP) (1.5 eq. 320 μmol, 136 mg) was added. When full conversion was observed via TLC (CH/EA 4:1), the reaction was quenched via the addition of Na.sub.2S.sub.2O.sub.3 (1 M. 5 mL) and sat. NaHCO.sub.3 (5 mL). The aqueous phase was extracted with DCM (3×10 mL) and the combined organic phase was dried over Na.sub.2SO.sub.4, filtered and evaporated to dryness. The crude product was purified via column chromatography (25 mL SiO.sub.2, eluent CH/EA 5:1).
[1800] Yield: 70 mg (202 μmol, 95%) orange solid
[1801] C.sub.18H.sub.21NO.sub.4S [347.43]
[1802] m.p.: 89-95° C.
[1803] R.sub.f: 0.38 (CH/EA 4:1)
[1804] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.85 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.02 (q, J=6.9 Hz, 2H), 2.53 (s, 3H), 1.58 (s, J=8.8 Hz, 9H), 1.37 (t, J=7.0 Hz, 3H).
[1805] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 190.7, 171.1, 162.8, 162.0, 149.8, 137.1, 129.0, 125.2, 115.0, 84.1, 63.9, 29.9, 28.2, 14.8.
Example 172: Ethyl 5-acetyl-2-(4-ethoxyphenyl)thiazole-4-carboxylate (RE-18)
[1806] ##STR00247##
[1807] An inert 50 mL round bottom flask equipped with magnetic stirring bar and Schlenk adapter was charged with RE-10 (1.0 eq., 164 μmol, 57 mg) and dissolved in 5.0 mL dry DCM. Et.sub.3SiH (2.5 eq., 410 μmol, 65 μL) and TFA (12 eq., 1.1 mmol, 160 μL) were added successively. The suspension was stirred at 40° C. When full conversion was observed via TLC (CH/EA 1:2) the reaction mixture was cooled down to RT and the solvent was removed under reduced pressure. The solid residue was in 5 mL EtOH and 5 drops H.sub.2SO.sub.4 were added. The reaction was stirred at reflux until full conversion was observed via TLC (CH/EA 3:4). The solvent was again removed under reduced pressure and the residue was taken up in EA (20 mL) and washed with NaHCO.sub.3 sat. (2×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (100 mL SiO.sub.2, eluent CH/EA 5:4).
[1808] Yield: 20 mg (63 μmol, 38%) off-white solid
[1809] C.sub.16H.sub.17NO.sub.4S [319.38]
[1810] m.p.: 78° C.
[1811] R.sub.f: 0.76 (CH/EA 4:3)
[1812] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.85 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.02 (q, J=6.9 Hz, 2H), 2.53 (s, 3H), 1.58 (s, J=8.8 Hz, 9H), 1.37 (t, J=7.0 Hz, 3H).
[1813] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 190.7, 171.1, 162.8, 162.0, 149.8, 137.1, 129.0, 125.2, 115.0, 84.1, 63.9, 29.9, 28.2, 14.8.
Example 173: tert-Butyl 2-(4-ethoxyphenyl)-5-isobutyrylthiazole-4-carboxylate (RE-16a)
[1814] ##STR00248##
[1815] According to the synthesis of RE-10, RE-13a (1.0 eq., 179 μmol, 68 mg) was oxidized using DMP. The crude product was purified via column chromatography (30 mL SiO.sub.2, eluent CH/EA 6:1).
[1816] Yield: 43 mg (115 μmol, 64%) orange solid
[1817] C.sub.20H.sub.25NO.sub.4S [375.48]
[1818] m.p.: 74° C.
[1819] R.sub.f: 0.43 (CH/EA 4:1)
[1820] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 7.91 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 4.08 (q, J=6.9 Hz, 2H), 3.19 (dt, J=13.6, 6.8 Hz, 1H), 1.62 (s, 9H), 1.43 (t, J=6.9 Hz, 3H), 1.23 (d, J=6.8 Hz, 6H).
[1821] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 198.0, 169.9, 162.4, 161.8, 149.3, 136.2, 128.9, 125.1, 115.0, 83.6, 63.9, 40.9, 28.1, 18.9, 14.8.
Example 174: tert-Butyl 5-(cyclopropanecarbonyl)-2-(4-ethoxyphenyl)thiazole-4-carboxylate (RE-16b)
[1822] ##STR00249##
[1823] According to the synthesis of RE-10, tert-butyl 5-(cyclopropyl(hydroxy)methyl)-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq., 202 μmol, 76 mg) was oxidized using DMP. The crude product was purified via column chromatography (40 mL SiO.sub.2, eluent CH/EA 8:1).
[1824] Yield: 64 mg (171 μmol, 84%) orange solid
[1825] C.sub.20H.sub.23NO.sub.4S [373.47]
[1826] m.p.: 119-122° C.
[1827] R.sub.f: 0.35 (CH/EA 4:1)
[1828] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ 7.85 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.02 (q, J=6.9 Hz, 2H), 2.42-2.26 (m, J=12.2, 7.8, 4.5 Hz, 1H), 1.57 (s, 9H), 1.37 (t, J=7.0 Hz, 3H), 1.28-1.18 (m, 2H), 1.06-0.95 (m, J=11.3, 3.5 Hz, 2H).
[1829] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 193.7, 170.1, 162.5, 161.8, 148.9, 137.7, 128.9, 125.2, 115.0, 83.6, 63.9, 28.1, 21.8, 14.8, 13.0.
Example 175: tert-Butyl 5-allyl-2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-4-274)
[1830] ##STR00250##
[1831] According to the synthesis of RE-10, tert-butyl 5-bromo-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq, 312 μmol, 120 mg) was converted to the corresponding Grignard reagent and treated with allyl bromide (1.1 eq., 343 μmol, 30 μL). The crude product was purified via column chromatography (25 mL SiO.sub.2, eluent CH/EA 9:1).
[1832] Yield: 90 mg (261 μmol, 83%) light yellow solid
[1833] C.sub.19H.sub.23NO.sub.3S [345.46]
[1834] m.p.: 95° C.
[1835] R.sub.f: 0.43 (CH/EA 6:1)
[1836] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.90 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 6.05 (ddt, J=13.0, 10.0, 6.5 Hz, 1H), 5.32-5.03 (m, 2H), 4.10 (q, J=6.9 Hz, 2H), 3.96 (d, J=6.4 Hz, 2H), 1.66 (s, 9H), 1.46 (t, J=7.0 Hz, 3H).
[1837] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 164.4, 161.8, 160.8, 145.2, 143.2, 135.6, 128.3, 126.0, 117.3, 114.8, 82.1, 63.8, 32.2, 28.4, 14.9.
Example 176: Ethyl 5-ethoxy-2-(4-ethoxyphenyl)thiazole-4-carboxylate (OKO-10)
[1838] ##STR00251##
[1839] In an inert Schlenk flask equipped with magnetic stirring bar Na (3.3 eq., 1.87 mmol, 43 mg) was fully dissolved in 7 mL anhydrous EtOH. The solution was cooled down to 0° C. using an ice bath and ethyl 5-bromo-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq., 560 μmol, 200 mg) was added. The reaction was allowed to warm to RT. As conversion was not complete after 1 h, the reaction mixture was heated to 70° C. and stirred overnight. When full conversion could be observed via TLC, the reaction was quenched by the addition of ice and extracted with DCM (2×15 mL). The organic phase was washed with Brine (1×30 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (200 mL SiO.sub.2, eluent CH/EA 4:1).
[1840] Yield: 45 mg (140 μmol, 25%) light yellow solid
[1841] C.sub.16H.sub.19NO.sub.4S [321.39]
[1842] m.p.: 81° C.
[1843] R.sub.f: 0.24 (CH/EA 4:1)
[1844] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.78 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 4.30 (q, J=7.0 Hz, 2H), 4.07 (q, J=6.9 Hz, 2H), 1.55 (t, J=7.0 Hz, 3H), 1.47-1.36 (m, J=12.3, 6.1 Hz, 6H).
[1845] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 167.9, 161.9, 160.7, 153.1, 127.8, 127.4, 126.2, 114.8, 74.5. 63.78, 60.9, 15.0, 14.9, 14.6.
Example 177: Isopropyl 2-(4-ethoxyphenyl)-5-(isopropoxythiazole-4-carboxylate (OKO-13)
[1846] ##STR00252##
[1847] In an inert Schlenk flask equipped with magnetic stirring bar Na (3.6 eq., 2.04 mmol, 47 mg) was fully dissolved in 10 mL anhydrous isopropanol. Ethyl 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq., 560 μmol, 175 mg) was added and the reaction mixture was heated to 80° C. and stirred overnight. When full conversion could be observed via TLC, the reaction was quenched by the addition of ice and extracted with DCM (2×15 mL). The organic phase was washed with Brine (1×30 mL), dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent CH/EA 8:1).
[1848] Yield: 52 mg (149 μmol, 27%) colorless solid
[1849] C.sub.18H.sub.23NO.sub.4S [349.45]
[1850] R.sub.f: 0.28 (CH/EA 4:1)
[1851] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.78 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.39-5.10 (m, J=12.5, 6.2 Hz, 1H), 4.49-4.29 (m, J=12.1, 6.1 Hz, 1H), 4.06 (q, J=6.9 Hz, 2H), 1.56-1.30 (m, 15H).
[1852] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 166.1, 161.6, 160.0, 154.2, 129.8, 127.7, 126.3, 114.3, 82.7, 68.3, 63.7, 22.2. 22.1, 14.8.
Intermediate Ethyl 2-chloro-5-iodothiazole-4-carboxylate (OKO-04)
[1853] ##STR00253##
[1854] In an inert Schlenk flask equipped with magnetic stirring bar ethyl 2-amino-5-iodothiazole-4-carboxylate (1.0 eq., 1.69 mmol, 505 mg) and CuCl.sub.2 (1.2 eq., 2.03 mmol, 271 mg) were dissolved in 8 mL MeCN anhydrous. The reaction mixture was heated to 80° C. and .sup.tBuONO (1.2 eq. 2.03 mmol, 270 μL) were added dropwise over 5 min. The reaction was stirred for another 15 min. When full conversion could be observed via TLC, the solvent was removed under reduced pressure. The residue was taken up in DCM (50 ml) and washed with water (5×200 H2O). The organic phase was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (100 mL SiO.sub.2, eluent CH/EA 12:1).
[1855] Yield: 132 mg (416 μmol, 25%) light yellow solid
[1856] C.sub.6H.sub.5ClINO.sub.2S [317.53]
[1857] m.p.: 81° C.
[1858] R.sub.f: 0.88 (DCM/MeOH 30:1)
[1859] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 4.44 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
[1860] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 160.5, 156.8, 146.6, 80.1, 62.3, 14.4.
Intermediate Ethyl 2-chloro-5-(trifluoromethyl)thiazole-4-carboxylate (OKO-07)
[1861] ##STR00254##
[1862] In a 25 mL round bottom flask equipped with magnetic stirring bar and Schienk adapter OKO-04 (1.0 eq., 334 μmol, 506 mg) and CuI (2.0 eq., 672 μmol, 128 mg) were dissolved in 2 mL DMF anhydrous. Difluorosulfonyl acetate (1.4 eq., 470 μmol, 140 μL) were added and the reaction mixture was stirred at 75° C. When full conversion could be observed via TLC, the reaction was quenched via the addition of water and extracted with EA (3×10 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (100 mL SiO.sub.2, eluent CH/EA 20:1).
[1863] Yield: 46 mg (177 μmol, 53%) off-white solid
[1864] C.sub.7H.sub.5ClF.sub.3NO.sub.2S [259.63]
[1865] R.sub.f: 0.63 (CH/EA 4:1)
[1866] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 4.44 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).
[1867] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 158.9, 153.6, 144.6, 144.6, 133.7, 133.2, 122.0, 118.4, 62.9, 14.0.
Example 178: Ethyl 2-(4-ethoxyphenyl)-5-(trifluoromethyl)thiazole-4-carboxylate (OKO-08)
[1868] ##STR00255##
[1869] In an inert Schienk flask equipped with magnetic stirring bar OKO-07 (1.0 eq., 177 μmol, 46 mg), 4-ethoxyphenylboronic acid (1.26 eq., 222 μmol, 37 mg), K.sub.3PO.sub.4 (2.0 eq., 354 μmol, 75 mg) and Pd[PPh.sub.3].sub.4 (0.06 eq., 10 μmol, 12 mg) were dissolved in 10 mL anhydrous dioxane and stirred at 100° C. When full conversion could be observed via TLC after 2 h, the reaction mixture was cooled down to RT and filtered over a pad of Celite. The solvent was removed under reduced pressure and the crude product was purified via column chromatography (20 mL SiO.sub.2, eluent CH/EA 10:1).
[1870] Yield: 32 mg (93 μmol, 52%) off-white solid
[1871] C.sub.15H.sub.14F.sub.3NO.sub.3S [345.34]
[1872] R.sub.f: 0.48 (CH/EA 4:1)
[1873] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.91 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.47 (q, J=7.1 Hz, 2H), 4.09 (q, J=6.9 Hz, 2H), 1.50-1.32 (m, J=12.3, 7.0 Hz, 6H).
[1874] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 162.1, 160.5, 146.5, 130.0, 129.4, 128.9, 124.4, 123.2, 119.6, 115.1, 64.0, 62.4, 14.8, 14.1.
Example 179: Ethyl (E)-2-styrylthiazole-4-carboxylate (AM-4-252)
[1875] ##STR00256##
[1876] According to General Procedure A, ethyl 2-bromothiazole-4-carboxylate (1.0 eq. 847 μmol, 200 mg) was coupled with (E)-styrylboronic acid (1.2 eq. 1.02 mmol, 150 mg). The crude product was purified via column chromatography (50 ml SiO.sub.2, eluent CH/EA 4:1) and preparative HPLC (method E).
[1877] Yield: 52 mg (200 μmol, 24%) colorless solid
[1878] C.sub.14H.sub.13NO.sub.2S [259.32]
[1879] m.p.: 82° C.
[1880] R.sub.f: 0.33 (CH/EA 4:1)
[1881] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) δ 8.08 (s, 1H), 7.60-7.29 (m, 7H), 4.45 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H).
[1882] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 167.8, 161.5, 147.9, 136.4, 135.4, 129.5, 129.1, 127.4, 126.5, 121.3, 61.7, 14.5.
Example 180: tert-Butyl 2-(phenylethynyl)thiazole-4-carboxylate (AM-4-251)
[1883] ##STR00257##
[1884] In an inert Schienk flask equipped with magnetic stirring bar ethyl 2-bromo-4-thiazolecarboxylate (1.0 eq., 2.12 mmol, 500 mg), CuI (0.03 eq., 64 μmol, 12 mg), and PdCl.sub.2(PPh3).sub.2 (0.03 eq., 64 μmol, 45 mg) were dissolved in 5 mL anhydrous DCM. Et.sub.3N (7.0 eq., 14.8 mmol, 2.1 mL) and phenylacetylene (1.5 eq., 3.18 mmol, 350 μL) were added successively. The reaction mixture was heated to reflux and stirred overnight. When full conversion could be observed via GC-MS, the reaction mixture was cooled down to RT, diluted with 10 mL DCM and filtered over a pad of Celite. The solvent was removed under reduced pressure. It was tried to purify the crude product via column chromatography for three times, however major impurities could not be separated. Still the product was used for the next step.
[1885] Yield: 323 mg (1.13 mmol, 53%, with major impurities) light yellow solid
[1886] C.sub.16H.sub.15NO.sub.2S [285.36]
[1887] m.p.: 136° C.
[1888] R.sub.f: 0.49 (CH/EA 4:1)
[1889] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.19 (s, 1H), 7.69-7.50 (m, 2H), 7.40 (dd, J=8.7, 4.4 Hz, 3H), 4.45 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H).
[1890] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 161.1, 149.5, 147.9, 132.2, 130.0, 128.7, 128.6, 121.1, 95.1, 81.91, 61.9, 14.5.
Example 181: Ethyl 2-phenethylthiazole-4-carboxylate (AM-4-257)
[1891] ##STR00258##
[1892] An inert 50 mL round bottom flask equipped with magnetic stirring bar and Schlenk adapter was charged with AM-4-251 (50% pure, 1.0 eq., 538 0 μmol, 277 mg). The starting material was dissolved in 15 mL anhydrous EtOH and the solution was degassed. Pd/C 10% (0.1 eq., 54 μmol, 57 mg) was added and the reaction mixture was purged with H.sub.2 and stirred vigorously overnight. When full conversion was observed via GC-MS, the reaction mixture was filtered over a pad of Celite and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (50 mL SiO.sub.2, eluent toluene/EA 15:1).
[1893] Yield: 123 mg (470 μmol, 87%) colorless oil
[1894] C.sub.14H.sub.15NO.sub.2S [261.34]
[1895] R.sub.f: 0.23 (toluene/EA 15:1)
[1896] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.03 (s, 1H), 7.27 (ddd, J=19.9, 19.2, 13.6 Hz, 7H), 4.43 (q, J=7.1 Hz, 2H), 3.44-3.31 (m, 2H), 3.17-3.03 (m, 2H), 1.41 (t, J=7.1 Hz, 3H).
[1897] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 171.0, 161.6, 147.0, 140.0, 129.1, 128.7, 128.6, 127.1, 126.6, 61.6, 36.1, 35.4, 14.5.
Examples 182 to 187
[1898] General Procedures
[1899] Suzuki Coupling Procedure A
[1900] A predried 20 mL Schlenk tube with magnetic stirring bar was charged with 5 mol-% PdCl.sub.2(dppf), 1.0 eq aryl halide, 1.0-1.3 eq boronic acid and 2.1 eq cesium fluoride in anhydrous DME. The reaction mixture was degassed by evacuation and purging with Ar (repeated three times) and placed in an oil bath at 80° C. After stirring for 21-96 h (reaction control via TLC and GC/MS) the reaction mixture was cooled to RT and filtered through a pad of Celite®. The filter cake was washed with an appropriate amount of EtOAc, the volatiles were removed under reduced pressure and the crude residue was died in oil-pump vacuum. Pure product was obtained via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc or toluene/EtOAc), unless otherwise stated.
[1901] Suzuki Coupling Procedure B
[1902] A 15-50 mL Schlenk-tube with magnetic stirring bar was evacuated and purged with Ar (repeated three times). The Schlenk-tube was subsequently charged with 5 mol-% Pd(OAc).sub.2, 10 mol-% SPhos, 1.2 eq boronic acid, 1.0 eq aryl halide (if solid) and 1,4-dioxane. At this point 1.0 eq aryl halide (if liquid) and a 3.4 M K.sub.3PO.sub.4 solution (degassed) was added via Eppendorf® pipette in an Ar counterstream. The reaction mixture was degassed by evacuation and purging with Ar (repeated three times) and placed in an oil bath at 60° C. After stirring for 8-18 h (reaction control via TLC and GC/MS) the reaction mixture was cooled to RT, the phases separated and the organic phase filtered through a pad of Celite®. The filter cake was washed with an appropriate amount of EtOAc, the volatiles were removed under reduced pressure and the crude residue was died in oil-pump vacuum. Pure product was obtained via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc).
[1903] (Additional) Preparative HPLC Methods
[1904] Method A: 0-2 min 50% of H.sub.2O and 50% CH.sub.3CN, 2-17 min linear to 100% CH.sub.3CN, 17-22 min 100% CH.sub.3CN with a flow of 15 mLmin.sup.−1.
[1905] Method B: 0-3 min 60% of H.sub.2O and 40% CH.sub.3CN, 3-37 min linear to 95% CH.sub.3CN, 37-42 min 95% CH.sub.3CN with a flow of 15 mLmin.sup.−1.
Example 182: Ethyl 2-phenylthiazole-4-carboxylate (CLF-3-197)
[1906] ##STR00259##
[1907] Phenylboronic acid (62.0 mg, 0.508 mmol, 1.2 eq), ethyl 2-bromothiazole-4-carboxylate (100.0 mg, 0.424 mmol, 1.0 eq) and potassium phosphate (726.5 mg, 3.423 mmol, 8.1 eq) in 6.0 mL 1,4-dioxane/H.sub.2O 5:1 (v/v) were reacted in presence of Pd(OAc).sub.2 (4.8 mg, 0.021 mmol, 5 mol-%) and SPhos (17.4 mg, 0.042 mmol, 10 mol-%) for 18 h at 60° C. according to general procedure B. The crude product was purified via flash column chromatography (15 g SiO.sub.2, cyclohexane/EtOAc 15:1 (v/v), column size 13×2 cm) to obtain the pure product as pale yellow wax-like compound.
[1908] Yield: 60.8 mg (0.261 mmol, 61%), pale yellow wax-like compound.
[1909] C.sub.12H.sub.11NO.sub.2S [233.29 g/mol].
[1910] R.sub.f=0.40 (cyclohexane/EtOAc=5:1 (v/v); staining: KMnO.sub.4).
[1911] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.15 (s, 1H, Ar—H), 8.06-7.94 (m, 2H, Ar—H), 7.54-7.36 (m, 3H, Ar—H), 4.45 (q, .sup.3J=7.1 Hz, 2H, CH.sub.2), 1.43 (t, .sup.3J=7.1 Hz, 3H, CH.sub.3).
[1912] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=169.0, 161.6, 148.2, 133.0, 130.8, 129.1, 127.1, 61.6, 14.5.
[1913] HRMS (DI-EI): Calcd. for C.sub.12H.sub.11NO.sub.2S: 233.0511; found: 233.0511.
Example 183: Ethyl 2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxylate (CM-02)
[1914] ##STR00260##
[1915] 4-(Trifluoromethyl)phenylboronic acid (95.4 mg, 0.502 mmol, 1.1 eq), ethyl 2-bromothiazole-4-carboxylate (107.9 mg, 0.457 mmol, 1.0 eq) and cesium fluoride (145.6 mg, 0.959 mmol, 2.1 eq) in 2.3 mL anhydrous DME were reacted in presence of PdCl.sub.2(dppf) (16.7 mg, 0.023 mmol, 5 mol-%) for 21 h at 80° C. according to general procedure A. After 21 h the temperature was increased to 100° C. and the reaction mixture was stirred for another 22 h. The crude product was purified via flash column chromatography (15 g SiO.sub.2, toluene/EtOAc 40:1 (v/v), column size 13×2 cm), followed by preparative RP-HPLC (method A).
[1916] Yield: 21.1 mg (0.070 mmol, 16%), colorless solid.
[1917] C.sub.13H.sub.10F.sub.3NO.sub.2S [301.28 g/mol].
[1918] mp=100° C.
[1919] R.sub.f=0.27 (toluene/EtOAc=40:1 (v/v); staining: KMnO.sub.4).
[1920] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.22 (s, 1H, Ar—H), 8.13 (d, .sup.3J=8.1 Hz, 2H, Ar—H), 7.71 (d, .sup.3J=8.2 Hz, 2H, Ar—H), 4.46 (q, .sup.3J=7.1 Hz, 2H, CH.sub.2), 1.44 (t, .sup.3J=7.1 Hz, 3H, CH.sub.3).
[1921] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.1, 161.4, 148.7, 136.0, 132.5 (q, .sup.2J.sub.CF=32.8 Hz), 128.0, 127.4, 126.2 (q, .sup.3J.sub.CF=3.8 Hz), 123.9 (q, .sup.1J.sub.CF=272.3 Hz), 61.8, 14.5.
[1922] HRMS (DI-EI): Calcd. for C.sub.13H.sub.10F.sub.3NO.sub.2S: 301.0384; found: 301.0389.
Example 184: Ethyl 2-(p-tolyl)thiazole-4-carboxylate (DA-04)
[1923] ##STR00261##
[1924] p-Tolylboronic acid (62.2 mg, 0.451 mmol, 1.1 eq), ethyl 2-bromothiazole-4-carboxylate (100.2 mg, 0.424 mmol, 1.0 eq) and cesium fluoride (136.8 mg, 0.900 mmol, 2.1 eq) in 2.0 mL anhydrous DME were reacted in presence of PdCl.sub.2(dppf) (16.0 mg, 0.022 mmol, 5 mol-%) for 92 h at 80° C. according to general procedure A. The crude product was purified via flash column chromatography (20 g SiO.sub.2, cyclohexane/EtOAc 10:1 (v/v), column size 13×2 cm), followed by preparative RP-HPLC (method B).
[1925] Yield: 58.1 mg (0.235 mmol, 55%), pale yellow solid.
[1926] C.sub.13H.sub.13NO.sub.2S [247.31 g/mol].
[1927] mp=39-41° C.
[1928] R.sub.f=0.16 (cyclohexane/EtOAc=10:1 (v/v); staining: KMnO.sub.4).
[1929] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.11 (s, 1H, Ar—H), 7.89 (d, .sup.3J=8.0 Hz, 2H, Ar—H), 7.25 (d, 3J=8.0 Hz, 2H, Ar—H), 4.44 (q, .sup.3J=7.1 Hz, 2H, CH.sub.2), 2.39 (s, 3H, CH.sub.3), 1.42 (t, .sup.3J=7.1 Hz, 3H, CH.sub.2CH.sub.3).
[1930] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=169.2, 161.6, 148.1, 141.2, 130.3, 129.8, 127.0, 126.8, 61.6, 21.6, 14.5.
[1931] HRMS (DI-EI): Calcd. for C.sub.13H.sub.13NO.sub.2S: 247.0667; found: 291.0655.
Example 185: Ethyl 2-(4-isopropylphenyl)thiazole-4-carboxylate (DA-06)
[1932] ##STR00262##
[1933] 4-Isopropylphenylboronic acid (73.2 mg, 0.446 mmol, 1.05 eq), ethyl 2-bromothiazole-4-carboxylate (100.6 mg, 0.424 mmol, 1.0 eq) and cesium fluoride (137.7 mg, 0.906 mmol, 2.1 eq) in 2.0 mL anhydrous DME were reacted in presence of PdCl.sub.2(dppf) (17.2 mg, 0.023 mmol, 5 mol-%) for 50 h at 80° C. according to general procedure A. The crude product was purified via flash column chromatography (17 g SiO.sub.2, cyclohexane/EtOAc 15:1 (v/v), column size 12×2 cm).
[1934] Yield: 23.5 mg (0.085 mmol, 20%), brownish oil.
[1935] C.sub.15H.sub.17NO.sub.2S [275.37 g/mol].
[1936] R.sub.f=0.35 (cyclohexane/EtOAc=5:1 (v/v); staining: KMnO.sub.4).
[1937] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.11 (s, 1H, Ar—H), 7.93 (d, .sup.3J=8.3 Hz, 2H, Ar—H), 7.30 (d, .sup.3J=8.0 Hz, 2H, Ar—H), 4.45 (q, .sup.3J=7.1 Hz, 2H, CH.sub.2), 3.03-2.87 (m, 1H, CH(CH.sub.3).sub.2), 1.43 (t, .sup.3J=7.1 Hz, 3H, CH.sub.2CH.sub.3), 1.28 (d, .sup.3J=6.9 Hz, 6H, CH(CH.sub.3).sub.2).
[1938] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=169.2, 161.7, 152.1, 148.1, 130.7, 127.2, 126.8, 61.6, 34.2, 23.9, 14.5.
[1939] HRMS (DI-EI): Calcd. for C.sub.15H.sub.17NO.sub.2S: 275.0980; found: 275.0978.
Example 186: Ethyl 2-(4-(tert-butyl)phenyl)thiazole-4-carboxylate (DA-08)
[1940] ##STR00263##
[1941] 4-tert-Butylphenylboronic acid (101.5 mg, 0.553 mmol, 1.3 eq), ethyl 2-bromothiazole-4-carboxylate (100.5 mg, 0.426 mmol, 1.0 eq) and cesium fluoride (139.1 mg, 0.915 mmol, 2.1 eq) in 2.0 mL anhydrous DME were reacted in presence of PdCl.sub.2(dppf) (16.1 mg, 0.022 mmol, 5 mol-%) for 71 h at 80° C. according to general procedure A. The crude product was purified 5 via flash column chromatography (17 g SiO.sub.2, cyclohexane/EtOAc 15:1 (v/v), column size 11×2 cm).
[1942] Yield: 60.5 mg (0.209 mmol, 49%), colorless solid.
[1943] C.sub.16H.sub.19NO.sub.2S [289.39 g/mol].
[1944] mp=50-52° C.
[1945] R.sub.f=0.44 (cyclohexane/EtOAc=5:1 (v/v); staining: KMnO.sub.4).
[1946] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.12 (s, 1H, Ar—H), 7.93 (d, .sup.3J=8.3 Hz, 2H, Ar—H), 7.46 (d, .sup.3J=8.3 Hz, 2H, Ar—H), 4.44 (q, .sup.3J=7.1 Hz, 2H, CH.sub.2), 1.42 (t, .sup.3J=7.1 Hz, 3H, CH.sub.3), 1.34 (s, 9H, (CH.sub.3).sub.3).
[1947] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=169.0, 161.5, 154.2, 148.0, 130.2, 126.8, 126.7, 125.9, 61.4, 35.0, 31.2, 14.4.
[1948] HRMS (DI-EI): Calcd. for C.sub.16H.sub.19NO.sub.2S: 289.1136; found: 289.1130.
Example 187: Ethyl 2-(4-(benzyloxy)phenyl)thiazole-4-carboxylate (BB-3-106)
[1949] ##STR00264##
[1950] 4-Benzyloxyphenylboronic acid (272.0 mg, 1.193 mmol, 1.2 eq), ethyl 2-bromothiazole-4-carboxylate (234.6 mg, 0.994 mmol, 1.0 eq) and potassium phosphate (1.59 g, 7.50 mmol, 7.5 eq) in 17 mL 1,4-dioxane/H.sub.2O 5:1 (v/v) were reacted in presence of Pd(OAc).sub.2 (11.2 mg, 0.050 mmol, 5 mol-%) and SPhos (40.6 mg, 0.099 mmol, 10 mol-%) for 8 h at 60° C. according to general procedure B. The crude product was purified via flash column chromatography (46 g SiO.sub.2, cyclohexane/EtOAc 6:1 (v/v), column size 8×3.5 cm) to obtain the pure product as pale pale brown solid.
[1951] Yield: 212.0 mg (0.625 mmol, 63%), pale brown solid.
[1952] C.sub.19H.sub.17NO.sub.3S [339.41 g/mol].
[1953] mp=112-115° C.
[1954] R.sub.f=0.30 (cyclohexane/EtOAc=4:1 (v/v); staining: KMnO.sub.4).
[1955] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.09 (s, 1H, Ar—H), 7.95 (d, .sup.3J=8.6 Hz, 2H, Ar—H), 7.54-7.29 (m, 5H, Ar—H), 7.03 (d, .sup.3J=8.6 Hz, 2H, Ar—H), 5.12 (s, 2H, CH.sub.2), 4.44 (q, .sup.3J=7.1 Hz, 2H, CH.sub.2CH.sub.3), 1.43 (t, .sup.3J=7.1 Hz, 3H, CH.sub.2CH.sub.3).
[1956] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=13C NMR (76 MHz, CDCl.sub.3) δ 168.8, 161.7, 160.9, 148.0, 136.5, 128.8, 128.7, 128.3, 127.6, 126.4, 126.1, 115.3, 70.3, 61.6, 14.5.
[1957] HRMS (DI-EI): Calcd. for C.sub.12H.sub.11NO.sub.2S: 339.0929; found: 339.0916.
Examples 188 to 206
[1958] General Procedures
[1959] General Procedure A (Suzuki Coupling)
[1960] A 50 mL Schlenk-tube with magnetic stirring bar was evacuated and purged with Ar (repeated three times). The Schlenk-tube was subsequently charged with 5 mol-% XPhos Pd G4, 1.5 eq boronic acid (or its derivative), 2.0 eq potassium carbonate, 1.0 eq aryl halide (if solid) and 1,4-dioxane/H.sub.2O 5:1 (v/v). At this point 1.0 eq aryl halide (if liquid) was added via Eppendorf® pipette in an Ar counterstream. The reaction mixture was degassed by evacuation and purging with Ar (repeated three times) and placed in an oil bath at 80° C. After stirring for 22-120 h (reaction control via TLC and HPLC/MS) the reaction mixture was cooled to RT and the filtered through a pad of Celite®. The filter cake was washed with an appropriate amount of EtOAc and the volatiles were removed under reduced pressure. Pure product was obtained via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc), followed by RP preparative HPLC.
[1961] General Procedure B (Suzuki Coupling)
[1962] A 15 mL Schlenk tube with magnetic stirring bar was dried with a heatgun, evacuated and purged with Ar. The Schlenk tube was charged with 1.0 eq isopropyl 6-chloro-4-methoxypicolinate (MC-22) 1.2 eq of the corresponding boronic acid, 2.1 eq cesium fluoride and 5.0 mol-% PdCl.sub.2(dppf) in DME abs. The red suspension was degassed (3×vacuum/Ar cycles) and heated to 80° C. in a pre-heated oil bath. After 5 d the mixture was cooled to RT, filtered through a pad of Celite® and the volatiles were removed under reduced pressure. The crude product was purified via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc), followed by RP preparative HPLC.
[1963] General Procedure C (DCC-Mediated Esterification)
[1964] A 15 mL Schlenk-tube with magnetic stirring bar was evacuated and purged with Ar (repeated three times). The Schlenk tube was charged with a mixture of 71.7 mg (0.295 mmol, 1.0 eq) 6-(4-ethoxyphenyl)picolinic acid (see NG-384) and 1.5-3.0 eq of the corresponding alcohol in 1.5 mL CH.sub.2Cl.sub.2 abs. The suspension was cooled to 0° C. and DMAP (3.6 mg, 29 μmol, 0.1 eq), followed by 84.8 mg (0.442 mmol, 1.5 eq) of EDC hydrochloride were added. The ice bath was removed and the pale-yellow solution was left to spontaneous warmup overnight (reaction control via TLC). The reaction mixture was diluted with 4.5 mL CH.sub.2Cl.sub.2, washed with 1 M HCl (2×3 mL), satd. NaHCO.sub.3 (3 mL) and H.sub.2O (3 mL). The phases were separated and the org. phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The crude product was purified via flash column chromatography (SiO2, cyclohexane/EtOAc).
[1965] General Procedure D (DCC-Mediated Esterification)
[1966] A 15 mL Schlenk-tube with magnetic stirring bar was evacuated and purged with Ar (repeated three times). The Schienk tube was charged with a mixture of 71.7 mg (0.295 mmol, 1.0 eq) 6-(4-ethoxyphenyl)picolinic acid (see NG-384) and 3.0 eq of the corresponding alcohol in 1.5 mL CH.sub.2Cl.sub.2 abs. The suspension was cooled to 0° C. and DMAP (3.6 mg, 29 μmol, 0.1 eq), followed by 84.8 mg (0.442 mmol, 1.5 eq) of EDC hydrochloride were added. The ice bath was removed and the pale-yellow solution was left to spontaneous warmup overnight (reaction control via TLC). The reaction mixture was diluted with 4.5 mL CH.sub.2Cl.sub.2, and washed with H.sub.2O (3×3 mL). The phases were separated and the org. phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The crude product was purified via flash column chromatography (SiO2, cyclohexane/EtOAc).
[1967] General Procedure E (DCC-Mediated Esterification)
[1968] A 15 mL Schlenk tube with magnetic stirring bar was dried with a heatgun, evacuated and purged with Ar. The Schlenk tube was charged with 40.0 mg (0.139 mmol, 1.0 eq) 6-(4-isopropoxyphenyl)-4-methoxypicolinic acid (see CLF-5-397) and 0.7 mL CH.sub.2Cl.sub.2 abs. The suspension was cooled to 0° C. (ice bath) and 3.0 eq of the corresponding alcohol, 1.7 mg (14 μmol, 0.1 eq) DMAP and 40.0 mg (0.209 mmol, 1.5 eq) EDC.HCl were added. The reaction mixture was stirred and left to spontaneous warm up to RT. After 3-16 h the yellow suspension was diluted with 2.2 mL CH.sub.2Cl.sub.2, washed with H.sub.2O (3×1.5 mL) and the phases separated. The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The crude product was purified via flash column chromatography (SiO.sub.2, cyclohexane/EtOAc).
[1969] (Additional) Preparative HPLC Methods
[1970] Method A: 26° C., flow rate 15 mL/min; 0.0-2.0 min MeCN/H.sub.2O=50:50 (v/v), 2.0-17.0 min linear increase to MeCN/H.sub.2O=100:0 (v/v), 17.0-22.0 min hold MeCN/H.sub.2O=100:0 (v/v), 22.0-23.0 min return to initial conditions.
[1971] Method B: 26° C., flow rate 15 mL/min; 0.0-2.0 min MeCN/H.sub.2O=10:90 (v/v), 2.0-17.0 min linear increase to MeCN/H.sub.2O=100:0 (v/v), 17.0-27.0 min hold MeCN/H.sub.2O=100:0 (v/v), 27.0-28.0 min return to initial conditions.
[1972] Method C: 26° C., flow rate 15 mL/min; 0.0-5.0 min MeCN/H.sub.2O=30:70 (v/v), 5.0-20.0 min linear increase to MeCN/H.sub.2O=100:0 (v/v), 20.0-30.0 min hold MeCN/H.sub.2O=100:0 (v/v), 30.0-31.0 min return to initial conditions.
Example 188: Ethyl 2-(4-hydroxyphenyl)thiazole-4-carboxylate
[1973] ##STR00265##
[1974] 4-Hydroxyphenylboronic acid (87.6 mg, 0.635 mmol, 1.5 eq), ethyl 2-bromothiazole-4-carboxylate (100 mg, 0.424 mmol, 1.0 eq) and potassium carbonate (117 mg, 0.847 mmol, 2.0 eq) in 6.0 mL 1,4-dioxane/H.sub.2O 5:1 (v/v) were reacted in presence of XPhos Pd G4 (18.2 mg, 21.2 μmol, 5 mol-%) for 22 h at 80° C. according to general procedure A. The crude product was purified via flash column chromatography (16 g SiO.sub.2, cyclohexane/EtOAc 5:1 (v/v), column size 11×2 cm), followed by preparative RP-HPLC (method A).
[1975] Yield: 35.2 mg (0.141 mmol, 33%), colorless solid.
[1976] mp=171° C.
[1977] C.sub.12H.sub.11NO.sub.3S [249.28 g/mol].
[1978] R.sub.f=0.22 (cyclohexane/EtOAc=5:1 (v/v); staining: CAM).
[1979] .sup.1H NMR (300 MHz, MeOD-d.sub.4): δ=8.25 (s, 1H, Ar—H), 7.85 (d, .sup.3J=8.7 Hz 1H, Ar—H), 6.88 (d, .sup.3J=8.7 Hz, 1H, Ar—H), 4.40 (q, .sup.3J=7.1 Hz, 2H, CH.sub.2), 1.40 (t, .sup.3J=7.1 Hz, 3H, CH.sub.3). .sup.13C NMR (76 MHz, MeOD-d.sub.4): δ=171.1, 162.9, 161.6, 148.4, 129.6 (2C), 127.8, 125.6, 116.9 (2C), 62.5, 14.6.
[1980] HRMS (DI-EI): Calcd. m/z for C.sub.12H.sub.11NO.sub.3S: 249.0460; found: 249.0461.
Example 189: Thiophen-2-ylmethyl 6-(4-ethoxyphenyl)picolinate
[1981] ##STR00266##
[1982] According to general procedure C; 101 mg (0.884 mmol, 3.0 eq) 2-thiophenemethanol, 18 h reaction time. Purification was performed via flash column chromatography (13 g SiO.sub.2, cyclohexane/EtOAc 5:1 (v/v), column size 10×2 cm).
[1983] Yield: 67.9 mg (0.200 mmol, 68%), colorless solid.
[1984] C.sub.19H.sub.17NO.sub.3S [339.41 g/mol].
[1985] mp=93-94° C.
[1986] R.sub.f=0.38 (cyclohexane/EtOAc=5:1 (v/v); staining: CAM).
[1987] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.14-7.91 (m, 3H, Ar—H), 7.89-7.74 (m, 2H, Ar—H), 7.38-7.30 (m, 1H, Ar—H), 7.23 (d, .sup.3J=2.6 Hz, 1H, Ar—H), 7.09-6.91 (m, 3H, Ar—H), 5.61 (s, 2H, CH.sub.2), 4.09 (q, .sup.3J=6.9 Hz, 2H, CH.sub.2), 1.44 (t, .sup.3J=6.9 Hz, 3H, CH.sub.3).
[1988] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.3, 160.4, 157.5, 147.8, 137.8, 137.6, 130.9, 128.7, 128.6 (2C), 127.1, 126.9, 122.9, 122.9′, 114.8 (2C), 63.7, 61.7, 14.9.
[1989] HRMS (DI-EI): Calcd. m/z for C.sub.19H.sub.17NO.sub.3S: 339.0929; found: 339.0929.
Example 190: Furan-2-ylmethyl 6-(4-ethoxyphenyl)picolinate
[1990] ##STR00267##
[1991] According to general procedure C; 86.7 mg (0.884 mmol, 3.0 eq) furfuryl alcohol, 18 h reaction time. Purification was performed via flash column chromatography (14 g SiO.sub.2, cyclohexane/EtOAc 5:1 (v/v), column size 7×2.5 cm).
[1992] Yield: 64.5 mg (0.199 mmol, 68%), off-white solid.
[1993] C.sub.19H.sub.17NO.sub.4 [323.35 g/mol].
[1994] mp=76-80° C.
[1995] R.sub.f=0.30 (cyclohexane/EtOAc=5:1 (v/v); staining: CAM).
[1996] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.10-7.90 (m, 3H, Ar—H), 7.89-7.74 (m, 2H, Ar—H), 7.55-7.37 (m, 1H, Ar—H), 6.98 (d, .sup.3J=8.7 Hz, 2H, Ar—H), 6.54 (d, .sup.3J=2.8 Hz, 2H, Ar—H), 6.45-6.32 (m, 1H, Ar—H), 5.40 (s, 2H, CH.sub.2) 4.09 (q, .sup.3J=6.9 Hz, 2H, CH.sub.2), 1.44 (t, .sup.3J=7.0 Hz, 3H, CH.sub.3). .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.2, 160.4, 157.5, 149.48, 147.8, 143.4, 137.6, 131.0, 128.6 (2C), 122.9 (2C), 114.8 (2C), 111.3, 110.8, 63.7, 59.2, 14.9.
[1997] HRMS (DI-EI): Calcd. m/z for C.sub.19H.sub.17NO.sub.4: 323.1158; found: 323.1155.
Example 191: 2-(Furan-2-yl)ethyl 6-(4-ethoxyphenyl)picolinate
[1998] ##STR00268##
[1999] According to general procedure C; 49.6 mg (0.442 mmol, 1.5 eq) 2-furanethanol, 20 h reaction time. Purification was performed via flash column chromatography (9 g SiO.sub.2, cyclohexane/EtOAc 5:1 (v/v), column size 7×2 cm).
[2000] Yield: 60.8 mg (0.180 mmol, 61%), colorless solid.
[2001] C.sub.20H.sub.19NO.sub.4 [337.38 g/mol].
[2002] mp=82-84° C.
[2003] R.sub.f=0.31 (cyclohexane/EtOAc=5:1 (v/v); staining: CAM).
[2004] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.10-7.75 (m, 5H, Ar—H), 7.42-7.30 (m, 1H, Ar—H), 6.99 (d, .sup.3J=8.8 Hz, 2H, Ar—H), 6.39-6.26 (m, 1H, Ar—H), 6.25-6.13 (m, 1H, Ar—H), 4.65 (t, .sup.3J=6.9 Hz, 2H, CH.sub.2CH.sub.2), 4.09 (q, .sup.3J=6.9 Hz, 2H, CH.sub.2CH.sub.3), 3.19 (t, .sup.3J=6.8 Hz, 2H, CH.sub.2CH.sub.2), 1.44 (t, .sup.3J=7.0 Hz, 3H, CH.sub.2CH.sub.3).
[2005] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.4, 160.4, 157.4, 151.9, 148.0, 141.6, 137.6, 131.0, 128.6 (2C), 122.8, 122.7, 114.8 (2C), 110.4, 106.7, 63.7, 63.6, 27.9, 14.9.
[2006] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.19NO.sub.4: 337.1314; found: 337.1330.
Example 192: Pyridin-2-ylmethyl 6-(4-ethoxyphenyl)picolinate
[2007] ##STR00269##
[2008] According to general procedure C; 96.5 mg (0.884 mmol, 3.0 eq) 2-pyridinemethanol, 19 h reaction time. Purification was performed via flash column chromatography (13 g SiO.sub.2, cyclohexane/EtOAc 5:1 (v/v), column size 7×2 cm).
[2009] Yield: 56.7 mg (0.170 mmol, 57%), colorless solid.
[2010] C.sub.20H.sub.18N.sub.2O.sub.3 [334.38 g/mol].
[2011] mp=124-127° C.
[2012] R.sub.f=0.37 (cyclohexane/EtOAc=1:1 (v/v); staining: CAM).
[2013] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.62 (d, J=4.0 Hz, 1H, Ar—H), 8.15-7.94 (m, 3H, Ar—H), 7.92-7.78 (m, 2H, Ar—H), 7.77-7.66 (m, 1H, Ar—H), 7.55 (d, .sup.3J=7.7 Hz, 1H, Ar—H), 7.32-7.16 (m, 1H, Ar—H), 6.99 (d, .sup.3J=8.8 Hz, 2H, Ar—H), 5.58 (s, 2H, CH.sub.2), 4.09 (q, .sup.3J=6.9 Hz, 2H, CH.sub.2), 1.44 (t, .sup.3J=7.0 Hz, 3H, CH.sub.3).
[2014] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.3, 160.4, 157.5, 156.01, 149.5, 147.8, 137.6, 137.0, 130.9, 128.6 (2C), 123.0 (3C), 121.9, 114.8 (2C), 67.8, 63.7, 14.9.
[2015] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.18N.sub.2O.sub.3: 334.1317; found: 334.1313.
Example 193: Pyridin-3-ylmethyl 6-(4-ethoxyphenyl)picolinate
[2016] ##STR00270##
[2017] According to general procedure D; 96.5 mg (0.884 mmol, 3.0 eq) 3-pyridinemethanol, 17 h reaction time. Purification was performed via flash column chromatography (10 g SiO.sub.2, cyclohexane/EtOAc 1:1 (v/v), column size 8×2 cm).
[2018] Yield: 71.3 mg (0.213 mmol, 72%), colorless solid.
[2019] C.sub.20H.sub.18N.sub.2O.sub.3 [334.38 g/mol].
[2020] mp=107-110° C.
[2021] R.sub.f=0.23 (cyclohexane/EtOAc=1:1 (v/v); staining: CAM).
[2022] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.78 (s, 1H, Ar—H), 8.68-8.52 (m, 1H, Ar—H), 8.15-7.92 (m, 3H, Ar—H), 7.91-7.72 (m, 3H, Ar—H), 7.42-7.28 (m, 1H, Ar—H), 6.98 (d, .sup.3J=8.8 Hz, 2H, Ar—H), 5.47 (s, 2H, CH.sub.2), 4.08 (q, .sup.3J=6.9 Hz, 2H, CH.sub.2), 1.43 (t, .sup.3J=7.0 Hz, 3H, CH.sub.3).
[2023] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.4, 160.4, 157.6, 149.9, 149.8, 147.6, 137.7, 136.3, 131.7, 130.8, 128.6 (2C), 123.6, 123.1, 122.8, 114.9 (2C), 64.8, 63.7, 14.9.
[2024] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.18N.sub.2O.sub.3: 334.1317; found: 334.1312.
Example 194: Pyridin-4-ylmethyl 6-(4-ethoxyphenyl)picolinate
[2025] ##STR00271##
[2026] According to general procedure D; 96.5 mg (0.884 mmol, 3.0 eq) 4-pyridinemethanol, 17 h reaction time. Purification was performed via flash column chromatography (10 g SiO.sub.2, cyclohexane/EtOAc 1:1 (v/v), column size 7×2 cm).
[2027] Yield: 61.8 mg (0.185 mmol, 63%), pale yellow solid.
[2028] C.sub.20H.sub.18N.sub.2O.sub.3[334.38 g/mol].
[2029] mp=101-106° C.
[2030] R.sub.f=0.78 (CH.sub.2Cl.sub.2/MeOH=15:1 (v/v), staining: CAM).
[2031] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.63 (d, .sup.3J=4.7 Hz, 2H, NCH), 8.03-7.98 (m, 3H, 2×Ph-H and 1×Py-H), 7.93-7.78 (m, 2H, Py-H), 7.40 (d, .sup.3J=4.8 Hz, 2H, NCHCH), 6.99 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 5.46 (s, 2H, CO.sub.2CH.sub.2), 4.09 (q, .sup.3J=7.0 Hz, 2H, CH.sub.2CH.sub.3), 1.44 (t, .sup.3J=7.0 Hz, 3H, CH.sub.3).
[2032] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.2, 160.5, 157.6, 150.2 (2C), 147.5, 145.1, 137.7, 130.8, 128.6 (2C), 123.2, 122.9, 122.0 (2C), 114.9 (2C), 65.3, 63.7, 14.9.
[2033] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.18N.sub.2O.sub.3: 334.1317; found: 334.1319.
Example 195: 2-(Thiophen-2-yl)ethyl 6-(4-ethoxyphenyl)picolinate
[2034] ##STR00272##
[2035] According to general procedure D; 271 μL (0.884 mmol, 3.0 eq) 2-thiopheneethanol, 15 h reaction time. Purification was performed via flash column chromatography (30 g SiO.sub.2, cyclohexane/EtOAc 10:1 (v/v), column size 10×3 cm).
[2036] Yield: 53.4 mg (0.151 mmol, 51%), beige solid.
[2037] C.sub.20H.sub.19NO.sub.3S [353.44 g/mol].
[2038] mp=73-78° C.
[2039] R.sub.f=0.94 (CH.sub.2Cl.sub.2/MeOH=15:1, staining: CAM).
[2040] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.05 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 8.00-7.95 (m, 1H, Py-H), 7.88-7.81 (m, 2H, Py-H), 7.23-7.13 (m, 1H, SCH), 7.08-6.91 (m, 4H, 2×Ph-H and 2×thiophene), 4.63 (t, .sup.3J=6.8, 2H, OCH.sub.2CH.sub.2), 4.10 (q, 3J=6.9 Hz, 2H, CH.sub.2CH.sub.3), 3.37 (t, .sup.3J=6.7 Hz, 2H, OCH.sub.2CH.sub.2) 1.45 (t, .sup.3J=7.0, 3H, CH.sub.3).
[2041] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.5, 160.4, 157.4, 147.9, 139.9, 137.6, 131.0, 128.6 (2C), 127.1, 125.9, 124.2, 122.8 (2C), 114.8 (2C), 65.9, 63.7, 29.5, 14.9.
[2042] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.19NO.sub.3S: 353.1086; found: 353.1093.
Example 196: 2-(Thiophen-3-yl)ethyl 6-(4-ethoxyphenyl)picolinate
[2043] ##STR00273##
[2044] According to general procedure D; 99.1 μL (0.884 mmol, 3.0 eq) 3-thiopheneethanol, 16 h reaction time. Purification was performed via flash column chromatography (20 g SiO.sub.2, cyclohexane/EtOAc 10:1 (v/v), column size 10×3 cm).
[2045] Yield: 61.5 mg (0.174 mmol, 59%), colorless solid.
[2046] C.sub.20H.sub.19NO.sub.3S [353.44 g/mol].
[2047] mp=73-76° C.
[2048] R.sub.f=0.96 (CH.sub.2Cl.sub.2/MeOH=15:1 (v/v), staining: CAM).
[2049] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.04 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 7.98-7.89 (m, 1H, Py-H), 7.88-7.80 (m, 2H, Py-H), 7.33-7.24 (m, 1H, SCHCH), 7.21-7.09 (m, 2H, Ar—H from thiophene), 7.00 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 4.61 (t, .sup.3J=6.9 Hz, 2H, OCH.sub.2CH.sub.2), 4.11 (q, .sup.3J=6.9 Hz, 2H, CH.sub.2CH.sub.3), 3.18 (t, .sup.3J=6.8 Hz, 2H, OCH.sub.2CH.sub.2), 1.45 (t, .sup.3J=7.0 Hz, 3H, CH.sub.3).
[2050] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.6, 160.4, 157.4, 148.1, 138.2, 137.6, 131.0, 128.7, 128.6 (2C), 125.7, 122.8, 122.6, 122.0, 114.9 (2C), 65.6, 63.7, 29.8, 14.92.
[2051] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.19NO.sub.3S: 353.1085; found: 353.1089.
Example 197: Thiophen-3-ylmethyl 6-(4-ethoxyphenyl)picolinate
[2052] ##STR00274##
[2053] According to general procedure D; 83.4 μL (0.884 mmol, 3.0 eq) 3-thiophenemethanol, 19 h reaction time. Purification was performed via flash column chromatography (15 g SiO.sub.2, cyclohexane/EtOAc 10:1 (v/v), column size 10×2 cm).
[2054] Yield: 61.1 mg (0.181 mmol, 62%), beige solid.
[2055] C.sub.19H.sub.17NO.sub.3S [339.41 g/mol].
[2056] mp=90-93° C.
[2057] R.sub.f=0.98 (CH.sub.2Cl.sub.2/MeOH=15:1 (v/v), staining: CAM).
[2058] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.09-7.92 (m, 3H, 2×Ph-H and 1×Py-H), 7.87-7.77 (m, 2H, Py-H), 7.44 (s, 1H, SCHC), 7.38-7.28 (m, 1H, SCHCH), 7.27-7.16 (m, 1H, SCHCH), 6.99 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 5.46 (s, 2H, CO.sub.2CH.sub.2), 4.09 (q, .sup.3J=6.9 Hz, 2H, CH.sub.2, CH.sub.3), 1.44 (t, .sup.3J=7.0 Hz, 3H, CH.sub.3).
[2059] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.4, 160.4, 157.5, 148.0, 137.6, 136.8, 131.0, 128.6 (2C), 127.9, 126.3, 124.8, 122.9, 122.8, 114.8 (2C), 63.7, 62.5, 14.9.
[2060] HRMS (DI-EI): Calcd. m/z for C.sub.19H.sub.17NO.sub.3S: 339.0929; found: 339.0925.
Example 198: Furan-3-ylmethyl 6-(4-ethoxyphenyl)picolinate
[2061] ##STR00275##
[2062] According to general procedure D; 76.2 μL (0.884 mmol, 3.0 eq) 3-furanmethanol, 18 h reaction time. Purification was performed via flash column chromatography (15 g SiO.sub.2, cyclohexane/EtOAc 10:1 (v/v), column size 10×2 cm).
[2063] Yield: 52.6 mg (0.163 mmol, 55%), pale yellow solid.
[2064] C.sub.19H.sub.17NO.sub.4 [323.35 g/mol].
[2065] mp=97-101° C.
[2066] R.sub.f=0.98 (CH.sub.2Cl.sub.2/MeOH=15:1 (v/v), staining: CAM).
[2067] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.07-7.91 (m, 3H, 2×Ph-H and 1×Py-H), 7.86-7.77 (m, 2H, Py-H), 7.60 (s, 1H, OCHC), 7.42 (s, 1H, OCHCH), 6.98 (d, .sup.3J=8.5 Hz, 2H, Ph-H), 6.56 (s, 1H, OCHCH), 5.32 (s, 2H, CO.sub.2CH.sub.2), 4.09 (q, .sup.3J=6.8 Hz, 2H, CH.sub.2CH.sub.3), 1.44 (t, .sup.3J=6.8 Hz, 3H, CH.sub.3).
[2068] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.5, 160.4, 157.5, 148.0, 143.5, 142.1, 137.6, 131.0, 128.6 (2C), 122.9, 122.8, 120.4, 114.8 (2C), 111.0, 63.7, 59.0, 14.9.
[2069] HRMS (DI-EI): Calcd. m/z for C.sub.19H.sub.17NO.sub.4: 323.1158; found: 323.1157.
Example 199: Thiazol-5-ylmethyl 6-(4-ethoxyphenyl)picolinate
[2070] ##STR00276##
[2071] According to general procedure D; 77.1 μL (0.884 mmol, 3.0 eq) 5-thiazolemethanol, 16 h reaction time. Purification was performed via flash column chromatography (10 g SiO.sub.2, cyclohexane/EtOAc 10:1.fwdarw.1:1 (v/v), column size 7×2 cm), followed by preparative RP-HPLC (method B).
[2072] Yield: 44.7 mg (0.131 mmol, 45%), pale yellow solid.
[2073] C.sub.18H.sub.16N.sub.2O.sub.3S [340.40 g/mol].
[2074] mp=75-80° C.
[2075] R.sub.f=0.98 (CH.sub.2Cl.sub.2/MeOH=15:1 (v/v), staining: CAM).
[2076] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=8.84 (s, 1H, SCHN), 8.08-7.91 (m, 4H, 2×Ph-H, 1×Ar—H from thiazole, 1×Py-H), 7.88-7.77 (m, 2H, Py-H), 6.98 (d, 3J=8.5 Hz, 2H, Ph-H), 5.65 (s, 2H, CO.sub.2CH.sub.2), 4.08 (q, .sup.3J=6.8 Hz, 2H, CH.sub.2CH.sub.3), 1.43 (t, .sup.3J=6.8 Hz, 3H, CH.sub.3).
[2077] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=165.3, 160.5, 157.6, 155.0, 147.4, 144.3, 137.7, 132.6, 130.8, 128.6 (2C), 123.2, 122.9, 114.9 (2C), 63.7, 58.9, 14.9.
[2078] HRMS (DI-EI): Calcd. m/z for C.sub.18H.sub.16N.sub.2O.sub.3S: 340.0882; found: 340.0885.
Example 200: Methyl 6-(4-isopropoxyphenyl)-4-methoxypicolinate
[2079] ##STR00277##
[2080] An inert 500 mL round bottom flask with Schienk adapter and a magnetic stirring bar was charged with a solution of 3.00 g (14.9 mmol, 1.0 eq) methyl 6-chloro-4-methoxypicolinate in 175 mL degassed DME abs. 4-Isopropoxyphenylboronic acid (3.48 g, 19.3 mmol, 1.3 eq), cesium fluoride (4.75 g, 31.2 mmol, 2.1 eq) and 540 mg (0.744 mmol, 5.0 mol-%) PdCl.sub.2(dppf) were added subsequently and the red suspension was heated to 80° C. (oil bath). After 21 h the reaction mixture was cooled to RT, filtered through a pad of Celite® and the filter cake was washed with EtOAc (4×50 mL). The solvent was removed under reduced pressure and the crude product was dried in oil-pump vacuum. Purification via flash column chromatography (570 g SiO.sub.2, cyclohexane/EtOAc 4:1 (v/v), column size 26×7.5 cm) yielded the product as a pale-yellow solid.
[2081] Yield: 3.93 g (13.0 mmol, 88%), colorless solid.
[2082] mp=87-90° C.
[2083] C.sub.17H.sub.19NO.sub.4 [301.34 g/mol].
[2084] R.sub.f=0.28 (cyclohexane/EtOAc=4:1 (v/v); staining: KMnO.sub.4).
[2085] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.94 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 7.54 (d, 4J=2.1 Hz, 1H, Py-H), 7.29 (d, 4J=2.1 Hz, 1H, Py-H), 6.95 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 4.62 (hept, .sup.3J=6.0 Hz, 1H, CH(CH.sub.3).sub.2), 4.00 (s, 3H, CO.sub.2CH.sub.3), 3.94 (s, 3H, OCH.sub.3), 1.34 (d, .sup.3J=6.0 Hz, 6H, CH(CH.sub.3).sub.2).
[2086] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.3, 166.3, 159.3, 159.2, 149.6, 131.1, 128.7 (2C), 116.1 (2C), 109.1, 109.0, 70.1, 55.7, 53.0, 22.1.
Intermediate 6-(4-isopropoxyphenyl)-4-methoxypicolinic acid
[2087] ##STR00278##
[2088] To the vigorously stirred solution of CLF-5-394 (3.93 g, 13.0 mmol, 1.0 eq) in 43 mL THF a solution of 2.19 g (52.2 mmol, 4.0 eq) LiOH×H.sub.2O in 65 mL H.sub.2O was added at RT. After 20 min the pale-yellow solution was acidified to pH=2 with 6 M HCl. The mixture was transferred into a separation funnel and the product extracted with EtOAc (3×110 mL). The phases were separated, the combined organic phases dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The crude product was dried in oil-pump vacuum and directly used without further purification.
[2089] Yield: 3.75 g (13.0 mmol, quant.), colorless solid.
[2090] C.sub.16H.sub.17NO.sub.4 [287.32 g/mol].
Example 201: Isopropyl 6-(4-isopropoxyphenyl)-4-methoxypicolinate
[2091] ##STR00279##
[2092] An inert 250 mL round bottom flask with a Schlenk adapter and a magnetic stirring bar was charged with a solution of CLF-5-397 (3.75 g, 31.0 mmol, 1.0 eq) and 5.0 mL (65 mmol, 5.0 eq) 2-propanol in 70 mL CH.sub.2Cl.sub.2 abs. The solution was cooled to 0° C. and DMAP (159 mg, 1.30 mmol, 0.1 eq), followed by 3.75 g (19.6 mmol, 1.5 eq) of EDC hydrochloride were added. The ice bath was removed and the pale-yellow solution was left to spontaneous warmup overnight. After 15 h reaction time the mixture was diluted with 70 mL CH.sub.2Cl.sub.2, transferred into a separation funnel and washed with H.sub.2O (2×70 mL). The phases were separated and the org. phase was evaporated. The crude product was dried in oil-pump vacuum and purified via flash column chromatography (550 g SiO.sub.2, cyclohexane/EtOAc 4:1 (v/v), column size 24×7.5 cm).
[2093] Yield: 3.89 g (11.8 mmol, 91%), colorless solid.
[2094] mp=70-71° C.
[2095] C.sub.19H.sub.23NO.sub.4 [329.40 g/mol].
[2096] R.sub.f=0.40 (cyclohexane/EtOAc=4:1 (v/v); staining: KMnO.sub.4).
[2097] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.99 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 7.51 (d, .sup.4J=2.1 Hz, 1H, Py-H), 7.30 (d, .sup.4J=2.1 Hz, 1H, Py-H), 6.96 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 5.31 (hept, .sup.3J=6.2 Hz, 1H, CO.sub.2CH(CH.sub.3).sub.2), 4.62 (hept, .sup.3J=5.6 Hz, 1H, OCH(CH.sub.3).sub.2), 3.95 (s, 3H, CO.sub.2CH.sub.3), 3.94 (s, 3H, OCH.sub.3), 1.43 (d, .sup.3J=6.2 Hz, 6H, CO.sub.2CH(CH.sub.3), 1.36 (d, .sup.3J=6.0 Hz, 6H, OCH(CH.sub.3).sub.2).
[2098] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.2, 165.2, 159.3, 159.0, 150.3, 131.2, 128.7 (2C), 116.0 (2C), 108.95, 109.0, 70.1, 69.6, 55.6, 22.1, 22.0.
[2099] HRMS (DI-EI): Calcd. m/z for C.sub.19H.sub.23NO.sub.4: 329.1627; found: 329.1628.
Example 202: sec-Butyl 6-(4-Isopropoxyphenyl)-4-methoxypicolinate
[2100] ##STR00280##
[2101] According to general procedure E; 38.2 μL (0.418 mmol, 3.0 eq) butan-2-ol, 16 h reaction time. Purification was performed via flash column chromatography (8 g SiO.sub.2, cyclohexane/EtOAc 8:1 (v/v), column size 10×1.5 cm).
[2102] Yield: 25.0 mg (72.8 μmol, 53%), beige solid.
[2103] C.sub.20H.sub.25NO.sub.4 [343.42 g/mol].
[2104] mp=68° C.
[2105] R.sub.f=0.93 (CH.sub.2Cl.sub.2/MeOH=9:1 (v/v)+AcOH, staining: KMnO.sub.4).
[2106] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.99 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 7.50 (d, .sup.4J=2.0 Hz, 1H, Py-H), 7.30 (d, .sup.4J=2.0 Hz, 1H, Py-H), 6.96 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 5.22-5.06 (m, 1H, CHCH.sub.2), 4.62 (hept, 3J=6.0 Hz, 1H, CH(CH.sub.3).sub.2), 3.94 (s, 3H, OCH.sub.3), 1.91-1.62 (m, 2H, CH.sub.2), 1.43-1.30 (m, 9H, 3×CH.sub.3), 1.01 (t, .sup.3J=7.4 Hz, 3H, CH.sub.2CH.sub.3).
[2107] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.2, 165.3, 159.3, 159.0, 150.3, 131.2, 128.7 (2C), 116.0 (2C), 109.0, 108.2, 74.0, 70.1, 55.6, 29.0, 22.1 (2C), 19.6, 9.9.
[2108] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.25NO.sub.4: 343.1783; found: 343.1781.
Example 203: Cyclobutyl 6-(4-isopropoxyphenyl)-4-methoxypicolinate
[2109] ##STR00281##
[2110] According to general procedure E; 32.7 μL (0.418 mmol, 3.0 eq) cyclobutanol, 3 h reaction time. Purification was performed via flash column chromatography (6 g SiO.sub.2, cyclohexane/EtOAc 8:1 (v/v), column size 22×1 cm), followed by preparative RP-HPLC (method C).
[2111] Yield: 29.8 mg (87.3 μmol, 63%), colorless solid.
[2112] C.sub.20H.sub.23NO.sub.4 [341.41 g/mol].
[2113] mp=116-118° C.
[2114] R.sub.f=0.96 (CH.sub.2Cl.sub.2/MeOH=9:1 (v/v)+AcOH, staining: KMnO.sub.4).
[2115] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.98 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 7.53 (d, .sup.4J=2.1 Hz, 1H, Py-H), 7.30 (d, .sup.4J=2.1 Hz, 1H, Py-H), 6.96 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 5.32-5.17 (m, 1H, CH), 4.62 (hept, .sup.3J=6.0 Hz, 1H, CH(CH.sub.3).sub.2), 3.94 (s, 3H, OCH.sub.3), 2.58-2.22 (m, 4H, CH.sub.2), 1.96-1.62 (m, 2H, CH.sub.2), 1.36 (d, .sup.3J=6.0 Hz, 6H, CH(CH.sub.3).sub.2).
[2116] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.3, 165.1, 159.3, 159.0, 149.8, 131.1, 128.7 (2C), 116.0 (2C), 108.9, 108.7, 70.4, 70.1, 55.6, 30.5 (2C), 22.1 (2C), 13.8.
[2117] HRMS (DI-EI): Calcd. m/z for C.sub.20H.sub.23NO.sub.4: 341.1627; found: 341.1633.
Example 204: Propan-2-yl-d.SUB.7 .6-(4-isopropoxyphenyl)-4-methoxypicolinate
[2118] ##STR00282##
[2119] According to general procedure E; 32.0 μL (0.418 mmol, 3.0 eq) 2-propanol-d.sub.8, 3 h reaction time. Purification was performed via flash column chromatography (6 g SiO.sub.2, cyclohexane/EtOAc 5:1 (v/v), column size 22×1 cm), followed by preparative RP-HPLC (method C).
[2120] Yield: 32.1 mg (95.4 μmol, 69%), colorless solid.
[2121] C.sub.19H.sub.16D.sub.7NO.sub.4 [336.44 g/mol].
[2122] mp=70-72° C.
[2123] R.sub.f=0.85 (CH.sub.2Cl.sub.2/MeOH=9:1 (v/v)+AcOH, staining: KMnO.sub.4).
[2124] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.99 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 7.50 (d, .sup.3J=2.0 Hz, 1H, Py-H), 7.29 (d, .sup.4J=2.0 Hz, 1H, Py-H), 6.96 (d, .sup.3J=8.7 Hz, 2H, Ph-H), 4.62 (hept, .sup.3J=6.0 Hz, 1H, CH(CH.sub.3).sub.2), 3.94 (s, 3H, OCH.sub.3), 1.36 (d, .sup.3J=6.0 Hz, 6H, CH(CH.sub.3).sub.2).
[2125] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.2, 165.2, 159.3, 159.0, 150.3, 131.2, 128.7 (2C), 116.0 (2C), 108.9, 108.4, 70.1, 55.6, 22.1 (2C), CO.sub.2CD and 2×CD.sub.3 not visible.
[2126] HRMS (DI-EI): Calcd. m/z for C.sub.19H.sub.16D.sub.7NO.sub.4: 336.2066; found: 336.2079.
Intermediate 6-Chloro-4-methoxypicolinic acid
[2127] ##STR00283##
[2128] 250 mg (1.24 mmol, 1.0 eq) methyl 6-chloro-4-methoxypicolinate were dissolved in 4.1 mL THF in a 25 mL round bottom flask with magnetic stirring bar and a solution of 208 mg (4.96 mmol, 4.0 eq) LiOH×H.sub.2O in 6.2 mL H.sub.2O was added under vigorous stirring at RT. After 30 min the pale yellow solution was acidified to pH=2 with 4 M HCl. The product was extracted with EtOAc (3×13 mL). The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the volatiles were removed under reduced pressure. The colorless solid was dried in oil-pump vacuum and used without further purification.
[2129] Yield: 228 mg (1.22 mmol, 98%), colorless solid.
[2130] C.sub.7H.sub.6ClNO.sub.3 [187.58 g/mol].
Intermediate Isopropyl 6-chloro-4-methoxypicolinate
[2131] ##STR00284##
[2132] A 30 mL Schlenk tube with magnetic stirring bar was dried with a heatgun, evacuated and purged with Ar. The Schlenk tube was charged with 228 mg (1.22 mmol, 1.0 eq) 6-chloro-4-methoxypicolinic acid (MC-21) and 6.0 mL CH.sub.2Cl.sub.2 abs. The suspension was cooled to 0° C. (ice bath) and subsequently 0.932 μL (12.2 mmol, 10.0 eq) propan-2-ol, 14.9 mg (0.122 mmol, 0.1 eq) DMAP and 350 mg (1.83 mmol, 1.5 eq) EDC.HCl were added. The reaction mixture was stirred and left to spontaneous warm up to RT. After 3 h the pale yellow suspension was diluted with 18.0 mL CH.sub.2Cl.sub.2, washed with H.sub.2O (3×12 mL) and the phases separated. The organic phase was dried over Na.sub.2SO.sub.4, filtered, and the solvent was removed under reduced pressure. The brown oil was purified via flash column chromatography (25 g SiO.sub.2, column size 7×3 cm, cyclohexane/EtOAc=5:1 (v/v)).
[2133] Yield: 216 mg (0.941 mmol, 77%) beige solid.
[2134] C.sub.10H.sub.12ClNO.sub.3 [229.66 g/mol].
[2135] mp=60-62° C.
[2136] R.sub.f=0.33 (cyclohexane/EtOAc=5:1 (v/v), staining: KMnO.sub.4).
[2137] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.51 (d, .sup.4J=2.0 Hz, 1H, Ar—H), 6.93 (d, .sup.4J=2.0 Hz, 1H, Ar—H), 5.24 (hept, .sup.3J=6.3 Hz, 1H, CH(CH.sub.3).sub.2), 3.88 (s, 3H, OCH.sub.3), 1.36 (d, .sup.3J=6.3 Hz, 6H, CH(CH.sub.3).sub.2).
[2138] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.9, 163.5, 152.7, 149.8, 112.3, 111.5, 70.1, 56.1, 21.8 (2C).
Example 205: Isopropyl 6-(4-ethylphenyl)-4-methoxypicolinate
[2139] ##STR00285##
[2140] Isopropyl 6-chloro-4-methoxypicolinate (MC-22) (72.8 mg, 0.317 mmol, 1.0 eq), 4-ethylphenylboronic acid (54.9 mg, 0.366 mmol, 1.2 eq) and cesium fluoride (97.2 mg, 64.0 μmol, 2.1 eq) in 2.7 mL DME abs. were reacted in presence of PdCl.sub.2(dppf) (11.2 mg, 15.3 μmol, 5.0 mol-%) for 5 d at 80° C. according to general procedure B. The crude product was purified via flash column chromatography (18 g SiO.sub.2, cyclohexane/EtOAc=5:1 (v/v), column size column size 12×2 cm), followed by preparative RP-HPLC (method C).
[2141] Yield: 39.3 mg (0.131 mmol, 41%), colorless solid.
[2142] C.sub.18H.sub.21NO.sub.3 [299.37 g/mol].
[2143] mp=51° C.
[2144] R.sub.f=0.42 (cyclohexane/EtOAc=5:1 (v/v), staining: KMnO.sub.4).
[2145] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.97 (d, .sup.3J=8.1 Hz, 2H, Ph-H), 7.54 (d, 4J=2.1 Hz, 1H, Py-H), 7.37-7.23 (m, 3H, 1×Py-H and 2×Ph-H), 5.31 (hept, .sup.3J=6.3 Hz, 1H, CH(CH.sub.3).sub.2), 3.94 (s, 3H, OCH.sub.3), 2.70 (q, .sup.3J=7.5 Hz, 2H, CH.sub.2), 1.43 (d, .sup.3J=6.2 Hz, 6H, CH(CH.sub.3).sub.2), 1.26 (t, .sup.3J=7.6 Hz, 3H, CH.sub.2CH.sub.3).
[2146] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.2, 165.1, 159.3, 150.4, 145.9, 136.3, 128.3 (2C), 127.3 (2C), 109.3, 109.0, 69.6, 55.6, 28.8, 22.0 (2C), 15.6.
[2147] HRMS (DI-EI): Calcd. m/z for C.sub.15H.sub.21NO.sub.3: 299.1521; found: 299.1528.
Example 206: Isopropyl 4-methoxy-6-(4-methoxyphenyl)picolinate
[2148] ##STR00286##
[2149] Isopropyl 6-chloro-4-methoxypicolinate (MC-22) (69.6 mg, 0.303 mmol, 1.0 eq), 4-methoxyphenylboronic acid (55.6 mg, 0.366 mmol, 1.2 eq) and cesium fluoride (97.2 mg, 64.0 μmol, 2.1 en) in 2.8 mL DME abs. were reacted in presence of PdCl.sub.2ddppf) 11.2 mg. 15.3 μmol, 5.0 mol-%) for 5 d at 80° C. according to general procedure B. The crude product was purified via flash column chromatography (13 g SiO.sub.2, cyclohexane/EtOAc=5:1 (v/v), column size column size 7×2.3 cm), followed by preparative RP-HPLC (method C).
[2150] Yield: 36.6 mg (0.121 mmol, 40%) colorless solid.
[2151] C.sub.17H.sub.19NO.sub.4 [301.34 g/mol].
[2152] mp=59-61° C.
[2153] R.sub.f=0.24 (cyclohexane/EtOAc=5:1 (v/v), staining: KMnO.sub.4).
[2154] .sup.1H NMR (300 MHz, CDCl.sub.3): δ=7.94 (d, .sup.3J=8.8 Hz, 2H, Ph-H), 7.43 (d, .sup.4J=2.1 Hz, 1H, Py-H), 7.22 (d, .sup.4J=2.1 Hz, 1H, Py-H), 5.23 (hept, .sup.3J=6.2 Hz, 1H, CH(CH.sub.3).sub.2), 3.86 (s, 3H, Py-OCH.sub.3), 3.77 (s, 3H, Ph-OCH.sub.3), 1.35 (d, .sup.3J=6.3 Hz, 6H, CH(CH.sub.3).sub.2).
[2155] .sup.13C NMR (76 MHz, CDCl.sub.3): δ=167.2, 165.1, 160.9, 158.9, 150.3, 131.4, 128.6 (2C), 114.1 (2C), 109.0, 108.4, 69.5, 55.6, 55.4, 22.0 (2C).
[2156] HRMS (DI-EI): Calcd. m/z for C.sub.17H.sub.19NO.sub.4: 301.1314; found: 301.1320.
Examples 207 to 236
[2157] General Procedures
[2158] Reversed Phase Preparative HPLC (Prep HPLC)
[2159] Reversed phase preparative HPLC purifications were performed on a Thermo Scientific UltiMate 3000 system. Detection was accomplished with a Dionex UltiMate Diode Array detector. The separations were carried out on a Macherey-Nagel 125/21 Nucleodur® 100-5 C18EC (125×21 mm, 5.0 μm) column. As eluents MeCN and water with 0.05% CF.sub.3COOH as additive was used. Following methods were applied: [2160] Method E 0.0 min-17.0 min linear increase 2 to 100% MeCN, 17.0-19.0 min 100% MeCN isocratic, 19.0-22.0 min linear decrease 100 to 2% MeCN, 22.0-24.0 min 2% MeCN isocratic, 12 mL/min, 30° C.
[2161] General Procedure C: Suzuki Coupling
[2162] In an inert Schienk flask equipped with magnetic stirring bar heterocyclic bromide (1.0 eq.), boronic acid (0.9 to 1.5 eq.) and K.sub.2CO.sub.3 (2.0 eq.) were dissolved in degassed abs. toluene (0.1 M). Pd[PPh.sub.3].sub.4 (4 mol %) was added and the reaction mixture was stirred at 80° C. The reaction was monitored via TLC. When full conversion was observed, the reaction mixture was cooled down to RT and filtered through a pad of Celite. The solvent was removed under reduced pressure and the crude product was purified via column chromatography or preparative HPLC, respectively.
[2163] General Procedure C: DCC-Mediated Esterification
[2164] In an inert 10 mL Schienk flask 2-(4-ethoxyphenyl)thiazole acid (1.0 eq.) was dissolved in abs. DCM (0.1 M). DMAP (0.2 eq.) and the corresponding alcohol (1.5 eq.) were added successively and the reaction mixture was cooled to 0° C. using an ice bath. DCC (1.5 eq.) was added and the cloudy reaction mixture was stirred at RT until full conversion was observed via TLC. The reaction mixture was filtered through a pad of Celite and the solvent was removed under reduced pressure. The crude product was purified via column chromatography or preparative HPLC, respectively.
[2165] General Procedure D: Ullmann-Type Coupling
[2166] In an inert 10 mL Schlenk flask tert-butyl 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq.), CuI (0.1 eq.) and K.sub.2C03 (2.0 eq.) were dissolved in abs. DMF (0.1 M). The corresponding amine (2.1 eq.) was added and the reaction mixture was stirred at 100° C. until full conversion was observed via TLC. The reaction mixture was quenched via the addition of sat. NH.sub.4Cl and extracted with EA. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography or preparative HPLC, respectively.
Example 207: Naphthalen-2-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-13/19)
[2167] ##STR00287##
[2168] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 2-naphthalenemethanol (1.5 eq., 602 μmol, 95 mg). The crude product was purified via column chromatography (38 g SiO.sub.2, eluent CH/EA 4.5:1).
[2169] Yield: 30 mg (78 μmol, 19%) colorless solid
[2170] C.sub.23H.sub.19NO.sub.3S [389.47]
[2171] m.p.: 135-138° C.
[2172] R.sub.f: 0.37 (CH/EA 4:1)
[2173] HR-MS [EI, M.sup.+]: calcd. 389.1086, found 389.1089.
[2174] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.11 (s, 1H, H5), 8.04-7.73 (m, 6H, H9/13/21/24/25/28), 7.65-7.42 (m, 3H, H20/26/27), 6.94 (d, J=8.6 Hz, 2H, H10/12), 5.58 (s, 2H, H18), 4.09 (q, J=13.8, 6.9 Hz, 2H, H15), 1.44 (t, J=6.9 Hz, 3H, H16).
[2175] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 161.5 (C.sub.q, C6), 161.3 (C.sub.q, C6), 147.6 (C.sub.q, C4), 133.4 (2C, C.sub.q, C19, C23), 128.7 (2C, CH, C9/13), 128.6, 128.2, 127.9, 127.9 (4 CH, C21/24/25/28), 126.8 (CH, C5), 126.5 (2C, CH, C26/27), 126.3 (CH, C20), 125.7 (C.sub.q, C22), 114.9 (2C, CH, C10/12), 67.3 (CH.sub.2, C18), 63.9 (CH.sub.2, C15), 14.9 (CH.sub.3, C16).
Example 208: Pont-4-yn-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-20/26)
[2176] ##STR00288##
[2177] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 802 μmol, 200 mg) was esterified with 4-pentyn-2-ol (1.5 eq., 1.20 mmol, 114 μL). The crude product was purified via column chromatography (30 g SiO.sub.2, eluent CH/EA 7:1) and preparative HPLC (method E).
[2178] Yield: 121 mg (384 μmol, 48%) colorless oil
[2179] C.sub.17H.sub.17NO.sub.3S [315.39]
[2180] R.sub.f: 0.23 (CH/EA 5:1)
[2181] HR-MS [EI, M.sup.+]: calcd. 315.0929, found 315.0926.
[2182] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.07 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H9/13), 6.94 (d, J=8.7 Hz, 2H, H10/12), 5.29 (q, J=12.1, 6.2 Hz, 1H, H18), 4.09 (q, J=7.0 Hz, 2H, H15), 2.67-2.51 (m, 2H, H19), 2.04 (s, 1H, H22), 1.50 (d, J=6.3 Hz, 3H, H20), 1.44 (t, J=7.0 Hz, 3H, H16).
[2183] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 161.3 (C.sub.q, C11), 160.8 (C.sub.q, C6), 147.7 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 126.6 (CH, C5), 125.6 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 79.8 (C.sub.q, C21), 70.8 (CH, C22), 69.9 (CH, C18), 63.8 (CH.sub.2, C15), 25.8 (CH.sub.2, C19), 19.3 (CH.sub.3, C20), 14.9 (CH.sub.3, C16).
Example 209: But-2-yn-1-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-27)
[2184] ##STR00289##
[2185] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 2-butyn-1-ol (1.5 eq., 602 μmol, 45 μL). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 7:1) and preparative HPLC (method E).
[2186] Yield: 33 mg (109 μmol, 27%) colorless solid
[2187] C.sub.16H.sub.15NO.sub.3S [301.36]
[2188] R.sub.f: 0.21 (CH/EA 7:1)
[2189] m.p.: 110-114° C.
[2190] HR-MS [EI, M.sup.+]: calcd. 301.0773, found 301.0770.
[2191] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.17 (s, 1H, H5), 7.97 (d, J=8.7 Hz, 2H, H9/13), 6.97 (d, J=8.7 Hz, 2H, H10/12), 4.96 (d, J=2.3 Hz, 2H, H18), 4.12 (q, J=7.0 Hz, 2H, H15), 1.91 (t, J=2.2 Hz, 3H, H21), 1.47 (t, J=7.0 Hz, 3H, H16).
[2192] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 161.3 (C.sub.q, C11), 161.0 (C.sub.q, C6), 147.2 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.1 (CH, C5), 125.6 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 83.8 (C.sub.q, C19), 73.2 (C.sub.q, C20), 63.8 (CH.sub.2, C15), 53.8 (CH.sub.2, C18), 14.9 (CH.sub.3, C16), 3.9 (CH.sub.3, C21).
Example 210: (S)-But-3-yn-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-30)
[2193] ##STR00290##
[2194] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with (S)-but-3-yn-2-ol (1.5 eq., 602 μmol, 50 μL). The crude product was purified via column chromatography (38 g SiO.sub.2, eluent CH/EA 8:1).
[2195] Yield: 86 mg (285 μmol, 70%) colorless solid
[2196] C.sub.16H.sub.15NO.sub.3S [301.36]
[2197] R.sub.f: 0.25 (CH/EA 8:1)
[2198] m.p.: 112-117° C.
[2199] HR-MS [EI, M.sup.+]: calcd. 301.0773, found 301.0769.
[2200] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.12 (s, 1H, H5), 7.94 (d, J=8.8 Hz, 2H, H9/13), 6.94 (d, J=8.8 Hz, 2H, H10/12), 5.79-5.63 (m, 1H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 2.51 (d, J=2.1 Hz, 1H, H20), 1.67 (d, J=6.7 Hz, 3H, H21), 1.44 (t, J=7.0 Hz, 3H, H16).
[2201] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 161.3 (C11), 160.4 (C.sub.q, C2), 147.2 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.0 (CH, C5), 125.7 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 82.0 (C.sub.q, C19), 73.6 (CH, C20), 63.8 (CH.sub.2, C15), 61.2 (CH, C18), 21.5 (CH.sub.3, C21), 14.9 (CH.sub.3, C16).
Example 211: (R)-But-3-yn-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-31)
[2202] ##STR00291##
[2203] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with (R)-but-3-yn-2-ol (1.5 eq., 602 μmol, 50 μL). The crude product was purified via column chromatography (38 g SiO.sub.2, eluent CH/EA 8:1).
[2204] Yield: 62 mg (206 μmol, 51%) colorless solid
[2205] C.sub.16H.sub.15NO.sub.3S [301.36]
[2206] R.sub.f: 0.25 (CH/EA 8:1)
[2207] m.p.: 120-117° C.
[2208] HR-MS [EI, M.sup.+]: calcd. 301.0773, found 301.0769.
[2209] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.12 (s, 1H, H5), 7.94 (d, J=8.8 Hz, 2H, H9/13), 6.94 (d, J=8.8 Hz, 2H, H10/12), 5.79-5.63 (m, 1H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 2.51 (d, J=2.1 Hz, 1H, H20), 1.67 (d, J=6.7 Hz, 3H, H21), 1.44 (t, J=7.0 Hz, 3H, H16).
[2210] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 161.3 (C11), 160.4 (C.sub.q, C2), 147.2 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.0 (CH, C5), 125.7 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 82.0 (C.sub.q, C19), 73.6 (CH, C20), 63.8 (CH.sub.2, C15), 61.2 (CH, C18), 21.5 (CH.sub.3, C21), 14.9 (CH.sub.3, C16).
Example 212: Butyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-32)
[2211] ##STR00292##
[2212] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 1-butanol (1.5 eq., 602 μmol, 55 μL). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 7:1).
[2213] Yield: 103 mg (337 μmol, 84%) colorless solid
[2214] C.sub.16H.sub.19NO.sub.3S [305.39]
[2215] R.sub.f: 0.42 (CH/EA 4:1)
[2216] m.p.: 61-65° C.
[2217] HR-MS [EI, M.sup.+]: calcd. 305.1086, found 305.1082.
[2218] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.06 (s, 1H, H5), 7.94 (d, J=8.8 Hz, 2H, H9/13), 6.94 (d, J=8.8 Hz, 2H, H10/12), 4.38 (t, J=6.7 Hz, 2H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 1.85-1.73 (m, 2H, H19), 1.53-1.38 (m, 5H, H16/20), 0.98 (t, J=7.3 Hz, 3H, H16).
[2219] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.9 (C.sub.q, C2), 161.8 (C.sub.q, C6), 161.2 (C.sub.q, C11), 148.0 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 126.2 (CH, C5), 125.8 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 65.4 (CH.sub.2, C18), 63.8 (CH.sub.2, C15), 30.9 (CH.sub.2, C19), 19.4 (CH.sub.2, C20), 14.9 (CH.sub.2, C16), 13.9 (CH.sub.3, C21).
Example 213: 2-(Thiophen-2-yl)ethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LYSU-07)
[2220] ##STR00293##
[2221] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 2-thiophenethanol (1.5 eq., 602 μmol, 68 μL). The crude product was purified via column chromatography (50 g SiO.sub.2, eluent CH/EA 19:1 to 12:1).
[2222] Yield: 140 mg (389 μmol, 97%) colorless solid
[2223] C.sub.18H.sub.17NO.sub.3S.sub.2[359.46]
[2224] m.p.: 76-78° C.
[2225] R.sub.f: 0.52 (CH/EA 4:1)
[2226] HR-MS [EI, M.sup.+]: calcd. 359.0650, found 359.0652.
[2227] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H9/13), 7.18 (d, J=4.9 Hz, 1H, H22), 7.08-6.81 (m, J=5.7, 3.1 Hz, 4H, H10/12/23/24), 4.58 (t, J=6.8 Hz, 2H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 3.33 (t, J=6.7 Hz, 2H, H19), 1.44 (t, J=7.0 Hz, 3H, H16).
[2228] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.4 (C.sub.q, C6), 161.2 (C.sub.q, C11), 147.6 (C.sub.q, C4), 139.8 (C.sub.q, C20), 128.7 (2C, CH, C9/13), 127.1 (CH; C24), 126.7 (CH, C5), 125.9 (CH, C23), 125.7 (C.sub.q, C8), 124.3 (CH, C22), 114.9 (2C, CH, C10/12), 65.6 (CH.sub.2, C18), 63.8 (CH.sub.2, C15), 29.5 (CH.sub.2, C19), 14.9 (CH.sub.3, C16).
Example 214: 2-(Thiophen-3-yl)ethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LYSU-08)
[2229] ##STR00294##
[2230] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 3-thiophenethanol (1.5 eq., 602 μmol, 69 μL). The crude product was purified via column chromatography (50 g SiO.sub.2, eluent CH/EA 19:1 to 12:1 to 9:1).
[2231] Yield: 134 mg (373 μmol, 91%) colorless solid
[2232] C.sub.18H.sub.17NO.sub.3S.sub.2[359.46]
[2233] m.p.: 76-78° C.
[2234] R.sub.f: 0.50 (CH/EA 4:1)
[2235] HR-MS [EI, M.sup.+]: calcd. 359.0650, found 359.0653.
[2236] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.05 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H9/13), 7.34-7.27 (m, 1H, H24), 7.12 (s, 1H, H21), 7.06 (d, J=4.8 Hz, 1H, H23), 6.95 (d, J=8.7 Hz, 2H, H10/12), 4.57 (t, J=7.0 Hz, 2H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 3.15 (t, J=7.0 Hz, 2H, H19), 1.44 (t, J=7.0 Hz, 3H, H16).
[2237] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.5 (C.sub.q, C6), 161.2 (C.sub.q, C11), 147.7 (C.sub.q, C4), 138.0 (C.sub.q, C20), 128.7 (2C, CH, C9/13), 128.5 (CH, C23), 126.5 (CH, C5), 125.8 (CH, C24), 125.7 (C.sub.q, C8), 121.9 (CH, C21), 114.9 (2C, CH, C10/12), 65.3 (CH.sub.2, C18), 63.8 (CH.sub.2, C15), 29.8 (CH.sub.2, C19), 14.9 (CH.sub.3, C16).
Example 215: Thiophen-3-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LYSU-11)
[2238] ##STR00295##
[2239] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 3-thiophenemethanol (1.5 eq., 602 μmol, 58 μL). The crude product was purified via column chromatography (50 g SiO.sub.2, eluent CH/EA 19:1 to 17:1 to 15:1 to 13:1).
[2240] Yield: 136 mg (394 μmol, 98%) colorless solid
[2241] C.sub.17H.sub.15NO.sub.3S.sub.2 [345.43]
[2242] m.p.: 79-81° C.
[2243] R.sub.f: 0.50 (CH/EA 4:1)
[2244] HR-MS [EI, M.sup.+]: calcd. 345.0493, found 345.0495
[2245] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.89 (s, 1H, H5), 7.73 (d, J=8.7 Hz, 2H, H9/13), 7.22 (s, J=14.5 Hz, 1H, H23), 7.17-7.08 (m, 1H, H21), 7.01 (d, J=4.8 Hz, 1H, H20), 6.74 (d, J=8.7 Hz, 2H, H10/12), 5.22 (s, 2H, H18), 3.89 (q, J=6.9 Hz, 2H, H15), 1.24 (t, J=6.9 Hz, 3H, H16).
[2246] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.4 (C.sub.q, C6), 161.2 (C.sub.q, C11), 147.6 (C.sub.q, C4), 136.7 (C.sub.q, C19), 128.7 (2C, CH, C9/13), 128.0 (CH, C20), 126.8 (CH, C5), 126.3 (CH, C21), 125.7 (C.sub.q, C8), 125.1 (CH, C23), 114.9 (2C, CH, C10/12), 63.8 (CH.sub.2, C15), 62.1 (CH.sub.2, C18), 14.9 (CH.sub.3, C16).
Example 216: Furan-3-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LYSU-12)
[2247] ##STR00296##
[2248] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 3-furanmethanol (1.5 eq., 602 μmol, 54 μL). The crude product was purified via column chromatography (50 g SiO.sub.2, eluent CH/EA 19:1 to 17:1 to 15:1 to 13:1).
[2249] Yield: 120 mg (364 μmol, 91%) colorless solid
[2250] C.sub.17H.sub.15NO.sub.4S [329.37]
[2251] m.p.: 82-84° C.
[2252] R.sub.f: 0.45 (CH/EA 4:1)
[2253] HR-MS [EI, M.sup.+]: calcd. 329.0722, found 329.0719.
[2254] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.01 (s, 1H, H5), 7.86 (d, J=8.7 Hz, 2H, H9/13), 7.51 (s, 1H, H23), 7.34 (s, 1H, H21), 6.87 (d, J=8.7 Hz, 2H, H10/12), 6.47 (s, 1H, H, H20), 5.21 (s, 2H, H18), 4.02 (q, J=6.9 Hz, 2H, H15), 1.37 (t, J=6.9 Hz, 3H, H16).
[2255] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 161.5 (C.sub.q, C6), 161.3 (C.sub.q, C11), 147.6 (C.sub.q, C4), 143.5 (CH, C21), 142.3 (CH, C23), 128.7 (2C, CH, C9/13), 126.7 (CH, C5), 125.7 (C.sub.q, C8), 120.4 (C.sub.q, C19), 114.9 (2C, CH, C10/12), 111.1 (CH, C20), 63.8 (CH.sub.2, C15), 58.6 (CH.sub.2, C18), 14.9 (CH.sub.3, C16).
Example 217: Thiazol-5-ylmethyl-2-(4-ethoxyphenyl)thiazole-4-carboxylate (LYSU-16)
[2256] ##STR00297##
[2257] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with thiazol-5-ylmethanol (1.5 eq., 602 μmol, 55 μL). The crude product was purified via column chromatography (50 g SiO.sub.2, eluent CH/EA 11:1 to 9:1 to 4:1).
[2258] Yield: 133 mg (384 μmol, 98%) colorless solid
[2259] C.sub.16H.sub.14N.sub.2O.sub.3S.sub.2 [346.42]
[2260] m.p.: 100-102° C.
[2261] R.sub.f: 0.60 (CH/EA 1:1)
[2262] HR-MS [EI, M.sup.+]: calcd. 346.0446, found 346.0443.
[2263] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.84 (s, 1H, H22), 8.11 (s, 1H, H5), 8.00 (s, 1H, H20), 7.92 (d, J=8.8 Hz, 2H, H9/13), 6.94 (d, J=8.8 Hz, 2H, H10/12), 5.61 (s, 2H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 1.44 (t, J=7.0 Hz, 3H, H16).
[2264] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.3 (C.sub.q, C2), 161.3 (C.sub.q, C11), 161.2 (C.sub.q, C6), 155.1 (CH, C22), 146.9 (C.sub.q, C4), 144.5 (CH, C20), 128.7 (2C, CH, C9/13), 127.4 (CH, C5), 125.5 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 63.8 (CH.sub.2, C15), 58.5 (CH.sub.2, C18), 14.8 (CH.sub.3, C16).
Example 218: Oxazol-4-ylmethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-5-305)
[2265] ##STR00298##
[2266] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.1 eq., 377 μmol, 94 mg) was esterified with oxazol-4-ylmethanol (1.0 eq., 343 μmol, 34 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 2.5:1) and preparative HPLC (method E).
[2267] Yield: 35 mg (106 μmol, 31%) colorless solid
[2268] C.sub.16H.sub.14N.sub.2O.sub.4S [330.36]
[2269] m.p.: 121° C.
[2270] R.sub.f: 0.36 (CH/EA 4:1)
[2271] HR-MS [EI, M.sup.+]: calcd. 330.0674, found 330.0671.
[2272] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.11 (s, 1H, H5), 8.02-7.87 (m, 3H, H9/13/22), 7.82 (s, 1H, H20), 6.93 (d, J=8.8 Hz, 2H, H10/12), 5.36 (s, 2H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 1.43 (t, J=7.0 Hz, 3H, H16).
[2273] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1 (C.sub.q, C2), 161.3 (2C, C.sub.q, C6/11), 151.4 (CH, C22), 147.1 (C.sub.q, C4), 138.3 (CH, C20), 135.5 (C.sub.q, C19), 128.7 (2C, CH, C9/13), 127.1 (CH, C5), 125.6 (C.sub.q, C8), 114.0 (2C, CH, C10/12), 63.8 (CH.sub.2, C15), 58.6 (CH.sub.2, C18), 14.9 (CH.sub.3, C16).
Example 219: (2-Methylthiazol-4-yl)methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-5-306a)
[2274] ##STR00299##
[2275] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with (2-methylthiazol-4-yl)methanol (1.5 eq., 451 μmol, 58 mg). The crude product was purified via column chromatography (20 g SiO.sub.2, eluent CH/EA 2.5:1).
[2276] Yield: 89 mg (247 μmol, 82%) colorless solid
[2277] C.sub.17H.sub.16N.sub.2O.sub.3S.sub.2 [360.45]
[2278] m.p.: 100° C.
[2279] R.sub.f:0.50 (CH/EA 1:1)
[2280] HR-MS [EI, M.sup.+]: calcd. 360.0602, found 360.0601.
[2281] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.12 (s, 1H, H5), 7.93 (d, J=8.8 Hz, 2H, H9/13), 7.26 (s, 1H, H20), 6.93 (d, J=8.8 Hz, 2H, H10/12), 5.46 (s, 2H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 2.73 (s, 3H, H24), 1.43 (t, J=7.0 Hz, 3H, H16).
[2282] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 166.7 (C.sub.q, C22), 161.2 (2 C.sub.q, C6/11), 150.6 (C.sub.q, C19), 147.3 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.0 (CH, C5), 125.7 (C.sub.q, C8), 118.1 (CH, C20), 114.9 (2C, CH, C10/12), 63.8 (CH.sub.2, C15), 62.4 (CH.sub.2, C18), 19.3 (CH.sub.3, C24), 14.9 (CH.sub.3, C16).
Example 220: Oxazol-5-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-5-306b)
[2283] ##STR00300##
[2284] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 301 μmol, 75 mg) was esterified with oxazol-5-ylmethanol (1.5 eq., 451 μmol, 48 mg). The crude product was purified via column chromatography (20 g SiO.sub.2, eluent CH/EA 2.5:1).
[2285] Yield: 53 mg (160 μmol, 40%) colorless solid
[2286] C.sub.16H.sub.14N.sub.2O.sub.4S [330.36]
[2287] m.p.: 116° C.
[2288] R.sub.f: 0.42 (CH/EA 1:1)
[2289] HR-MS [EI, M.sup.+]: calcd. 330.0674, found 330.0669.
[2290] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.11 (s, 1H, H5), 7.99-7.78 (m, 3H, H9/13/22), 7.25 (s, J=2.9 Hz, 1H, H20), 6.94 (d, J=8.8 Hz, 2H, H10/12), 5.42 (s, 2H, H18), 4.08 (q, J=7.0 Hz, 2H, H15), 1.43 (t, J=7.0 Hz, 3H, H16).
[2291] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.3 (C.sub.q, C2), 161.3 (C.sub.q, C11), 161.0 (C.sub.q, C6), 151.9 (C.sub.q, C19), 151.9 (CH, C22), 146.8 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.6 (CH, C20), 127.4 (CH; C5), 125.5 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 63.8 (CH.sub.2, C16), 56.1 (CH.sub.2, C18), 14.9 (CH.sub.3, C16).
Example 221: (5-Methylthiophen-2-yl)methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-25)
[2292] ##STR00301##
[2293] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with (5-methylthiopen-2-yl)methanol (1.5 eq., 602 μmol, 77 mg). The crude product was purified via column chromatography (38 g SiO.sub.2, eluent CH/EA 9:1).
[2294] Yield: 43 mg (120 μmol, 30%) off-white solid
[2295] C.sub.18H.sub.17NO.sub.3S.sub.2[359.46]
[2296] m.p.: 55-58° C.
[2297] R.sub.f: 0.27 (CH/EA 9:1)
[2298] HR-MS [EI, M.sup.+]: calcd. 359.0650, found 359.0648.
[2299] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H, H5), 7.92 (d, J=8.5 Hz, 2H, H9/13), 7.08-6.82 (m, 3H, H10/12/20), 6.64 (s, 1H, H21), 5.46 (s, 2H, H18), 4.08 (q, J=6.4 Hz, 2H, H15), 2.47 (s, 3H, H24), 1.44 (t, J=6.7 Hz, 3H, H16).
[2300] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.3 (C.sub.q, C6), 161.2 (C.sub.q, C11), 147.5 (CH, C4), 142.1 (C.sub.q, C19), 135.3 (C.sub.q, C22), 129.1 (CH, C20), 128.7 (2C, CH, C9/13), 126.9 (CH, C5), 125.7 (C.sub.q, C8), 125.1 (CH, C21), 114.9 (2C, CH, C10/12), 63.8 (CH.sub.2, C15), 61.6 (CH.sub.2, C18), 15.5 (CH.sub.3, C24), 14.9 (CH.sub.3, C16).
Example 222: (5-Methlyfuran-2-yl)methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-34)
[2301] ##STR00302##
[2302] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with (5-methylfuran-2-yl)methanol (1.5 eq., 602 μmol, 68 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 7:1).
[2303] Yield: 122 mg (356 μmol, 89%) yellowish solid
[2304] C.sub.18H.sub.17NO.sub.3S.sub.2 [343.40]
[2305] m.p.: 73-79° C.
[2306] R.sub.f: 0.33 (CH/EA 4:1)
[2307] HR-MS [EI, M.sup.+]: calcd. 343.0878, found 343.0876.
[2308] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, 1H, H5), 7.93 (d, J=8.6 Hz, 2H, H9/13), 6.93 (d, J=8.6 Hz, 2H, H10/12), 6.39 (d, J=2.5 Hz, 1H, H20), 5.96 (s, 1H, H21), 5.29 (s, 2H, H18), 4.08 (d, J=6.9 Hz, 2H, H15), 2.31 (s, 3H, H24), 1.44 (t, J=6.9 Hz, 3H, H16).
[2309] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.3 (C.sub.q, C11), 161.2 (C.sub.q, C6), 153.4 (C.sub.q, C19), 147.6 (C.sub.q, C4), 147.5 (C.sub.q, C22), 128.7 (2C, CH, C9/13), 126.9 (CH, C5), 125.7 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 112.5 (CH, C20), 106.8 (CH, C21), 63.8 (CH.sub.2, C15), 59.1 (CH.sub.2, C18), 14.9 (CH.sub.3, C16), 13.8 (CH.sub.3, C24).
Example 223: (5-Chlorothiophen-2-yl)methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-39)
[2310] ##STR00303##
[2311] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 281 μmol, 70 mg) was esterified with (5-chlorothiophen-2-yl)methanol (1.25 eq., 350 μmol, 52 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 4:1).
[2312] Yield: 51 mg (134 μmol, 47%) yellowish solid
[2313] C.sub.17H.sub.14ClNO.sub.3S.sub.2[379.87]
[2314] m.p.: 77-81° C.
[2315] R.sub.f: 0.38 (CH/EA 4:1)
[2316] HR-MS [EI, M.sup.+]: calcd. 379.0104, found 379.0104
[2317] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.10 (s, 1H, H5), 7.92 (d, J=8.8 Hz, 2H, H9/13), 7.07-6.89 (m, 3H, H10/12/20), 6.81 (d, J=3.7 Hz, 1H, H21), 5.43 (s, 2H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 1.44 (t, J=6.9 Hz, 3H, H16).
[2318] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.2 (C.sub.q, C2), 161.3 (C.sub.q, C11), 161.3 (C.sub.q, C6), 147.2 (C.sub.q, C4), 136.5 (C.sub.q, C19), 131.9 (C.sub.q, C22), 128.7 (2C, CH; C9/13), 128.4 (CH, C20), 127.2 (CH, C5), 125.9 (CH, C21), 125.6 (C.sub.q, C8), 114.9 (2C, CH; C10/12), 63.8 (CH.sub.2, C15), 61.4 (CH.sub.2, C18), 14.9 (CH.sub.3, C16).
Example 224: (5-Bromothiophen-2-yl)methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LS-40)
[2319] ##STR00304##
[2320] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with (5-bromothiophen-2-yl)methanol (1.25 eq., 500 μmol, 96 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 6:1).
[2321] Yield: 148 mg (349 μmol, 87%) yellowish solid
[2322] C.sub.17H.sub.14BrNO.sub.3S.sub.2 [424.33]
[2323] m.p.: 73-77° C.
[2324] R.sub.f: 0.23 (CH/EA 4:1)
[2325] HR-MS [EI, M.sup.+]: calcd. 424.9578, found 424.9576.
[2326] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.10 (s, 1H, H5), 7.92 (d, J=8.6 Hz, 2H, H9/13), 6.93 (d, J=8.6 Hz, 4H, H10/12/20/21), 5.45 (s, 2H, H18), 4.08 (q, J=6.8 Hz, 2H, H15), 1.43 (t, J=6.9 Hz, 3H, H16).
[2327] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.2 (C.sub.q, C2), 161.4 (C.sub.q, C11), 161.2 (C.sub.q, C6), 147.1 (C.sub.q, C4), 139.4 (C.sub.q, C19), 129.7 (CH, C21), 129.3 (CH, C20), 128.7 (2C, CH, C9113), 127.2 (CH, C5), 125.6 (C.sub.q, C8), 114.9 (2C, CH, C10/12), 114.2 (C.sub.q, C22), 63.8 (CH.sub.2, C15), 61.2 (CH.sub.2, C18), 14.9 (CH.sub.3, C16).
Example 22: 1-(Thiazol-2-yl)ethyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (LYSU-15)
[2328] ##STR00305##
[2329] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 1-(thiazol-2-yl)ethan-1-ol (1.5 eq., 602 μmol, 79 mg).
[2330] The crude product was purified via column chromatography (50 g SiO.sub.2, eluent CH/EA 19:1 to 17:1 to 9:1).
[2331] Yield: 144 mg (400 μmol, quant.) colorless solid
[2332] C.sub.17H.sub.16N.sub.2O.sub.3S.sub.2 [360.45]
[2333] m.p.: 64-66°
[2334] R.sub.f: 0.73 (CH/EA 1:1)
[2335] HR-MS [EI, M.sup.+]: calcd. 360.0602, found 360.0605.
[2336] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.15 (s, 1H, H5), 7.94 (d, J=8.7 Hz, 2H, H9/13), 7.79 (d, J=3.2 Hz, 1H, H21), 7.34 (d, J=3.2 Hz, 1H, H22), 6.94 (d, J=8.8 Hz, 2H, H10/12), 6.46 (q, J=6.5 Hz, 1H, H18), 4.08 (q, J=6.9 Hz, 2H, H15), 1.87 (d, J=6.6 Hz, 3H, H24), 1.44 (t, J=7.0 Hz, 3H, H16).
[2337] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 170.1 (C.sub.q, C19), 169.2 (C.sub.q, C2), 161.3 (C.sub.q, C11), 160.3 (C.sub.q, C6), 147.1 (C.sub.q, C4), 142.9 (CH, C5), 128.7 (2C, CH, C9/13), 127.2 (CH, C21), 125.6 (C.sub.q, C8), 119.6 (CH, C22), 114.9 (2C, CH, C10/12), 70.7 (CH, C18), 63.8 (CH.sub.2, C15), 20.9 (CH.sub.3, C24), 14.9 (CH.sub.3, C16).
Intermediate: Ethyl 2-diazo-3-oxopentanoate (S1a)
[2338] ##STR00306##
[2339] In a 250 mL Schlenk flask, 4-acetamidobenzenesulfonyl azide (1.1 eq., 6.24 mmol, 1.51 g) was dissolved in 40 mL abs. MeCN and cooled down to 0° C. Ethyl 3-oxovalerate (1.0 eq., 5.68 mmol, 810 μL) and Et.sub.3N (3.0 eq., 17 mmol, 2.36 mL) were added dropwise. After 15 min, the cooling bath was removed and the reaction mixture was stirred at RT overnight. When full conversion was observed via TLC, the colorless precipitate was removed by filtration and rinsed with 20 mL Et.sub.2O/pentane (1:1). The solvent was removed under reduced pressure. The yellow oil was diluted with 10 mL Et.sub.2O/pentane (1:1) and the colorless precipitate was again removed by filtration. The solvent was removed on a rotary evaporator, yielding a yellow oil, which was used in the next step without further purification.
[2340] Yield: 982 mg (5.77 mmol, 98%) yellow oil
[2341] C.sub.7H.sub.10N.sub.2O.sub.3[170.17]
[2342] R.sub.f: 0.50 (CH/EA 4:1)
[2343] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 4.23 (q, J=7.1 Hz, 2H, H6), 2.79 (q, J=7.3 Hz, 2H, H4), 1.26 (t, J=7.1 Hz, 3H, H7), 1.07 (t, J=7.3 Hz, 3H, H5).
[2344] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 193.7 (C.sub.q, C3), 161.6 (C.sub.q, C1), 61.5 (CH.sub.2, C6), 33.9 (CH.sub.2, C4), 14.5 (CH.sub.3, C7), 8.4 (CH.sub.3, C5).
Intermediate: Ethyl 2-diazo-4-methyl-3-oxopentanoate (S1b)
[2345] ##STR00307##
[2346] According to the synthesis of ethyl 2-diazo-3-oxopentanoate (S1a), ethyl isoburyrylacetate (1.0 eq., 5.68 mmol, 920 μL) was converted to the diazo-derivative.
[2347] Yield: 1.04 g (5.64 mmol, 98%) yellow oil
[2348] C.sub.8H.sub.12N.sub.2O.sub.3 [184.20]
[2349] R.sub.f: 0.60 (CH/EA 4:1)
[2350] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 4.29 (q, J=7.1 Hz, 2H, H7), 3.66-3.46 (m, J=13.6, 6.8 Hz, 1H, H4), 1.33 (t, J=7.1 Hz, 3H, H8), 1.13 (d, J=6.8 Hz, 6H, H5/6).
[2351] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 197.2 (C.sub.q, C3), 161.3 (C.sub.q, C1), 61.5 (CH.sub.2, C7), 36.9 (CH, C4), 18.7 (2C, CH.sub.3, C5/6), 14.5 (CH.sub.3, C8).
Intermediate: Ethyl 2-(4-ethoxybenzamido)-3-oxopentanoate (S2a)
[2352] ##STR00308##
[2353] A 50 mL three-necked flask with magnetic stirring bar was equipped with a stopper, a closed air condenser and a stopcock connected to the Schlenk line. The flask was charged with 4-ethoxybenzamide (1.0 eq., 2.42 mmol, 401 mg), Rh.sub.2(OAc).sub.4 (3 mol %, 28.2 mg) and 5 mL abs. DCE. In a 50 ml round-bottom flask with magnetic stirring bar and Schlenk adapter, 5 mL of a 1.1 M solution of S1a in abs. DCE were prepared. Using a syringe pump, 3.00 mL (1.4 eq., 3.39 mmol) of the 1.1 M solution of S1a were added through a septum within 16 h (rate: 187 μL/h). A stopcock connected to the Schienk line and a bubbler was fitted on top of the air condenser to maintain a continuous argon flow. The valve on the bottom neck was closed as soon as the addition of S1a started. The reaction was heated to 90° C. and stirred overnight. TLC analysis indicated full conversion of the starting material. The brown suspension was transferred into a round bottom flask and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (75 g SiO.sub.2, CH/EA 5:2).
[2354] Yield: 539 mg (1.75 mmol, 72%) yellowish solid
[2355] C.sub.16H.sub.21NO.sub.5 [307.35]
[2356] m.p.: 68° C.
[2357] R.sub.f: 0.55 (CH/EA 1:1)
[2358] HR-MS [EI, M.sup.+]: calcd. 307.1420, found 307.1423.
[2359] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.73 (d, J=8.8 Hz, 2H, H15/19), 7.14 (d, 1H, H11) 6.86 (d, J=8.8 Hz, 2H, H16/18), 5.35 (d, J=6.4 Hz, 1H, H6), 4.23 (q, J=7.1 Hz, 2H, H2), 4.01 (q, J=6.9 Hz, 2H, H21), 2.75 (m, 2H, H9), 1.37 (t, J=6.9 Hz, 3H, H22), 1.25 (t, J=7.1 Hz, 3H, H1), 1.07 (t, J=7.2 Hz, 3H, H10).
[2360] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 202.1 (C.sub.q, C7), 166.6 (C.sub.q, C4), 166.4 (C.sub.q, C12), 162.1 (C.sub.q, C17), 129.2 (2 CH, C15/19), 125.1 (C.sub.q, C14), 114.3 (.sub.C.sub.
Intermediate: Ethyl 2-(4-ethoxybenzamido)-4-methyl-3-oxopentanoate (S2b)
[2361] ##STR00309##
[2362] According to the synthesis of S2a, S2b was obtained from ethyl 2-diazo-4-methyl-3-oxopentanoate (S1b) (1.1 M in DCE, 1.4 eq., 3.39 mmol, 3 mL) and 4-ethoxybenzamide (1.0 eq., 2.49 mmol, 412 mg). The product was purified via preparative HPLC (method E).
[2363] Yield: 524 mg (1.63 mmol, 65%) yellowish oil
[2364] C.sub.17H.sub.23NO.sub.5 [321.37
[2365] R.sub.f: 0.45 (CH/EA 1:1)
[2366] HR-MS [EI, M.sup.+]: calcd. 321.1576, found 321.1577.
[2367] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.73 (d, J=8.8 Hz, 2H, H-16/20), 7.16 (d, J=10.4 Hz, 1H, H-12), 6.85 (d, J=8.8 Hz, 2H, H-17/19), 5.51 (d, J=6.6 Hz, 1H, H-6), 4.27 (q, J=7.1 Hz, 2H, H-2), 4.01 (q, J=5.6 Hz, 2H, H-22), 3.14-2.98 (m, 1H, H-9), 1.36 (m, J=21.4 Hz, 3H, H-23), 1.24 (t, J=7.1 Hz, 3H, H-1), 1.18 (d, J=7.0 Hz, 3H, H-10), 1.08 (d, J=6.7 Hz, 3H, H-11).
[2368] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 205.6 (C.sub.q, C7), 166.7 (C.sub.q, C4), 166.7 (C.sub.q, C13), 162.3 (C.sub.q, C18), 129.3 (2 CH, C16/20), 125.2 (C.sub.q, C15), 114.5 (2 CH, C16/18), 63.9 (CH.sub.2, C22), 62.8 (CH, C6), 61.4 (CH.sub.2, C2), 39.0 (CH, C9), 19.0-17.8 (CH.sub.3, C10/11), 14.8 (CH.sub.3, C23), 14.2 (CH.sub.3, C1).
Example 226: Ethyl 2-(4-ethoxyphenyl)-5-ethylthiazole-4-carboxylate (RE-26a)
[2369] ##STR00310##
[2370] In a 50 mL round bottom flask equipped with magnetic stirring bar and Schienk adapter, ethyl 2-(4-ethoxybenzamido)-3-oxopentanoate (S2a) (1.0 eq., 1.56 mmol, 480 mg) was dissolved in 15 mL abs. THF. Lawesson's reagent (2.0 eq., 3.13 mmol, 1.27 g) was added and the reaction was stirred at 70° C. overnight. When full conversion was observed via TLC, the reaction mixture was cooled down to RT and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (50 g SiO.sub.2, CH/EA 6:1).
[2371] Yield: 135 mg (442 μmol, 28%) yellowish solid
[2372] C.sub.18H.sub.19NO.sub.3S [305.39]
[2373] m.p.: 74-78° C.
[2374] R.sub.f: 0.31 (CH/EA 1:1)
[2375] HR-MS [EI, M.sup.+]: calcd. 305.1086, found 305.1091.
[2376] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.86 (d, J=8.8 Hz, 2H, H12/18), 6.92 (d, J=8.8 Hz, 2H, H13/15), 4.43 (d, J=7.1 Hz, 2H, H9), 4.08 (q, J=6.9 Hz, 2H, H18), 3.26 (q, J=7.4 Hz, 2H, H20), 1.43 (t, J=7.0 Hz, 6H, H10/19), 1.36 (t, J=7.5 Hz, 3H, H21).
[2377] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 164.0 (Cq, C2), 162.8 (Cq, C6), 160.8 (Cq, C14), 151.6 (Cq, C5), 141.2 (Cq, C4), 128.3 (2C, CH, C12/16), 126.0 (Cq, C11), 114.8 (2C, CH, C13/15), 63.8 (CH2, C18), 61.2 (CH2, C9), 21.5 (CH2, C20), 16.2 (CH3, C21), 14.9 (CH3, C19), 14.5 (CH3, C10).
Example 227: Ethyl 2-(4-ethoxyphenyl)-5-isopropylthiazole-4-carboxylate (RE-26b)
[2378] ##STR00311##
[2379] In a 50 mL round bottom flask equipped with magnetic stirring bar and Schlenk adapter, ethyl 2-(4-ethoxybenzamido)-4-methyl-3-oxopentanoate (S2b) (1.0 eq., 1.40 mmol, 450 mg) was dissolved in 15 mL abs. THF. Lawesson's reagent (2.0 eq., 2.80 mmol, 1.13 g) was added and the reaction was stirred at 70° C. overnight. When full conversion was observed via TLC, the reaction mixture was cooled down to RT and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (75 g SiO.sub.2, CH/EA 6:1).
[2380] Yield: 124 mg (388 μmol, 28%) yellow solid
[2381] C.sub.17H.sub.21NO.sub.3S [319.39]
[2382] m.p.: 78-84° C.
[2383] R.sub.f: 0.31 (CH/EA 1:1)
[2384] HR-MS [EI, M.sup.+]: calcd. 319.1242, found 319.1244.
[2385] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.86 (d, J=8.8 Hz, 2H, H12/16), 6.92 (d, J=8.7 Hz, 2H, H13/15), 4.43 (d, J=7.1 Hz, 2H, H9), 4.15-3.99 (m, 3H, H18/20), 1.44 (t, J=7.1 Hz, 6H, H10/19), 1.37 (d, J=6.8 Hz, 6H, H21/22).
[2386] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 163.9 (Cq, C2), 162.8 (Cq, C6), 160.8 (Cq, C14), 157.9 (Cq, C4), 140.5 (Cq C5), 128.3 (2C, CH, C12/16), 126.1 (Cq, C11), 114.8 (2C, CH, C13/15), 63.8 (CH2, C18), 61.3 (CH2, C9), 28.2 (CH, C20), 25.3 (2C, CH3, C21/22), 14.9 (CH3, C19), 14.5 (CH3, C10).
Example 228: Ethyl 5-butoxy-2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-4-292)
[2387] ##STR00312##
[2388] In an inert Schlenk flask, NaH (60% in mineral oil, 3.1 eq., 1.45 mmol, 58 mg) was suspended in 5 mL abs. dioxane. Ethyl 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq., 0.48 mmol, 150 mg) and n-butanol (3.0 eq., 1.44 mmol, 132 μL) were added. The flask was equipped with a bubbler and the reaction was stirred at 80° C. for 2 d. After full conversion was observed via TLC, the reaction was quenched via addition of 5 mL H.sub.2O. The reaction mixture was acidified to pH=2 and extracted with 2×10 mL EA. The solvent was removed under reduced pressure and the residue was taken up in 15 mL EtOH. H.sub.2SO.sub.4 (80 μL) was added and the mixture was stirred at 80° C. overnight. The solvent was again removed under reduced pressure, the residue was taken up in EA and washed with 1×10 mL sat. NaHCO.sub.3. The organic layer was dried over Na.sub.2SO.sub.4, filtered and the solvent was removed under reduced pressure. The crude product was purified via column chromatography (13 g SiO.sub.2, eluent 8:1 to 6:1) and preparative HPLC (method E).
[2389] Yield: 36 mg (140 μmol, 22%) colorless solid
[2390] C.sub.18H.sub.23NO.sub.4S [349.45]
[2391] m.p. 62° C.
[2392] R.sub.f: 0.35 (CH/EA 4:1)
[2393] HR-MS [EI, M.sup.+]: calcd. 349.1348, found 349.1346.
[2394] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.70 (d, J=8.7 Hz, 2H; H10/14), 6.83 (d, J=8.7 Hz, 2H, H11/13), 4.33 (q, J=7.1 Hz, 2H; H7), 4.15 (t, J=6.4 Hz, 2H, H17), 3.99 (q, J=6.9 Hz, 2H, H15), 1.89-1.71 (m, 2H, H18), 1.56-1.41 (m, 2H, H19), 1.34 (q, J=6.9 Hz, 6H, H8/16), 0.92 (t, J=7.4 Hz, 3H, H20).
[2395] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 168.1 (C.sub.q, C2), 161.9 (C.sub.q, C11), 160.6 (C.sub.q, C6), 152.9 (C.sub.q, C4), 127.7 (2C, CH, C10/14), 127.2 (C.sub.q, C9), 126.2 (C.sub.q, C5), 114.8 (2C, CH, C11/13), 78.5 (CH.sub.2, C17), 63.7 (CH.sub.2, C15), 60.8 (CH.sub.2, C7), 31.4 (CH.sub.2, C18), 19.1 (CH.sub.2, C19), 14.9 (CH.sub.3, C16), 14.5 (CH.sub.3, C8), 13.8 (CH.sub.3, C20).
Example 229: tert-Butyl 2-(4-ethoxyphenyl)-5-morpholinothiazole-4-carboxylate (AM-4-293)
[2396] ##STR00313##
[2397] According to general procedure D, tert-butyl 5-chloro-2-(4-ethoxyphenyl)thiazole-4-carboxylate (1.0 eq., 88 μL, 30 mg) was coupled with morpholine (2.1 eq., 185 μmol, 15 μL). As no conversion could be observed after 20 h, additional 10 mg CuI (0.6 eq.,) and 30 μL morpholine (4.2 eq.) were added and the temperature was raised to 110° C. The reaction was stirred for further 17 h. The crude product was purified via column chromatography (8 g SiO.sub.2, eluent CH/EA 5:1).
[2398] Yield: 20 mg (51 μmol, 58%) yellowish solid
[2399] C.sub.20H.sub.26N.sub.2O.sub.4S [390.50]
[2400] m.p.: 127° C.
[2401] R.sub.f: 0.35 (CH/EA 4:1)
[2402] HR-MS [EI, M.sup.+]: calcd. 390.1613, found 390.1616.
[2403] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 7.80 (d, J=8.6 Hz, 2H, H9/13), 6.90 (d, J=8.6 Hz, 2H, H10/12), 4.06 (q, J=13.9, 6.9 Hz, 2H, H15), 3.88 (d, J=4.4 Hz, 4H, 24/26), 3.21 (d, J=4.3 Hz, 4H, H23/27), 1.63 (s, 9H, H19/20/21), 1.43 (t, J=6.9 Hz, 3H, H16).
[2404] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): (ppm) δ 161.6 (C.sub.q, C2), 161.1 (C.sub.q, C11), 160.5 (C.sub.q, C6), 155.9 (C.sub.q, C5), 132.0 (C.sub.q, C5), 127.8 (2C, CH, C9/13), 126.4 (C.sub.q, C8), 114.8 (2C, CH, C10/12), 81.6 (C.sub.q, C18), 66.6 (2C, CH.sub.2, C24/26), 63.7 (CH.sub.2, C15), 54.5 (2C, CH.sub.2, C23127), 28.6 (3C, CH.sub.3, C19/20/21), 14.9 (CH.sub.3, C16).
Example 230: 1,1,1-Trifluoro-3-methylbutan-2-yl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-3-220a)
[2405] ##STR00314##
[2406] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 401 μmol, 100 mg) was esterified with 1,1,1,-trifluoro-3-methylbutan-2-ol (1.5 eq., 602 μmol, 75 μL). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 12:1).
[2407] Yield: 93 mg (249 μmol, 62%) colorless solid
[2408] C.sub.17H.sub.18F.sub.3NO.sub.3S [373.39]
[2409] m.p.: 96° C.
[2410] R.sub.f: 0.47 (CH/EA 4:1)
[2411] HR-MS [EI, M.sup.+]: calcd. 373.0959, found 373.0963.
[2412] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.15 (s, 1H, H5), 7.95 (d, J=8.7 Hz, 2H, H9/13), 6.95 (d, J=8.7 Hz, 2H, H10/12), 5.42 (dt, J=14.1, 7.2 Hz, 1H, H18), 4.09 (q, J=6.9 Hz, 2H, H15), 2.31 (td, J=13.1, 6.5 Hz, 1H, H19), 1.44 (t, J=6.9 Hz, 3H, H16), 1.10 (d, J=6.5 Hz, 6H, H21/22).
[2413] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.4 (C.sub.q, C2), 161.4 (C.sub.q, C11), 159.8 (C.sub.q, C6), 146.2 (C.sub.q, C4), 128.7 (2C, CH, C9/13), 127.6 (CH, C5), 125.5 (C.sub.q, C8), 115.0 (2C, CH, C10/12), 74.1 (q, CH, C18), 63.9 (CH.sub.2, C15), 28.2 (CH, C19), 19.2 (CH.sub.3, C21), 17.6 (CH.sub.3, C22), 14.9 (CH.sub.3, C16).
Intermediate: Thiophen-3-ylmethyl 2-bromothiazole-4-carboxylate (S4)
[2414] ##STR00315##
[2415] According to general procedure C, 2-bromothiazole-4-carboxylic acid (1.0 eq., 4.81 mmol, 1.0 g) was esterified with 3-thiophenemethanol (1.5 eq., 7.21 mmol, 680 μL). The crude product was purified via column chromatography (125 g SiO.sub.2, eluent CH/EA 8:1).
[2416] Yield: 1.22 g (4.01 mmol, 84%) colorless solid
[2417] C.sub.9H.sub.6BrNO.sub.2S.sub.2 [304.18]
[2418] m.p.: 107° C.
[2419] R.sub.f: 0.53 (CH/EA 4:1)
[2420] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.12 (s, 1H, H5), 7.40 (s, 1H, H11), 7.31 (dd, J=4.6, 2.7 Hz, 1H, H9), 7.17 (d, J=3.9 Hz, 1H, H8), 5.39 (s, 2H, H6).
[2421] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 160.0 (C.sub.q, C12), 147.1 (C.sub.q, C4), 137.1 (C.sub.q, C7), 136.3 (C.sub.q, C2), 131.3 (CH, C5), 128.1 (CH, C8), 126.4 (CH, C9), 125.5 (CH, C11), 62.4 CH.sub.2, C6).
Example 231: Thiophen-3-ylmethyl 2-(4-methoxyphenyl)thiazole-4-carboxylate (AM-5-309a)
[2422] ##STR00316##
[2423] According to general procedure A, thiophen-3-ylmethyl 2-bromothiazole-4-carboxylate (S4) (1.0 eq., 395 μmol, 120 mg) was coupled with 4-methoxyphenylboronic acid (1.2 eq., 473 μmol, 72 mg). The crude product was purified twice via column chromatography (25 g SiO.sub.2, eluent CH/EA 6:1 and 13 g SiO.sub.2, eluent toluene/EA 20:1).
[2424] Yield: 62 mg (187 μmol, 47%) colorless solid
[2425] C.sub.16H.sub.13NO.sub.3S.sub.2[331.40]
[2426] m.p.: 91° C.
[2427] R.sub.f: 0.39 (CH/EA 4:1)
[2428] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.09 (s, 1H, H5), 7.94 (d, J=8.8 Hz, 2H, H9/13), 7.42 (d, J=1.8 Hz, 1H, H20), 7.32 (dd, J=4.9, 3.0 Hz, 1H, H18), 7.20 (dd, J=4.8, 0.9 Hz, 1H, H17), 6.95 (d, J=8.8 Hz, 2H, H10/12), 5.41 (s, 2H, H15), 3.86 (s, 3H, H22).
[2429] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0 (C.sub.q, C2), 161.8 (C.sub.q, C11), 161.4 (C.sub.q, C6), 147.6 (C.sub.q, C4), 136.7 (C.sub.q, C16), 128.7 (2 CH, C9/13), 128.0 (CH, C17), 126.8 (CH, C5), 126.3 (CH, C18), 125.9 (C.sub.q, C8), 125.1 (CH, C20), 114.4 (2 CH, C10/12), 62.9 (CH.sub.2, C15), 55.6 (CH.sub.3, C22).
Example 232: Thiophen-3-ylmethyl 2-(4-propoxyphenyl)thiazole-4-carboxylate (AM-5-309b)
[2430] ##STR00317##
[2431] According to general procedure A, thiophen-3-ylmethyl 2-bromothiazole-4-carboxylate (1.0 eq., 395 μmol, 120 mg) was coupled with 4-propoxyphenylboronic acid (1.2 eq., 473 μmol, 85 mg). The crude product was purified twice via column chromatography (38 g SiO.sub.2, eluent CH/EA 4:1 and 13 g SiO.sub.2, eluent toluene/EA 20:1).
[2432] Yield: 74 mg (206 μmol, 52%) colorless solid
[2433] C.sub.18H.sub.17NO.sub.3S.sub.2 [359.46]
[2434] m.p.: 89° C.
[2435] R.sub.f: 0.49 (CH/EA 4:1)
[2436] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.41 (s, 1H), 7.32 (dd, J=4.9, 3.0 Hz, 1H), 7.20 (d, J=3.9 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 5.41 (s, 2H), 3.97 (t, J=6.5 Hz, 2H), 1.93-1.75 (m, 2H), 1.05 (t, J=7.4 Hz, 3H).
[2437] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1, 161.5, 161.4, 147.6, 136.7, 128.7, 128.0, 126.7, 126.3, 125.6, 125.1, 114.9, 69.8, 62.1, 22.7, 10.6.
Example 233: Thiophen-3-ylmethyl 2-(4-Isopropoxyphenyl)thiazole-4-carboxylate (AM-5-309c)
[2438] ##STR00318##
[2439] According to general procedure A, thiophen-3-ylmethyl 2-bromothiazole-4-carboxylate (1.5 eq., 395 μmol, 120 mg) was coupled with 4-isopropoxyphenylboronic acid (1.0 eq., 256 μmol, 46 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 8:1).
[2440] Yield: 75 mg (209 μmol, 81%) colorless solid
[2441] C.sub.18H.sub.17NO.sub.3S.sub.2 [359.46]
[2442] m.p.: 93° C.
[2443] R.sub.f: 0.49 (CH/EA 4:1)
[2444] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.08 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.41 (s, 1H), 7.32 (dd, J=4.8, 3.0 Hz, 1H), 7.20 (d, J=3.9 Hz, 1H), 6.92 (d, J=8.8 Hz, 2H), 5.41 (s, 2H), 4.68-4.55 (m, J=12.0, 6.0 Hz, 1H), 1.36 (d, J=6.0 Hz, 6H).
[2445] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.1, 161.4, 160.3, 147.6, 136.7, 128.7, 128.0, 126.7, 126.3, 125.5, 125.1, 116.0, 70.2, 62.1, 22.1.
Example 234: Thiophen-3-ylmethyl 2-(4-(tert-butyl)phenyl)thiazole-4-carboxylate (AM-5-309d)
[2446] ##STR00319##
[2447] According to general procedure A, thiophen-3-ylmethyl 2-bromothiazole-4-carboxylate (1.0 eq., 395 μmol, 120 mg) was coupled with 4-tert-butylphenylboronic acid (1.2 eq., 473 μmol, 84 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 12:1).
[2448] Yield: 66 mg (185 μmol, 47%) colorless solid
[2449] C.sub.19H.sub.19NO.sub.2S.sub.2 [357.49]
[2450] m.p.: 131° C.
[2451] R.sub.f: 0.59 (CH/EA 4:1)
[2452] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.13 (s, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.42 (s, 1H), 7.33 (dd, J=4.8, 3.0 Hz, 1H), 7.21 (d, J=3.9 Hz, 1H), 5.42 (s, 2H), 1.35 (s, 9H).
[2453] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.2, 161.4, 154.4, 147.7, 136.7, 130.2, 128.0, 127.2, 126.9, 126.3, 126.1, 125.1, 62.1, 35.1, 31.3.
Example 235: Thiophen-3-ylmethyl 2-(4-(dimethylamino)phenyl)thiazole-4-carboxylate (AM-5-309e)
[2454] ##STR00320##
[2455] According to general procedure A, thiophen-3-ylmethyl 2-bromothiazole-4-carboxylate (1.0 eq., 395 μmol, 120 mg) was coupled with 4-dimethylaminophenylboronic acid (1.2 eq., 473 μmol, 78 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 6:1).
[2456] Yield: 77 mg (224 μmol, 57%) colorless solid
[2457] C.sub.17H.sub.16N.sub.2O.sub.2S.sub.2 [344.45]
[2458] m.p.: 159° C.
[2459] R.sub.f: 0.49 (CH/EA 4:1)
[2460] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.01 (s, 1H), 7.87 (d, J=8.9 Hz, 2H), 7.41 (s, 1H), 7.32 (dd, J=4.9, 3.0 Hz, 1H), 7.20 (d, J=3.9 Hz, 1H), 6.70 (d, J=8.9 Hz, 2H), 5.41 (s, 2H), 3.03 (s, 6H).
[2461] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.9, 161.6, 152.1, 147.3, 136.8, 128.4, 128.0, 126.3, 125.7, 125.0, 121.1, 111.8, 62.0, 40.3.
Example 236: (2-(4-Ethoxyphenyl)thiazol-4-yl)methyl 2-(4-ethoxyphenyl)thiazole-4-carboxylate (AM-4-302)
[2462] ##STR00321##
[2463] According to general procedure C, 2-(4-ethoxyphenyl)thiazole-4-carboxylic acid (1.0 eq., 225 μmol, 56 mg) was esterified with (2-(4-ethoxyphenyl)thiazol-4-yl)methanol (1.3 eq., 292 μmol, 69 mg). The crude product was purified via column chromatography (25 g SiO.sub.2, eluent CH/EA 4:1).
[2464] Yield: 93 mg (249 μmol, 62%) colorless solid
[2465] C.sub.17H.sub.18F.sub.3NO.sub.3S [373.39]
[2466] R.sub.f: 0.76 (CH/EA 1:1)
[2467] .sup.1H-NMR (300 MHz, CDCl.sub.3): δ (ppm) 8.14 (s, 1H), 7.91 (dd, J=16.1, 8.8 Hz, 4H), 7.33 (s, 1H), 6.93 (d, J=8.7 Hz, 4H), 5.54 (s, 2H), 4.08 (q, J=6.9 Hz, 4H), 1.43 (t, J=6.9 Hz, 6H).
[2468] .sup.13C-NMR (75.5 MHz, CDCl.sub.3): δ (ppm) 169.0, 168.8, 161.3, 161.2, 160.8, 151.7, 147.4, 128.7, 128.3, 127.0, 126.3, 125.7, 117.2, 114.9, 63.8, 63.8, 62.7, 14.8.
Example 237: Biological Experiments (I)
[2469] Determination of IC.sub.50 Values of Human ATGL Inhibitors
[2470] Triglyceride (TG) hydrolase activity was measured as previously described (Schweiger M et al., Methods in Enzymology, 2014, 538:171-93). In brief, TG hydrolase activity was determined by adding recombinant purified CGI-58 to Expi cell lysates expressing human ATGL. For determination of cross-species reactivity Expi lysates expressing ATGL from different model organisms (e.g. mouse, rat, rhesus monkey, goat, etc.) were used. Samples were incubated with DMSO (carrier) or increasing concentrations of ATGL inhibitors dissolved in DMSO. TG substrate was prepared by emulsifying 330 μM radiolabelled triolein (40,000 c.p.m./nmol) and 45 μM phosphatidylcholine/phosphatidylinositol (3:1) in 100 mM potassium phosphate buffer (pH 7.0) by sonication and adjusting to 5% essentially FA-free BSA. TG substrate was added to the reaction mixture and incubated for 1 h at 37° C. in the water bath. The reaction was terminated by adding methanol/chloroform/heptane (10:9:7) and 0.1 M potassium carbonate with 0.1 M boric acid (pH 10.5). After centrifugation at 800 g for 15 min the radioactivity in the upper phase was determined by liquid scintillation counting and the rate of FA hydrolysis was calculated. IC.sub.50 values were determined as inhibitor concentration capable of inhibiting TG hydrolase activity by 50% as compared to DMSO control. Samples were measured as duplicates. The determination of IC.sub.50 values for human ATGL is illustrated in
[2471] The IC.sub.50 values of a range of exemplary compounds of formula (I) against human ATGL as well as their inhibitory effect on murine ATGL (in % inhibition at 50 μM compound) are summarized in the following table:
TABLE-US-00001 Inhibition Inhibition of of human murine ATGL Compound ATGL − IC.sub.50 [μM] at 50 μM − mean [%] Example 2 NG-385 20 μM 5.9% Example 6 NG-399 3 μM 0.0% Example 8 NG-402 10 μM 9.1% Example 11 NG-416 5 μM 1.8% Example 12 NG-417 25 μM 0.0% Example 13 NG-418 8 μM Example 14 NG-423 10 μM 6.1% Example 15 NG-427 6 μM 0.0% Example 16 NG-428 3 μM 18.1% Example 18 NG-433 10 μM 0.0% Example 19 NG-434 3 μM 3.9% Example 20 NG-441 4 μM Example 21 NG-445 5 μM 0.0% Example 23 NG-451 15 μM 16.0% Example 24 NG-460 25 μM 38.0% Example 25 NG-466 8 μM 10.9% Example 26 NG-470 12 μM 23.1% Example 27 NG-474 3 μM 0.0% Example 28 NG-480 12 μM 0.0% Example 29 NG-487 6 μM 0.0% Example 30 NG-488 8 μM 0.0% Example 31 NG-489 12 μM 6.0% Example 32 NG-490 6 μM 18.6% Example 35 NG-497 1 μM 0.0% Example 36 NG-510 8 μM 9.6% Example 37 NG-512 10 μM 22.8% Example 38 NG-513 5 μM 5.7% Example 40 NG-530 10 μM Example 41 NG-531 3 μM 28.2% Example 42 NG-534 10 μM 6.2% Example 43 NG-536 2 μM 9.8% Example 45 NG-550 10 μM Example 48 NG-561 25 μM Example 49 NG-562 20 μM Example 51 NG-576 15 μM 31.8% Example 53 NG-582 1.5 μM 0.0% Example 54 NG-584 20 μM 0.0% Example 55 NG-590 3 μM 1.4% Example 56 NG-592 7 μM 0.0% Example 57 NG-593 2 μM Example 58 NG-594 7 μM 0.0% Example 59 NG-595 3 μM Example 61 NG-597 1 μM Example 62 NG-598 2 μM Example 63 NG-599 6 μM Example 64 NG-601 6 μM Example 65 NG-602 6 μM Example 66 NG-605 10 μM Example 67 NG-608 2 μM Example 68 NG-609 1.5 μM 0.0% Example 69 NG-610 1 μM Example 70 NG-613 3 μM 0.0% Example 71 NG-614 2 μM Example 73 NG-616 3 μM Example 76 NG-619 10 μM 5.1% Example 77 NG-620 5 μM 0.0% Example 80 NG-634 50 μM 3.4% Example 83 NG-637 2.5 μM 0.1% Example 84 NG-639 10 μM 0.0% Example 85 NG-642 3 μM 0.0% Example 86 NG-643 1.5 μM 0.0% Example 87 NG-647 3 μM 0.0% Example 88 NG-648 25 μM 0.0% Example 89 NG-652 25 μM 0.0% Example 90 NG-658 3 μM Example 91 NG-662 50 μM Example 92 NG-666 3 μM Example 93 STS-9 20 μM Example 94 STS-15 2 μM 0.0% Example 95 STS-18 3 μM 13.1% Example 96 STS-19 10 μM Example 97 STS-25 20 μM Example 98 CLF-3-205 12 μM 0.0% Example 99 CLF-3-206 12 μM 37.3% Example 100 CLF-3-213 20 μM 0.0% Example 101 AM-50 2.5 μM 23.6% Example 102 AM-1-71 6 μM 21.5% Example 103 AM-1-74 25 μM 33.9% Example 104 AM-1-75 12 μM 0.0% Example 105 AM-1-82 3 μM 12.2% Example 106 AM-1-93a 5 μM 21.6% Example 108 AM-1-98 5 μM 8.0% Example 109 AM-2-102a 10 μM 0.0% Example 110 AM-2-102b 25 μM 0.0% Example 111 AM-2-102c 25 μM 0.0% Example 112 AM-1-103 10 μM 1.3% Example 113 AM-1-109 6 μM 24.6% Example 114 AM-2-178a 3 μM 7.0% Example 116 AM-2-180b 12 μM 0.0% Example 117 AM-3-183b 3 μM 7.4% Example 118 AM-3-190a 25 μM 0.0% Example 120 AMU-18 4 μM 40.5% Example 121 AMU-19 12 μM 41.2% Example 122 NP22c 8 μM 2.1% Example 123 NP22d 3 μM 10.6% Example 124 AM-62 17 μM 33.7% Example 125 AM-2-137 25 μM 11.1% Example 126 AM-2-139 5 μM 2.2% Example 127 AM-2-179 5 μM 0.0% Example 129 AM-3-183a 6 μM 5.1% Example 130 AM-3-187a 3 μM 13.9% Example 133 AM-3-188b 25 μM 0.0% Example 135 AM-3-210 3 μM 5.8% Example 136 AM-3-213a 20 μM 9.8% Example 139 AM-3-239e 15 μM 0.0% Example 143 AM-4-254 20 μM 16.8% Example 147 AMU-21 3 μM 30.0% Example 148 AMU-28 2 μM Example 149 AMU-29 3 μM Example 150 TSch-61a 5 μM 6.3% Example 151 TSch-61d 2.5 μM 12.1% Example 152 TSch-62a 10 μM 74.0% Example 153 TSch-62b 5 μM 42.2% Example 155 LS-8 15 μM Example 156 LS-9 15 μM Example 157 LS-11 0.9 μM Example 158 LS-12 15 μM Example 159 LS-17 20 μM Example 160 LS-18 15 μM Example 164 OKO-06 25 μM Example 165 OKO-31 5 μM Example 167 LS-7 10 μM Example 171 RE-10 5 μM Example 172 RE-18 20 μM Example 173 RE-16a 12 μM Example 174 RE-16b 25 μM Example 177 OKO-13 25 μM 0.0% Example 187 BB-3-106 15 μM 10.2%
[2472] It has thus been demonstrated that the compounds of formula (I) exhibit a remarkably potent inhibitory activity against human ATGL, which renders these compounds highly advantageous for human medicinal use.
[2473] Moreover, various exemplary compounds have additionally been found to exhibit cross-species reactivity, inhibiting not only human ATGL but also murine ATGL. This property makes the corresponding compounds particularly suitable for preclinical development, as they can readily be tested in mouse models. For instance, the compound of Example 152 (Tsch-62A) exhibits a particularly advantageous cross-species activity, as illustrated in
Example 238: Biological Experiments (II)
[2474] Methods
[2475] Ki Values [nM]
[2476] For determination of Ki values, lysates from Expi cells overexpressing human ATGL were incubated with recombinant purified ATGL co-activator CGI-58 and ATGL inhibitors at a single concentration dependent on the previously determined IC.sub.50. Increasing concentrations of substrate containing radiolabeled triolein were added and liberated FA were extracted and quantified by liquid scintillation. Inhibitors were dissolved in DMSO which was used as control. Ki was determined via non-linear regression analysis. Samples were measured in triplicates.
[2477] IC.sub.50 SGBS FA Release [μM]
[2478] Human differentiated SGBS adipocytes were pretreated with DMSO or ATGL inhibitors for 2 h. Subsequently, lipolysis was stimulated with 1 μM Isoproterenol for 1 h and fatty acid release was determined from media via NEFA Reagent (Wako Diagnostics). Samples were measured in triplicates.
[2479] IC.sub.50 SGBS Glycerol Release [μM]
[2480] Human differentiated SGBS adipocytes were pretreated with DMSO or ATGL inhibitors for 2 h. Subsequently, lipolysis was stimulated with 1 μM Isoproterenol for 1 h and glycerol release was determined from media via Free glycerol reagent (Sigma Aldrich). Samples were measured in triplicates.
[2481] IC.sub.50 hMADS FA Release [μM]
[2482] Human differentiated hMADS adipocytes were pretreated with DMSO or ATGL inhibitors for 2 h. Subsequently, lipolysis was stimulated with 1 μM Isoproterenol for 1 h and fatty acid release was determined from media via NEFA Reagent (Wako Diagnostics). Samples were measured in triplicates.
[2483] IC.sub.50 hMADS Glycerol Release [μM]
[2484] Human differentiated hMADS adipocytes were pretreated with DMSO or ATGL inhibitors for 2 h. Subsequently, lipolysis was stimulated with 1 μM Isoproterenol for 1 h and glycerol release was determined from media via Free glycerol reagent (Sigma Aldrich). Samples were measured in triplicates.
[2485] IC.sub.50 3 T3 FA Release [μM]
[2486] Mouse differentiated 3T3-L1 adipocytes were pretreated with DMSO or ATGL inhibitors for 2 h. Subsequently, lipolysis was stimulated with 1 μM Isoproterenol for 1 h and fatty acid release was determined from media via NEFA Reagent (Wako Diagnostics). Samples were measured in triplicates.
[2487] IC.sub.50 3T3 Glycerol Release [μM]
[2488] Mouse differentiated 3T3-L1 adipocytes were pretreated with DMSO or ATGL inhibitors for 2 h. Subsequently, lipolysis was stimulated with 1 μM Isoproterenol for 111 and glycerol release was determined from media via Free glycerol reagent (Sigma Aldrich). Samples were measured in triplicates.
[2489] Mouse ATGL Inhibition [% Inhibition at 50 μM]
[2490] Lysates from Expi cells overexpressing ATGL from mouse (Mus musculus) were incubated with recombinant purified ATGL co-activator CGI-58 and ATGL inhibitors at 50 μM. Subsequently, substrate containing radiolabeled triolein was added and liberated FA were extracted and quantified by liquid scintillation. Inhibitors were dissolved in DMSO which was used as control. Samples were measured in triplicates.
[2491] Rat ATGL Inhibition [% Inhibition at 50 μM]
[2492] Lysates from Expi cells overexpressing ATGL from rat (Rattus norvegicus) were incubated with recombinant purified ATGL co-activator CGI-58 and ATGL inhibitors at 50 μM. Subsequently, substrate containing radiolabeled triolein was added and liberated FA were extracted and quantified by liquid scintillation. Inhibitors were dissolved in DMSO which was used as control. Samples were measured in triplicates.
[2493] Rhesus Monkey ATGL inhibition [% Inhibition at 50 μM]
[2494] Lysates from Expi cells overexpressing ATGL from rhesus monkeys (Macaca mulatta) were incubated with recombinant purified ATGL co-activator CGI-58 and ATGL inhibitors at 50 μM. Subsequently, substrate containing radiolabeled triolein was added and liberated FA were extracted and quantified by liquid scintillation. Inhibitors were dissolved in DMSO which was used as control. Samples were measured in triplicates.
[2495] Pig vWAT Inhibition [% Inhibition at 50 μM]
[2496] Lysates from visceral adipose tissue of pigs (Sus scrofa) were incubated with recombinant purified ATGL co-activator CGI-58 and ATGL inhibitors at 50 μM. Subsequently, substrate containing radiolabeled triolein was added and liberated FA were extracted and quantified by liquid scintillation. Inhibitors were dissolved in DMSO which was used as control. Samples were measured in triplicates.
[2497] Goat ATGL inhibition [% Inhibition at 50 μM]
[2498] Lysates from Expi cells overexpressing ATGL from goat (Capra hircus) were incubated with recombinant purified ATGL co-activator CGI-58 and ATGL inhibitors at 50 μM. Subsequently, substrate containing radiolabeled triolein was added and liberated FA were extracted and quantified by liquid scintillation. Inhibitors were dissolved in DMSO which was used as control. Samples were measured in triplicates.
[2499] hPNPLA9 Off-Target Inhibition [% Inhibition at 100 μM]
[2500] Expi lysates expressing hPNPLA9 were treated with 100 μM Inhibitors and incubated with 1 mM C8 monoacylglycerol substrate (containing 5 mM CHAPS, 50 mM NaPh buffer ph7.4, 0.15 M NaCl) for 40 min. Glycerol release was determined via Free glycerol reagent (Sigma Aldrich). Samples measured in triplicates,
[2501] hPNPLA6 Off-Target Inhibition [% Inhibition at 100 μM]
[2502] Expi lysates expressing hPNPLA6 were treated with 100 μM Inhibitors and incubated with 1 mM C8 monoacylglycerol substrate (containing 5 mM CHAPS, 50 mM NaPh buffer ph7.4, 0.15 M NaCl) for 40 min, Glycerol release was determined via Free glycerol reagent (Sigma Aldrich). Samples measured in triplicates.
[2503] mMGL Off-Target Inhibition [% Inhibition at 100 μM]
[2504] Lysates from E. coli expressing mMGL were treated with 100 μM Inhibitors and incubated with 1 mM rac-OG substrate for 10 min. Enzyme activity was measured using the Free Glycerol Reagent. Samples measured in triplicates.
[2505] hHSL Off-Target Inhibition [% Inhibition at 100 μM]
[2506] Expi lysates expressing hHSL were preincubated with 100 μM Inhibitors for 30 min and incubated with 1 mM pNV substrate for 30 min. Samples measured in triplicates.
[2507] Tox HepG2 (LDH) Seen from [μM]
[2508] HepG2 cells were seeded in 96 well plates and at 50% confluency treated with DMSO (0.5% final conc.) or ATGL Inhibitors for 24 h in DMEM+P/S+3% heat inactivated FCS (3 h at 62° C.). Subsequently, LDH activity of 50 μl medium was determined via the Roche LDH Kit. Samples measured in triplicates.
[2509] Tox AML-12 (LDH) seen from [μM]
[2510] AML-12 cells were seeded in 96 well plates and at 80% confluency treated with DMSO (0.5% final conc.) or ATGL Inhibitors for 24 h in DMEM+P/S+3% heat inactivated FCS (3 h at 62° C.). Subsequently, medium was centrifuged at 300 g for 3 min, and LDH activity of 50 μl supernatant was determined via the Roche LDH Kit. Samples measured in triplicates.
[2511] Tox PBMC (LDH) Seen from [μM]
[2512] Human primary peripheral blood mononuclear cell from MUG were seeded in 96 well plates treated with DMSO (0.25% final conc.) or ATGL Inhibitors for 24 h in RPMI+P/S+5% heat inactivated FCS (3 h at 62° C.). Subsequently, LDH activity of 10 μl supernatant was determined via the Roche LDH Kit. Samples measured in triplicates.
[2513] Stability in Human Serum [% Rest after 3 h Incubation]
[2514] Inhibitors were incubated in human serum for 0 or 3 h at 37° C. and subsequently extracted with the MTBE method and analyzed via HPLC MS. Samples measured in triplicates.
[2515] The results obtained in these experiments are summarized in the following tables as well as
TABLE-US-00002 Inhibition of human ATGL % Inhibition of murine ATGL Compound IC.sub.50 [μM] at 50 μM at 25 μM Example 202 MC-18 3 μM Example 203 MC-19 10 μM Example 204 MC-20 1 μM Example 205 MC-23 3 μM Example 206 MC-24 5 μM Example 208 LS-20/26 10 μM 59% Example 209 LS-27 10 μM 76% Example 210 LS-30 <3 μM 60% 47% Example 211 LS-31 <3 μM 82% 73% Example 223 LS-39 12 μM 71% Example 224 LS-40 12 μM 68% Example 227 RE-26b 50 μM 44% Example 212 LS-32 7 μM 56% 47% Example 215 LYSU-1 1 <3 μM 81% 71% Example 216 LYSU-12 <3 μM 81% 70% Example 225 LYSU-15 50 μM 68% Example 217 LYSU-16 20 μM 77% Example 230 AM-3-220a 50 μM Example 218 AM-5-305 20 μM Example 220 AM-5-306b 30 μM Example 231 AM-5-309a 30 μM Example 232 AM-5-309b 12 μM Example 233 AM-5-309C 10 μM Example 201 CLF-4-326 <3 μM 45% Example 189 CLF-4-332 25 μM 87% Example 190 CLF-4-333 15 μM 80% Example 197 MC-07 30 μM 75% Example 198 MC-08 20 μM 82%
TABLE-US-00003 Efficacy Off-targets mouse rat rhesus pig goat hPNPLA9 hPNPLA6 mMGL hHSL Toxicity Stability IC50 IC50 IC50 ATGL ATGL monkey vWAT ATGL off-target off-target off-target off-target Tox Tox Tox Stability IC50 SGBS IC50 IC50 3T3 3T3 inhibi - inhibi - ATGL inhibi - inhibi - inhibi - inhibi - inhibi - inhibi - HepG2 AML-12 PBMC in human SGBS glyc- hMADS hMADS FA glyc- tion [% tion [% inhibition tion [% tion [% tion [% tion [% tion [% tion [% (LDH) (LDH) (LDH) serum Ki FA erol FA glycerol re- erol inhibi- inhibi- [% inhibi- inhibi- inhibi- inhibi- inhibi- inhibi- seen seen seen [% rest values release release release release lease release tion at tion at inhibition tion at tion at tion at tion at tion at tion at from from from after 3 h [nM] [μM) [μM) [μM) [μM) [μM) [μM) 50 μM] 50 μM] at 50 μM] 50 μM 50 μM 100 μM] 100 μM] 100 μM] 100 μM] [μM] [μM] [μM] incubation] Example 105 3 3 (AM-1-82) Example 101 2500 3 3 30 — — 25 (AM-50) Example 120 1200 40 — (AMU-18) — 5 Example 148 2 3 30 (AMU-28) Example 201 0 0 95 0 0 0 0 0 0 — 200 100 (CLF-4-326) Example 189 10 70 15 50 0 0 0 0 200 25 (CLF-4-332) Example 190 12 25 6 25 40 70 0 25 0 0 0 0 — 200 0 (CLF-4-333) Example 157 210 2.5 5 — (LS-11) Example 209 40 70 0 25 0 0 0 40 200 100 75 (LS-27) Example 210 0.6 1 15 90 5 20 0 0 0 0 — 200 100 (LS-30) Example 211 0.9 0.9 4 20 60 50 100 5 30 0 0 0 40 — 100 90 (LS-31) Example 212 40 70 5 20 0 0 0 0 — 200 50 (LS-32) Example 223 40 65 15 40 0 0 0 40 — — 80 (LS-39) Example 224 40 70 15 40 0 0 70 95 — — (LS-40) Example 215 3 4 6 15 60 50 70 15 50 0 0 0 30 — — 80 (LYSU-11) Example 216 0.8 10 25 50 70 15 50 0 0 0 30 — 50 60 (LYSU-12) 1 Example 6 2 0 (NG-399) Example 35 500 1 2 0 0 0 — — 75 (NG-497) Example 41 2500 — — 75 (NG-531) Example 43 470 3 — 80 (NG-536) Example 53 550 — 80 (NG 582) 80 Example 61 420 2 50 — 75 (NG-597) Example 68 270 1 — 80 (NG 609) Example 69 830 — — 80 (NG 610) 80 Example 86 470 1 — 80 (NG-643) Example 123 20 (NP 22D) Example 152 8200 12 10 10 10 0 0 0 0 25 200 — — 80 (TSch-62A)
[2516] These results further confirm that the compounds of formula (I) are highly potent inhibitors of human ATGL, and that they exhibit advantageous properties in terms of efficacy, off-target effects, toxicity and stability.