Substituted heterocyclic compounds as allosteric modulators of group II metabotropic glutamate receptors
11472806 · 2022-10-18
Assignee
Inventors
- Anne-Laure Blayo (Souffelweyersheim, FR)
- Thomas Catelain (Strasbourg, FR)
- Ismet Dorange (Stockholm, SE)
- Cédric Genet (Kientzheim, FR)
- Baptiste Manteau (Ways, BE)
- Stanislas Mayer (Eschau, FR)
- Stephan Schann (Illkirch, FR)
Cpc classification
A61P25/14
HUMAN NECESSITIES
G01N33/6872
PHYSICS
C07D223/18
CHEMISTRY; METALLURGY
C07D401/10
CHEMISTRY; METALLURGY
A61K31/4985
HUMAN NECESSITIES
C07D401/04
CHEMISTRY; METALLURGY
C07D519/00
CHEMISTRY; METALLURGY
International classification
C07D401/10
CHEMISTRY; METALLURGY
C07D223/18
CHEMISTRY; METALLURGY
Abstract
The present invention provides novel heterocyclic compounds of the general formula (I), including novel compounds of formula (Ia), and pharmaceutical compositions containing them. Moreover, the compounds of formula (I) or (Ia) and the pharmaceutical compositions containing them are provided for use in the treatment and/or prophylaxis of conditions associated with altered glutamatergic signalling and/or functions, and/or conditions which can be affected by alteration of glutamate level or signalling in mammals. The compounds of formula (I) or (Ia) can act as modulators of nervous system receptors sensitive to glutamate, in particular as modulators of metabotropic glutamate receptors (mGluRs), which makes them particularly suitable for the treatment and/or prophylaxis of acute and chronic neurological and/or psychiatric disorders. The present invention further provides compounds of formula (I) or (Ia) that are modulators of metabotropic glutamate receptors (mGluRs), particularly positive allosteric modulators of mGluRs, and more specifically positive allosteric modulators of mGluR3. ##STR00001##
Claims
1. A compound of formula (Ia): ##STR00462## wherein: A is phenyl; B is a heteroaryl group; X and Y are each C; Z is O, S or N(—R.sup.Z); each is independently a single bond or a double bond; R.sup.Z is selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further wherein, if R.sup.Z is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; each R.sup.1 is independently a group -L.sup.1-R.sup.11; each L.sup.1 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10 haloalkyl, —CN, —OR.sup.12, —NR.sup.12R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —SO.sub.2NR.sup.12R.sup.12, and —NR.sup.12SO.sub.2R.sup.12, 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—, —NR.sup.12—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.11 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.1 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.12R.sup.12, —OR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SO.sub.2NR.sup.12R.sup.12, —NR.sup.12SO.sub.2R.sup.12, and —SO.sub.3R.sup.12, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13, and further wherein, if R.sup.11 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13; each R.sup.12 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.12 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.12 are attached to the same nitrogen atom, then these two groups R.sup.12 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.11 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.13 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; n is an integer of 0 to 4; R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a cycloalkyl or a heterocycloalkyl; R.sup.4 is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, cycloalkyl, and heterocycloalkyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —O—(C.sub.1-C.sub.10 haloalkyl), —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl, and further wherein, if R.sup.4 is cycloalkyl or heterocycloalkyl, then said cycloalkyl or said heterocycloalkyl is optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl; each R.sup.5 is independently a group -L.sup.5-R.sup.51; each L.sup.5 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10 haloalkyl, —CN, —OR.sup.52, —NR.sup.52R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —SO.sub.2NR.sup.52R.sup.52, and —NR.sup.52SO.sub.2R.sup.52, 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—, —NR.sup.52—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.51 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.52R.sup.52, —OR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SO.sub.2NR.sup.52R.sup.52, —NR.sup.52SO.sub.2R.sup.52, and —SO.sub.3R.sup.52, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53, and further wherein, if R.sup.51 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53; each R.sup.52 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.52 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.52 are attached to the same nitrogen atom, then these two groups R.sup.52 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.51 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.53 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; and m is an integer of 0 to 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
2. The compound of claim 1, wherein said compound is selected from: 10-chloro-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(6-Fluoro-pyridin-3-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(5-Fluoro-pyridin-2-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-chloro-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(6-Fluoro-pyridin-3-yl)-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 9-Chloro-2-(methoxymethyl)-5-methyl-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; 2-(Methoxymethyl)-5-methyl-9-(6-fluoro-pyridin-3-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; 2-(Methoxymethyl)-5-methyl-9-(5-fluoro-pyridin-2-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof.
3. A compound of formula (Ia): ##STR00463## wherein: A is phenyl; B is a heteroaryl group, said heteroaryl group being different from indolyl and from 1,3-benzodioxolyl, X and Y are each C; Z is O, S or N(—R.sup.Z); each is independently a single bond or a double bond; R.sup.Z is selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.1 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further wherein, if R.sup.Z is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; each R.sup.1 is independently a group -L.sup.1-R.sup.11; each L.sup.1 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10 haloalkyl, —CN, —OR.sup.12, —NR.sup.12R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —SO.sub.2NR.sup.12R.sup.12, and —NR.sup.12SO.sub.2R.sup.12, 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—, —NR.sup.12—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.11 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.12R.sup.12, —OR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SO.sub.2NR.sup.12R.sup.12, —NR.sup.12SO.sub.2R.sup.12, and —SO.sub.3R.sup.12, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13, and further wherein, if R.sup.11 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13; each R.sup.12 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.12 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.12 are attached to the same nitrogen atom, then these two groups R.sup.12 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.11 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.13 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; n is an integer of 0 to 4; R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a cycloalkyl or a heterocycloalkyl; R.sup.4 is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, cycloalkyl, and heterocycloalkyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —O—(C.sub.1-C.sub.10 haloalkyl), —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl, and further wherein, if R.sup.4 is cycloalkyl or heterocycloalkyl, then said cycloalkyl or said heterocycloalkyl is optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl; each R.sup.5 is independently a group -L.sup.5-R.sup.51; each L.sup.5 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10haloalkyl, —CN, —OR.sup.52, —NR.sup.52R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —SO.sub.2NR.sup.52R.sup.52, and —NR.sup.52SO.sub.2R.sup.52, 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—, —NR.sup.5—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.51 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.52R.sup.52, —OR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SOR.sup.52NR.sup.52R.sup.52, —NR.sup.52SO.sub.2R.sup.52, and —SO.sub.3R.sup.52, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53, and further wherein, if R.sup.51 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53; each R.sup.52 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.52 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.52 are attached to the same nitrogen atom, then these two groups R.sup.52 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.51 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.53 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; and m is an integer of 0 to 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
4. The compound of claim 3, wherein said compound is selected from: 10-chloro-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(6-Fluoro-pyridin-3-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(5-Fluoro-pyridin-2-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-chloro-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1-cyclopropan]-5(6H)-one; 10-(6-Fluoro-pyridin-3-yl)-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 9-Chloro-2-(methoxymethyl)-5-methyl-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; 2-(Methoxymethyl)-5-methyl-9-(6-fluoro-pyridin-3-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; 2-(Methoxymethyl)-5-methyl-9-(5-fluoro-pyridin-2-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof.
5. A pharmaceutical composition comprising a compound of formula (Ia): ##STR00464## wherein: A is phenyl; B is a heteroaryl group, said heteroaryl group being different from indolyl and from 1,3-benzodioxolyl; X and Y are each C; Z is O, S or N(—R.sup.Z); each is independently a single bond or a double bond; R.sup.Z is selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further wherein, if R.sup.Z is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; each R.sup.1 is independently a group -L.sup.1-R.sup.11; each L.sup.1 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10 haloalkyl, —CN, —OR.sup.12, —NR.sup.12R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —SO.sub.2NR.sup.12R.sup.12, and —NR.sup.12SO.sub.2R.sup.12, 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—, —NR.sup.12—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.11 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.1 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.12R.sup.12, —OR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SO.sub.2NR.sup.12R.sup.12, —NR.sup.12SO.sub.2R.sup.12, and —SO.sub.3R.sup.12, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13, and further wherein, if R.sup.11 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13; each R.sup.12 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.12 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.12 are attached to the same nitrogen atom, then these two groups R.sup.12 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.11 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.13 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; n is an integer of 0 to 4; R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a cycloalkyl or a heterocycloalkyl; R.sup.4 is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, cycloalkyl, and heterocycloalkyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —O—(C.sub.1-C.sub.10 haloalkyl), —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl, and further wherein, if R.sup.4 is cycloalkyl or heterocycloalkyl, then said cycloalkyl or said heterocycloalkyl is optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl; each R.sup.5 is independently a group -L.sup.5-R.sup.51; each L.sup.5 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10 haloalkyl, —CN, —OR.sup.52, —NR.sup.52R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —SO.sub.2NR.sup.52R.sup.52 and —NR.sup.52SO.sub.2R.sup.52, 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—, —NR.sup.52—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.51 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.52R.sup.52, —OR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SO.sub.2NR.sup.52R.sup.52, —NR.sup.52SO.sub.2R.sup.52, and —SO.sub.3R.sup.52, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53, and further wherein, if R.sup.51 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53; each R.sup.52 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.52 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.52 are attached to the same nitrogen atom, then these two groups R.sup.52 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.51 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.53 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; and m is an integer of 0 to 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and optionally a pharmaceutically acceptable excipient.
6. A method of treating a condition in a subject, the method comprising the administration of a compound of the general formula (Ia): ##STR00465## wherein: A is phenyl; B is a heteroaryl group; X and Y are each C; Z is O, S or N(—R.sup.Z); each is independently a single bond or a double bond; R.sup.Z is selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further wherein, if R.sup.Z is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; each R.sup.1 is independently a group -L.sup.1-R.sup.11; each L.sup.1 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10 haloalkyl, —CN, —OR.sup.12, —NR.sup.12R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —SO.sub.2NR.sup.12R.sup.12 and —NR.sup.12SO.sub.2R.sup.12, 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—, —NR.sup.12—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.11 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.12R.sup.12, —OR.sup.12, —SR.sup.12, —SOR.sup.12, —SO.sub.2R.sup.12, —COR.sup.12, —COOR.sup.12, —OCOR.sup.12, —CONR.sup.12R.sup.12, —NR.sup.12COR.sup.12, —SO.sub.2NR.sup.12R.sup.12, —NR.sup.12SO.sub.2R.sup.12, and —SO.sub.3R.sup.12, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13, and further wherein, if R.sup.11 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.11-R.sup.13; each R.sup.12 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.12 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.12 are attached to the same nitrogen atom, then these two groups R.sup.12 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.11 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.13 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; n is an integer of 0 to 4; R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a cycloalkyl or a heterocycloalkyl; R.sup.4 is selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, cycloalkyl, and heterocycloalkyl, wherein said alkyl, said alkenyl and said alkynyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —O—(C.sub.1-C.sub.10 haloalkyl), —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl, and further wherein, if R.sup.4 is cycloalkyl or heterocycloalkyl, then said cycloalkyl or said heterocycloalkyl is optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), and cycloalkyl; each R.sup.5 is independently a group -L.sup.5-R.sup.51; each L.sup.5 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 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-C.sub.10 haloalkyl, —CN, —OR.sup.52, —NR.sup.52R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —SO.sub.2NR.sup.52R.sup.52 and —NR.sup.52SO.sub.2R.sup.52, 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—, —NR.sup.52—, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.51 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NR.sup.52R.sup.52, —OR.sup.52, —SR.sup.52, —SOR.sup.52, —SO.sub.2R.sup.52, —COR.sup.52, —COOR.sup.52, —OCOR.sup.52, —CONR.sup.52R.sup.52, —NR.sup.52COR.sup.52, —SO.sub.2NR.sup.52R.sup.52, —NR.sup.52SO.sub.2R.sup.52, and —SO.sub.3R.sup.52, wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53, and further wherein, if R.sup.51 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —CHO, —CO(C.sub.1-C.sub.10 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.10 alkyl), —OCO(C.sub.1-C.sub.10 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.10 alkyl), —CO—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—CO—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-CO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.10 alkyl), —SO.sub.2—N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)-SO.sub.2—(C.sub.1-C.sub.10 alkyl), cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and -L.sup.51-R.sup.53; each R.sup.52 is independently selected from hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, wherein if R.sup.52 is C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, then said alkyl, said alkenyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl, and further if two groups R.sup.52 are attached to the same nitrogen atom, then these two groups R.sup.52 may also together form a C.sub.2-C.sub.8 alkylene; each L.sup.51 is independently selected from a bond, C.sub.1-C.sub.10 alkylene, C.sub.2-C.sub.10 alkenylene, and C.sub.2-C.sub.10 alkynylene, 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-C.sub.10 alkyl)-, —CO—, —S—, —SO—, and —SO.sub.2—; each R.sup.53 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —SH, and —S(C.sub.1-C.sub.10 alkyl), wherein said aryl, said heteroaryl, said cycloalkyl, said heterocycloalkyl, said cycloalkenyl and said heterocycloalkenyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.10 haloalkyl, —CN, C.sub.1-C.sub.10 alkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, —OH, —O(C.sub.1-C.sub.10 alkyl), —(C.sub.1-C.sub.10 alkylene)-OH, —(C.sub.1-C.sub.10 alkylene)-O(C.sub.1-C.sub.10 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.10 alkyl), —N(C.sub.1-C.sub.10 alkyl)(C.sub.1-C.sub.10 alkyl), cycloalkyl, and heterocycloalkyl; and m is an integer of 0 to 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof; b to a subject in need thereof, wherein the condition is selected from: epilepsy; Alzheimer's disease; Parkinson's disease; Huntington's disease; Amyotrophic lateral sclerosis; schizophrenia; anxiety; and chronic pain.
7. The method of claim 6, wherein the condition is Parkinson's disease.
8. The method of claim 6, wherein B is a monocyclic 5- or 6-membered heteroaryl.
9. The method of claim 6, wherein R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a C.sub.3-C.sub.5 cycloalkyl.
10. The method of claim 6, wherein R.sup.4 is C.sub.1-C.sub.4 alkyl, wherein said alkyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —O—(C.sub.1-C.sub.4 haloalkyl), —CN, —OH and —O(C.sub.1-C.sub.4 alkyl).
11. The method of claim 6, wherein said compound is selected from: 10-chloro-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(6-Fluoro-pyridin-3-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(5-Fluoro-pyridin-2-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-chloro-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 10-(6-Fluoro-pyridin-3-yl)-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one; 9-Chloro-2-(methoxymethyl)-5-methyl-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; 2-(Methoxymethyl)-5-methyl-9-(6-fluoro-pyridin-3-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; 2-(Methoxymethyl)-5-methyl-9-(5-fluoro-pyridin-2-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof.
12. The method of claim 6, wherein the subject to be treated is a human.
13. The method of claim 6, wherein the method comprises administering orally said compound to the subject.
14. A method of treating a condition in a subject, the method comprising the administration of a compound as defined in claim 3 or a pharmaceutical composition comprising said compound and optionally a pharmaceutically acceptable excipient, to a subject in need thereof, wherein said condition is selected from: epilepsy; Alzheimer's disease; Parkinson's disease; Huntington's disease; Amyotrophic lateral sclerosis; schizophrenia; anxiety; and chronic pain.
Description
EXAMPLES
(1) In this section, the term “compound” refers to a synthesis intermediate, and the term “example” refers to a compound of the general formula (I) according to the invention.
(2) The compounds/examples 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/example defined by the chemical formula and the compound/example defined by the chemical name, and particularly relates to the compound/example defined by the chemical formula.
EXPERIMENTAL
Experimental Section
(3) All reagents were commercial grade and used without further purification. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Silica gel generally used for column chromatography was SDS silica gel (60AAC 40-63 μM). Thin layer chromatography was carried out using pre-coated silica gel F-254plate. .sup.1H NMR spectra were recorded on a Bruker AMX-400 spectrometer. Proton chemical shifts are listed relative to residual CDCl.sub.3 (7.27 ppm), DMSO-D6 (2.51 ppm) or D.sub.2O (4.60 ppm). Splitting patterns are designated as s (singlet), d (doublet), dd (double-doublet), t (triplet), tt (triplet-triplet), dt (doublet-triplet), q (quartet), quint (quintuplet), sex (sextuplet), sept (septuplet), m (multiplet), b (broad).
(4) Electrospray MS spectra were obtained on a Waters micromass platform LCMS spectrometer. All mass spectra were full-scan experiments (mass range 100-800 amu). Mass spectra were obtained using electro spray ionization. The HPLC system was a Waters platform with a 2767 sample manager, a 2525 pump, a photodiode array detector (190-400 nM). The column used was an XBridge C.sub.18 3.5 μM (4.6×50 mm) in analytical mode and an XBridge C18 OBD 5 μM (30×100 mm) in preparative mode. The mobile phase in both cases consisted in an appropriate gradient of A and B. A was water with 0.05% of TFA and B was MeOH with 0.05% of TFA. Flow rate was 1 mL per min in analytical mode and 25 mL min in preparative mode. All LCMS were performed at room temperature. At the end of each preparative HPLC, the tubes were collected and TFA was neutralized with potassium carbonate before extraction or filtration of the product. Microwave experiments were performed on a Biotage Initiator. The microwave modulates the power in order to reach the selected temperature as fast as possible. The time of each experiment is the time at the selected temperature.
(5) Melting Points are measure on a Barnstead Electrothermal 9100 and are not corrected.
General Procedure I: Formation of Intermediate C from the Corresponding Nitrile a and Methyl Ester B (Scheme 1)
(6) Method (i): Under Oil Bath Heating:
(7) At 0° C., to a suspension of sodium hydride (60% dispersion in oil, 1.5 equiv.) in DMF or DMA (0.80 mol.Math.L.sup.−1), a solution of methyl ester B (1.0 equiv.) in DMF or DMA (0.65 mol.Math.L.sup.−1) was slowly added, followed after 15 minutes by a solution of nitrile A (1.1 equiv.) in DMF or DMA (0.65 mol.Math.L.sup.−1). The reaction mixture was stirred at 70° C. (oil bath) for 3 hours, before being poured into an ice cold saturated aqueous solution of NH.sub.4Cl and extracted twice with CH.sub.2Cl.sub.2. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated under vacuum and purified by flash column chromatography on silica gel (using a gradient of EtOAc in cyclohexane as eluent) to afford the product.
(8) Method (ii): Under Microwave Irradiation:
(9) Under inert atmosphere, a mixture of nitrile A (1.0 equiv.), methyl ester B (1.0 equiv.) and cesium carbonate (2.5 equiv.) in DMF or DMA (0.20 mol.Math.L.sup.−1) was submitted to microwave irradiation at 130° C. for 10 minutes. The reaction mixture was neutralized with aqueous HCl (1N) and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by flash column chromatography on silica gel (using a gradient of EtOAc in cyclohexane as eluent) to afford the product.
Compound 1: 1-(5-Bromo-2-cyano-pyridin-3-yl)-1H-pyrrole-2-carboxylic acid methyl ester
(10) Compound 1 was obtained according to general procedure I(ii), starting from 5-bromo-3-fluoropyridine-2-carbonitrile and pyrrole-2-carboxylic acid methyl ester. It was isolated as a yellow solid in 53% yield. M/Z (M[.sup.79Br]+H).sup.+=306.
Compound 2: 1-(2-Chloro-5-cyano-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid methyl ester
(11) Compound 2 was obtained according to general procedure I (i), starting from 4,6-dichloro-nicotinonitrile and pyrrole-2-carboxylic acid methyl ester, from 0° C. to 25° C. over 1 hour. Purification by column chromatography on silica gel: 25 μm particle size (using 0% to 10% ethyl acetate in cyclohexane as eluent) afforded the product as a white solid in 22% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.06 (s, 1H, Ar); 8.06 (s, 1H, Ar); 7.47 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.19 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.51 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.70 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=261.9.
Compound 3: 3-Chloro-5-(2-methyl-pyridin-3-yl)-pyrazine-2-carbonitrile
(12) Under inert atmosphere, a mixture of 3,5-dichloropyrazine-2-carbonitrile (1 equiv.), 2-methylpyridine-3-boronic acid pinacol ester (1 equiv.), cesium carbonate (3 equiv.) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.1 equiv.) in dioxane (0.10 mol.Math.L.sup.−1) and water (0.80 mol.Math.L.sup.−1) was heated at 80° C. for 1 hour. The reaction mixture was hydrolysed and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated under vacuum and purified by flash column chromatography on silica gel (using 20% to 100% ethyl acetate (EtOAc) in cyclohexane as eluent) to afford the product as a brown solid in 57% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.17 (s, 1H, Ar); 8.65 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.02 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.46 (dd, J 7.8, 4.8 Hz, 1H, Ar); 2.62 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=230.9.
Compound 4: 1-[3-Cyano-6-(2-methyl-pyridin-3-yl)-pyrazin-2-yl]-1H-pyrrole-2-carboxylic acid methyl ester
(13) Compound 4 was obtained according to general procedure I(i), starting from compound 3 and pyrrole-2-carboxylic acid methyl ester, from 0° C. to 25° C. over 3 hours. Purification by column chromatography on silica gel (using 90% to 100% ethyl acetate in cyclohexane as eluent) afforded the product as a brown oil in 49% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.28 (s, 1H, Ar); 8.64 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.10 (dd, J 7.7, 1.6 Hz, 1H, Ar); 7.61 (dd, J 2.8, 1.7 Hz, 1H, Ar); 7.46 (dd, 7.7, 4.8 Hz, 1H, Ar); 7.21 (dd, J 3.8, 1.7 Hz, 1H, Ar); 6.54 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.71 (s, 3H, CH.sub.3); 2.61 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=320.0.
Compound 5: 4-Chloro-1-(2-chloro-5-cyano-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid methyl ester
(14) Compound 5 was obtained according to general procedure I(i), starting from 4,6-dichloro-nicotinonitrile and 4-chloro-1H-pyrrole-2-carboxylic acid methyl ester, from 0° C. to 25° C. over 1 hour. Purification by column chromatography on silica gel: 25 μm particle size (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow solid in 38% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.10 (s, 1H, Ar); 8.15 (s, 1H, Ar); 7.72 (d, J 1.4 Hz, 1H, Ar); 7.24 (d, J 1.4 Hz, 1H, Ar); 3.71 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl][.sup.35Cl]+H)+=296.1.
General Procedure II: Formation of Azepinone D or D1 from Intermediate C or C1 (Schemes 1 and 3)
(15) Under anhydrous conditions, at room temperature, ethylmagnesium bromide (1M solution in THF, 2.0 equiv.) was added dropwise to a solution of intermediate C or C1 (1.0 equiv.) and titanium isopropoxide (1.0 equiv.) in THF (0.20 mol.Math.L.sup.−1). The reaction mixture was stirred at room temperature for 3 hours to give a dark brown solution. When the reaction was not complete, 1.0-2.0 equiv. of ethylmagnesium bromide (1M solution in THF) was added again and the reaction mixture further stirred for 1 hour at room temperature. After cooling at 0° C., the reaction mixture was hydrolyzed with aqueous HCl (1N) and extracted twice with CH.sub.2Cl.sub.2. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated under vacuum and purified by flash column chromatography on silica gel (using a gradient of ethyl acetate in cyclohexane) to afford the product.
Compound 6: 2′-Chlorospiro[cyclopropane-1,5′-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7′(6′H)-one
(16) Compound 6 (which can also be referred to as 9-chloro-spiro[6,1′-cyclopropan]-5,8,10b-triaza-benzo[e]azulen-4-one) was obtained according to general procedure II, starting from compound 2. The reaction was completed by addition of more ethylmagnesium bromide (1M solution in THF, 1 equiv.) and titanium isopropoxide (1 equiv.). Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) afforded compound 6 as a beige solid in 42% yield. M/Z (M[.sup.35Cl]+H).sup.+=260.5.
Compound 7: 2′,9′-Dichlorospiro[cyclopropane-1,5′-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7′(6′H)-one
(17) Compound 7 was obtained according to general procedure II, starting from compound 5. The reaction was completed by addition of more ethylmagnesium bromide (1M solution in THF, 1 equiv.) and titanium isopropoxide (1 equiv.). Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) afforded compound 7 as a beige solid in 72% yield. M/Z (M[.sup.35Cl][.sup.35Cl]+H).sup.+=294.5.
General Procedure III: Formation of N-Substituted Azepinone F or F1 from Azepinone D or D1 with Electrophile E (Schemes 1 and 3)
(18) Under anhydrous conditions, to a solution of azepinone D or D1 (1.0 equiv.) in DMF (0.10 mol.Math.L.sup.−1) cooled by an ice bath, NaH (60% dispersion in mineral oil, 1.7 equiv.) was added in 3 portions. The mixture was stirred for 15 minutes, then electrophile E (2.0 equiv.) was added and the reaction mixture was stirred at room temperature. When the reaction was complete, the mixture was hydrolysed with an aqueous HCl solution (1N) and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated under vacuum and purified by flash column chromatography on silica gel.
Example 1: 2′-Chloro-6′-methylspiro[cyclopropane-1,5′-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7′(6′H)-one
(19) ##STR00374##
(20) Example 1 (which can also be referred to as 9-chloro-5-methyl-spiro[6,1′-cyclopropan]-5,8,10b-triaza-benzo[e]azulen-4-one) was obtained according to general procedure III, starting from compound 6 in presence of iodomethane. The reaction mixture was stirred at room temperature for 3 hours. Purification by flash column chromatography on silica gel (using 50% ethyl acetate in cycloheaxane as eluent) afforded the product as a white solid in 95% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.51 (s, 1H, Ar); 7.80 (s, 1H, Ar); 7.67 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.96 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.50 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 1.61 (m, 1H, cyclopropyl); 1.48 (m, 1H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=273.9.
Example 2: 2,9′-Dichloro-6′-methylspiro[cyclopropane-1,5′-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7′(6′H)-one
(21) ##STR00375##
(22) Example 2 was obtained according to general procedure II, starting from compound 7 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by flash column chromatography on silica gel (using 0% to 10% methanol in dichloromethane as eluent) and trituration in diisopropylether afforded the product as a brown solid in 56% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.53 (s, 1H, Ar); 7.87 (d, J 1.9 Hz, 1H, Ar); 7.83 (s, 1H, Ar); 6.96 (d, J 1.9 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.64 (m, 1H, cyclopropyl); 1.52 (m, 1H, cyclopropyl); 1.00 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl][.sup.35Cl]+H).sup.+=308.5.
General Procedure IV: Formation of Azepinone H, H1 or H2 from Azepinone F, F1 or F2 and Boronic Acid Derivatives G (Schemes 1, 2, 3 and 4)
(23) Method (i):
(24) Under inert atmosphere, a mixture of halide F, F1- or F2 (1.0 equiv.), boronic acid derivative G (1.5 equiv.) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.10 equiv.) in a mixture of DMF or DMA (0.10 mol.Math.L.sup.−1) and aqueous K.sub.2CO.sub.3 (1.2 mol.Math.L.sup.−1) was heated at 110° C. for 16 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
(25) Method (ii):
(26) Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of halide F, F1 or F2 (1.0 equiv.), boronic acid derivative G (1.5 equiv.) and tripotassium phosphate (2.0 equiv.) in dioxane (0.15 mol.Math.L.sup.−1) and water (1.0 mol.Math.L.sup.−1). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
(27) General Procedure V: Formation of HCl Salt
(28) Method (i): in DCM:
(29) To a solution of the free base in dichloromethane, HCl (2N solution in Et.sub.2O, 5 equiv.) was added. The resulting precipitate was collected, washed with Et.sub.2O and dried at 50° C. under reduced pressure with P.sub.2O.sub.5.
(30) Method (ii): Concentration from MeOH:
(31) To a solution or suspension of the free base in methanol, HCl (1.25N solution in MeOH, 5 equiv.) was added. The mixture was vigorously stirred, then concentrated. The residue was taken in Et.sub.2O. The resulting solid was collected, washed with Et.sub.2O and dried at 50° C. under reduced pressure with P.sub.2O.sub.5.
Example 3: 2′-(2-Methyl-pyridin-3-yl)-6′-methylspiro[cyclopropane-1,5′-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7′(6 .SUP.1.H)-one
(32) ##STR00376##
(33) Example 3 (which can also be referred to as 9-(2-methyl-pyridin-3-yl)-5-methyl-spiro[6,1′-cyclopropan]-5,8,10b-triaza-benzo[e]azulen-4-one) was obtained according to general procedure IV(i), starting from example 1 and 2-methylpyridine-3-boronic acid pinacol ester, using dioxane as solvent at 100° C. for 3 hours. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded example 3 as a beige solid in 63% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (s, 1H, Ar); 8.53 (dd, J 4.8, 1.8 Hz, 1H, Ar); 7.93 (dd, J 7.7, 1.8 Hz, 1H, Ar); 7.82 (s, 1H, Ar); 7.73 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.36 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.97 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.50 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 2.57 (s, 3H, CH.sub.3); 1.59 (m, 1H, cyclopropyl); 1.53 (m, 1H, cyclopropyl); 0.98 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=331.0. MP=250° C.
Example 4: 9′-Chloro-2′-(2-methyl-pyridin-3-yl)-6′-methylspiro[cyclopropane-1,5′-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7′(6′H)-one
(34) ##STR00377##
(35) Example 4 was obtained according to general procedure IV(i), starting from example 2 and 2-methylpyridine-3-boronic acid pinacol ester, using dioxane as solvent at 100° C. for 1 hour. Purification by flash column chromatography on silica gel (0% to 10% MeOH in dichloromethane) afforded example 4 as a white solid in 25% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.81 (s, 1H, Ar); 8.52 (dd, J 4.8, 1.8 Hz, 1H, Ar); 7.95-7.92 (m, 2H, Ar); 7.85 (s, 1H, Ar); 7.36 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.96 (d, J 1.9 Hz, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 2.57 (s, 3H, CH.sub.3); 1.69 (m, 1H, cyclopropyl); 1.56 (m, 1H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.96 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=365.4.
Example 5: 9′-(1-Methyl-1H-pyrazol-5-yl)-2′-(2-methyl-pyridin-3-yl)-6′-methylspiro[cyclopropane-1,5′-pyrido[3,4-f]pyrrolo[1,2-a][1,4]diazepin]-7′(6H)-one
(36) ##STR00378##
(37) Example 5 was obtained according to general procedure IV(ii), starting from example 4 and 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole, using tBuXPhos precatalyst, at 100° C. for 1 hour. Purification by flash column chromatography on silica gel (0% to 10% MeOH in dichloromethane) afforded example 5 as a white solid in 38% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.81 (s, 1H, Ar); 8.55 (dd, J 4.8, 1.8 Hz, 1H, Ar); 8.04 (d, J 1.9 Hz, 1H, Ar); 7.99 (s, 1H, Ar); 7.92 (dd, J 7.7, 1.8 Hz, 1H, Ar); 7.41 (d, J 1.9 Hz, 1H, Ar); 7.37 (dd, J 7.7, 4.8 Hz, 1H, Ar); 7.27 (d, J 1.9 Hz, 1H, Ar); 6.56 (d, J 1.9 Hz, 1H, Ar); 4.00 (s, 3H, CH.sub.3); 2.99 (s, 3H, COH.sub.3); 2.57 (s, 3H, CH.sub.3); 1.73 (m, 1H, cyclopropyl); 1.57 (m, 1H, cyclopropyl); 1.06 (m, 1H, cyclopropyl); 0.70 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=411.6.
Compound 8: 1-(6-Cyano-2′-methyl-[3,3′]bipyridinyl-5-yl)-1H-pyrrole-2-carboxylic acid methyl ester
(38) Under inert atmosphere, a mixture of compound 1 (1.0 equiv.), 2-methylpyridine-3-boronic acid pinacol ester (1.3 equiv.), cesium fluoride (3.0 equiv.) and Pd(PPh.sub.3).sub.4 (0.1 equiv.) in anhydrous THF (0.15 mol.Math.L.sup.−1) was heated at 70° C. for 16 hours. After cooling to room temperature, the reaction mixture was neutralized with aqueous NaHCO.sub.3 and extracted twice with EtOAc. The combined organic layers were dried with brine, over MgSO.sub.4, concentrated and purified by flash column chromatography on silica gel (using 0% to 80% EtOAc in cyclohexane as eluent) to afford the product as a white solid in 77% yield. 1H-NMR (400 MHz, DMSO-D6): 8.90 (d, J 2.0 Hz, 1H, Ar); 8.57 (dd, J 4.8, 1.8 Hz, 1H, Ar); 8.33 (d, J 2.0 Hz, 1H, Ar); 7.81 (dd, J 7.7, 1.8 Hz, 1H, Ar); 7.51 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.40 (dd, J 7.7, 4.8 Hz, 1H, Ar); 7.18 (d, J 3.8, 1.8 Hz, 1H, Ar); 6.50 (d, J 3.8, 2.8 Hz, 1H, Ar); 3.68 (s, 3H, CH.sub.3); 2.49 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=319.3.
Compound 9: 9-(2-Methyl-pyridin-3-yl)-5,6-dihydro-5,7,10b-triaza-benzo[e]azulen-4-one
(39) At 0° C., sodium borohydrate (10 equiv.) was slowly added to a mixture of compound 8 (1.0 equiv.) and cobalt chloride hexahydrate (2.0 equiv.) in methanol (0.15 mol.Math.L.sup.−1). The reaction mixture was subjected to microwave irradiation at 120° C. for 20 minutes. After cooling to room temperature, the reaction mixture was neutralized with an aqueous solution of ammonium chloride (NH.sub.4Cl) and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by flash column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) to afford the product as a beige solid in 40% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.54-8.47 (m, 3H, Ar+NH); 8.07 (d, J 1.8 Hz, 1H, Ar); 7.80 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.66 (d, J 2.9, 1.9 Hz, 1H, Ar); 7.37 (dd, J 7.7, 4.9 Hz, 1H, Ar); 6.96 (d, J 3.8, 1.9 Hz, 1H, Ar); 6.47 (dd, J 3.8, 2.9 Hz, 1H, Ar); 4.30 (d, J 5.6 Hz, 2H, CH.sub.2); 2.25 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=291.3.
Example 6: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-5,7,10b-triaza-benzo[e]azulen-4-one, dihydrochloride
(40) ##STR00379##
(41) Example 6 was prepared according to general procedure III, starting from compound 9 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1.5 hour. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a white solid in 48% yield. Salt formation was performed by method V(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.85 (dd, J 5.8, 1.4 Hz, 1H, Ar); 8.64 (d, J 1.8 Hz, 1H, Ar); 8.55 (dd, J 7.7, 1.4 Hz, 1H, Ar); 8.24 (d, J 1.8 Hz, 1H, Ar); 7.99 (d, J 7.7, 5.8 Hz, 1H, Ar); 7.62 (dd, J 2.9, 1.8 Hz, 1H, Ar); 6.97 (d, J 3.8, 1.8 Hz, 1H, Ar); 6.51 (dd, J 3.8, 2.9 Hz, 1H, Ar); 4.57 (s, 2H, CH.sub.2); 3.14 (s, 3H, CH.sub.3); 2.77 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=305.2. MP>250° C.
Compound 10: 9-(2-Methyl-pyridin-3-yl)-5,6-dihydro-5,7,10,10b-tetraaza-benzo[e]azulen-4-one
(42) Under hydrogen atmosphere (P=1 atm), a suspension of compound 4 (1 equiv.), palladium 10% on charcoal (0.1 equiv.) and concentrated aqueous HCl (12%, 5 equiv.) in methanol (0.10 mol.Math.L.sup.−1) was stirred at room temperature for 2 hours. Pd/C was filtered off on celite and the filtrate was concentrated under vacuum. The resulting brown oil was dissolved in dioxane (0.20 mol.Math.L.sup.−1) and aqueous sodium bicarbonate (0.40 mol.Math.L.sup.−1) was added. The reaction mixture was stirred at room temperature for 2 days. The organic phase was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by trituration in small quantities of EtOAc and Et.sub.2O afforded the product as a yellow powder in 68% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (s, 1H, Ar); 8.59 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.52 (t, J 5.2 Hz, 1H, NH); 8.03 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.83 (dd, J 2.9, 1.8 Hz, 1H, Ar); 7.42 (d, J 7.8, 4.8 Hz, 1H, Ar); 7.06 (d, J 3.8, 1.8 Hz, 1H, Ar); 6.52 (dd, J 3.8, 2.9 Hz, 1H, Ar); 4.38 (d, J 5.2 Hz, 2H, CH.sub.2); 2.63 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=292.0.
Example 7: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-5,7,10,10b-tetraaza-benzo[e]azulen-4-one, dihydrochloride
(43) ##STR00380##
(44) Example 7 was prepared according to general procedure III, starting from compound 10 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a beige solid in 31% yield. Salt formation was performed by method V(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.91 (s, 1H, Ar); 8.79 (dd, J 5.1, 1.5 Hz, 1H, Ar); 8.51 (d, J 7.7 Hz, 1H, Ar); 7.82 (dd, J 7.7, 5.1 Hz, 1H, Ar); 7.80 (dd, J 2.9, 1.9 Hz, 1H, Ar); 7.05 (d, J 3.7, 1.9 Hz, 1H, Ar); 6.53 (dd, J 3.7, 2.9 Hz, 1H, Ar); 4.64 (s, 2H, CH.sub.2); 3.15 (s, 3H, CH.sub.3); 2.80 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=306.0. MP>250° C.
Compound 11: 1-(3,6-Dichloro-pyridazin-4-yl)-1H-pyrrole-2-carboxylic acid methyl ester
(45) Under dry atmosphere, in a sealed vial, a mixture of 3,4,6-trichloropyridazine (1.2 equiv.), methyl 2-pyrrole carboxylate (1.0 equiv.) and cesium carbonate (1.7 equiv.) in anhydrous DMA (0.10 mol.Math.L.sup.−1) was heated at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was neutralized with aqueous NH.sub.4Cl and extracted twice with EtOAc. The combined organic layers were washed with water, dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 15% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 43% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.46 (s, 1H, Ar); 7.39 (dd, J 2.7, 1.8 Hz, 1H, Ar); 7.16 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.50 (dd, J 3.8, 2.7 Hz, 1H, Ar); 3.68 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl][.sup.35Cl]+H).sup.+=272.4.
Compound 12: 1-[3-Chloro-6-(2-methyl-pyridin-3-yl)-pyridazin-4-yl]-1H-pyrrole-2-carboxylic acid methyl ester
(46) Compound 12 was prepared according to procedure IV(ii), starting from compound 11 and 2-methylpyridine-3-boronic acid pinacol ester, and using PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 instead of XPhos precatalyst. Purification by flash column chromatography on silica gel (using 0% to 60% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 63% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.63 (d, J 4.3 Hz, 1H, Ar); 8.36 (s, 1H, Ar); 7.98 (d, J 7.6 Hz, 1H, Ar); 7.46-7.42 (m, 2H, Ar); 7.16 (d, J 3.4 Hz, 1H, Ar); 6.50 (t, J 3.3 Hz, 1H, Ar); 3.68 (s, 3H, CH.sub.3); 2.58 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=329.4.
Compound 13: 1-[3-Cyano-6-(2-methyl-pyridin-3-yl)-pyridazin-4-yl]-1H-pyrrole-2-carboxylic acid methyl ester
(47) Under inert atmosphere, a mixture of compound 12 (1.0 equiv.), zinc cyanide (2.0 equiv.) and bis(tri-tert-butylphosphine)palladium (0.10 equiv.) in anhydrous DMA (0.20 mol.Math.L.sup.−1) was heated at 130° C. for 1 hour. After cooling to room temperature, the reaction mixture was taken in aqueous NaHCO.sub.3 and extracted twice with EtOAc. The combined organic layers were washed with water, dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 60% EtOAc in cyclohexane as eluent) afforded the product as a colorless oil in 73% yield. M/Z (M+H).sup.+=320.5.
Example 8: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-5,7,8,10b-tetraaza-benzo[e]azulen-4-one, dihydrochloride
(48) ##STR00381##
(49) Example 8 was prepared according to a similar sequence as example 7, starting from compound 13. Purification by flash column chromatography on silica gel (0% to 10% MeOH in dichloromethane) afforded the product as a white solid in 34% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.55 (dd, J 4.7, 1.8 Hz, 1H, Ar); 8.09 (s, 1H, Ar); 7.92 (d, J 7.7, 1.8 Hz, 1H, Ar); 7.74 (dd, J 2.9, 1.8 Hz, 1H, Ar); 7.37 (dd, J 7.7, 4.7 Hz, 1H, Ar); 6.97 (d, J 3.7, 1.8 Hz, 1H, Ar); 6.51 (dd, J 3.7, 2.9 Hz, 1H, Ar); 4.73 (s, 2H, CH.sub.2); 3.10 (s, 3H, CH.sub.3); 2.51 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=306.5. MP>250° C.
Compound 14: (2,6-Dichloro-pyridin-3-ylmethyl)-methyl-amine
(50) A solution of 2,6-dichloropyridine-3-carboxaldehyde (1.0 equiv.) and methylamine (2M solution in THF, 2.0 equiv.) in MeOH (0.2 mol.Math.L.sup.−1) was stirred at room temperature for 1 hour. Sodium borohydride (8.0 equiv.) was slowly added and the reaction mixture was stirred for 1 hour at room temperature before being hydrolysed and extracted twice with dichloromethane. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded the product as a colorless oil in 84% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.97 (d, J 8.0 Hz, 1H, Ar); 7.57 (d, J 8.0 Hz, 1H, Ar); 3.68 (s, 2H, CH.sub.2); 2.29 (s, 3H, CH.sub.3). Proton for NH not observed.
Compound 15: 1H-Pyrrole-2-carboxylic acid (2,6-dichloro-pyridin-3-ylmethyl)-methyl-amide
(51) At 0° C., to a solution of compound 14 (1.0 equiv.) and triethylamine (5.0 equiv.) in dichloromethane (0.15 mol.Math.L.sup.−1), 1H-pyrrole-2-carbonyl chloride (1.3 equiv.) was slowly added. The reaction mixture was stirred at room temperature for 1 hour before being hydrolyzed with NaHCO.sub.3 and extracted twice with dichloromethane. The combined organic layers were dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded the product as a beige solid in 79% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.65 (bs, 1H, NH); 7.77 (d, J 8.0 Hz, 1H, Ar); 7.64 (d, J 8.0 Hz, 1H, Ar); 6.99 (m, 1H, Ar); 6.59 (bs, 1H, Ar); 6.20 (m, 1H, Ar); 4.81 (m, 2H, Ar); 3.37 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl][.sup.35Cl]+H).sup.+=284.5.
Example 9: 9-Chloro-5-methyl-5,6-dihydro-5,10,10b-triaza-benzo[e]azulen-4-one
(52) ##STR00382##
(53) At room temperature, sodium hydride (60% dispersion in oil, 1.2 equiv.) was added to a solution of compound 15 in dry DMA (0.15 mol.Math.L−1). After 10 minutes stirring, the reaction mixture was heated at 100° C. for 1 hour before being hydrolyzed with NH.sub.4Cl and extracted twice with EtOAc. The combined organic layers were dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded example 9 as a beige solid in 71% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.19 (d, J 7.8 Hz, 1H, Ar); 7.71 (dd, J 2.9, 1.9 Hz, 1H, Ar); 7.60 (d, J 7.8 Hz, 1H, Ar); 7.03 (dd, J 3.7, 1.9 Hz, 1H, Ar); 6.51 (dd, J 3.7, 2.9 Hz, 1H, Ar); 4.46 (s, 2H, CH.sub.2); 3.13 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H)+=248.5.
Example 10: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-5,10,10 b-triaza-benzo[e]azulen-4-one
(54) ##STR00383##
(55) Example 10 was prepared according to general procedure IV(i), starting from example 9 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded the product as a beige solid in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.52 (dd, J 4.8, 1.8 Hz, 1H, Ar); 8.17 (d, J 7.7 Hz, 1H, Ar); 7.91 (dd, J 7.7, 1.8 Hz, 1H, Ar); 7.74 (dd, J 2.8, 1.9 Hz, 1H, Ar); 7.64 (d, J 7.7 Hz, 1H, Ar); 7.36 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.95 (dd, J 3.8, 1.9 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.45 (s, 2H, CH.sub.2); 3.10 (s, 3H, CH.sub.3); 2.59 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=305.6.
Compound 16: (5-Chloro-3-fluoro-pyridin-2-ylmethyl)-methyl-amine
(56) Compound 16 was prepared according to procedure of compound 14, starting from 5-chloro-3-fluoropyridine-2-carbaldehyde. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded the product as a yellow oil in 68% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.48 (d, J 2.1 Hz, 1H, Ar); 8.03 (dd, J 9.5, 2.1 Hz, 1H, Ar); 3.77 (d, J 2.3 Hz, 2H, CH.sub.2); 2.27 (s, 3H, OH.sub.3); 2.15 (bs, 1H, NH).
Example 11: 3-(5-Methyl-4-oxo-5,6-dihydro-4H-5,7,1 b-triaza-benzo[e]azulen-9-yl)-benzonitrile
(57) ##STR00384##
(58) Example 11 was prepared according to synthetic route of scheme 2, in a similar sequence as for example 10, and starting from compound 16. 3-benzonitrile boronic acid was used in the last step with general procedure IV(i). Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 11 as a white solid in 25% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.88 (d, J 1.9, Hz, 1H, Ar); 8.45 (s, 1H, Ar); 8.36 (d, J 1.9 Hz, 1H, Ar); 8.25 (d, J 7.9 Hz, 1H, Ar); 7.94 (d, J 7.9 Hz, 1H, Ar); 7.79 (dd, J 2.8, 1.9 Hz, 1H, Ar); 7.75 (t, J 7.9 Hz, 1H, Ar); 6.95 (dd, J 3.8, 1.9 Hz, 1H, Ar); 6.51 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.53 (s, 2H, CH.sub.2); 3.11 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=315.5.
Example 12: 9-Imidazo[1,2-a]pyridin-6-yl-5-methyl-5,6-dihydro-5,7,10b-triaza-benzo[e]azulen-4-one
(59) ##STR00385##
(60) Example 12 was prepared according to procedure of example 11 and using imidazo[1,2-a]pyridine-6-boronic acid in the last step with general procedure IV(i). Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 12 as a white solid in 26% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.22 (d, J 1.8 Hz, 1H, Ar); 8.91 (d, J 1.9, Hz, 1H, Ar); 8.38 (d, J 1.9 Hz, 1H, Ar); 8.04 (s, 1H, Ar); 7.85 (d, J 9.5, 1.8 Hz, 1H, Ar); 7.82 (dd, J 2.8, 1.9 Hz, 1H, Ar); 7.78 (d, J 9.5 Hz, 1H, Ar); 7.72 (d, J 1.2 Hz, 1H, Ar); 7.02 (dd, J 3.8, 1.9 Hz, 1H, Ar); 6.57 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.59 (s, 2H, CH.sub.2); 3.18 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=330.5.
Compound 17: 1H-Pyrrole-2-carboxylic acid (2,4-dichloro-pyrimidin-5-ylmethyl)-methyl-amide
(61) Under dry atmosphere, at −78° C., a solution of 2,4-dichloro-5-iodomethylpyridine (1.0 equiv.) in anhydrous THF (0.30 mol.Math.L.sup.−1) was added dropwise to a solution of methylamine (3.0 equiv.) in anhydrous THF (0.30 mol.Math.L.sup.−1). After 30 minutes, always at −78° C., a solution of 1H-pyrrole-2-carbonyl chloride (1.0 equiv.) in anhydrous THF (0.30 mol.Math.L.sup.−1) was added dropwise and the reaction mixture was allowed to reach room temperature over 1 hour. At 0° C., the reaction mixture was neutralized by addition of aqueous HCl (1N) and extracted twice with dichloromethane. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 40% ethyl acetate in cyclohexane as eluent) afforded the product as a white solid in 32% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.50 (bs, 1H, NH); 8.63 (s, 1H, Ar); 6.93 (m, 1H, Ar); 6.59 (m, 1H, Ar); 6.14 (m, 1H, Ar); 4.74 (s, 2H, CH.sub.2); 3.27 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl][.sup.35Cl]+H).sup.+=285.4.
Example 13: 9-Chloro-5-methyl-5,6-dihydro-5,8,10,10b-tetraaza-benzo[e]azulen-4-one
(62) ##STR00386##
(63) At 0° C., to a solution of compound 17 (1.0 equiv.) in anhydrous DMA (0.10 mol.Math.L.sup.−1), sodium hydride (1.1 equiv.) was slowly added and the reaction mixture was stirred at room temperature for 2 hours. At 0° C., the reaction mixture was neutralized by addition of aqueous HCl (1N) and extracted twice with EtOAc. The combined extracts were washed with water, dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by trituration in iPr.sub.2O afforded example 13 as a yellow solid in 87% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.90 (s, 1H, Ar); 7.76 (dd, J 3.1, 1.9 Hz, 1H, Ar); 7.09 (dd, J 3.7, 1.9 Hz, 1H, Ar); 6.54 (t, J 3.3 Hz, 1H, Ar); 4.44 (s, 2H, CH.sub.2); 3.08 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=249.5.
Example 14: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-5,8,10,10 b-tetraaza-benzo[e]azulen-4-one
(64) ##STR00387##
(65) Example 14 was prepared according to general procedure IV(i) starting from example 13 in presence of 2-methylpyridine-3-boronic acid pinacol ester and heating at 80° C. for 1 hour. Purification by flash column chromatography on silica gel (using 0% to 6% MeOH in dichloromethane as eluent) and tritutation in iPr.sub.2O afforded example 14 as a beige solid in 29% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.10 (s, 1H, Ar); 8.59 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.32 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.93 (dd, J 3.0, 1.9 Hz, 1H, Ar); 7.41 (dd, J 7.8, 4.8 Hz, 1H, Ar); 7.09 (dd, J 3.6, 1.9 Hz, 1H, Ar); 6.54 (t, J 3.3 Hz, 1H, Ar); 4.51 (s, 2H, CH.sub.2); 3.14 (s, 3H, CH.sub.3); 2.79 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=306.6.
Compound 18: 1-(4-Bromo-2-fluoro-phenyl)-cyclobutanecarbonitrile
(66) Under dry atmosphere, at 0° C., a solution of 4-bromo-2-fluorobenzylcyanide (1.0 equiv.) and 1,3-dibromopropane (1.1 equiv.) in diethylether (3.0 mol.Math.L.sup.−1) was added dropwise to a suspension of sodium hydride (2.2 equiv.) in anhydrous DMA (0.10 mol.Math.L.sup.−1). The resulting yellow mixture was stirred at room temperature for 1 hour. At 0° C., the reaction mixture was neutralized by addition of aqueous ammonium chloride and extracted twice with ethyl acetate. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 10% ethyl acetate in cyclohexane as eluent) afforded the product as a colorless oil in 63% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.66 (dd, J 10.3, 1.9 Hz, 1H, Ar); 7.52-7.49 (m, 1H, Ar); 7.40 (t, J 8.4 Hz, 1H, Ar); 2.77-2.61 (m, 4H, cyclobutyl); 2.31 (m, 1H, cyclobutyl); 1.97 (m, 1H, cyclobutyl). Product not observed in mass spectrum ES+.
Compound 19: 1-(4-Bromo-2-fluoro-phenyl)-cyclobutanecarboxylic acid
(67) Aqueous hydrogen peroxide (2.0 equiv.) was added to a suspension of compound 18 (1.0 equiv.) and potassium carbonate (0.2 equiv.) in DMSO (0.10 mol.Math.L.sup.−1). The reaction mixture was stirred at room temperature for 16 hours before being partitioned between water and ethyl acetate and extracted twice with ethyl acetate. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded the intermediate carboxamide as a colorless oil in quantitative yield. M/Z (M[.sup.79Br]+H).sup.+=272.5.
(68) The carboxamide (1.0 equiv.) was dissolved in dioxane (0.20 mol.Math.L.sup.−1) and an aqueous 3N solution of HCl (0.20 mol.Math.L.sup.−1) was added. The resulting solution was heated at 100° C. for 16 hours. After cooling to room temperature, the mixture was extracted twice with ethyl ecetate. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum to give compound 19 as a white solid in 99% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 12.52 (bs, 1H, COOH); 7.46 (dd, J 10.3, 1.9 Hz, 1H, Ar); 7.40 (dd, J 8.1, 1.9 Hz, 1H, Ar); 7.30 (t, J 8.4 Hz, 1H, Ar); 2.66 (m, 2H, cyclobutyl); 2.42 (m, 2H, cyclobutyl); 2.10 (m, 1H, cyclobutyl); 1.84 (m, 1H, cyclobutyl). M/Z (M[.sup.79Br]+H)+=273.5.
Compound 20: 1-(4-Bromo-2-fluoro-phenyl)-cyclobutylamine
(69) Diphenylphosphonyl azide (1.3 equiv.) was added to a solution of compound 19 (1.0 equiv.) and triethylamine (1.3 equiv.) in dioxane (0.30 mol.Math.L.sup.−1). The reaction mixture was stirred at room temperature for 2 hours before being treated with water and extracted twice with dichloromethane. The crude isocyanate was dissolved in aqueous HCl (2N, 0.10 mol.Math.L.sup.−1) and the resulting solution was heated at 60° C. for 16 hours. After cooling to room temperature, the mixture was neutralized with potassium carbonate and extracted twice with ethyl ecetate. The combined extracts were dried with brine and MgSO.sub.4, filtered and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded compound 20 as a colorless residue in 80% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.43 (dd, J 10.3, 1.9 Hz, 1H, Ar); 7.35 (dd, J 8.1, 1.9 Hz, 1H, Ar); 7.24 (t, J 8.4 Hz, 1H, Ar); 2.39 (m, 2H, cyclobutyl); 2.09 (m, 5H, 3H cyclobutyl+NH.sub.2); 1.67 (m, 1H, cyclobutyl). M/Z (M[.sup.79Br]+H—NH.sub.2).sup.+=229.4.
Compound 21: 1H-Pyrrole-2-carboxylic acid [1-(4-bromo-2-fluoro-phenyl)-cyclobutyl]-amide
(70) Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.3 equiv.) was added to a solution of compound 20 (1.0 equiv.) and diisopropylethylamine (3.0 equiv.) in THF (0.20 mol.Math.L.sup.−1). The reaction mixture was stirred at room temperature for 16 hours before being treated with water and extracted twice with ethyl acetate. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded compound 21 as a white solid in 98% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.25 (bs, 1H, NH); 8.46 (s, 1H, NH); 7.46 (t, J 8.5 Hz, 1H, Ar); 7.40 (dd, J 10.8, 1.9 Hz, 1H, Ar); 7.34 (dd, J 8.3, 1.9 Hz, 1H, Ar); 6.86 (m, 1H, Ar); 6.81 (m, 1H, Ar); 6.05 (m, 1H, Ar); 2.59 (m, 4H, cyclobutyl); 2.06 (m, 1H, cyclobutyl); 1.80 (m, 1H, cyclobutyl). M/Z (M[79Br]+H).sup.+=337.4.
Compound 22: 9-Bromo-5,6-dihydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclobutan]-4-one
(71) A suspension of compound 21 (1.0 equiv.) and potassium carbonate (2.0 equiv.) in anhydrous DMA (0.15 mol.Math.L.sup.−1) was subjected to microwave irradiation at 190° C. for 1 hour and again at 210° C. for 1 hour to complete the conversion. After cooling to room temperature, the reaction mixture was treated with water and extracted twice with ethyl acetate. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 80% ethyl acetate in cyclohexane as eluent) afforded compound 22 as a beige solid in 57% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.68 (s, 1H, NH); 7.68 (d, J 1.9 Hz, 1H, Ar); 7.57 (dd, J 8.2, 1.9 Hz, 1H, Ar); 7.53 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.46 (d, J 8.2 Hz, 1H, Ar); 6.85 (dd, J 3.6, 1.8 Hz, 1H, Ar); 6.39 (dd, J 3.6, 2.8 Hz, 1H, Ar); 2.85 (m, 1H, cyclobutyl); 2.42 (m, 1H, cyclobutyl); 1.97 (m, 1H, cyclobutyl); 1.84 (m, 1H, cyclobutyl); 1.67 (m, 2H, cyclobutyl). M/Z (M[.sup.79Br]+H).sup.+=317.4.
Example 15: 9-Bromo-5-methyl-5,6-dihydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclobutan]-4-one
(72) ##STR00388##
(73) Example 15 was obtained according to general procedure III, starting from compound 22 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by column chromatography on silica gel (using 0% to 70% EtOAc in cyclohexane as eluent) afforded the product as a white solid in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.77 (d, J 1.9 Hz, 1H, Ar); 7.67 (d, J 8.3 Hz, 1H, Ar); 7.60 (dd, J 8.3, 1.9 Hz, 1H, Ar); 7.50 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.79 (dd, J 3.6, 1.8 Hz, 1H, Ar); 6.39 (dd, J 3.6, 2.8 Hz, 1H, Ar); 2.85 (m, 1H, cyclobutyl); 2.81 (s, 3H, CH.sub.3); 2.64 (m, 1H, cyclobutyl); 2.07 (m, 1H, cyclobutyl); 1.69 (m, 1H, cyclobutyl); 1.39 (m, 2H, cyclobutyl). M/Z (M[.sup.79Br]+H).sup.+=331.4.
Example 16: 9-(6-Fluoro-pyridin-3-yl)-5-methyl-5,6-dihydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclobutan]-4-one
(74) ##STR00389##
(75) Example 16 was prepared according to general procedure IV(i) starting from example 15 in presence of 6-fluoro-3-pyridinylboronic acid, at 100° C. for 2 hours. Purification by flash column chromatography on silica gel (using 0% to 100% EtOAc in cyclohexane as eluent) afforded example 16 as a beige solid in 93% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.70 (d, J 2.0 Hz, 1H, Ar); 8.44 (dt, J 8.3, 2.6 Hz, 1H, Ar); 7.86-7.83 (m, 2H, Ar); 7.75 (dd, J 8.0, 1.9 Hz, 1H, Ar); 7.65 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.33 (dd, J 8.5, 2.6 Hz, 1H, Ar); 6.81 (dd, J 3.6, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.6, 2.8 Hz, 1H, Ar); 2.94 (m, 1H, cyclobutyl); 2.85 (s, 3H, CH.sub.3); 2.68 (m, 1H, cyclobutyl); 2.12 (m, 1H, cyclobutyl); 1.73 (m, 1H, cyclobutyl); 1.43 (m, 2H, cyclobutyl). M/Z (M+H).sup.+=348.6.
Example 17: 9-(2-Methyl-pyridin-3-yl)-5-methyl-5,6-dihydro-spiro[benzo[f]pyrrolo[, 2-a][1,4]diazepine-6,1′-cyclobutan]-4-one
(76) ##STR00390##
(77) Example 17 was prepared according to general procedure IV(i), starting from example 15 and heating at 100° C. for 2 hours. Purification by flash column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 17 as a beige solid in 92% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.49 (dd, J 4.8, 1.6 Hz, 1H, Ar); 7.80 (d, J 8.0 Hz, 1H, Ar); 7.76 (dd, J 7.7, 1.6 Hz, 1H, Ar); 7.57 (d, J 1.7 Hz, 1H, Ar); 7.52 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.46 (dd, J 8.0, 1.7 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.80 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.38 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.97-2.90 (m, 1H, cyclobutyl); 2.86 (s, 3H, CH.sub.3); 2.74-2.66 (m, 1H, cyclobutyl); 2.52 (s, 3H, CH.sub.3); 2.17-2.07 (m, 1H, cyclobutyl); 1.77-1.70 (m, 1H, cyclobutyl); 1.50-1.42 (m, 2H, cyclobutyl). M/Z (M+H).sup.+=344.5.
Example 18: 9-(6-Fluoro-pyridin-2-yl)-5-methyl-5,6-dihydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclobutan]-4-one
(78) ##STR00391##
(79) Under inert atmosphere, PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.10 equiv.) was added to a suspension of example 15 (1.0 equiv.), bispinacolatodiboron (1.2 equiv.) and potassium acetate (2.7 equiv.) in dioxane (0.15 mol.Math.L.sup.−1). The reaction mixture was heated at 100° C. for 3 hours. After cooling to room temperature, potassium carbonate (3.0 equiv.) and a solution of 2-bromo-5-fluoropyridine (2.0 equiv.) in dioxane (0.90 mol.Math.L.sup.−1) were successively added. The reaction mixture was heated at 100° C. for 2 hours. After cooling to room temperature, the reaction mixture was treated with water and extracted twice with ethyl acetate. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 100% ethyl acetate in cyclohexane as eluent) and trituration in diethyl ether afforded example 18 as a white solid in 84% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.70 (d, J 3.0 Hz, 1H, Ar); 8.22 (dd, J 8.8, 4.4 Hz, 1H, Ar); 8.13 (d, J 1.7 Hz, 1H, Ar); 8.09 (dd, J 8.1, 1.7 Hz, 1H, Ar); 7.88 (dt, J 8.8, 3.0 Hz, 1H, Ar); 7.84 (d, J 8.1 Hz, 1H, Ar); 7.59 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.81 (dd, J 3.6, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.6, 2.8 Hz, 1H, Ar); 2.93 (m, 1H, cyclobutyl); 2.85 (s, 3H, CH.sub.3); 2.68 (m, 1H, cyclobutyl); 2.12 (m, 1H, cyclobutyl); 1.72 (m, 1H, cyclobutyl); 1.44 (m, 2H, cyclobutyl). M/Z (M+H).sup.+=348.5.
General Procedure VI: Preparation of Intermediate C1 from Halogeno-Benzonitrile A and (Hetero)Aromatic Boronic Acid or Ester B1 (Scheme 3)
(80) Under inert atmosphere, a mixture of halogeno-benzonitrile A (1.0 equiv.), boronic acid derivative B1 (1.1 equiv.) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.10 equiv.) in a mixture of dioxane (0.10 mol.Math.L) and aqueous K.sub.2CO.sub.3 (1.2 mol.Math.L) was heated at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
Compound 23: 4-Chloro-2-iodo-benzonitrile
(81) Under inert atmosphere, a mixture of 4-chlorobenzonitrile (1 equiv.), N-iodosuccinimide (1.1 equiv.), p-toluenesulfonic acid (0.5 equiv.), palladium acetate (0.05 equiv.) in 1,2-dichloroethane (0.2 mol.Math.L.sup.−1) was heated at 70° C. for 16 hours. The mixture was concentrated under vacuum and purified by column chromatography on silica gel (using 0% to 50% EtOAc in cyclohexane as eluent) to afford the product as a white solid in 44% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.21 (d, J 2.0 Hz, 1H, Ar); 7.88 (d, J 8.3 Hz, 1H, Ar); 7.69 (dd, J 8.3, 2.0 Hz, 1H, Ar). Product not observed in mass spectrum ES+.
Compound 24: 4-Bromo-2-iodo-benzonitrile
(82) Compound 24 was prepared according to procedure of compound 23, starting from 4-bromobenzonitrile. Purification by column chromatography on silica gel (using 0% to 10% EtOAc in cyclohexane as eluent) afforded compound 24 as a white solid in 41% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.33 (d, J 1.8 Hz, 1H, Ar); 7.84-7.70 (m, 2H, Ar). Product not observed in mass spectrum ES+.
Compound 25: 5′-Chloro-2′-cyano-biphenyl-2-carboxylic acid methyl ester
(83) Compound 25 was prepared according to general procedure VI, starting from compound 23 and 2-methoxycarbonyl-phenylboronic acid. Purification by column chromatography on silica gel (using 0% to 20% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 60% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.06 (dd, J 7.8, 1.2 Hz, 1H, Ar); 7.94 (d, J 8.3 Hz, 1H, Ar); 7.78-7.74 (m, 1H, Ar); 7.69-7.64 (m, 2H, Ar); 7.59 (d, J 1.9 Hz, 1H, Ar); 7.45 (dd, J 7.7, 1.2 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=239.8.
Compound 26: 5′-Bromo-4-chloro-2′-cyano-biphenyl-2-carboxylic acid methyl ester
(84) Compound 26 was prepared according to general procedure VI, starting from compound 24 and 5-Chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester. Purification by column chromatography on silica gel (using 0% to 10% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 36% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.04 (d, J 8.2 Hz, 11H, Ar); 7.87-7.81 (m, 3H, Ar); 7.75 (d, J 1.8 Hz, 1H, Ar); 7.51 (d, J 8.2 Hz, 1H, Ar); 3.68 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl][.sup.80Br]+H).sup.+=319.9.
Compound 27: 10-Chloro-6,7-dihydro-spiro[dibenzo[c, e]azepine-7,1′-cyclopropan]-5-one
(85) Compound 27 was obtained according to general procedure II, starting from compound 25. The reaction was completed by addition of ethylmagnesium bromide (1M solution in THF, 1 equiv.) and titanium isopropoxide (1 equiv.). Purification by column chromatography on silica gel (using 10% to 60% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 72% yield. M/Z (M[.sup.35Cl]+H).sup.+=269.9.
Compound 28: 10-Bromo-3-chloro-6,7-dihydro-spiro[dibenzo[c,e]azepine-7,1′-cyclopropan]-5-one
(86) Compound 28 was obtained according to general procedure II, starting from compound 26. The reaction was completed by addition of ethylmagnesium bromide (1M solution in THF, 2.5 equiv.) and titanium isopropoxide (1 equiv.). Purification by column chromatography on silica gel (using 10% to 60% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 60% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.08 (s, 1H, NH); 7.83 (s, 1H, Ar); 7.75-7.70 (m, 3H, Ar); 7.60 (d, J 8.0 Hz, 1H, Ar); 7.33 (d, J 8.0 Hz, 1H, Ar); 1.47 (m, 1H, cyclopropyl); 1.13 (m, 1H, cyclopropyl); 0.77 (m, 1H, cyclopropyl); 0.32 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl][.sup.80Br]+H).sup.+=349.9.
Example 19: 10-Chloro-6-methyl-6,7-dihydro-spiro[dibenzo[c,e]azepine-7,1′-cyclopropan]-5-one
(87) ##STR00392##
(88) Example 19 was obtained according to general procedure III, starting from compound 27 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by column chromatography on silica gel (using 0% to 50% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 58% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.75-7.73 (m, 2H, Ar); 7.67-7.61 (m, 2H, Ar); 7.57-7.53 (m, 1H, Ar); 7.47 (m, 2H, Ar); 2.94 (s, 3H, CH.sub.3); 1.39 (m, 2H, cyclopropyl); 0.81 (m, 1H, cyclopropyl); 0.32 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=239.8.
Example 20: 10-Bromo-3-chloro-6-methyl-6,7-dihydro-spiro[dibenzo[c,e]azepine-7,1′-cyclopropan]-5-one
(89) ##STR00393##
(90) Example 20 was obtained according to general procedure III, starting from compound 26 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by column chromatography on silica gel (using 0% to 2% MeOH in dichloromethane as eluent) afforded the product as a white solid in 90% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.89 (s, 1H, Ar); 7.71-7.67 (m, 3H, Ar); 7.69 (d, J 8.0 Hz, 1H, Ar); 7.42 (d, J 8.0 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.42 (m, 2H, cyclopropyl); 0.90 (m, 1H, cyclopropyl); 0.35 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl][.sup.80Br]+H).sup.+=364.2.
Example 21: 10-(2-Methyl-pyridin-3-yl)-6-methyl-6,7-dihydro-spiro[dibenzo[c,e]azepine-7,1′-cyclopropan]-5-one, hydrochloride
(91) ##STR00394##
(92) Example 21 was prepared according to general procedure IV(ii), starting from example 19 and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 20% to 100% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 67% yield. Salt formation was performed according to method V(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (dd, J 5.5, 1.3 Hz, 1H, Ar); 8.40 (d, J 7.9 Hz, 1H, Ar); 7.85 (dd, J 7.9, 5.5 Hz, 1H, Ar); 7.82 (d, J 1.6 Hz, 1H, Ar); 7.77 (dd, J 7.7, 1.3 Hz, 1H, Ar); 7.71 (dd, J 7.7, 1.0 Hz, 1H, Ar); 7.66-7.61 (m, 2H, Ar); 7.57-7.53 (m, 2H, Ar); 2.99 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.87 (m, 1H, cyclopropyl); 0.39 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=340.9. MP>250° C.
Example 22: 3-Chloro-10-(2-methyl-pyridin-3-yl)-6-methyl-6,7-dihydro-spiro[dibenzo[c, e]azepine-7,1′-cyclopropan]-5-one
(93) ##STR00395##
(94) Example 22 was prepared according to general procedure IV(i), starting from example 20 and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded the product as a white solid in 61% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.47 (dd, J 4.9, 1.4 Hz, 1H, Ar); 7.76-7.69 (m, 4H, Ar); 7.67 (dd, J 8.5, 2.2 Hz, 1H, Ar); 7.55 (d, J 7.9 Hz, 1H, Ar); 7.47 (dd, J 7.7, 1.4 Hz, 1H, Ar); 7.31 (dd, J 7.7, 4.9 Hz, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 2.47 (s, 3H, CH.sub.3); 1.46 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.40 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=375.3.
Example 23: 3-(2-Methyl-2H-pyrazol-3-yl)-10-(2-methyl-pyridin-3-yl)-6-methyl-6,7-dihydro-spiro[dibenzo[c, e]azepine-7,1′-cyclopropan]-5-one
(95) ##STR00396##
(96) Example 23 was obtained according to general procedure IV(ii), starting from example 22 and 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and heating at 100° C. for 1 hour. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded example 23 as a yellow solid in 18% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.46 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.85 (d, J 1.7 Hz, 1H, Ar); 7.82 (d, J 8.0 Hz, 1H, Ar); 7.78 (dd, J 8.3, 1.7 Hz, 1H, Ar); 7.74-7.71 (m, 2H, Ar); 7.57 (d, J 7.8 Hz, 1H, Ar); 7.51 (d, J 1.9 Hz, 1H, Ar); 7.48 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.54 (d, J 1.9 Hz, 1H, Ar); 3.92 (s, 3H, CH.sub.3); 2.99 (s, 3H, CH.sub.3); 2.49 (s, 3H, CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.42 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=421.6.
Compound 29: 4-Chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde
(97) Under inert atmosphere, a mixture of 2-bromo-4-chlorobenzaldehyde (1.0 equiv.), bispinacolatodiboron (2.0 equiv.), potassium acetate (2.0 equiv.) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.1 equiv.) in dioxane (0.10 mol.Math.L.sup.−1) was heated at 80° C. for 3 hours. After cooling, the reaction mixture was hydrolyzed and extracted twice with EtOAc. The combined organic layers were dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using dichloromethane as eluent) afforded the product as a beige solid in 55% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 10.27 (s, 1H, CHO); 7.93 (d, J 8.2 Hz, 1H, Ar); 7.74 (dd, J 8.2, 2.1 Hz, 1H, Ar); 7.69 (d, J 2.1 Hz, 1H, Ar); 1.35 (s, 12H, 4CH.sub.3).
Compound 30: 3-(5-Chloro-2-formyl-phenyl)-pyridine-2-carboxylic acid methyl ester
(98) Under inert atmosphere, a mixture of compound 29 (1.0 equiv.), methyl 3-bromopicolinate (1.0 equiv.), cesium fluoride (3.0 equiv.) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.10 equiv.) in anhydrous THF (0.20 mol.Math.L.sup.−1) was heated at 70° C. for 3 hours. After cooling, the reaction mixture was hydrolyzed and extracted twice with EtOAc. The combined organic layers were dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 60% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 33% yield. M/Z (M[.sup.35Cl]+H).sup.+=276.5.
Compound 31: 3-(5-Chloro-2-formyl-phenyl)-pyridine-2-carboxylic acid methylamide
(99) A solution of compound 30 (1.0 equiv.) and methylamine (10 equiv.) in THF (0.2 mol.Math.L.sup.−1) was heated at 80° C. for 4 days before being concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 7% MeOH in dichloromethane as eluent) afforded the product as a colorless oil in 82% yield. M/Z (M[.sup.35Cl]+H).sup.+=275.5.
Example 24: 10-Chloro-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a,c]cyclohepten-5-one
(100) ##STR00397##
(101) A mixture of compound 31 (1.0 equiv.), trifluoroacetic acid (2.0 equiv.) and triethylsilane (3.0 equiv.) in anhydrous acetonitrile (0.1 mol.Math.L.sup.−1) was refluxed for 16 hours. After cooling, the reaction mixture was neutralyzed with aqueous sodium bicarbonate and extracted twice with EtOAc. The combined organic layers were dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded example 24 as a beige solid in 59% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (dd, J 4.7, 1.6 Hz, 1H, Ar); 8.16 (d, J 8.1, 1.6 Hz, 1H, Ar); 7.86 (d, J 2.1 Hz, 1H, Ar); 7.66-7.61 (m, 2H, Ar); 7.55 (dd, J 8.1, 2.1 Hz, 1H, Ar); 4.29 (d, J 15.2 Hz, 1H, CHaHb); 4.24 (d, J 15.2 Hz, 1H, CHaHb); 3.04 (s, 3H, OH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=259.5.
Example 25: 3-(6-Methyl-5-oxo-6,7-dihydro-5H-4,6-diaza-dibenzo[a,c]cyclohepten-10-yl)-benzonitrile
(102) ##STR00398##
(103) Example 25 was prepared according to general procedure IV(ii), starting from example 24 and 3-cyanophenylboronic acid. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) afforded example 25 as a beige solid in 66% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (dd, J 4.6, 1.5 Hz, 1H, Ar); 8.36-8.34 (m, 2H, Ar); 8.18-8.13 (m, 2H, Ar); 7.87-7.84 (m, 2H, Ar); 7.72-7.65 (m, 3H, Ar); 4.37 (d, J 15.0 Hz, 1H, CHaHb); 4.28 (d, J 15.0 Hz, 1H, CHaHb); 3.07 (s, 3H, CH.sub.3); M/Z (M+H).sup.+=326.4.
Compound 32: (2-Bromo-4-chloro-benzyl)-methyl-carbamic acid tert-butyl ester
(104) To a solution of 2-bromo-4-chlorobenzaldehyde (1.0 equiv.) in MeOH (0.20 mol.Math.L.sup.−1), methylamine (2M solution in THF, 1.1 equiv.) was added and the reaction mixture was stirred at room temperature for 2 hours. Sodium borohydride (1.2 equiv.) was slowly added and the resulting yellow mixture was stirred at room temperature for 1 hour. MeOH was removed under vacuum and the residue was dissolved in a mixture of THF (0.30 mol.Math.L.sup.−1) and saturated aqueous sodium bicarbonate (0.30 mol.Math.L.sup.−1). Di-tert-butyl-dicarbonate (1.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 hours, before being hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 91% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.77 (d, J 2.1 Hz, 1H, Ar); 7.50 (dd, J 8.3, 2.1 Hz, 1H, Ar); 7.15 (d, J 8.3 Hz, 1H, Ar); 4.40 (s, 2H, CH.sub.2); 2.82 (s, 3H, CH.sub.3); 1.38 (s, 9H, tert-butyl). M/Z (M[.sup.35Cl][.sup.79Br]-tertbutyl)+=280.4.
Compound 33: [4-Chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-methyl-carbamic acid tert-butyl ester
(105) Compound 33 was prepared according to procedure of compound 29, starting from compound 32 and heating at 100° C. for 3 hours. Purification by flash column chromatography on silica gel (using 0% to 40% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 77% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.49 (d, J 2.4 Hz, 1H, Ar); 7.42 (dd, J 8.3, 2.4 Hz, 1H, Ar); 7.03 (d, J 8.3 Hz, 1H, Ar); 4.48 (s, 2H, CH.sub.2); 2.65 (s, 3H, CH.sub.3); 1.29 (s, 9H, tert-butyl); 1.19 (s, 12H, 4CH.sub.3). M/Z (M[.sup.35Cl]-tertbutyl).sup.+=326.5.
General Procedure VII: Preparation of Intermediate C3 by Cross-Coupling Reaction Between Boronic A3 and Ester B2 (Scheme 5)
(106) Under inert atmosphere, tetrakis(triphenylphosphine)palladium (0.10 equiv.) was added to a suspension of boronic acid or ester A3 (1.0 equiv.), halogeno-derivative B2 (1.0 equiv.) in dioxane (0.15 mol.Math.L.sup.−1) and aqueous K.sub.2CO.sub.3 (1.2 mol.Math.L.sup.−1). The reaction mixture was heated at 100° C. for 2 hours. After cooling, the reaction mixture was diluted in water and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
Compound 34: 3-{2-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-5-chloro-phenyl}-pyridine-2-carboxylic acid methyl ester
(107) Compound 34 was prepared according to general procedure VII, starting from compound 33 and methyl 3-bromopicolinate. Purification by flash column chromatography on silica gel (using 0% to 50% ethyl acetate in cyclohexane as eluent) afforded the product as a colorless oil in 79% yield. M/Z (M[.sup.35Cl]-tertbutyl).sup.+=335.5.
General Procedure VIII: Preparation of Cyclized Compound F2 by Protecting Group Removal and Cyclization of Intermediate C3 (Scheme 5 and 6)
(108) Intermediate C3 (1.0 equiv.) was dissolved in dichloromethane (0.15 mol.Math.L.sup.−1) and TFA was added (0.15 mol.Math.L.sup.−1). The reaction mixture was stirred at room temperature for 1 hour, before being concentrated under vacuum. The resulting crude oil was dissolved in dioxane (0.10 mol.Math.L.sup.−1) and triethylamine (3.0 equiv.) and the reaction mixture was heated at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
Example 24 (Alternative Preparation: 10-Chloro-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(109) Example 24 was prepared, this time using general procedure VIII and starting from compound 34. Purification by flash column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded the product as a white solid in 84% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (dd, J 4.7, 1.6 Hz, 1H, Ar); 8.16 (d, J 8.1, 1.6 Hz, 1H, Ar); 7.86 (d, J 2.1 Hz, 1H, Ar); 7.66-7.61 (m, 2H, Ar); 7.55 (dd, J 8.1, 2.1 Hz, 1H, Ar); 4.29 (d, J 15.2 Hz, 1H, CHaHb); 4.24 (d, J 15.2 Hz, 1H, CHaHb); 3.04 (s, 3H, CH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=259.5.
Example 26: 6-Methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(110) ##STR00399##
(111) Example 26 was prepared according to general procedure IV(ii), starting from example 24 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 0% to 6% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 26 as a brown solid in 97% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.73 (dd, J 4.5, 1.5 Hz, 1H, Ar); 8.49 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.19 (d, J 8.1, 1.5 Hz, 1H, Ar); 7.80 (d, J 1.5 Hz, 1H, Ar); 7.75 (dd, J 7.7, 1.5 Hz, 1H, Ar); 7.68 (d, J 7.7 Hz, 1H, Ar); 7.63 (dd, J 8.1, 4.5 Hz, 1H, Ar); 7.53 (dd, J 7.7, 1.6 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.8 Hz, 1H, Ar); 4.37 (d, J 15.0 Hz, 1H, CHaHb); 4.28 (d, J 15.0 Hz, 1H, CHaHb); 3.10 (s, 3H, CH.sub.3); 2.48 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=316.5.
Example 27: 10-(6-Fluoro-pyridin-3-yl)-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(112) ##STR00400##
(113) Example 27 was prepared according to general procedure IV(i) starting from example 24 in presence of 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 1 hour. Purification by preparative HPLC afforded example 27 as a white solid in 65% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (dd, J 4.6, 1.5 Hz, 1H, Ar); 8.70 (d, J 2.4 Hz, 1H, Ar); 8.44 (dt, J 8.0, 2.4 Hz, 1H, Ar); 8.33 (dd, J 8.0, 1.5 Hz, 1H, Ar); 8.09 (d, J 1.7 Hz, 1H, Ar); 7.82 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.70 (d, J 7.8 Hz, 1H, Ar); 7.66 (dd, J 8.0, 4.6 Hz, 1H, Ar); 7.32 (dd, J 8.6, 2.8 Hz, 1H, Ar); 4.37 (d, J 15.0 Hz, 1H, CHaHb); 4.28 (d, J 15.0 Hz, 1H, CHaHb); 3.08 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=320.5.
Example 28: 10-(5-Fluoro-pyridin-2-yl)-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(114) ##STR00401##
(115) Under inert atmosphere, XPhos precatalyst (0.10 equiv.) was added to a suspension of example 24 (1.0 equiv.), bispinacolatodiboron (1.2 equiv.) and potassium acetate (2.7 equiv.) in dioxane (0.15 mol.Math.L.sup.−1). The reaction mixture was heated at 100° C. for 2 hours. After cooling to room temperature, the mixture was filtered off through celite with EtOAc and the filtrate was concentrated under vacuum. The residue was dissolved in dioxane (0.15 mol.Math.L.sup.−1) and potassium carbonate (3.0 equiv.) and a solution of 2-bromo-5-fluoropyridine (1.2 equiv.) in dioxane (0.90 mol.Math.L−1) were successively added. Under inert atmosphere, PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.10 equiv.) was added and the reaction mixture was heated at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was hydrolyzed and extracted twice with ethyl acetate. The combined organic extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by preparative HPLC afforded example 28 as a white solid in 52% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (dd, J 4.6, 1.5 Hz, 1H, Ar); 8.69 (d, J 3.0 Hz, 1H, Ar); 8.39 (d, J 1.8 Hz, 1H, Ar); 8.26 (dd, J 8.0, 1.5 Hz, 1H, Ar); 8.22 (d, J 8.7, 4.6 Hz, 1H, Ar); 8.15 (dd, J 7.9, 1.8 Hz, 1H, Ar); 7.87 (dt, J 8.7, 3.0 Hz, 1H, Ar); 7.70 (d, J 7.9 Hz, 1H, Ar); 7.67 (dd, J 8.0, 4.6 Hz, 1H, Ar); 4.37 (d, J 15.0 Hz, 1H, CHaHb); 4.27 (d, J 15.0 Hz, 1H, CHaHb); 3.08 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=320.6.
Compound 35: 3-{2-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-5-chloro-phenyl}-6-fluoro-pyridine-2-carboxylic acid methyl ester
(116) Compound 35 was prepared according to general procedure VII, starting from compound 33 and methyl 3-bromo-6-fluoropicolinate. Purification by flash column chromatography on silica gel (using 0% to 40% ethyl acetate in cyclohexane as eluent) afforded the product as a colorless oil in 79% yield. M/Z (M[.sup.35Cl]-boc).sup.+=309.6.
Example 29: 10-Chloro-3-fluoro-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a,c]cyclohepten-5-one
(117) ##STR00402##
(118) Example 29 was prepared using general procedure VIII and starting from compound 35. Purification by flash column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded the product as a yellow oil in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.38 (t, J 8.2 Hz, 1H, Ar); 7.87 (s, 1H, Ar); 7.62 (d, J 8.2 Hz, 1H, Ar); 7.55 (d, J 8.1 Hz, 1H, Ar); 7.48 (dd, J 8.2, 2.5 Hz, 1H, Ar); 4.36 (d, J 15.0 Hz, 1H, CHaHb); 4.26 (d, J 15.0 Hz, 1H, CHaHb); 3.04 (s, 3H, CH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=277.5.
Example 30: 3-Fluoro-6-methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(119) ##STR00403##
(120) Example 30 was prepared according to general procedure IV(ii), starting from example 29 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 2 hours. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) and trituration in iPr.sub.2O afforded example 30 as a white solid in 66% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.49 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.42 (t, J 8.1 Hz, 1H, Ar); 7.80 (d, J 1.7 Hz, 1H, Ar); 7.74 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.68 (d, J 7.7 Hz, 1H, Ar); 7.53 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.46 (dd, J 8.6, 3.3 Hz, 1H, Ar); 7.32 (dd, J 7.7, 4.8 Hz, 1H, Ar); 4.44 (d, J 15.0 Hz, 1H, CHaHb); 4.30 (d, J 15.0 Hz, 1H, CHaHb); 3.09 (s, 3H, CH.sub.3); 2.51 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=334.7.
Example 31: 3-Fluoro-10-(6-fluoro-pyridin-3-yl)-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(121) ##STR00404##
(122) Example 31 was prepared according to general procedure IV(ii) starting from example 29 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 2 hours. Purification by column chromatography on silica gel (using 0% to 100% EtOAc in cyclohexane as eluent) and trituration in iPr.sub.2O afforded example 31 as a white solid in 89% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.70 (d, J 2.6 Hz, 1H, Ar); 8.56 (t, J 8.1 Hz, 1H, Ar); 8.44 (dt, J 8.3, 2.6 Hz, 1H, Ar); 8.09 (d, J 1.7 Hz, 1H, Ar); 7.83 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.71 (d, J 7.8 Hz, 1H, Ar); 7.51 (dd, J 8.6, 3.3 Hz, 1H, Ar); 7.32 (dd, J 8.6, 2.6 Hz, 1H, Ar); 4.43 (d, J 15.0 Hz, 1H, CHaHb); 4.30 (d, J 15.0 Hz, 1H, CHaHb); 3.07 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=338.6.
Example 32: 3-Fluoro-10-(5-fluoro-pyridin-2-yl)-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(123) ##STR00405##
(124) Example 32 was prepared according to procedure of example 28 starting from example 29. Purification by column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 32 as a white solid in 31% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 2.9 Hz, 1H, Ar); 8.48 (t, J 8.2 Hz, 1H, Ar); 8.38 (d, J 1.7 Hz, 1H, Ar); 8.22 (dd, J 8.8, 4.3 Hz, 1H, Ar); 8.15 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.88 (dt, J 8.8, 2.9 Hz, 1H, Ar); 7.70 (d, J 7.9 Hz, 1H, Ar); 7.50 (dd, J 8.5, 3.4 Hz, 1H, Ar); 4.44 (d, J 15.0 Hz, 1H, CHaHb); 4.29 (d, J 15.0 Hz, 1H, CHaHb); 3.07 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=338.5.
Example 33: 10-Chloro-3-methoxy-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a,c]cyclohepten-5-one
(125) ##STR00406##
(126) A solution of example 29 (1.0 equiv.) and sodium methoxide (4.0 equiv.) in anhydrous MeOH (0.20 mol.Math.L.sup.−1) was stirred at room temperature for 16 hours. The solvent was removed under vacuum and the residue was taken in an aqueous solution of NH.sub.4Cl and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered and concentrated under vacuum. Purification by column chromatography on silica gel (using EtOAc as eluent) afforded example 33 as a white solid in quantitative yield. M/Z (M.sup.[35]Cl+H).sup.+=289.6.
Example 34: 10-(5-Fluoro-pyridin-2-yl)-3-methoxy-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(127) ##STR00407##
(128) Example 34 was prepared according to procedure of example 28 starting from example 33. Purification by column chromatography on silica gel (using 0% to 100% EtOAc in cyclohexane as eluent) and trituration in Et.sub.2O afforded example 34 as a white solid in 42% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.68 (d, J 2.9 Hz, 1H, Ar); 8.32 (d, J 1.7 Hz, 1H, Ar); 8.21 (dd, J 8.8, 4.4 Hz, 1H, Ar); 8.17 (d, J 8.6 Hz, 1H, Ar); 8.09 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.86 (dt, J 8.8, 2.9 Hz, 1H, Ar); 7.67 (d, J 7.9 Hz, 1H, Ar); 7.11 (d, J 8.6 Hz, 1H, Ar); 4.37 (d, J 15.0 Hz, 1H, CHaHb); 4.26 (d, J 15.0 Hz, 1H, CHaHb); 3.95 (s, 3H, CH.sub.3); 3.06 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=350.5.
Example 35: 10-(6-Fluoro-pyridin-3-yl)-3-methoxy-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(129) ##STR00408##
(130) Example 35 was prepared according to general procedure IV(ii) starting from example 33 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 2 hours. Purification by column chromatography on silica gel (using 0% to 100% EtOAc in cyclohexane as eluent) and trituration in Et.sub.2O afforded example 35 as a white solid in 81% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.68 (d, J 2.6 Hz, 1H, Ar); 8.42 (dt, J 8.2, 2.6 Hz, 1H, Ar); 8.25 (d, J 8.7 Hz, 1H, Ar); 8.02 (d, J 1.7 Hz, 1H, Ar); 7.76 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.67 (d, J 7.9 Hz, 1H, Ar); 7.31 (dd, J 8.5, 2.8 Hz, 1H, Ar); 7.10 (d, J 8.6 Hz, 1H, Ar); 4.37 (d, J 15.0 Hz, 1H, CHaHb); 4.26 (d, J 15.0 Hz, 1H, CHaHb); 3.95 (s, 3H, CH.sub.3); 3.06 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=350.5.
Example 36: 3-Methoxy-6-methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(131) ##STR00409##
(132) Example 36 was prepared according to general procedure IV(ii) starting from example 33 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 2 hours. Purification by preparative HPLC and trituration in pentane afforded example 36 as a white solid in 62% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.49 (dd, J 4.7, 1.5 Hz, 1H, Ar); 8.11 (d, J 8.6 Hz, 1H, Ar); 7.74-7.72 (m, 2H, Ar); 7.65 (d, J 7.8 Hz, 1H, Ar); 7.47 (dd, J 7.6, 1.5 Hz, 1H, Ar); 7.32 (dd, J 7.6, 4.7 Hz, 1H, Ar); 7.07 (d, J 8.6 Hz, 1H, Ar); 4.38 (d, J 15.0 Hz, 1H, CHaHb); 4.27 (d, J 15.0 Hz, 1H, CHaHb); 3.94 (s, 3H, CH.sub.3); 3.08 (s, 3H, CH.sub.3); 2.49 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=346.6.
Example 37: 3-Hydroxy-6-methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(133) ##STR00410##
(134) To a solution of example 30 (1.0 equiv.) in dioxane (0.10 mol.Math.L.sup.−1) was added a 2M aqueous solution of NaOH (10 equiv.) and the solution was subjected to microwave irradiation at 110° C. for 15 minutes. The reaction mixture was neutralized with an aqueous solution of NH.sub.4Cl and extracted twice with ethyl acetate. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 37 as a white solid in 86% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.49 (bs, 1H, NH or OH); 8.48 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.90 (d, J 9.6 Hz, 1H, Ar); 7.71 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.65 (d, J 1.7 Hz, 1H, Ar); 7.62 (d, J 7.7 Hz, 1H, Ar); 7.43 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.31 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.61 (d, J 9.6 Hz, 1H, Ar); 4.45 (d, J 14.4 Hz, 1H, CHaHb); 4.32 (d, J 14.4 Hz, 1H, CHaHb); 3.08 (s, 3H, CH.sub.3); 2.47 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=332.5.
Compound 36: 3-{2-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-5-chloro-phenyl}-6-methyl-pyridine-2-carboxylic acid methyl ester
(135) Compound 36 was prepared according to general procedure VII, starting from compound 33 and methyl 3-bromo-6-methylpicolinate. Purification by flash column chromatography on silica gel (using 0% to 50% ethyl acetate in cyclohexane as eluent) afforded the product as a beige oil in 95% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.66 (d, J 7.9 Hz, 1H, Ar); 7.52-7.46 (m, 2H, Ar); 7.22 (d, J 8.3 Hz, 1H, Ar); 7.14 (d, J 2.1 Hz, 1H, Ar); 4.17 (d, J 15.9 Hz, 1H, CHaHb); 4.06 (d, J 15.9 Hz, 1H, CHaHb); 3.61 (s, 3H, CH.sub.3); 2.54 (s, 3H, CH.sub.3); 1.29 (bs, 9H, tert-butyl); 1.28 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]).sup.+=405.6.
Example 38: 10-Chloro-3,6-dimethyl-6,7-dihydro-4,6-diaza-dibenzo[a,c]cyclohepten-5-one
(136) ##STR00411##
(137) Example 38 was prepared using general procedure VIII and starting from compound 36. Purification by flash column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded the product as a white solid in 88% yield. 1H-NMR (400 MHz, DMSO-D6): 8.03 (d, J 8.1 Hz, 1H, Ar); 7.82 (d, J 2.0 Hz, 1H, Ar); 7.59 (d, J 8.1 Hz, 1H, Ar); 7.52-7.49 (m, 2H, Ar); 4.27 (d, J 15.0 Hz, 1H, CHaHb); 4.21 (d, J 15.0 Hz, 1H, CHaHb); 3.02 (s, 3H, CH.sub.3); 2.57 (s, 3H, CH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=273.6.
Example 39: 10-(6-Fluoro-pyridin-3-yl)-3,6-dimethyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(138) ##STR00412##
(139) Example 39 was prepared according to general procedure IV(ii) starting from example 38 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 2 hours. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 39 as a white solid in 90% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 2.6 Hz, 1H, Ar); 8.42 (dt, J 8.2, 2.6 Hz, 1H, Ar); 8.21 (d, J 8.1 Hz, 1H, Ar); 8.05 (d, J 1.7 Hz, 1H, Ar); 7.78 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.68 (d, J 7.8 Hz, 1H, Ar); 7.52 (d, J 8.1 Hz, 1H, Ar); 7.32 (dd, J 8.6, 2.6 Hz, 1H, Ar); 4.34 (d, J 15.0 Hz, 1H, CHaHb); 4.25 (d, J 15.0 Hz, 1H, CHaHb); 3.06 (s, 3H, CH.sub.3); 2.59 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=334.6.
Example 40: 10-(5-Fluoro-pyridin-2-yl)-3,6-dimethyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(140) ##STR00413##
(141) Example 40 was prepared according to procedure of example 28 starting from example 38. Purification by column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 40 as a white solid in 84% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 2.9 Hz, 1H, Ar); 8.35 (d, J 1.7 Hz, 1H, Ar); 8.21 (dd, J 8.8, 4.3 Hz, 1H, Ar); 8.14-8.10 (m, 2H, Ar); 7.87 (dt, J 7.8, 1.7 Hz, 1H, Ar); 7.68 (d, J 7.9 Hz, 1H, Ar); 7.53 (d, J 8.1 Hz, 1H, Ar); 4.35 (d, J 15.0 Hz, 1H, CHaHb); 4.25 (d, J 15.0 Hz, 1H, CHaHb); 3.06 (s, 3H, CH.sub.3); 2.59 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=334.5.
Example 41: 3,6-Dimethyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(142) ##STR00414##
(143) Example 41 was prepared according to general procedure IV(ii) starting from example 38 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 2 hours. Purification by column chromatography on silica gel (using 0% to 6% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 41 as a white solid in 89% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.48 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.07 (d, J 8.1 Hz, 1H, Ar); 7.75 (d, J 1.7 Hz, 1H, Ar); 7.73 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.65 (d, J 7.7 Hz, 1H, Ar); 7.50-7.47 (m, 2H, Ar); 7.32 (d, J 7.7, 4.8 Hz, 1H, Ar); 4.35 (d, J 15.0 Hz, 1H, CHaHb); 4.25 (d, J 15.0 Hz, 1H, CHaHb); 3.08 (s, 3H, CH.sub.3); 2.58 (s, 3H, CH.sub.3); 2.49 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=330.5.
Compound 37: 3-{2-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-5-chloro-phenyl}-5-methyl-pyridine-2-carboxylic acid methyl ester
(144) Compound 37 was prepared according to general procedure VII, starting from compound 33 and methyl 3-bromo-5-methylpicolinate. Purification by flash column chromatography on silica gel (using 0% to 100% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.56 (s, 1H, Ar); 7.65 (s, 1H, Ar); 7.48 (dd, J 8.2, 2.0 Hz, 1H, Ar); 7.22 (d, J 8.2 Hz, 1H, Ar); 7.16 (d, J 2.0 Hz, 1H, Ar); 4.16 (d, J 15.9 Hz, 1H, CHaHb); 4.07 (d, J 15.9 Hz, 1H, CHaHb); 3.62 (s, 3H, CH.sub.3); 2.55 (s, 3H, CH.sub.3); 2.39 (s, 3H, CH.sub.3); 1.32 (bs, 9H, tert-butyl). M/Z (M[.sup.35Cl]).sup.+=405.6.
Example 42: 10-Chloro-2,6-dimethyl-6,7-dihydro-4,6-diaza-dibenzo[a,c]cyclohepten-5-one
(145) ##STR00415##
(146) Example 42 was prepared using general procedure VIII and starting from compound 37. Purification by flash column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded the product as a colorless oil in 79% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.59 (d, J 2.0 Hz, 1H, Ar); 7.99 (d, J 2.0 Hz, 1H, Ar); 7.86 (d, J 2.1 Hz, 1H, Ar); 7.61 (d, J 8.1 Hz, 1H, Ar); 7.54 (dd, J 8.1, 2.1 Hz, 1H, Ar); 4.28 (d, J 15.0 Hz, 1H, CHaHb); 4.22 (d, J 15.0 Hz, 1H, CHaHb); 3.04 (s, 3H, CH.sub.3); 2.44 (s, 3H, CH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=273.5.
Example 43: 2,6-Dimethyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(147) ##STR00416##
(148) Example 43 was prepared according to general procedure IV(ii) starting from example 42 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 1 hour. Purification by preparative HPLC afforded example 43 as a white solid in 25% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.57 (d, J 1.6 Hz, 1H, Ar); 8.49 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.02 (d, J 1.6 Hz, 1H, Ar); 7.79 (d, J 1.7 Hz, 1H, Ar); 7.74 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.66 (d, J 7.7 Hz, 1H, Ar); 7.51 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.33 (d, J 7.7, 4.8 Hz, 1H, Ar); 4.35 (d, J 15.0 Hz, 1H, CHaHb); 4.26 (d, J 15.0 Hz, 1H, CHaHb); 3.09 (s, 3H, OH.sub.3); 2.49 (s, 3H, CH.sub.3); 2.42 (s, 3H, OH.sub.3). M/Z (M+H).sup.+=330.5.
Example 44: 10-(6-Fluoro-pyridin-3-yl)-2,6-dimethyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(149) ##STR00417##
(150) Example 44 was prepared according to general procedure IV(ii) starting from example 42 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 44 as a beige solid in 46% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.70 (d, J 2.6 Hz, 1H, Ar); 8.59 (d, J 2.0 Hz, 1H, Ar); 8.44 (dt, J 8.1, 2.5 Hz, 1H, Ar); 8.15 (d, J 2.0 Hz, 1H, Ar); 8.08 (d, J 1.7 Hz, 1H, Ar); 7.81 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.69 (d, J 7.8 Hz, 1H, Ar); 7.33 (dd, J 8.6, 2.6 Hz, 1H, Ar); 4.35 (d, J 15.0 Hz, 1H, CHaHb); 4.25 (d, J 15.0 Hz, 1H, CHaHb); 3.06 (s, 3H, CH.sub.3); 2.45 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=334.6.
Compound 38: 3-{2-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-5-chloro-phenyl}-5-fluoro-pyridine-2-carboxylic acid methyl ester
(151) Compound 38 was prepared according to general procedure VII, starting from compound 33 and methyl 3-bromo-5-fluoropicolinate. Purification by flash column chromatography on silica gel (using 0% to 100% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 71% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (bs, 1H, Ar); 7.91 (dd, J 9.1, 2.5 Hz, 1H, Ar); 7.56 (d, J 7.9 Hz, 1H, Ar); 7.34-7.29 (m, 2H, Ar); 4.25 (s, 2H, CH.sub.2); 3.69 (s, 3H, CH.sub.3); 2.60 (s, 3H, CH.sub.3); 1.36 (bs, 9H, tert-butyl). M/Z (M[.sup.35Cl]-tBu+H).sup.+=353.5.
Example 45: 10-Chloro-2-fluoro-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a,c]cyclohepten-5-one
(152) ##STR00418##
(153) Example 45 was prepared using general procedure VIII and starting from compound 38. Purification by flash column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded the product as a colorless oil in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 2.7 Hz, 1H, Ar); 8.16 (dd, J 9.8, 2.7 Hz, 1H, Ar); 7.92 (d, J 2.1 Hz, 1H, Ar); 7.64 (d, J 8.1 Hz, 1H, Ar); 7.58 (dd, J 8.1, 2.1 Hz, 1H, Ar); 4.33 (d, J 15.0 Hz, 1H, CHaHb); 4.25 (d, J 15.0 Hz, 1H, CHaHb); 3.57 (s, 3H, CH.sub.3); 3.04 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=277.5.
Example 46: 2-Fluoro-6-methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(154) ##STR00419##
(155) Example 46 was prepared according to general procedure IV(ii) starting from example 45 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 1 hour. Purification by flash column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 46 as a beige solid in 46% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (d, J 2.7 Hz, 1H, Ar); 8.49 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.18 (d, J 9.8, 2.7 Hz, 1H, Ar); 7.85 (d, J 1.7 Hz, 1H, Ar); 7.76 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.69 (d, J 7.7 Hz, 1H, Ar); 7.56 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.33 (d, J 7.7, 4.8 Hz, 1H, Ar); 4.41 (d, J 15.0 Hz, 1H, CHaHb); 4.30 (d, J 15.0 Hz, 1H, CHaHb); 3.11 (s, 3H, CH.sub.3); 2.50 (s, 3H, CH.sub.3). M/Z (M+H).sup.+334.5.
Example 47: 2-Fluoro-10-(6-fluoro-pyridin-3-yl)-6-methyl-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(156) ##STR00420##
(157) Example 47 was prepared according to general procedure IV(ii) starting from example 45 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 1 hour. Purification by preparative HPLC afforded example 47 as a beige solid in 43% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 2.7 Hz, 1H, Ar); 8.73 (d, J 2.6 Hz, 1H, Ar); 8.46 (dt, J 8.2, 2.6 Hz, 1H, Ar); 8.34 (dd, J 9.8, 2.7 Hz, 1H, Ar); 8.13 (d, J 1.7 Hz, 1H, Ar); 7.85 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.72 (d, J 7.8 Hz, 1H, Ar); 7.33 (dd, J 8.6, 2.6 Hz, 1H, Ar); 4.41 (d, J 15.0 Hz, 1H, CHaHb); 4.28 (d, J 15.0 Hz, 1H, CHaHb); 3.07 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=338.5.
Example 48: 2-Methoxy-6-methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-4,6-diaza-dibenzo[a, c]cyclohepten-5-one
(158) ##STR00421##
(159) A solution of example 46 (1.0 equiv.) and sodium methoxide (1.5 equiv.) in anhydrous MeOH (0.20 mol.Math.L−1) was subjected to microwave irradiation at 130° C. for 30 minutes. The solvent was removed under vacuum and the residue was taken in water and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum to afford example 48 as a white solid in 61% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.49 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.43 (d, J 2.8 Hz, 1H, Ar); 7.88 (d, J 1.7 Hz, 1H, Ar); 7.75 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.67 (d, J 7.7 Hz, 1H, Ar); 7.63 (d, J 2.8 Hz, 1H, Ar); 7.53 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.33 (d, J 7.7, 4.8 Hz, 1H, Ar); 4.36 (d, J 15.0 Hz, 1H, CHaHb); 4.26 (d, J 15.0 Hz, 1H, CHaHb); 3.96 (s, 3H, CH.sub.3); 3.08 (s, 3H, CH.sub.3); 2.51 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=346.6.
Compound 39: 1-(4-Chloro-2-iodo-phenyl)-cyclopropanecarboxylic acid
(160) To a solution of 1-(4-chloro-phenyl)-cyclopropanecarboxylic acid (1.0 equiv.) in anhydrous DMF (0.10 mol.Math.L.sup.−1) was added [acetoxy(phenyl)-iodanyl]acetate (1.2 equiv.), palladium diacetate (0.15 equiv.) and iodine (1.2 equiv.). The reaction mixture was stirred at 60° C. for 16 hours with foil covered. After cooling to room temperature, the mixture was hydrolyzed with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over Na.sub.2SO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 10% to 50% ethyl acetate in petroleum ether as eluent) afforded compound 39 as a brown solid in 50% yield. M/Z (M[.sup.35Cl]+H).sup.+=322.9.
Compound 40: 1-(4-Chloro-2-iodo-phenyl)-cyclopropylamine
(161) To a solution of compound 39 (1.0 equiv.) in tert-butanol (0.30 mol.Math.L.sup.−1) was added triethylamine (1.1 equiv.) and diphenyl phosphoryl azide (1.1 equiv.) and the reaction mixture was heated at 85° C. for 3 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with aqueous NaHCO.sub.3, water, dried with Na.sub.2SO.sub.4, filtered off and concentrated under vacuum. The residue was suspended in aqueous HCl (3N, 0.50 mol.Math.L.sup.−1) and heated at 85° C. for 16 hours. After cooling to room temperature, pH was adjusted to 8 with aqueous Na.sub.2CO.sub.3 and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried with Na.sub.2SO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 10% to 25% ethyl acetate in petroleum ether as eluent) afforded compound 40 as a light yellow oil in 27% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.84 (d, J 1.6 Hz, 1H, Ar); 7.29-7.23 (m, 2H, Ar); 1.28-1.24 (m, 2H, cyclopropyl), 0.90-0.87 (m, 2H, cyclopropyl). Protons for NH.sub.2 were not observed. M/Z (M[.sup.35Cl]-NH.sub.2+H)+=276.7.
Compound 41: [1-(4-Chloro-2-iodo-phenyl)-cyclopropyl]-carbamic acid tert-butyl ester
(162) A mixture of compound 40 (1.0 equiv.), triethylamine (1.5 equiv.) and di-tert-butyl dicarbonate (1.1 equiv.) in dichloromethane (0.30 mol.Math.L.sup.−1) was stirred at 30° C. for 16 hours. The reaction mixture was washed with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. Purification by column chromatography on silica gel (using petroleum ether as eluent) afforded compound 41 as a light yellow solid in 55% yield. .sup.1H-NMR (400 MHz, MeOD-D4): 7.86 (s, 1H, Ar); 7.53 (d, J 8.0 Hz, 1H); 7.32 (d, J 8.0 Hz, 1H); 4.62 (bs, 1H, NH); 1.37 (s, 9H, tert-butyl); 1.24-1.22 (m, 2H, cyclopropyl), 1.09-1.07 (m, 2H, cyclopropyl). M/Z (M[.sup.35Cl]-tBu+H).sup.+=337.9.
Compound 42: [1-(4-Chloro-2-iodo-phenyl)-cyclopropyl]-methyl-carbamic acid tert-butyl ester
(163) At 0° C., to a solution of compound 41 (1.0 equiv.) in anhydrous DMF (0.10 mol.Math.L.sup.−1) was added sodium hydride (60% dispersion in oil, 1.3 equiv.) and the reaction mixture was stirred for 15 minutes at 0° C. Iodomethane (1.3 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour before being neutralized by an aqueous solution of NH.sub.4Cl and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded the product as a colorless oil in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.92 (d, J 2.0 Hz, 1H, Ar); 7.81 (bs, 1H, Ar); 7.48 (d, J 8.4 Hz, 1H, Ar); 3.04 (s, 3H, CH.sub.3); 1.40-1.36 (m, 12H, tert-butyl+cyclopropyl); 1.20-1.17 (m, 1H, cyclopropyl). M/Z (M[.sup.35C]-tBu+H).sup.+=352.4.
Compound 43: {1-[4-Chloro-2-(2-fluoro-pyridin-3-yl)-phenyl]-cyclopropyl}-methyl-carbamic acid tert-butyl ester
(164) Compound 43 was prepared according to general procedure VII, starting from compound 42 and 2-fluoro-3-pyridine boronic acid. Purification by flash column chromatography on silica gel (using 0% to 40% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 71% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.30 (d, J 4.4 Hz, 1H, Ar); 7.96-7.92 (m, 1H, Ar); 7.65-7.56 (m, 1H, Ar); 7.49-7.44 (m, 2H, Ar); 7.25 (d, J 2.2 Hz, 1H, Ar); 1.90 (bs, 3H, CH.sub.3); 1.28 (s, 9H, tert-butyl); 1.28-1.16 (m, 2H, cyclopropyl); 1.06-0.90 (m, 2H, cyclopropyl). M/Z (M[.sup.35Cl]-tBu+H).sup.+=321.5.
Compound 44: {1-[4-Chloro-2-(6-cyano-pyridin-2-yl)-phenyl]-cyclopropyl}-methyl-carbamic acid tert-butyl ester
(165) A solution of compound 43 (1.0 equiv.) and tetraethylammonium cyanide (5.0 equiv.) in anhydrous DMF (0.15 mol.Math.L.sup.−1) was heated at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture was treated with an aqueous solution of NaHCO.sub.3 and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 50% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow solid in 84% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (dd, J 4.5, 1.4 Hz, 1H, Ar); 8.06 (dd, J 8.0, 1.4 Hz, 1H, Ar); 7.84 (dd, J 8.0, 4.5 Hz, 1H, Ar); 7.61 (d, J 8.4 Hz, 1H, Ar); 7.52 (dd, J 8.4, 2.3 Hz, 1H, Ar); 7.38 (d, J 2.3 Hz, 1H, Ar); 1.99 (s, 3H, CH.sub.3); 1.27 (s, 9H, tert-butyl); 1.43-1.32 (m, 1H, cyclopropyl); 1.27-1.16 (m, 2H, cyclopropyl); 0.94-0.87 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]-tBu+H).sup.+=328.5.
Compound 45: {1-[2-(6-Carbamoyl-pyridin-2-yl)-4-chloro-phenyl]-cyclopropyl}-methyl-carbamic acid tert-butyl ester
(166) To a suspension of compound 44 (1.0 equiv.) and potassium carbonate (0.4 equiv.) in DMSO (0.10 mol.Math.L.sup.−1) was added a solution of hydrogen peroxide (30% in water, 3.0 equiv) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded the product as a white solid in 94% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.65 (dd, J 4.4, 1.8 Hz, 1H, Ar); 7.95 (bs, 1H, NHaHb); 7.68-7.61 (m, 2H, Ar); 7.56 (bs, 1H, NHaHb); 7.33-7.31 (m, 2H, Ar); 6.98 (d, J 2.3 Hz, 1H, Ar); 2.99 (s, 3H, CH.sub.3); 1.30 (s, 9H, tert-butyl); 1.30-1.22 (m, 1H, cyclopropyl); 1.12-1.07 (m, 1H, cyclopropyl); 0.95-0.84 (m, 2H, cyclopropyl). M/Z (M[.sup.35Cl]-boc+H).sup.+=302.6.
Example: 10-chloro-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one
(167) ##STR00422##
(168) To a solution of compound 45 (1.0 equiv.) in dichloromethane (0.30 mol.Math.L.sup.−1) was added TFA (0.30 mol.Math.L.sup.−1) and the reaction mixture was subjected to microwave irradiation at 150° C. for 5 minutes. After cooling to room temperature, the reaction mixture was treated with an aqueous solution of NaHCO.sub.3 and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded the product as a white solid in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.73 (dd, J 4.6, 1.4 Hz, 1H, Ar); 8.14 (dd, J 8.0, 1.4 Hz, 1H, Ar); 7.87 (s, 1H, Ar); 7.64 (d, J 8.0, 4.6 Hz, 1H, Ar); 7.52 (d, J 8.0 Hz, 1H, Ar); 7.50 (d, J 8.0 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.45-1.39 (m, 2H, cyclopropyl); 0.85-0.79 (m, 1H, cyclopropyl); 0.35-0.29 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=285.5.
Example 50: 10-(6-Fluoro-pyridin-3-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one
(169) ##STR00423##
(170) Example 50 was prepared according to general procedure IV(ii) starting from example 49 and 6-fluoro-3-pyridinylboronic acid, at 100° C. for 2 hours. Purification by flash column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 50 as a white solid in 87% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.73 (dd, J 4.7, 1.5 Hz, 1H, Ar); 8.68 (d, J 2.6 Hz, 1H, Ar); 8.42 (dt, J 8.2, 2.6 Hz, 1H, Ar); 8.31 (dd, J 8.0, 1.5 Hz, 1H, Ar); 8.10 (d, J 1.8 Hz, 1H, Ar); 7.79 (dd, J 7.9, 1.8 Hz, 1H, Ar); 7.66 (dd, J 8.0, 4.7 Hz, 1H, Ar); 7.60 (d, J 7.9 Hz, 1H, Ar); 7.32 (dd, J 8.6, 2.8 Hz, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 1.51-1.42 (m, 2H, cyclopropyl); 0.89-0.83 (m, 1H, cyclopropyl); 0.38-0.33 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=346.6.
Example 51: 10-(5-Fluoro-pyridin-2-yl)-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one
(171) ##STR00424##
(172) Example 51 was prepared according to procedure of example 28 starting from example 49. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 51 as a white solid in 87% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.73 (dd, J 4.7, 1.5 Hz, 1H, Ar); 8.69 (d, J 3.0 Hz, 1H, Ar); 8.39 (d, J 1.8 Hz, 1H, Ar); 8.25-8.20 (m, 2H, Ar); 8.13 (dd, J 8.0, 1.8 Hz, 1H, Ar); 7.87 (dt, J 8.7, 3.0 Hz, 1H, Ar); 7.67 (dd, J 8.0, 4.7 Hz, 1H, Ar); 7.60 (d, J 8.0 Hz, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 1.52-1.42 (m, 2H, cyclopropyl); 0.89-0.83 (m, 1H, cyclopropyl); 0.39-0.34 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=346.6.
Compound 46: {1-[4-Chloro-2-(6-methoxy-pyridin-3-yl)-phenyl]-cyclopropyl}-methyl-carbamic acid tert-butyl ester
(173) Compound 46 was prepared according to general procedure VII, starting from compound 42 and 6-methoxy-3-pyridinyl boronic acid. Purification by flash column chromatography on silica gel (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded the product as a colorless oil in 87% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.10 (d, J 2.4 Hz, 1H, Ar); 7.67 (dd, J 8.5, 2.4 Hz, 1H, Ar); 7.61 (bs, 1H, Ar); 7.41 (dd, J 8.5, 2.4 Hz, 1H, Ar); 7.13 (d, J 2.4 Hz, 1H, Ar); 6.91 (d, J 8.5 Hz, 1H, Ar); 3.90 (s, 3H, CH.sub.3); 1.98 (bs, 3H, CH.sub.3); 1.29 (s, 11H, tBu+2H cyclopropyl); 1.05-1.01 (m, 2H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=389.5.
Compound 47: {1-[4-Chloro-2-(2-cyano-6-methoxy-pyridin-3-yl)-phenyl]-cyclopropyl}-methyl-carbamic acid tert-butyl ester
(174) At 0° C., to a solution of compound 46 (1.0 equiv.) in dichloromethane (0.10 mol.Math.L.sup.−1) was added 3-chloroperbenzoic acid (3.2 equiv.) and the reaction mixture was stirred at room temperature for 5 days. The reaction mixture was taken in aqueous NaOH (1M) and extracted with dichloromethane. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum to give the crude pyridinyl-N-oxide in quantitative yield. M/Z (M[.sup.35Cl]+H).sup.+=405.6.
(175) To a solution of the crude pyridinyl-N-oxide in anhydrous acetonitrile (0.10 mol.Math.L.sup.−1) were added triethylamine (4.0 equiv.) and trimethylsilylcyanide (6.0 equiv.). The reaction mixture was subjected to microwave irradiation at 130° C. for 30 minutes. After cooling to room temperature, the mixture was treated with an aqueous solution of NaHCO.sub.3 and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 30% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow solid in 78% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.91 (d, J 8.6 Hz, 1H, Ar); 7.59 (d, J 8.5 Hz, 1H, Ar); 7.49 (dd, J 8.6, 2.3 Hz, 1H, Ar); 7.33 (d, J 2.3 Hz, 1H, Ar); 7.28 (d, J 8.5 Hz, 1H, Ar); 3.94 (s, 3H, CH.sub.3); 1.40 (s, 3H, CH.sub.3); 1.27 (s, 9H, tBu); 1.27-1.15 (m, 2H, cyclopropyl); 1.05-0.90 (m, 2H, cyclopropyl). M/Z (M[.sup.35Cl]-tBu+H).sup.+=358.5.
Compound 48: {1-[2-(2-Carbamoyl-6-methoxy-pyridin-3-yl)-4-chloro-phenyl]-cyclopropyl}-methyl-carbamic acid tert-butyl ester
(176) Compound 48 was prepared according to procedure of compound 45, starting from compound 47. Purification by flash column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded the product as a white solid in 63% yield. M/Z (M[.sup.35Cl]-boc+H).sup.+=332.5.
Example 52: 10-chloro-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one
(177) ##STR00425##
(178) To a solution of compound 48 (1.0 equiv.) in dichloroethane (0.20 mol.Math.L.sup.−1) was added TFA (0.20 mol.Math.L.sup.−1) and the reaction mixture was heated at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was treated with an aqueous solution of NaHCO.sub.3 and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (0% to 3% MeOH in dichloromethane as eluent) afforded the product as a white solid in 95% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.06 (d, J 8.6 Hz, 1H, Ar); 7.79 (d, J 1.7 Hz, 1H, Ar); 7.48 (d, J 8.0 Hz, 11H, Ar); 7.45 (d, J 8.0, 1.7 Hz, 1H, Ar); 7.07 (d, J 8.6 Hz, 1H, Ar); 3.94 (s, 3H, CH.sub.3); 2.91 (s, 3H, CH.sub.3); 1.47-1.37 (m, 2H, cyclopropyl); 0.93-0.88 (m, 1H, cyclopropyl); 0.37-0.32 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=315.5.
Example 53: 10-(6-Fluoro-pyridin-3-yl)-3-methoxy-6-methylspiro[benzo[c]pyrido[3,2-e]azepine-7,1′-cyclopropan]-5(6H)-one
(179) ##STR00426##
(180) Example 53 was prepared according to general procedure IV(ii) starting from example 52 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 2 hours. Purification by flash column chromatography on silica gel (using 0% to 60% EtOAc in cyclohexane as eluent) and trituration in Et.sub.2O afforded example 53 as a white solid in 80% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.68 (d, J 2.6 Hz, 1H, Ar); 8.42 (dt, J 8.2, 2.6 Hz, 1H, Ar); 8.25 (d, J 8.6 Hz, 1H, Ar); 8.04 (d, J 1.7 Hz, 1H, Ar); 7.74 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.58 (d, J 7.9 Hz, 1H, Ar); 7.32 (dd, J 8.6, 2.6 Hz, 1H, Ar); 7.11 (d, J 8.6 Hz, 1H, Ar); 3.95 (s, 3H, CH.sub.3); 2.95 (s, 3H, CH.sub.3); 1.52-1.42 (m, 2H, cyclopropyl); 0.97-0.93 (m, 1H, cyclopropyl); 0.41-0.37 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=376.5.
General Procedure IX: Preparation of Intermediate C2 from Benzaldehyde Boronic Acid or Ester A2 and (Hetero)Aromatic Halide B2 (Scheme 4)
(181) Under inert atmosphere, a mixture of benzaldehyde boronic acid or ester A2 (1.0 equiv.), (hetero)aromatic halide B2 (1.0 equiv.) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.10 equiv.) in a mixture of dioxane (0.10 mol.Math.L) and aqueous K.sub.3PO.sub.4 (1.2 mol.Math.L.sup.1) was heated at 80° C. for 1 hour. After cooling to room temperature, the reaction mixture was hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
General Procedure X: Preparation of Cyclized Compound F2 by Reductive Amination of Intermediate C2 (Scheme 4)
(182) A mixture of intermediate C2 (1.0 equiv.), acetic acid (1.0 equiv.), primary amine E2 (5.0 equiv.) and sodium acetoxyborohydride (5.0 equiv.) in MeOH (0.20 mol.Math.L.sup.1) and THF (0.20 mol.Math.L.sup.−1) was stirred at room temperature overnight, then heated at 60° C. for 3 hours. Several additions of E2 and sodium acetoxyborohydride are often required until reaction completion. After cooling to room temperature, the reaction mixture was hydrolyzed with sodium bicarbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified to afford the product.
Compound 49: 3-(5-Chloro-2-formyl-phenyl)-thiophene-2-carboxylic acid methyl ester
(183) Compound 49 was prepared according to general procedure IX, starting from compound 29 and methyl 3-bromothiophene-2-carboxylate. Purification by column chromatography on silica gel (using 0% to 10% ethyl acetate in cyclohexane as eluent) afforded the product as a beige solid in 36% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.67 (s, 1H, CHO); 8.00 (d, J 5.1 Hz, 1H, Ar); 7.87 (d, J 8.3 Hz, 1H, Ar); 7.63 (dd, J 8.3, 2.2 Hz, 1H, Ar); 7.46 (d, J 2.2 Hz, 1H, Ar); 7.24 (d, J 5.1 Hz, 1H, Ar); 3.60 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]-MeOH).sup.+=250.5.
Example 54: 9-Chloro-5-methyl-5,6-dihydro-3-thia-5-aza-benzo[e]azulen-4-one
(184) ##STR00427##
(185) Example 54 was prepared according to general procedure X, starting from compound 49 and methylamine. Purification by column chromatography on silica gel (using 0% to 50% ethyl acetate in cyclohexane as eluent) afforded example 54 as a white solid in 33% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.92 (d, J 5.3 Hz, 1H, Ar); 7.81 (d, J 2.1 Hz, 1H, Ar); 7.63-7.60 (m, 2H, Ar); 7.50 (dd, J 8.1, 2.1 Hz, 1H, Ar); 4.32 (s, 2H, CH.sub.2); 3.89 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=264.5.
Example 55: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-3-thia-5-aza-benzo[e]azulen-4-one
(186) ##STR00428##
(187) Example 55 was prepared according to general procedure IV(ii), starting from example 54 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded example 55 as a brown solid in 26% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.55 (dd, J 4.9, 1.7 Hz, 1H, Ar); 7.96 (d, J 5.2 Hz, 1H, Ar); 7.81 (d, J 1.7 Hz, 1H, Ar); 7.77-7.73 (m, 2H, Ar); 7.69 (d, J 5.2 Hz, 1H, Ar); 7.54 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.39 (dd, J 7.7, 4.9 Hz, 1H, Ar); 4.45 (s, 2H, CH.sub.2); 3.20 (s, 3H, CH.sub.3); 2.53 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=321.5.
Example 56: 3-(5-Methyl-4-oxo-5,6-dihydro-4H-3-thia-5-aza-benzo[e]azulen-9-yl)-benzonitrile
(188) ##STR00429##
(189) Example 56 was prepared according to general procedure IV(ii), starting from example 55 and 3-cyanophenylboronic acid. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in iPr.sub.2O afforded example 56 as a beige solid in 47% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.34 (m, 1H, Ar); 8.14 (m, 1H, Ar); 8.08 (d, J 1.8 Hz, 1H, Ar); 7.94 (d, J 5.2 Hz, 1H, Ar); 7.86 (m, 1H, Ar); 7.82-7.79 (m, 2H, Ar); 7.72-7.67 (m, 2H, Ar); 4.38 (s, 2H, OH.sub.2); 3.12 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=331.5.
Compound 50: 4-Iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-3-carboxylic acid ethyl ester
(190) At 0° C., to a solution of 4-iodo-1H-pyrazole-3-carboxylic acid ethyl ester (1.0 equiv.) in anhydrous THF (0.20 mol.Math.L.sup.−1), sodium hydride (60% in oil, 1.5 equiv.) was slowly added. The reaction mixture was stirred at 0° C. for 30 minutes, before dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (1.1 equiv.). The reaction mixture was stirred at room temperature for 3 hours before being hydrolysed with aqueous sodium bicarbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 3% MeOH in dichloromethane as eluent) afforded the product as a yellow oil in 96% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.25 (s, 1H, Ar); 5.46 (s, 2H, CH.sub.2); 4.28 (q, J 7.3 Hz, 2H, CH—CH.sub.3); 3.54 (m, 2H, CH.sub.2); 1.30 (t, J 7.3 Hz, 3H, CH.sub.2—CH.sub.3); 0.83 (m, 2H, CH.sub.2); −0.04 (s, 9H, TMS). M/Z (M+H).sup.+=397.4.
Compound 51: 4-(5-Chloro-2-formyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole-3-carboxylic acid ethyl ester
(191) Compound 51 was prepared according to general procedure IX, starting from compound 29 and compound 50. Purification by column chromatography on silica gel (using 0% to 40% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 46% yield. M/Z (M[.sup.35Cl]+H).sup.+=409.5.
Compound 52: 9-Chloro-5-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(192) Compound 52 was prepared according to general procedure X, starting from compound 51 and methylamine. Purification by column chromatography on silica gel (using 0% to 2% MeOH in dichloromethane as eluent) afforded the product as a brown oil in 21% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.54 (s, 1H, Ar); 7.70 (d, J 2.1 Hz, 1H, Ar); 7.57 (d, J 8.2 Hz, 1H, Ar); 7.39 (dd, J 8.2, 2.1 Hz, 1H, Ar); 5.53 (s, 2H, CH.sub.2); 4.27 (s, 2H, CH.sub.2); 3.63 (m, 2H, CH.sub.2); 3.07 (s, 3H, CH.sub.3); 0.87 (m, 2H, CH.sub.2); −0.04 (s, 9H, TMS). M/Z (M[.sup.35Cl]+H).sup.+=378.4.
Example 57: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(193) ##STR00430##
(194) Example 57 was prepared according to general procedure IV(ii), starting from compound 52 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 80° C. for 2 hours. Purification by column chromatography on silica gel (using 0% to 50% ethyl acetate in cyclohexane as eluent) afforded the SEM-protected intermediate as a beige solid in 52% yield. M/Z (M+H).sup.+=435.7.
(195) SEM removal was performed by heating the SEM-protected intermediate in a mixture of ethanol (0.02 mol.Math.L.sup.−1) and aqueous HCl (3N, 0.06 mol.Math.L.sup.−1) at 80° C. overnight. After cooling to room temperature, the reaction mixture was neutralysed with aqueous sodium bicarbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded example 57 as a beige solid in 37% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 13.85 (bs, 1H, NH); 8.48 (dd, J 4.9, 1.7 Hz, 1H, Ar); 8.17 (bs, 1H, Ar); 7.72 (s, 1H, Ar); 7.66 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.63 (d, J 7.7 Hz, 1H, Ar); 7.36 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.32 (dd, J 7.7, 4.9 Hz, 1H, Ar); 4.36 (s, 2H, CH.sub.2); 3.13 (s, 3H, CH.sub.3); 2.46 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=305.6.
Compound 53: 3-(5-Chloro-2-formyl-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester
Compound 53 was prepared according to general procedure IX, starting from compound 29
(196) and methyl 3-bromopyrrole-2-carboxylate and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 0% to 45% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 63% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 12.26 (bs, 1H, NH); 9.80 (s, 1H, CHO); 7.85 (d, J 8.4 Hz, 1H, Ar); 7.57 (dd, J 8.4, 2.1 Hz, 1H, Ar); 7.47 (d, J 2.1 Hz, 1H, Ar); 7.16 (d, J 2.1 Hz, 1H, Ar); 6.39 (d, J 2.1 Hz, 1H, Ar); 3.60 (s, 3H, CH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=264.5.
Example 58: 9-Chloro-5-methyl-5,6-dihydro-3H-3,5-diaza-benzo[e]azulen-4-one
(197) ##STR00431##
(198) Example 58 was prepared according to general procedure X, starting from compound 53 and methylamine. Purification by column chromatography on silica gel (using 0% to 2% MeOH in dichloromethane as eluent) afforded the product as a beige solid in 54% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.90 (bs, 1H, NH); 7.66 (d, J 2.2 Hz, 1H, Ar); 7.52 (d, J 8.1 Hz, 1H, Ar); 7.32 (dd, J 8.1, 2.2 Hz, 1H, Ar); 7.05 (t, J 2.9 Hz, 1H, Ar); 6.65 (t, J 2.6 Hz, 1H, Ar); 4.25 (s, 2H, CH.sub.2); 3.06 (s, 3H, CH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=247.5.
Example 59: 5-Methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-3H-3,5-diaza-benzo[e]azulen-4-one
(199) ##STR00432##
(200) Example 59 was prepared according to general procedure IV(ii), starting from example 58 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 59 as a brown solid in 64% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.83 (bs, 1H, NH); 8.48 (d, J 4.9, 1.7 Hz, 1H, Ar); 7.68 (d, J 7.7 Hz, 1H, Ar); 7.62 (d, J 1.7 Hz, 1H, Ar); 7.58 (d, J 7.7 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.9 Hz, 1H, Ar); 7.29 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.04 (t, J 2.8 Hz, 1H, Ar); 6.64 (t, J 2.6 Hz, 1H, Ar); 4.32 (s, 2H, CH.sub.2); 3.10 (s, 3H, CH.sub.3); 2.46 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=304.5.
Example 60: 6-Methyl-O-(2-methyl-pyridin-3-yl)-6,7-dihydro-1,6-diaza-dibenzo[a, c]cyclohepten-5-one
(201) ##STR00433##
(202) Example 60 was obtained according to synthetic route of scheme 5, in a similar way as for example 26, and starting from compound 33 and methyl 2-bromopyridine-3-carboxylate. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 60 as a white solid in 88% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.84 (dd, J 4.6, 1.7 Hz, 1H, Ar); 8.49 (dd, J 4.7, 1.6 Hz, 1H, Ar); 8.24 (d, J 8.0, 1.7 Hz, 1H, Ar); 7.98 (d, J 1.7 Hz, 1H, Ar); 7.70-7.66 (m, 2H, Ar); 7.58-7.55 (m, 2H, Ar); 7.32 (dd, J 7.7, 4.7 Hz, 1H, Ar); 4.39 (m, 2H, CH.sub.2); 3.15 (s, 3H, CH.sub.3); 2.50 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=316.6.
Example 61: 3-(6-Methyl-5-oxo-6,7-dihydro-5H-1,6-diaza-dibenzo[a,c]cyclohepten-10-yl)-benzonitrile
(203) ##STR00434##
(204) Example 61 was obtained according to synthetic route of scheme 5 in a similar way as for example 60 and using 3-benzonitrile boronic acid in the last step with general procedure IV(ii). Purification by column chromatography on silica gel (using 0% to 3% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 61 as a white solid in 87% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.88 (dd, J 4.7, 1.8 Hz, 1H, Ar); 8.30 (d, J 1.8 Hz, 1H, Ar); 8.25-8.22 (m, 2H, Ar); 8.09 (m, 1H, Ar); 7.90-7.85 (m, 2H, Ar); 7.72-7.68 (m, 2H, Ar); 7.59 (dd, J 7.8, 4.7 Hz, 1H, Ar); 4.39 (m, 2H, CH.sub.2); 3.13 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=326.5.
Example 62: 6-Methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-3,6-diaza-dibenzo[a, c]cyclohepten-5-one
(205) ##STR00435##
(206) Example 62 was obtained according to synthetic route of scheme 5 in a similar way as for example 26 and starting from compound 33 and methyl 4-bromopyridine-3-carboxylate. Purification by column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 62 as a white solid in 71% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.95 (s, 1H, Ar); 8.73 (d, J 5.3 Hz, 1H, Ar); 8.49 (dd, J 4.7, 1.6 Hz, 1H, Ar); 7.82 (d, J 1.7 Hz, 1H, Ar); 7.76-7.63 (m, 2H, Ar); 7.70 (d, J 7.7 Hz, 1H, Ar); 7.59 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.7 Hz, 1H, Ar); 4.40 (d, J 14.8 Hz, 1H, CHaHb); 4.31 (d, J 14.8 Hz, 1H, CHaHb); 3.13 (s, 3H, CH.sub.3); 2.50 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=316.5.
Example 63: 6-Methyl-10-(2-methyl-pyridin-3-yl)-6,7-dihydro-2,6-diaza-dibenzo[a, c]cyclohepten-5-one
(207) ##STR00436##
(208) Example 63 was obtained according to synthetic route of scheme 4 in a similar way as for example 55 and starting from compound 29 and 3-bromo-isonicotinic acid ethyl ester. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) afforded example 63 as a white solid in 44% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.99 (s, 1H, Ar); 8.73 (d, J 5.0 Hz, 1H, Ar); 8.49 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.86 (d, J 1.7 Hz, 11H, Ar); 7.77-7.74 (m, 2H, Ar); 7.70 (d, J 7.7 Hz, 1H, Ar); 7.55 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.8 Hz, 1H, Ar); 4.35 (d, J 14.8 Hz, 1H, CHaHb); 4.30 (d, J 14.8 Hz, 1H, CHaHb); 3.13 (s, 3H, CH.sub.3); 2.48 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=316.6.
Compound 54: 4-Iodo-1-methoxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester
(209) Compound 54 was prepared according to procedure of compound 50, using methoxymethyl chloride instead of 2-(trimethylsilyl)ethoxymethyl chloride. Purification by flash column chromatography on silica gel (using 0% to 50% ethyl acetate in cyclohexane as eluent) afforded the product as a colorless oil in 20% yield (minor isomer). .sup.1H-NMR (400 MHz, DMSO-D6): 8.27 (s, 1H, Ar); 5.43 (s, 2H, CH.sub.2); 4.29 (q, J 7.1 Hz, 2H, CH.sub.2—CH.sub.3); 3.25 (s, 3H, CH.sub.3); 1.31 (t, J 7.1 Hz, 3H, CH.sub.2—CH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): correlation observed between CH.sub.2 of methoxymethyl and CH of pyrazole. M/Z (M+H).sup.+=311.5.
Compound 55: 4-{2-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-5-chloro-phenyl}-1-methoxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester
(210) Compound 55 was prepared according to general procedure VII, starting from compounds 54 and 33 and heating at 80° C. for 17 hours. Purification by flash column chromatography on silica gel (using 0% to 50% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.12 (s, 1H, Ar); 7.46 (dd, J 8.1, 2.1 Hz, 1H, Ar); 7.25 (d, J 2.1 Hz, 1H, Ar); 7.18 (d, J 8.1 Hz, 1H, Ar); 5.48 (s, 2H, CH.sub.2); 4.20 (s, 2H, CH.sub.2); 4.12 (q, J 7.1 Hz, 2H, CH.sub.2—CH.sub.3); 3.31 (s, 3H, CH.sub.3); 2.58 (s, 3H, CH.sub.3); 1.37 (s, 9H, tert-butyl); 1.10 (t, J 7.1 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M[.sup.35Cl]-boc+H).sup.+=338.4.
Example 64: 9-Chloro-2-methoxymethyl-5-methyl-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(211) ##STR00437##
(212) Example 64 was prepared according to general procedure XI, starting from compound 55 and heating at 110° C. for 4 hours. Purification by flash column chromatography on silica gel (using 0% to 1% MeOH in dichloromethane as eluent) afforded example 64 as a beige solid in 71% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.55 (s, 1H, Ar); 7.73 (d, J 2.1 Hz, 1H, Ar); 7.57 (d, J 8.0 Hz, 1H, Ar); 7.39 (dd, J 8.0, 2.1 Hz, 1H, Ar); 5.50 (s, 2H, CH.sub.2); 4.29 (s, 2H, CH.sub.2); 3.34 (s, 3H, CH.sub.3); 3.07 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=292.5.
Example 65: 2-Methoxymethyl-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(213) ##STR00438##
(214) Example 65 was prepared according to general procedure IV(ii), starting from example 64 and 2-methylpyridine-3-boronic acid pinacol ester and heating at 100° C. for 1 hour. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) and trituration in iPr.sub.2O afforded example 65 as a beige solid in 73% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.53 (s, 1H, Ar); 8.48 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.68-7.66 (m, 2H, Ar); 7.63 (d, J 7.7 Hz, 1H, Ar); 7.37 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.32 (dd, J 7.7, 4.8 Hz, 1H, Ar); 5.50 (s, 2H, CH.sub.2); 4.37 (s, 2H, CH.sub.2); 3.33 (s, 3H, CH.sub.3); 3.12 (s, 3H, CH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): correlation observed between CH.sub.2 of methoxymethyl and CH of pyrazole. M/Z (M+H).sup.+=349.5.
Example 66: 2-Methoxymethyl-5-methyl-9-(6-fluoro-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(215) ##STR00439##
(216) Example 66 was prepared according to general procedure IV(ii), starting from example 64 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 1 hour. Purification by preparative HPLC afforded example 66 as a white solid in 20% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.65 (d, J 2.0 Hz, 1H, Ar); 8.60 (s, 1H, Ar); 8.38 (dt, J 8.3, 2.7 Hz, 1H, Ar); 8.00 (d, J 1.7 Hz, 1H, Ar); 7.69 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.65 (d, J 7.8 Hz, 1H, Ar); 7.32 (dd, J 8.5, 2.7 Hz, 1H, Ar); 5.53 (s, 2H, CH.sub.2); 4.35 (s, 2H, CH.sub.2); 3.35 (s, 3H, CH.sub.3); 3.10 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=353.5.
Example 67: 2-Methoxymethyl-5-methyl-9-(6-fluoro-pyridin-2-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(217) ##STR00440##
(218) Under inert atmosphere, XPhos precatalyst (0.10 equiv.) was added to a suspension of example 64 (1.0 equiv.), bispinacolatodiboron (1.2 equiv.) and potassium acetate (2.7 equiv.) in dioxane (0.15 mol.Math.L.sup.−1). The reaction mixture was heated at 100° C. for 1 hour. After cooling to room temperature, the mixture was filtered off on celite with ethyl acetate and the filtrate was concentrated under vacuum. Potassium carbonate (3.0 equiv.), a solution of 2-bromo-5-fluoropyridine (1.2 equiv.) in dioxane (0.10 mol.Math.L.sup.−1) and PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (0.10 equiv.) were successively added. The reaction mixture was heated at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was treated with water and extracted twice with dichloromethane. The combined organic extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by preparative HPLC afforded example 67 as a white solid in 38% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.68 (d, J 2.9 Hz, 1H, Ar); 8.61 (s, 1H, Ar); 8.30 (d, J 1.8 Hz, 1H, Ar); 8.16 (dd, J 8.8, 4.4 Hz, 1H, Ar); 8.01 (dd, J 7.9, 1.8 Hz, 1H, Ar); 7.87 (dt, J 8.8, 2.9 Hz, 1H, Ar); 7.65 (d, J 7.9 Hz, 1H, Ar); 5.53 (s, 2H, CH.sub.2); 4.35 (s, 2H, CH.sub.2); 3.35 (s, 3H, CH.sub.3); 3.11 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=353.5. MP=97-99° C.
Example 68: 2,5-Dimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(219) ##STR00441##
(220) At 0° C., to a solution of example 57 (1.0 equiv.) in anhydrous DMF (0.10 mol.Math.L.sup.−1) was added sodium hydride (60% suspension in oil, 1.3 equiv.) and the reaction mixture was stirred for 1 hour at room temperature. Iodomethane (1.1 equiv.) was added and the reaction mixture was stirred for 1 hour at room temperature before being treated with an aqueous solution of NaHCO.sub.3 and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum. Purification by preparative HPLC afforded example 68 as a white solid in 12% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.56 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.37 (s, 1H, Ar); 7.75 (dd, J 7.5 Hz, 1.6 Hz, 1H, Ar); 7.68-7.66 (m, 2H, Ar); 7.42-7.39 (m, 2H, Ar); 4.38 (s, 2H, CH.sub.2); 4.03 (s, 3H, CH.sub.3); 3.16 (s, 3H, CH.sub.3); 2.53 (s, 3H, COH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): correlation observed between N—CH.sub.3 of pyrazole and OH of pyrazole. M/Z (M+H).sup.+=319.6.
Example 69: 3,5-Dimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(221) ##STR00442##
(222) Example 69 was obtained as example 68 regioisomer in the same procedure. Purification by preparative HPLC afforded example 69 as a white solid in 6% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.49 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.06 (s, 1H, Ar); 7.73 (d, J 1.7 Hz, 1H, Ar); 7.67 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.63 (d, J=7.7 Hz, 1H, Ar); 7.38 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.32 (dd, J 7.7, 4.8 Hz, 1H, Ar); 4.37 (s, 2H, CH.sub.2); 4.10 (s, 3H, CH.sub.3); 3.12 (s, 3H, CH.sub.3); 2.47 (s, 3H, CH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): absence of correlation between N—CH.sub.3 of pyrazole and CH of pyrazole. M/Z (M+H).sup.+=319.6.
Example 70: 2-Ethyl-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(223) ##STR00443##
(224) A suspension of example 57 (1.0 equiv.), potassium carbonate (2.5 equiv.) and iodoethane (1.2 equiv.) in anhydrous DMF (0.10 mol.Math.L.sup.−1) was heated at 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was treated with an aqueous solution of NaHCO.sub.3 and extracted twice with EtOAc. The combined extracts were dried with brine and MgSO.sub.4, filtered and concentrated under vacuum. Purification by preparative HPLC afforded example 70 as a white solid in 3% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.57 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.38 (s, 1H, Ar); 7.82 (d, J 7.7 Hz 1H, Ar); 7.64-7.62 (m, 2H, Ar); 7.45 (dd, J 7.5, 4.8 Hz, 1H, Ar); 7.37 (dd, J 7.5, 1.6 Hz, 1H, Ar); 4.34 (s, 2H, CH.sub.2); 4.26 (q, J 7.2 Hz, 2H, CH.sub.2—CH.sub.3); 3.11 (s, 3H, CH.sub.3); 2.51 (s, 3H, CH.sub.3); 1.47 (t, J 7.2 Hz, 3H, CH.sub.2—CH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): correlation observed between N—CH.sub.2 of pyrazole and CH of pyrazole. M/Z (M+H)+=333.6.
Example 71: 3-Ethyl-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(225) ##STR00444##
(226) Example 71 was obtained as example 70 regioisomer in the same procedure. Purification by preparative HPLC afforded example 71 as a white solid in 2% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.54 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.08 (s, 1H, Ar); 7.80-7.75 (m, 2H, Ar); 7.65 (d, J 7.7 Hz, 1H, Ar); 7.43-7.39 (m, 2H, Ar); 4.49 (q, J 7.2 Hz, 2H, CH.sub.2—CH.sub.3); 4.37 (s, 2H, CH.sub.2); 3.13 (s, 3H, CH.sub.3); 2.51 (s, 3H, CH.sub.3); 1.42 (t, J 7.2 Hz, 3H, CH.sub.2—CH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): absence of correlation between N—CH.sub.2 of pyrazole and CH of pyrazole. M/Z (M+H).sup.+=333.6.
Example 72: 2-(2-Methoxy-ethyl)-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(227) ##STR00445##
(228) Example 72 was prepared according to procedure of example 68, using 2-bromoethyl methyl ether instead of iodomethane. Purification by preparative HPLC afforded example 72 as a white solid in 26% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.54 (dd, J 4.8, 1.5 Hz, 1H, Ar); 8.35 (s, 1H, Ar); 7.79 (d, J 7.7 Hz 1H, Ar); 7.64-7.62 (m, 2H, Ar); 7.42 (dd, J 7.5, 4.8 Hz, 1H, Ar); 7.37 (dd, J 7.5, 1.5 Hz, 1H, Ar); 4.39 (t, J 5.0 Hz, 2H, CH.sub.2—CH.sub.2); 4.34 (s, 2H, CH.sub.2); 3.78 (t, J 5.0 Hz, 2H, CH—CH.sub.2); 3.26 (s, 3H, CH.sub.3); 3.11 (s, 3H, CH.sub.3); 2.50 (s, 3H, CH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): correlation observed between N—CH.sub.2 of pyrazole and CH of pyrazole. M/Z (M+H).sup.+=363.6.
Example 72: 3-(2-Methoxy-ethyl)-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-2H-2,3,5-triaza-benzo[e]azulen-4-one
(229) ##STR00446##
(230) Example 73 was obtained as example 72 regioisomer in the same procedure. Purification by preparative HPLC afforded example 73 as a white solid in 16% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.53 (dd, J 4.8, 1.5 Hz, 1H, Ar); 8.09 (s, 1H, Ar); 7.78-7.75 (m, 2H, Ar); 7.67-7.62 (m, 1H, Ar); 7.41-7.39 (m, 2H, Ar); 4.67 (bs, 2H, CH.sub.2—CH.sub.2); 4.35 (s, 2H, CH.sub.2); 3.71 (t, J 5.1 Hz, 2H, CH.sub.2—CH.sub.2); 3.22 (s, 3H, CH.sub.3); 3.12 (s, 3H, CH.sub.3); 2.50 (s, 3H, CH.sub.3). NOESY .sup.1H/.sup.1H NMR (400 MHz, DMSO-D6): absence of correlation between N—CH.sub.2 of pyrazole and CH of pyrazole. M/Z (M+H).sup.+=363.6.
Compound 56: (3-(ethoxycarbonyl)-1-(methoxymethyl)-1H-pyrazol-4-yl)boronic acid
(231) Under dry atmosphere, at −78° C., to a solution of compound 54 (1.0 equiv.) and 2-isopropyl-4,4,5,5-tetramethyl-1,2,3-dioxaborolane (3.0 equiv.) in anhydrous THF (0.10 mol.Math.L.sup.11) was added butyllithium (1.6N in hexanes, 2.9 equiv.) dropwise. The reaction mixture was stirred for 2 hours at −78° C. before being hydrolyzed by an aqueous solution of K.sub.2CO.sub.3 and washed with EtOAc. The aqueous phase was acidified with aqueous HCl (1N) and extracted twice with dichloromethane. The combined extracts were dried with brine and MgSO.sub.4, filtered off and concentrated under vacuum to afford compound 56 as a yellow oil in 93% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.12 (s, 1H, Ar); 5.43 (s, 2H, CH.sub.2); 4.26 (q, J 7.2 Hz, 2H, CH.sub.2—CH.sub.3); 3.23 (s, 3H, CH.sub.3); 1.29 (t, J 7.2 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M+H).sup.+=229.6.
Compound 57: 3-[2-(1-tert-Butoxycarbonylamino-cyclopropyl)-5-chloro-phenyl]-1-methoxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester
(232) Under inert atmosphere, a suspension of compound 41 (1.0 equiv.), compound 56 (1.3 equiv.) and tetrakis(triphenylphosphine)palladium (0.1 equiv.) in aqueous potassium carbonate (1.2M, 3.0 equiv) and dioxane (0.20 mol.Math.L.sup.−1) was heated at 100° C. for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried with brine and over MgSO.sub.4, filtered off and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 20% EtOAc in cyclohexane as eluent) afforded compound 57 as a light yellow solid in 92% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.07 (s, 1H, Ar); 7.66-7.63 (m, 1H, Ar); 7.33 (dd, J 8.4, 2.3 Hz, 1H, Ar); 7.13 (d, J 2.3 Hz, 1H, Ar); 6.75 (bs, 1H, NH); 5.49 (s, 2H, CH.sub.2); 4.06 (q, J 7.0 Hz, 2H, CH—OH.sub.3); 3.33 (s, 3H, CH.sub.3); 1.30 (s, 9H, tert-butyl); 1.03 (t, J 7.0 Hz, 3H, CH.sub.2—CH.sub.3); 1.45-0.70 (m, 3H, cyclopropyl); 0.51-0.30 (m, 1H, cyclopropyl). M/Z (M[.sup.31Cl]-boc+H).sup.+=350.6.
Compound 58: 9-Chloro-2-(methoxymethyl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one
(233) Compound 58 was prepared according to general procedure XI, starting from compound 57 and heating at 100° C. for 16 hours. Purification by column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded compound 58 as a beige solid in 80% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.62 (s, 1H, NH); 8.56 (s, 1H, Ar); 7.71 (d, J 2.1 Hz, 1H, Ar); 7.37 (d, J 8.1 Hz, 1H, Ar); 7.32 (dd, J 8.1, 2.1 Hz, 1H, Ar); 5.51 (s, 2H, CH.sub.2); 3.43 (s, 3H, CH.sub.3); 1.40-0.71 (m, 3H, cyclopropyl); 0.48-0.18 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H)+=304.5.
Example 74: 9-Chloro-2-(methoxymethyl)-5-methyl-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one
(234) ##STR00447##
(235) Example 74 was obtained according to general procedure III, starting from compound 58 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by column chromatography on silica gel (using 0% to 3% MeOH in dichloromethane as eluent) afforded the product as a white solid in 98% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.53 (s, 1H, Ar); 7.72 (d, J 2.1 Hz, 1H, Ar); 7.47 (d, J 8.2 Hz, 1H, Ar); 7.35 (dd, J 8.2, 2.1 Hz, 1H, Ar); 5.51 (s, 2H, CH.sub.2); 3.33 (s, 3H, CH.sub.3); 2.93 (s, 3H, CH.sub.3); 1.49-1.39 (m, 2H, cyclopropyl); 0.97-0.91 (m, 1H, cyclopropyl); 0.42-0.37 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=318.5.
Example 75: 2-(Methoxymethyl)-5-methyl-9-(6-fluoro-pyridin-3-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one
(236) ##STR00448##
(237) Example 75 was prepared according to general procedure IV(ii), starting from example 74 and 6-fluoro-3-pyridinylboronic acid and heating at 100° C. for 2 hours. Purification by column chromatography on silica gel (using EtOAc as eluent) afforded the product as a white solid in 85% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.63 (d, J 2.6 Hz, 1H, Ar); 8.59 (s, 1H, Ar); 8.36 (dt, J 8.1, 2.6 Hz, 1H, Ar); 8.00 (d, J 1.9 Hz, 1H, Ar); 7.65 (dd, J 7.8, 1.9 Hz, 1H, Ar); 7.56 (d, J 7.8 Hz, 1H, Ar); 7.31 (dd, J 8.5, 2.6 Hz, 1H, Ar); 5.54 (AB system, J 10.6 Hz, 2H, CH.sub.2); 3.35 (s, 3H, CH.sub.3); 2.96 (s, 3H, CH.sub.3); 1.55-1.42 (m, 2H, cyclopropyl); 1.00-0.95 (m, 1H, cyclopropyl); 0.46-0.41 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=379.5. MP=198-200° C.
Example 76: 2-(Methoxymethyl)-5-methyl-9-(5-fluoro-pyridin-2-yl)-2H-spiro[benzo[c]pyrazolo[4,3-e]azepine-6,1′-cyclopropan]-4(5H)-one
(238) ##STR00449##
(239) Example 76 was prepared according to procedure of example 67, starting from example 74. Purification by preparative HPLC afforded the product as a white solid in 36% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.67 (d, J 2.9 Hz, 1H, Ar); 8.60 (s, 1H, Ar); 8.29 (d, J 1.8 Hz, 1H, Ar); 8.14 (dd, J 8.8, 4.5 Hz, 1H, Ar); 7.98 (dd, J 8.0, 1.8 Hz, 1H, Ar); 7.86 (dt, J 8.8, 2.9 Hz, 1H, Ar); 7.55 (d, J 8.0 Hz, 1H, Ar); 5.54 (s, 2H, CH.sub.2); 3.35 (s, 3H, CH.sub.3); 2.97 (s, 3H, CH.sub.3); 1.55-1.42 (m, 2H, cyclopropyl); 1.00-0.95 (m, 1H, cyclopropyl); 0.47-0.41 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=379.5. MP=219-223° C.
Compound 59: 2-(5-Chloro-2-formyl-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester
(240) Compound 59 was prepared according to general procedure IX, starting from 2-bromo-4-chlorobenzaldehyde and N-boc-2-pyrroleboronic acid and heating at 80° C. for 3 hours. Purification by column chromatography on silica gel (using 0% to 20% ethyl acetate in cyclohexane as eluent) afforded the product as a yellow oil in 68% yield. M/Z (M[.sup.35Cl]-boc+H).sup.+=205.9.
Compound 60: 2-(5-Chloro-2-methylaminomethyl-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester
(241) A solution of compound 59 (1.0 equiv.) and 40% aqueous methylamine (1.5 equiv.) in MeOH (0.1 mol.Math.L.sup.−1) was stirred for 2 hours at room temperature, before addition of sodium borohydride (1.5 equiv.). The reaction mixture was stirred at room temperature for 3 hours before being hydrolyzed with aqueous ammonium chloride and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum to give the product as a white solid in 90% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.20 (s, 1H, NH); 7.46 (d, J 2.2 Hz, 1H, Ar); 7.34 (dd, J 8.3, 2.2 Hz, 1H, Ar); 7.11 (d, J 8.3 Hz, 1H, Ar); 6.91 (m, 1H, Ar), 6.24 (m, 1H, Ar); 6.17 (m, 1H, Ar); 4.52 (s, 2H, CH.sub.2); 2.72 (s, 3H, CH.sub.3); 1.32 (s, 9H, tert-butyl).
Compound 61: [4-Chloro-2-(1H-pyrrol-2-yl)-benzyl]-methyl-amine
(242) To a solution of compound 60 (1.0 equiv.) in dichloromethane (0.10 mol.Math.L.sup.−1), TFA (0.20 mol.Math.L.sup.−1) was added dropwise and the reaction mixture was stirred at room temperature for 30 minutes. TFA was neutralized by slow addition of aqueous sodium bicarbonate and the mixture was extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) afforded the product as a brown oil in 44% yield. M/Z (M[.sup.35Cl]+H).sup.+=220.9.
Example 77: 10-Chloro-6-methyl-6,7-dihydro-benzo[e]pyrrolo[1,2-c][1,3]diazepin-5-one
(243) ##STR00450##
(244) At 0° C., to a solution of compound 61 (1.0 equiv.) in anhydrous DMA (0.10 mol.Math.L.sup.−1), sodium hydride (60% in oil, 3.0 equiv.) was slowly added. The reaction mixture was stirred at 0° C. for 5 minutes, before addition of 1,1′-carbonyldiimidazole (1.5 equiv.). The reaction mixture was stirred at room temperature for 1 hour, before being hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by trituration in pentane afforded example 77 as a white solid in 67% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.70 (d, J 2.1 Hz, 1H, Ar); 7.51 (d, J 8.0 Hz, 1H, Ar); 7.46 (dd, J 3.1, 1.8 Hz, 1H, Ar); 7.36 (dd, J 8.0, 2.1 Hz, 1H, Ar); 6.79 (dd, J 3.5, 1.8 Hz, 1H, Ar), 6.39 (t, J 3.3 Hz, 1H, Ar); 4.30 (s, 2H, CH.sub.2); 3.10 (s, 3H, CH.sub.3); M/Z (M[.sup.35Cl]+H).sup.+=246.9.
Example 78: 10-(6-Fluoro-pyridin-3-yl)-6-methyl-6,7-dihydro-benzo[e]pyrrolo[1,2-c][1,3]diazepin-5-one
(245) ##STR00451##
(246) Example 78 was prepared according to general procedure IV(ii), starting from example 77 and 6-fluoro-3-pyridinylboronic acid. Purification by column chromatography on silica gel (using 0% to 5% MeOH in dichloromethane as eluent) and trituration in Et.sub.2O afforded example 78 as a yellow solid in 72% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.64 (d, J 2.2 Hz, 1H, Ar); 8.38 (td, J 8.2, 2.2 Hz, 1H, Ar); 7.95 (d, J 1.5 Hz, 1H, Ar); 7.65 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.60 (d, J 7.8 Hz, 1H, Ar), 7.46 (dd, J 3.1, 1.8 Hz, 1H, Ar); 7.31 (dd, J 8.6, 2.8 Hz, 1H, Ar); 6.89 (dd, J 3.5, 1.8 Hz, 1H, Ar); 6.40 (t, J 3.3 Hz, 1H, Ar); 4.36 (s, 2H, CH.sub.2); 3.13 (s, 3H, CH.sub.3); M/Z (M+H).sup.+=308.0.
Example 79: 6-Methyl-O-(2-methyl-pyridin-3-yl)-6,7-dihydro-benzo[e]pyrrolo[1,2-c][1,3]diazepin-5-one, hydrochloride
(247) ##STR00452##
(248) Example 79 was prepared according to general procedure IV(ii), starting from example 77 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by column chromatography on silica gel (using 0% to 4% MeOH in dichloromethane as eluent) afforded example 79 as a beige powder in 71% yield. Salt formation was performed according to method V(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (dd, J 5.6, 1.3 Hz, 1H, Ar); 8.37 (d, J 7.7 Hz, 1H, Ar); 7.87 (dd, J 7.7, 5.6 Hz, 1H, Ar); 7.76 (d, J 1.7 Hz, 1H, Ar); 7.65 (d, J 7.7 Hz, 1H, Ar); 7.48 (dd, J 3.1, 1.8 Hz, 1H, Ar); 7.44 (dd, J 7.7, 1.7 Hz, 1H, Ar), 6.77 (dd, J 3.5, 1.8 Hz, 1H, Ar); 6.40 (t, J 3.3 Hz, 1H, Ar); 4.39 (s, 2H, CH.sub.2); 3.15 (s, 3H, CH.sub.3); 2.68 (s, 3H, CH.sub.3); M/Z (M+H).sup.+=304.0.
Compound 62: {[(2-Bromo-4-chloro-benzyl)-methyl-carbamoyl]-methyl}-carbamic acid tert-butyl ester
(249) A mixture of (2-bromo-4-chloro-benzyl)-methylamine (1 equiv., prepared as described in the procedure of compound 32), N-(tert-butoxycarbonyl)glycine (1.1 equiv.), BOP (1.1 equiv.) and diisopropylethylamine (2.2 equiv.) in dichloromethane (0.15 mol.Math.L.sup.−1) was stirred at room temperature for 5 hours. The reaction mixture was hydrolyzed and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 1% MeOH in dichloromethane as eluent) afforded the product as a yellow oil in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.77 (d, J 2.0 Hz, 1H, Ar); 7.44 (dd, J 8.4, 2.0 Hz, 1H, Ar); 7.16 (d, J 8.4 Hz, 1H, Ar); 6.78 (t, J 5.6 Hz, 1H, NH); 4.50 (s, 2H, CH.sub.2); 3.91 (d, J 5.6 Hz, 2H, CH.sub.2); 2.98 (s, 3H, CH.sub.3), 1.35 (s, 9H, tert-butyl). M/Z (M[.sup.35C][.sup.80Br]-Boc).sup.+=293.5.
Compound 63: 8-Chloro-4-methyl-3-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepine-1-carboxylic acid tert-butyl ester
(250) Under inert atmosphere, a mixture of compound 62 (1.0 equiv.), cesium carbonate (1.5 equiv.) and XantPhos precatalyst (0.05 equiv.) in toluene (0.20 mol.Math.L.sup.−1) was heated at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture was hydrolyzed with sodium bicarbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 100% ethyl acetate in cyclohexane as eluent) and trituration in pentane afforded the product as a yellow solid in 64% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.52 (d, J 8.1 Hz, 1H, Ar); 7.42 (d, J 2.2 Hz, 1H, Ar); 7.38 (d, J 8.1, 2.2 Hz, 1H, Ar); 4.40 (s, 2H, CH.sub.2); 4.31 (s, 2H, CH.sub.2); 2.99 (s, 3H, CH.sub.3); 1.37 (s, 9H, tertbutyl). M/Z (M[.sup.35Cl]+H-tBu).sup.+=255.5.
Compound 64: 4-Methyl-8-(2-methyl-pyridin-3-yl)-3-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepine-1-carboxylic acid tert-butyl ester
(251) Compound 64 was prepared according to general procedure IV(ii), starting from compound 63 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by column chromatography on silica gel (using 0% to 10% MeOH in dichloromethane as eluent) afforded the product as a brown oil in 94% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.48 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.60-7.58 (m, 2H, Ar); 7.35-7.30 (m, 3H, Ar); 4.46 (s, 2H, CH.sub.2); 4.34 (s, 2H, CH.sub.2); 3.04 (s, 3H, CH); 2.44 (s, 3H, CH.sub.3); 1.36 (s, 9H, tertbutyl). M/Z (M+H).sup.+=368.4.
Example 80: 4-Methyl-8-(2-methyl-pyridin-3-yl)-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(252) ##STR00453##
(253) To a solution of compound 64 (1.0 equiv.) in dichloromethane (0.10 mol.Math.L.sup.−1) was added a 4N solution of HCl in dioxane (10 equiv.) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum to afford example 80 as a beige solid in 82% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.41 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.51 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.25 (d, J 7.7, 4.8 Hz, 1H, Ar); 7.01 (d, J 7.4 Hz, 1H, Ar); 6.46-6.44 (m, 2H, Ar); 6.31 (t, J 5.1 Hz, 1H, NH); 4.67 (s, 2H, CH.sub.2); 4.09 (d, J 5.1 Hz, 2H, CH.sub.2); 3.00 (s, 3H, CH.sub.3); 2.47 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=268.6.
Example 81: 4-Methyl-8-(2-methyl-pyridin-3-yl)-1-phenethyl-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(254) ##STR00454##
(255) To a solution of example 80 (1.0 equiv.), phenylacetaldehyde (3.0 equiv.) and acetic acid (1.0 equiv.) in anhydrous THF (0.20 mol.Math.L.sup.−1), was added sodium triacetoxyborohydride (3.0 equiv.) portionwise. The reaction mixture was stirred at room temperature for 2 days, before being hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by preparative HPLC afforded example 81 as a colorless oil in 6% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.50 (dd, J 4.8, 1.8 Hz, 1H, Ar); 7.56 (dd, J 7.7, 1.8 Hz, 1H, Ar); 7.35-7.19 (m, 7H, Ar); 6.76-6.72 (m, 2H, Ar); 4.65 (s, 2H, CH.sub.2); 4.14 (s, 2H, CH.sub.2); 3.57 (t, J 7.5 Hz, 2H, CH.sub.2); 3.02 (s, 3H, CH.sub.3); 2.90 (t, J 7.5 Hz, 2H, CH.sub.2); 2.47 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=372.5.
Example 82: 1-Benzyl-4-methyl-8-(2-methyl-pyridin-3-yl)-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(256) ##STR00455##
(257) Example 82 was prepared according to procedure of example 81, using benzaldehyde instead of phenylacetaldehyde. Purification by preparative HPLC afforded example 82 as a beige solid in 37% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.39 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.46 (dd, J 7.7, 1.8 Hz, 1H, Ar); 7.35-7.30 (m, 4H, Ar); 7.26-7.20 (m, 3H, Ar); 6.71 (dd, J 7.6, 1.6 Hz, 1H, Ar); 6.66 (d, J 1.6 Hz, 1H, Ar); 4.70 (s, 2H, CH.sub.2); 4.51 (s, 2H, CH.sub.2); 4.11 (s, 2H, CH.sub.2); 3.01 (s, 3H, CH.sub.3); 2.18 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=358.5.
Example 83: 4-Methyl-8-(2-methyl-pyridin-3-yl)-1-pyridin-4-yl-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(258) ##STR00456##
(259) Under inert atmosphere, a mixture of example 80 (1.0 equiv.), 4-bromopyridine (1.2 equiv.), potassium tertbutoxide (3.0 equiv.), Ruphos ligand (0.1 equiv.) and Pd.sub.2dba.sub.3 (0.1 equiv.) in dioxane (0.10 mol.Math.L.sup.−1) was heated at 80° C. for 1 hour. After cooling, the reaction mixture was hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by preparative HPLC afforded example 83 as a brown solid in 3% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.47 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.23 (d, J 6.4 Hz, 2H, Ar); 7.70 (d, J 7.7 Hz, 1H, Ar); 7.66 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.43 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.37 (d, J 1.7 Hz, 1H, Ar); 7.31 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.78 (d, J 6.4 Hz, 2H, Ar); 4.52 (s, 2H, CH.sub.2); 4.41 (s, 2H, CH.sub.2); 3.00 (s, 3H, CH.sub.3); 2.47 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=345.0.
Example 84: 4-Methyl-8-(2-methyl-pyridin-3-yl)-1-phenyl-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(260) ##STR00457##
(261) Example 84 was obtained according to procedure of example 83, using bromobenzene instead of 4-bromopyridine and heating at 100° C. for 1 hour. Purification by preparative HPLC afforded example 84 as a brown solid in 10% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.41 (dd, J 4.8, 1.7 Hz, 1H, Ar); 7.52 (dd, J 7.7, 1.7 Hz, 1H, Ar); 7.46 (dd, J 7.7 Hz, 1H, Ar); 7.29-7.22 (m, 3H, Ar); 7.07 (dd, J 7.7, 1.8 Hz, 1H, Ar); 6.99-6.92 (m, 3H, Ar); 6.83 (d, J 1.8 Hz, 1H, Ar); 4.58 (s, 2H, CH.sub.2); 4.42 (s, 2H, CH.sub.2); 2.99 (s, 3H, CH.sub.3); 2.34 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=344.5.
Example 85: 8-(2-Fluoro-pyridin-3-yl)-4-methyl-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(262) ##STR00458##
(263) Example 85 was prepared in a similar sequence as for example 82, starting from compound 63 and 2-fluoro-3-pyridineboronic acid. Example 85 was isolated as an orange solid in 82% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.21-8.18 (m, 1H, Ar); 8.02-7.97 (m, 1H, Ar); 7.45-7.41 (m, 1H, Ar); 7.06 (d, J 7.7 Hz, 1H, Ar); 6.71-6.65 (m, 2H, Ar); 6.34 (bs, 1H, Ar); 4.61 (s, 2H, CH.sub.2); 4.04 (s, 2H, CH.sub.2); 2.93 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=272.0.
Example 86: 8-(2-Fluoro-pyridin-3-yl)-1,4-dimethyl-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(264) ##STR00459##
(265) Example 86 was prepared according to general procedure ill, starting from example 85 and iodomethane. Purification by column chromatography on silica gel (using 50% to 100% ethyl acetate in cyclohexane as eluent) afforded example 86 as a white solid in 65% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.24-8.21 (m, 1H, Ar); 8.13-8.08 (m, 1H, Ar); 7.47-7.43 (m, 1H, Ar); 7.24 (d, J 7.7 Hz, 1H, Ar); 7.00-6.96 (m, 2H, Ar); 4.60 (s, 2H, CH.sub.2); 4.01 (s, 2H, CH.sub.2); 2.96 (s, 3H, CH.sub.3); 2.95 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=286.0.
Example 87: 8-(6-Fluoro-pyridin-3-yl)-4-methyl-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(266) ##STR00460##
(267) Example 87 was prepared in a similar sequence as for example 80, starting from compound 63 and 2-fluoro-5-pyridineboronic acid. Example 87 was isolated as a red solid in 7% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.39-8.38 (m, 1H, Ar); 8.13-8.09 (m, 1H, Ar); 7.25-7.22 (m, 1H, Ar); 7.06 (d, J 8.3 Hz, 1H, Ar); 6.77-6.75 (m, 2H, Ar); 4.60 (s, 2H, CH.sub.2); 4.04 (s, 2H, CH.sub.2); 2.92 (s, 3H, CH.sub.3). Proton for NH not observed. M/Z (M+H).sup.+=271.9.
Example 88: 1-Acetyl-8-(6-fluoro-pyridin-3-yl)-4-methy-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one
(268) ##STR00461##
(269) To a solution of example 87 (1.0 equiv.) and diisopropylethylamine (3.0 equiv.) in anhydrous DMA (0.10 mol.Math.L.sup.−1), acetyl chloride (3.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was hydrolyzed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by column chromatography on silica gel (using 0% to 8% MeOH in dichloromethane as eluent) afforded example 88 as a beige solid in 45% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.64 (m, 1H, Ar); 8.37 (m, 1H, Ar); 7.91 (s, 1H, Ar); 7.79 (d, J 7.5 Hz, 1H, Ar); 7.71 (d, J 7.5 Hz, 1H, Ar); 7.31 (dd, J 8.3, 2.2 Hz, 1H, Ar); 4.48 (bs, 4H, 2CH.sub.2); 3.03 (s, 3H, CH.sub.3); 1.90 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=314.0.
Example 89: Human mGluR3 Positive Allosteric Modulator Evaluation Using Ca++ Functional Assay
(270) Compounds of the present invention were tested successively for their agonist and positive allosteric modulator activities on human mGluR3 (hmGluR3) transiently over-expressed in HEK-293 cells. Compounds exert agonist activity if they are able to activate hmGluR3 by themselves, i.e., in absence of the endogenous agonist glutamate; and they exert positive allosteric modulator activity if they increase the action of the endogenous agonist glutamate.
(271) Cell Culture and Transfection:
(272) HEK-293 cells were maintained in Modified Eagle's Medium supplemented with 10% Foetal Calf Serum, 1% Penicillin/Streptomycin and 1% non-essential amino acids at 37° C./5% CO.sub.2. Cells were co-transfected by electroporation with four DNA plasmids encoding hmGluR3, a chimeric G protein allowing redirection of the activation signal toward intracellular calcium pathway, and two glutamate transporters so as to decrease extracellular glutamate levels and avoid receptor desensitization (Brabet I et al., Neuropharmacology 37(8), 1043-51, 1998). After transfection, cells were seeded in 75 cm.sup.2 culture flasks, and cultured for 24 h.
(273) Calcium Assa EC50 determination:
(274) Receptor activity was detected by changes in intracellular calcium measured using the fluorescent Ca.sup.2+ sensitive dye, Fluo4AM (Molecular Probes).
(275) The day of the assay, medium was aspirated and replaced during 3 hrs by freshly prepared buffer B (HBSS 1×, Hepes 20 mM, MgSO.sub.4-7H.sub.2O 1 mM, Na.sub.2CO.sub.3 3.3 mM, CaCl.sub.2-2H.sub.2O 1.3 mM, 0.5% BSA, Probenecid 2.5 mM). Then, cells were loaded at 37° C./5% CO.sub.2 for 1.5 hrs with buffer B containing 1 μM Fluo4AM, 0.1 mg/mL Pluronic Acid, 7 μg/mL Glutamate Pyruvate Transaminase and 2 mM sodium pyruvate. Afterwards cells were washed with buffer B. Cells were then detached from the 75 cm.sup.2 culture flasks with Accutase® (5 min incubation at 37° C.), centrifuged (5 min at 840 rpm), resuspended in buffer B and finally seeded at a density of 30,000 cells/well in black-walled clear-bottom 384-well plates. Addition of compounds on cells and intracellular Ca.sup.2+ measurements (excitation 485 nm, emission 525 nm) were performed by the fluorescence microplate reader FLIPR Tetra (Molecular Devices).
(276) Agonist and positive allosteric modulator activities of compounds were consecutively evaluated on the same cells plate. Agonist activity was first tested during 10 min with the addition of compound alone on the cells. Then, the cells were stimulated by an EC50 glutamate concentration and fluorescence was recorded for additional 3 min. EC50 glutamate concentration is the concentration giving 50% of the maximal glutamate response. Agonist and/or positive allosteric modulator activity(ies) were evaluated in comparison to basal signal or signal evoked by EC50 glutamate concentration alone, respectively.
(277) For potency determination, a dose-response test was performed using 20 concentrations of each compound of the invention. Dose-response curves were fitted using the sigmoïdal dose-response (variable slope) analysis in XLfit Scientific Curve Fitting for Excel (IDBS). EC50 of agonist/EC50 of positive allosteric modulator activity(ies) were calculated. Dose-response experiments were all performed in duplicate, two times independently.
(278) The compounds of the present invention were found to have no agonist activity on hmGluR3. The EC50 of the hmGluR3 positive allosteric modulator compounds of the present invention are preferably 1 μM or less.
(279) The following list represents selected examples of the compounds of the present invention showing mGluR3 positive allosteric modulator activity with an EC50>10 μM: Examples: 6, 11 and 12.
(280) The following list represents selected examples of the compounds of the present invention showing mGluR3 positive allosteric modulator activity with 1 μM<EC50<10 μM: Examples: 3, 7, 22, 30, 31, 32, 43, 46, 57, 68, 72.
(281) The following list represents selected examples of the compounds of the present invention showing mGluR3 positive allosteric modulator activity with 0.1 μM<EC50<1 μM: Examples: 17, 18, 21, 23, 25, 26, 27, 28, 34, 36, 39, 40, 41, 44, 47, 48, 52, 55, 59, 65, 66, 67, 70.
(282) The following list represents selected examples of the compounds of the present invention showing mGluR3 positive allosteric modulator activity with an EC50<0.1 μM: Examples: 16, 35, 50, 51, 53, 75, 76.