Substituted tricyclic 1,4-benzodiazepinone derivatives as allosteric modulators of group II metabotropic glutamate receptors

Abstract

The present invention provides novel tricyclic 1,4-benzodiazepinone derivatives of the general formula (I) and pharmaceutical compositions containing them. Moreover, the compounds of formula (I) 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 tricyclic 1,4-benzodiazepinone derivatives of formula (I) 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 tricyclic 1,4-benzodiazepinone derivatives of formula (I) 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 the general formula (I): ##STR00252## wherein: X.sub.1, X.sub.2 and X.sub.3 are each independently C or N; each is independently a single bond or a double bond, wherein at least one of any two adjacent bonds is a single bond; each R.sup.1 is independently a group -L.sup.1-R.sup.11; each L.sup.1 is a bond; each R.sup.11 is independently selected from the group consisting of: phenyl, imidazo[1,2-a]pyridinyl, and heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; wherein said phenyl, said imidazo[1,2-a]pyridinyl and said heteroaryl are each optionally substituted with one or more groups independently selected from the group consisting of 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 having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, and -L.sup.11-R.sup.13; each L.sup.11 is independently selected from the group consisting of 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 the group consisting of —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 the group consisting of aryl, heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, 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 the group consisting of 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 1 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 C.sub.3-C.sub.5 cycloalkyl; or R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl; 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 the group consisting of —OH and —O(C.sub.1-C.sub.4 alkyl); each R.sup.5 is independently a group -L.sup.5-R.sup.51; each L.sup.5 is independently selected from the group consisting of a bond and methylene; each R.sup.51 is independently selected from the group consisting of: phenyl; heteroaryl having 5 or 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.3-C.sub.7 cycloalkyl; heterocycloalkyl having 5, 6 or 7 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; —CN; C.sub.1-C.sub.4 alkyl; —NR.sup.52R.sup.52; —COOR.sup.52; and —CONR.sup.52R.sup.52; wherein said phenyl, said heteroaryl, said cycloalkyl, and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of 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 having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, and -L.sup.51-R.sup.53; each R.sup.52 is independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl; each L.sup.51 is independently selected from the group consisting of 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 the group consisting of —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 the group consisting of aryl, heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms, 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 the group consisting of 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 at least two of X.sub.1, X.sub.2 and X.sub.3 are each C, and the other one of X.sub.1, X.sub.2 and X.sub.3 is C or N.

3. The compound of claim 1, wherein X.sub.1, X.sub.2 and X.sub.3 are each C.

4. The compound of claim 1, wherein: n is 1; each L.sup.1 is a bond; and each R.sup.11 is independently selected from the group consisting of phenyl, pyridinyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, and imidazo[1,2-a]pyridinyl, wherein said phenyl, said pyridinyl, said pyrazolyl, said oxazolyl, said thiazolyl, said pyrimidinyl, said pyridazinyl, said pyrazinyl and said imidazo[1,2-a]pyridinyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —(C.sub.1-C.sub.4 alkylene)-OH, —(C.sub.1-C.sub.4 alkylene)-O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —OCO(C.sub.1-C.sub.4 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—CO—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-SO.sub.2—(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms.

5. The compound of claim 1, wherein n is 1, wherein R.sup.1 is attached to position 9 of the tricyclic moiety comprised in formula (I), as indicated in the following: ##STR00253## and wherein said R.sup.1 is selected from the group consisting of phenyl, pyridinyl, and imidazo[1,2-a]pyridinyl, wherein said phenyl, said pyridinyl and said imidazo[1,2-a]pyridinyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and —COOH.

6. The compound of claim 1, wherein R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl; or wherein R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a cyclopropyl.

7. The compound of claim 1, wherein R.sup.2 and R.sup.3 are not both hydrogen.

8. The compound of claim 1, wherein R.sup.4 is selected from the group consisting of methyl and methoxymethyl.

9. The compound of claim 1, wherein each R.sup.51 is independently selected from the group consisting of: phenyl; heteroaryl having 5 or 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.3-C.sub.7 cycloalkyl; heterocycloalkyl having 5, 6 or 7 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; —CN; C.sub.1-C.sub.4 alkyl; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); wherein said phenyl, said heteroaryl, said cycloalkyl and said heterocycloalkyl are each optionally substituted with one or more groups independently selected from the group consisting of halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —(C.sub.1-C.sub.4 alkylene)-OH, —(C.sub.1-C.sub.4 alkylene)-O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —OCO(C.sub.1-C.sub.4 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—CO—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-SO.sub.2—(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl having 5 to 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms.

10. The compound of claim 1, wherein: R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen and C.sub.1-C.sub.4 alkyl, wherein R.sup.2 and R.sup.3 are not both hydrogen, or R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a C3-C.sub.5 cycloalkyl; and R.sup.4 is C.sub.1-C.sub.4 alkyl, wherein said alkyl is optionally substituted with one group selected from the group consisting of —OH and —O(C.sub.1-C.sub.4 alkyl).

11. The compound of claim 1, wherein: R.sup.2 and R.sup.3 are each independently selected from the group consisting of hydrogen, methyl, and ethyl, wherein R.sup.2 and R.sup.3 are not both hydrogen, or R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a cyclopropyl; and R.sup.4 is methyl which is optionally substituted with —OCH.sub.3.

12. A compound selected from the group consisting of: 9-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methoxymethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-(methyl-d.sub.3)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,9-Dibromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-2-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-3-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-7-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-10-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-8-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-2-phenyl-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-6,6-spirocyclopropyl-5-methyl-2-phenyl-5,6-dihydro-3,5,10b-triaza-benzo[e]azulen-4-one; 8-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 7-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Bromo-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Bromo-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Bromo-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Bromo-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methoxymethyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-ethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-methylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3,5-dimethyl-1H-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-trifluoromethyl-1H-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-methyl-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-methyl-pyrazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoro-2-methylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-fluoropyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-trifluoromethylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-methylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3,4-dimethoxy-phenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-amino-5-trifluoromethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(imidazo[1,2-a]pyridin-6-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-morpholin-4-yl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-cyanophenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-(1H-tetrazol-5-yl)-phenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-pyrimidin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-methyl-oxazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-methylthiazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-acetonitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-acrylonitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-propionitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-chloropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-(Methyl-d3)-9-(6-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2,6-dimethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-methyl-pyrazin-2-yl)-5,6-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-methyl-pyrimidin-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-propylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-cyclopropylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-(Methyl-d3)-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2,4-dimethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-hydroxypyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(5-trifluoromethylpyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridazin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methoxycarbonylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 7-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 7-Fluoro-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Fluoro-5-Methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Fluoro-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-2-chloro-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-2-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-2-chloro-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-3-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 1-Bromo-5-methyl-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-1-(2-methyl-2H-pyrazol-3-yl)9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5,8-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Morpholin-4-yl-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5,7-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5,10-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Cyano-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-(2-Methyl-pyridin-3-yl)-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-pyridin-3-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzoic acid; 5-Methyl-2-phenyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-amino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2,6-dimethyl-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(5-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-trifluoromethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(4-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyrimidin-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-methyl-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2,6-dimethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-pyrazin-2-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-pyridazin-3-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(5-fluoro-pyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-methyl-2-phenyl-9-(6-ethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-dimethylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Dimethylamino-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-methoxy-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-cyano-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-methylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-dimethylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Morpholin-4-yl-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2,6-Dimethyl-pyridin-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,9-Diphenyl-5-methyl-2-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(4-Amino-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2,6-Dimethyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(6-Amino-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(4-Methoxy-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(3-Cyano-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(3-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(Oxazol-5-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzoic acid; 9-(1H-pyrazol-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(4-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(1H-pyrazol-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Cyano-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyrrolidin-1-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]imidazo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; N,N-dimethyl-3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide; N,N-dimethyl-3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide; 5-Methyl-2-(pyridine-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,5-Dimethyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(pyridine-4-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(1H-pyrazol-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(SH)-one; 5-Methyl-2-(3-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(4-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(4-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(3-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-cyano-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-dimethylamino-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-cyclopropyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-cyclopentyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(thiazol-2-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(thiazol-2-yl)-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-dimethylamino-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-fluorophenyl)-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methyl-2-phenyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-(6-Amino-pyridin-3-yl)-5-methyl-2-phenyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-2-phenyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Ethyl-9-(2-methylpyridin-3-yl)-2-phenyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(2-ethyl-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(6-methyl-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-(Methyl-d3)-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-bromo-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(3-cyanophenyl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(pyridazin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-(Methyl-d3)-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-bromo-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(pyridazin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(3-cyanophenyl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(oxazol-5-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(3H-imidazol-4-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(1H-imidazol-2-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-2-(1H-imidazol-2-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-(Methyl-d3)-9-(6-fluoro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-bromo-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-dimethylamino-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-chloro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-cyanophenyl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridazin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(cyclopentanecarbonyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-acetyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(cyclopentylmethyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-ethyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,5-Dimethyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,5-Dimethyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(morpholin-4-ylmethyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-difluoromethyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Hydroxymethyl-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Hydroxymethyl-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Hydroxymethyl-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Methoxymethyl-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Methoxymethyl-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Methoxymethyl-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methyl-1,2,3,3a-tetrahydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methylpyridin-3-yl)-1,2,3,3a-tetrahydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-4-one; 5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,4]diazepin-4-one; 9-Bromo-5,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-Bromo-5-methyl-6-ethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,4]diazepin-4-one; 5,6-Dimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-(6-Dimethylamino-pyridin-3-yl)-5,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 6-Ethyl-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5,6,6-Trimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-Chloro-5,6,6-trimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5,6,6-Trimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof.

13. A pharmaceutical composition comprising the compound as defined in claim 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable excipients.

Description

(1) The invention is also described by the following illustrative figures. The appended figures show:

(2) FIG. 1: Neuroprotective effects on cortical primary neurons were shown for a compound of formula (I) in an NMDA-induced neurotoxicity assay (see Example 225).

(3) FIG. 2: Neuroprotective effects on striatal primary neurons were shown for a compound of formula (I) in an NMDA-induced neurotoxicity assay (see Example 226).

(4) The present invention relates, in particular, to the following items: 1. A compound of the general formula (I):

(5) ##STR00023## wherein: X.sub.1, X.sub.2 and X.sub.3 are each independently C or N; each is independently a single bond or a double bond, wherein at least one of any two adjacent bonds is a single bond; Z is O, S or N(—R.sup.Z); 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; or R.sup.2 and R.sup.3 are each independently selected from hydrogen, halogen, C.sub.1-C.sub.10 haloalkyl, 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), —SH, —S(C.sub.1-C.sub.10 alkyl), —SO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—(C.sub.1-C.sub.10 alkyl), —CN, 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 one or both of R.sup.2 and R.sup.3 is/are 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; or R.sup.2 and R.sup.3 together form a divalent group selected from ═O, ═S, ═NH and ═N(C.sub.1-C.sub.10 alkyl); 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, for use as a medicament. 2. A compound of the general formula (I):

(6) ##STR00024## wherein: X.sub.1, X.sub.2 and X.sub.3 are each independently C or N; each is independently a single bond or a double bond, wherein at least one of any two adjacent bonds is a single bond; Z is O, S or N(—R.sup.Z); 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; or R.sup.2 and R.sup.3 are each independently selected from hydrogen, halogen, C.sub.1-C.sub.10 haloalkyl, 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), —SH, —S(C.sub.1-C.sub.10 alkyl), —SO—(C.sub.1-C.sub.10 alkyl), —SO.sub.2—(C.sub.1-C.sub.10 alkyl), —CN, 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 one or both of R.sup.2 and R.sup.3 is/are 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; or R.sup.2 and R.sup.3 together form a divalent group selected from ═O, ═S, ═NH and ═N(C.sub.1-C.sub.10 alkyl); 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; with the proviso that the following compounds are excluded from formula (I): 5-allyl-3,3a,5,6-tetrahydro-1H-benzo[f]pyrrolo-[1,2-a][1,4]diazepin-4(2H)-one; 5-butyl-3,3a,5,6-tetrahydro-1H-benzo[f]pyrrolo-[1,2-a][1,4]diazepin-4(2H)-one; 5-methyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5-methyl-5,6-dihydro-3,5,10b-triaza-benzo[e]azulen-4-one; 5-methyl-4-oxo-5,6-dihydro-4H-1,2,5,10b-tetraaza-benzo[e]azulene-3-carboxylic acid ethyl ester; 5-methyl-4-oxo-5,6-dihydro-4H-1,2,5,10b-tetraaza-benzo[e]azulene-3-carboxylic acid methyl ester; 5-methyl-5,6-dihydro-1,5,10b-triaza-benzo[e]azulen-4-one; 9-fluoro-5-methyl-5,6-dihydro-1,5,10b-triaza-benzo[e]azulen-4-one; 8-methoxy-5-methyl-5,6-dihydro-1,5,10b-triaza-benzo[e]azulen-4-one; 3-bromo-5-methyl-5,6-dihydro-1,5,10b-triaza-benzo[e]azulen-4-one; 5-(4-chloro-butyl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; and 5-(4-chloro-butyl)-benzo[f]pyrrolo[1,2-a][1,4]diazepine-4,6-dione. 3. The compound for use according to item 1 or the compound of item 2, wherein at least two of X.sub.1, X.sub.2 and X.sub.3 are each C, and the other one of X.sub.1, X.sub.2 and X.sub.3 is C or N. 4. The compound for use according to item 1 or 3 or the compound of item 2 or 3, wherein the fused 5-membered ring moiety containing X.sub.1, X.sub.2 and X.sub.3 is selected from:

(7) ##STR00025## 5. The compound for use according to item 1, 3 or 4 or the compound of any one of items 2 to 4, wherein the fused 5-membered ring moiety containing X.sub.1, X.sub.2 and X.sub.3 is:

(8) ##STR00026## 6. The compound for use according to any one of items 1 and 3 to 5 or the compound of any one of items 2 to 5, wherein Z is O. 7. The compound for use according to any one of items 1 and 3 to 6 or the compound of any one of items 2 to 6, wherein each L.sup.1 is independently selected from a bond and C.sub.1-C.sub.10 alkylene, wherein said alkylene is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —SH, and —S(C.sub.1-C.sub.4 alkyl), and further wherein one or two —CH.sub.2— units comprised in said alkylene is/are each optionally replaced by a group independently selected from —O—, —NH—, —N(C.sub.1-C.sub.4 alkyl)-, —CO—, and —SO.sub.2—. 8. The compound for use according to any one of items 1 and 3 to 7 or the compound of any one of items 2 to 7, wherein each L.sup.1 is independently selected from a bond and C.sub.1-C.sub.4 alkylene. 9. The compound for use according to any one of items 1 and 3 to 8 or the compound of any one of items 2 to 8, wherein each R.sup.11 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —OH, and —O(C.sub.1-C.sub.4 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.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —(C.sub.1-C.sub.4 alkylene)-OH, —(C.sub.1-C.sub.4 alkylene)-O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —OCO(C.sub.1-C.sub.4 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—CO—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-SO.sub.2—(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and further wherein, if R.sup.11 is C.sub.1-C.sub.4 alkyl, then said alkyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —OCO(C.sub.1-C.sub.4 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—CO—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-SO.sub.2—(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 10. The compound for use according to any one of items 1 and 3 to 9 or the compound of any one of items 2 to 9, wherein each R.sup.11 is independently selected from: phenyl; heteroaryl having 5 to 10 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.3-C.sub.7 cycloalkyl; heterocycloalkyl having 5, 6 or 7 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.5-C.sub.7 cycloalkenyl; and heterocycloalkenyl having 5, 6 or 7 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; wherein said phenyl, 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.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —(C.sub.1-C.sub.4 alkylene)-OH, —(C.sub.1-C.sub.4 alkylene)-O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 11. The compound for use according to any one of items 1 and 3 to 10 or the compound of any one of items 2 to 10, wherein each R.sup.11 is independently selected from phenyl, pyridinyl, and imidazo[1,2-a]pyridinyl, wherein said phenyl, said pyridinyl and said imidazo[1,2-a]pyridinyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and —COOH. 12. The compound for use according to any one of items 1 and 3 to 11 or the compound of any one of items 2 to 11, wherein each R.sup.11 is independently pyridinyl, wherein said pyridinyl is optionally substituted with one or two groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and —COOH. 13. The compound for use according to any one of items 1 and 3 to 12 or the compound of any one of items 2 to 12, wherein n is 0, 1 or 2. 14. The compound for use according to any one of items 1 and 3 to 13 or the compound of any one of items 2 to 13, wherein n is 1. 15. The compound for use according to item 14 or the compound of item 14, wherein R.sup.1 is attached to the tricyclic moiety comprised in formula (I) at position 8 or 9, preferably at position 9, wherein the numbering is as indicated in the following:

(9) ##STR00027## 16. The compound for use according to any one of items 1 and 3 to 6 or the compound of any one of items 2 to 6, wherein n is 1, wherein R.sup.1 is attached to position 9 of the tricyclic moiety comprised in formula (I), and wherein R.sup.1 is selected from: phenyl; heteroaryl having 5 to 10 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.3-C.sub.7 cycloalkyl; heterocycloalkyl having 5, 6 or 7 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.5-C.sub.7 cycloalkenyl; and heterocycloalkenyl having 5, 6 or 7 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; wherein said phenyl, 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.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —(C.sub.1-C.sub.4 alkylene)-OH, —(C.sub.1-C.sub.4 alkylene)-O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 17. The compound for use according to item 16 or the compound of item 16, wherein R.sup.1 is selected from phenyl, pyridinyl, and imidazo[1,2-a]pyridinyl, wherein said phenyl, said pyridinyl and said imidazo[1,2-a]pyridinyl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and —COOH. 18. The compound for use according to item 16 or 17 or the compound of item 16 or 17, wherein R.sup.1 is pyridinyl, and wherein said pyridinyl is optionally substituted with one or two groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), and —COOH. 19. The compound for use according to any one of items 16 to 18 or the compound of any one of items 16 to 18, wherein R.sup.1 is pyridinyl which is substituted with one methyl or fluoro group. 20. The compound for use according to any one of items 1 and 3 to 19 or the compound of any one of items 2 to 19, 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, or R.sup.2 and R.sup.3 are each independently selected from hydrogen, halogen, C.sub.1-C.sub.4 alkyl, —OH, and —O(C.sub.1-C.sub.4 alkyl). 21. The compound for use according to any one of items 1 and 3 to 20 or the compound of any one of items 2 to 20, 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. 22. The compound for use according to any one of items 1 and 3 to 21 or the compound of any one of items 2 to 21, wherein R.sup.2 and R.sup.3 are mutually linked to form, together with the carbon atom that they are attached to, a cyclopropyl. 23. The compound for use according to any one of items 1 and 3 to 22 or the compound of any one of items 2 to 22, 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). 24. The compound for use according to any one of items 1 and 3 to 23 or the compound of any one of items 2 to 23, wherein R.sup.4 is methyl. 25. The compound for use according to any one of items 1 and 3 to 24 or the compound of any one of items 2 to 24, wherein each L.sup.5 is independently selected from a bond and C.sub.1-C.sub.10 alkylene, wherein said alkylene is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —SH, and —S(C.sub.1-C.sub.4 alkyl), and further wherein one or two —CH.sub.2— units comprised in said alkylene is/are each optionally replaced by a group independently selected from —O—, —NH—, —N(C.sub.1-C.sub.4 alkyl)-, —CO—, and —SO.sub.2—. 26. The compound for use according to any one of items 1 and 3 to 25 or the compound of any one of items 2 to 25, wherein each L.sup.5 is independently selected from a bond and C.sub.1-C.sub.4 alkylene. 27. The compound for use according to any one of items 1 and 3 to 26 or the compound of any one of items 2 to 26, wherein each R.sup.51 is independently selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —OH, and —O(C.sub.1-C.sub.4 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.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —(C.sub.1-C.sub.4 alkylene)-OH, —(C.sub.1-C.sub.4 alkylene)-O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —OCO(C.sub.1-C.sub.4 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—CO—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-SO.sub.2—(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and further wherein, if R.sup.51 is C.sub.1-C.sub.4 alkyl, then said alkyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —CHO, —CO(C.sub.1-C.sub.4 alkyl), —COOH, tetrazolyl, —COO(C.sub.1-C.sub.4 alkyl), —OCO(C.sub.1-C.sub.4 alkyl), —CO—NH.sub.2, —CO—NH(C.sub.1-C.sub.4 alkyl), —CO—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—CO—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-CO—(C.sub.1-C.sub.4 alkyl), —SO.sub.2—NH.sub.2, —SO.sub.2—NH(C.sub.1-C.sub.4 alkyl), —SO.sub.2—N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), —NH—SO.sub.2—(C.sub.1-C.sub.4 alkyl), —N(C.sub.1-C.sub.4 alkyl)-SO.sub.2—(C.sub.1-C.sub.4 alkyl), cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 28. The compound for use according to any one of items 1 and 3 to 27 or the compound of any one of items 2 to 27, wherein each R.sup.51 is independently selected from: phenyl; heteroaryl having 5 or 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); —OH; and —O(C.sub.1-C.sub.4 alkyl); wherein said phenyl and said heteroaryl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); and further wherein, if R.sup.51 is C.sub.1-C.sub.4 alkyl, then said alkyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl). 29. The compound for use according to any one of items 1 and 3 to 28 or the compound of any one of items 2 to 28, wherein R.sup.51 is oxadiazolyl, wherein said oxadiazolyl is optionally substituted with one group selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl). 30. The compound for use according to any one of items 1 and 3 to 24 or the compound of any one of items 2 to 24, wherein each L.sup.5 is independently a bond or C.sub.1-C.sub.4 alkylene, and wherein each R.sup.51 is independently selected from: phenyl; heteroaryl having 5 or 6 ring members, wherein 1, 2 or 3 ring members are heteroatoms selected independently from O, S and N, and the remaining ring members are carbon atoms; C.sub.1-C.sub.4 haloalkyl; C.sub.1-C.sub.4 alkyl; —NH.sub.2; —NH(C.sub.1-C.sub.4 alkyl); —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); —OH; and —O(C.sub.1-C.sub.4 alkyl); wherein said phenyl and said heteroaryl are each optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl); and further wherein, if R.sup.51 is C.sub.1-C.sub.4 alkyl, then said alkyl is optionally substituted with one or more groups independently selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl). 31. The compound for use according to any one of items 1, 3 to 24 and 30 or the compound of any one of items 2 to 24 and 30, wherein L.sup.5 is a bond, and R.sup.51 is oxadiazolyl, wherein said oxadiazolyl is optionally substituted with one group selected from halogen, C.sub.1-C.sub.4 haloalkyl, —CN, C.sub.1-C.sub.4 alkyl, —OH, —O(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NH(C.sub.1-C.sub.4 alkyl), and —N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl). 32. The compound for use according to any one of items 1 and 3 to 31 or the compound of any one of items 2 to 31, wherein m is 0 or 1. 33. The compound for use according to item 32 or the compound of item 32, wherein the group R.sup.5, if present, is attached to the ring atom X.sub.2 depicted in formula (I). 34. The compound for use according to any one of items 1 and 3 to 33 or the compound of any one of items 2 to 33, wherein m is 0. 35. The compound for use according to item 1 or the compound of item 2, wherein said compound is selected from: 9-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methoxymethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-(methyl-d.sub.3)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,9-Dibromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-2-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-3-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-7-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-10-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-8-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-2-phenyl-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-6,6-spirocyclopropyl-5-methyl-2-phenyl-5,6-dihydro-3,5,10b-triaza-benzo[e]azulen-4-one; 8-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 7-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Bromo-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Bromo-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Bromo-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Bromo-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methoxymethyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-ethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-methylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3,5-dimethyl-1H-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-trifluoromethyl-1H-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-methyl-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-methyl-pyrazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoro-2-methylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-fluoropyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-trifluoromethylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-methylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3,4-dimethoxy-phenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-amino-5-trifluoromethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(imidazo[1,2-a]pyridin-6-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-morpholin-4-yl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-cyanophenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-(1H-tetrazol-5-yl)-phenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-pyrimidin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-methyl-oxazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-methylthiazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-acetonitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-acrylonitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-propionitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-chloropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-(Methyl-d.sub.3)-9-(6-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2,6-dimethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-methyl-pyrazin-2-yl)-5,6-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(4-methyl-pyrimidin-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-propylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-cyclopropylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-(Methyl-d.sub.3)-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2,4-dimethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-hydroxypyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(5-trifluoromethylpyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridazin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methoxycarbonylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 7-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 7-Fluoro-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Fluoro-5-Methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Fluoro-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-2-chloro-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-2-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-2-chloro-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-3-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 1-Bromo-5-methyl-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-1-(2-methyl-2H-pyrazol-3-yl)9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5,8-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Morpholin-4-yl-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5,7-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5,10-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-Cyano-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 10-(2-Methyl-pyridin-3-yl)-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-pyridin-3-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzoic acid; 5-Methyl-2-phenyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-amino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2,6-dimethyl-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(5-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-trifluoromethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(4-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyrimidin-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-methyl-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2,6-dimethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-pyrazin-2-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-pyridazin-3-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(5-fluoro-pyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-methyl-2-phenyl-9-(6-ethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-dimethylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Dimethylamino-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-methoxy-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-cyano-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(6-methylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(2-dimethylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 8-Morpholin-4-yl-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2,6-Dimethyl-pyridin-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,9-Diphenyl-5-methyl-2-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(4-Amino-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2,6-Dimethyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(6-Amino-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(4-Methoxy-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(3-Cyano-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(3-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(Oxazol-5-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzoic acid; 9-(1H-pyrazol-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(4-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(1H-pyrazol-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Cyano-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-phenyl-9-(pyrrolidin-1-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-(2-Methyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]imidazo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; N,N-dimethyl-3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide; N,N-dimethyl-3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide; 5-Methyl-2-(pyridine-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,5-Dimethyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(pyridine-4-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(1H-pyrazol-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(3-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(4-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(4-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(3-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-cyano-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-dimethylamino-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-cyclopropyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-cyclopentyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(thiazol-2-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(thiazol-2-yl)-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-dimethylamino-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-fluorophenyl)-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methyl-2-phenyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-(6-Amino-pyridin-3-yl)-5-methyl-2-phenyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-2-phenyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Ethyl-9-(2-methylpyridin-3-yl)-2-phenyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(2-ethyl-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(6-methyl-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-(Methyl-d.sub.3)-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-bromo-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(3-cyanophenyl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(pyridazin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde; 5-Methyl-9-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-(Methyl-d.sub.3)-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-bromo-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(pyridazin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(3-cyanophenyl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(oxazol-5-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(3H-imidazol-4-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(1H-imidazol-2-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-2-(1H-imidazol-2-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-fluoro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-(Methyl-d.sub.3)-9-(6-fluoro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-bromo-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-dimethylamino-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(6-chloro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(3-cyanophenyl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(pyridazin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(cyclopentanecarbonyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-acetyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(cyclopentylmethyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-ethyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,5-Dimethyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2,5-Dimethyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(morpholin-4-ylmethyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methyl-pyridin-3-yl)-2-difluoromethyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Hydroxymethyl-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Hydroxymethyl-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Hydroxymethyl-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Methoxymethyl-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Methoxymethyl-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 2-Methoxymethyl-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 9-Bromo-5-methyl-1,2,3,3a-tetrahydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-(2-methylpyridin-3-yl)-1,2,3,3a-tetrahydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one; 5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-4-one; 5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,4]diazepin-4-one; 9-Bromo-5,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-Bromo-5-methyl-6-ethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one; 5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,4]diazepin-4-one; 5,6-Dimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-(6-Dimethylamino-pyridin-3-yl)-5,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 6-Ethyl-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5,6,6-Trimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 9-Chloro-5,6,6-trimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; 5,6,6-Trimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one; and pharmaceutically acceptable salts, solvates and prodrugs thereof. 36. A pharmaceutical composition comprising a compound as defined in any one of items 1 to 35 and optionally a pharmaceutically acceptable excipient. 37. A compound as defined in any one of items 1 to 35 or the pharmaceutical composition of item 36 for use in the treatment and/or prophylaxis of a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling. 38. Use of a compound as defined in any one of items 1 to 35 for the preparation of a medicament for the treatment and/or prophylaxis of a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling. 39. A method of treating and/or preventing a condition associated with altered glutamatergic signalling and/or functions, and/or a condition which can be affected by alteration of glutamate level or signalling, the method comprising the administration of a compound as defined in any one of items 1 to 35 or the pharmaceutical composition of item 36 to a subject in need of such treatment or prevention. 40. The compound for use according to item 37 or the pharmaceutical composition for use according to item 37 or the use of item 38 or the method of item 39, wherein the condition to be treated or prevented is selected from: epilepsy; dementias; parkinsonism and movement disorders; motor neuron disease; amyotrophic lateral sclerosis; neurodegenerative and/or hereditary disorders of the nervous system; disorders of the peripheral nervous system; multiple sclerosis and other demyelinating diseases of the nervous system; infantile cerebral palsy; hemiplegia and hemiparesis, and other paralytic syndromes; cerebrovascular disorders; migraine; headache; myoneural disorders; disorders of the eye and visual pathways; intracranial trauma/injury; trauma/injury to nerves and spinal cord; poisoning; neurological and psychiatric adverse effects of drugs, medicinal and biological substances; disturbance of sphincter control and sexual function; mental retardation, learning disorders, motor skill disorders, communication disorders, pervasive developmental disorders, attention deficit and disruptive behaviour disorders, feeding and eating disorders, TIC disorders, and elimination disorders; delirium and other cognitive disorders; substance related disorders; schizophrenia and other psychotic disorders; mood disorders; anxiety disorders; eating disorders; sleep disorders; medication-induced movement disorders; endocrine and metabolic diseases; acute and chronic pain; nausea and vomiting; irritable bowel syndrome; and cancers. 41. A compound as defined in any one of items 1 to 35 or the pharmaceutical composition of item 36 for use in the treatment and/or prophylaxis of Parkinson's disease. 42. Use of a compound as defined in any one of items 1 to 35 for the preparation of a medicament for the treatment and/or prophylaxis of Parkinson's disease. 43. A method of treating and/or preventing Parkinson's disease in a subject, the method comprising the administration of a compound as defined in any one of items 1 to 35 or the pharmaceutical composition of item 36 to a subject in need thereof. 44. The method of item 39, 40 or 43, wherein said subject is a human. 45. In vitro use of a compound as defined in any one of items 1 to 35 as a positive allosteric modulator of mGluR3. 46. A method for identifying an agent that binds to metabotropic glutamate receptor 3 (mGluR3), comprising the following steps: (a) contacting mGluR3 with the compound of any one of items 1 to 35, wherein said compound is radio-labeled or fluorescence-labeled, under conditions that permit binding of the compound to mGluR3, thereby generating bound, labeled compound; (b) detecting a signal that corresponds to the amount of bound, labeled compound in the absence of test agent; (c) contacting the bound, labeled compound with a test agent; (d) detecting a signal that corresponds to the amount of bound labeled compound in the presence of test agent; and (e) comparing the signal detected in step (d) to the signal detected in step (b) to determine whether the test agent binds to mGluR3.

(10) The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

EXAMPLES

(11) 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.

(12) 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.

(13) Experimental:

(14) Experimental Section.

(15) 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), td (triplet-doublet), q (quartet), quint (quintuplet), sex (sextuplet), sept (septuplet), m (multiplet), b (broad). 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.

(16) Melting Points are measure on a Barnstead Electrothermal 9100 and are not corrected.

(17) General Procedure I: Formation of Intermediate C, C′ and C″ from the Corresponding Fluoro-Benzonitrile A and Methyl Ester B, B′ and B″ (Scheme 1 and 2).

(18) Method (i): Under Oil Bath Heating:

(19) At 0° C., to a suspension of sodium hydride (60% dispersion in oil, 1.5 equiv.) in DMF (0.80 mol.Math.L.sup.−1), a solution of methyl ester B, B′ or B″ (1.0 equiv.) in DMF (0.65 mol.Math.L.sup.−1) was slowly added, followed after 15 minutes by a solution of fluorobenzonitrile A (1.1 equiv.) in DMF (0.65 mol.Math.L.sup.−1).

(20) 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.

(21) Method (ii): Under Microwave Irradiation:

(22) Under inert atmosphere, a mixture of fluorobenzonitrile A (1.0 equiv.), methyl ester B, B′ or B″ (1.0 equiv.) and cesium carbonate (2.5 equiv.) in DMF (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 then 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-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(23) Compound 1 was obtained according to general procedure I(i), starting from 4-bromo-2-fluorobenzonitrile and methyl-2-pyrrole carboxylate. It was isolated as a white solid in 80% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.91 (m, 3H, Ar); 7.38 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.11 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.66 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]—OCH.sub.3+H).sup.+=275.

Compound 2: 4-Bromo-1-(5-bromo-2-cyano-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(24) Compound 2 was obtained according to general procedure I(ii), starting from 4-bromo-2-fluorobenzonitrile and 4-Bromo-1H-pyrrole-2-carboxylic acid methyl ester. It was isolated as a white solid in 72% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.02 (d, J 1.6 Hz, 1H, Ar); 7.96 (d, J 8.2 Hz, 1H, Ar); 7.93 (dd, J 8.2, 1.6 Hz, 1H, Ar); 7.65 (d, J 1.9 Hz, 1H, Ar); 7.18 (d, J 1.9 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br][.sup.80Br]+H).sup.+=385.

Compound 3: 4-Chloro-1-(5-bromo-2-cyano-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(25) Compound 3 was obtained according to general procedure I(ii), starting from 4-bromo-2-fluorobenzonitrile and 4-chloro-1H-pyrrole-2-carboxylic acid methyl ester. It was isolated as a beige solid in 46% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.03 (d, J 1.6 Hz, 1H, Ar); 7.96 (d, J 8.2 Hz, 1H, Ar); 7.93 (dd, J 8.2, 1.6 Hz, 1H, Ar); 7.64 (d, J 1.9 Hz, 1H, Ar); 7.14 (d, J 1.9 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+=339.

Compound 4: 3-Chloro-1-(5-bromo-2-cyano-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(26) Compound 4 was obtained according to general procedure I(ii), starting from 4-bromo-2-fluorobenzonitrile and 3-chloro-1H-pyrrole-2-carboxylic acid methyl ester. It was isolated as a white solid in 43% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.00 (d, J 1.6 Hz, 1H, Ar); 7.95 (d, J 8.2 Hz, 1H, Ar); 7.92 (dd, J 8.2, 1.6 Hz, 1H, Ar); 7.45 (d, J 3.1 Hz, 1H, Ar); 6.59 (d, J 3.1 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+=339.

Compound 5: 1-(5-Bromo-2-cyano-3-fluorophenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(27) Compound 5 was obtained according to general procedure I(i), starting from 4-bromo-2,6-difluorobenzonitrile and methyl-2-pyrrole carboxylate. It was isolated as a white solid in 72% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.13 (dd, J 8.8, 1.6 Hz, 1H, Ar); 7.87 (m, 1H, Ar); 7.41 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.13 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.45 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.68 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=323.

Compound 6: 1-(5-Bromo-2-cyano-6-fluorophenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(28) Compound 6 was obtained according to general procedure I(i), starting from 4-bromo-2,3-difluorobenzonitrile and methyl-2-pyrrole carboxylate. It was isolated as a yellow oil in 24% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.09 (dd, J 8.5, 6.6 Hz, 1H, Ar); 7.85 (dd, J 8.5, 1.5 Hz, 1H, Ar); 7.47 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.16 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.49 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.68 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=323.

Compound 7: 1-(5-Bromo-2-cyano-4-fluorophenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(29) Compound 7 was obtained according to general procedure I(i), starting from 4-bromo-2,5-difluorobenzonitrile and methyl-2-pyrrole carboxylate. It was isolated as a white solid in 47% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.22 (d, J 8.3 Hz, 1H, Ar); 8.14 (d, J 6.3 Hz, 1H, Ar); 7.37 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.11 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=323.

Compound 8: 1-(5-Bromo-2-cyano-phenyl)-4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester

(30) Compound 8 was obtained according to general procedure I(ii), starting from 4-bromo-2-fluorobenzonitrile and 4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester. It was isolated as a white solid in 70% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.06 (d, J 1.7 Hz, 1H, Ar); 7.97 (d, J 8.4 Hz, 1H, Ar); 7.93 (m, 2H, Ar); 7.70 (m, 2H, Ar); 7.55 (d, J 1.9 Hz, 1H, Ar); 7.39 (m, 2H, Ar); 7.24 (m, 1H, Ar); 3.70 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]—OCH.sub.3+H).sup.+=349.

Compound 9: 2-(5-Bromo-2-cyano-phenyl)-5-phenyl-2H-pyrazole-3-carboxylic acid methyl ester a and its undesired isomer b

(31) ##STR00028##

(32) Compound 9 was obtained according to general procedure I(ii), starting from 4-bromo-2-fluorobenzonitrile and methyl 3-phenyl-1H-pyrazole-5-carboxylate. It was isolated as a white solid in 29% yield as a 1:1 mixture of isomers a and b. The mixture was taken to the next step without separation. M/Z (M[.sup.79Br]+H).sup.+=382.0.

Compound 10: 1-(5-Bromo-2-cyano-phenyl)-4-phenyl-1H-imidazole-2-carboxylic acid ethyl ester

(33) Compound 10 was obtained according to general procedure I(ii), starting from 4-bromo-2-fluorobenzonitrile and 4-phenyl-1H-imidazole-2-carboxylic acid ethyl ester. It was isolated as a white solid in 81% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.33 (s, 1H, Ar); 8.23 (d, J 1.7 Hz, 1H, Ar); 8.06 (d, J 8.3 Hz, 1H, Ar); 8.01 (dd, J 8.3, 1.7 Hz, 1H, Ar); 7.89 (m, 2H, Ar); 7.46 (m, 2H, Ar); 7.34 (m, 1H, Ar); 4.24 (q, J 7.0 Hz, 2H, CH.sub.2—CH.sub.3); 1.19 (t, J 7.0 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=396.0.

Compound 11: 1-(4-Bromo-2-cyano-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(34) Compound 11 was obtained according to general procedure I(i), starting from 5-bromo-2-fluorobenzonitrile and methyl-2-pyrrole carboxylate. It was isolated as a white solid in 75% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.33 (d, J 2.2 Hz, 1H, Ar); 8.03 (dd, J 8.4, 2.2 Hz, 1H, Ar); 7.54 (d, J 8.4 Hz, 1H, Ar); 7.36 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.12 (dd, J 3.9, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.9, 2.8 Hz, 1H, Ar); 3.66 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]—OCH.sub.3+H).sup.+=275.

Compound 12: 1-(3-Bromo-2-cyano-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(35) Compound 12 was obtained according to general procedure I(i), starting from 6-bromo-2-fluorobenzonitrile and methyl-2-pyrrole carboxylate. It was isolated as a beige solid in 81% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.99 (dd, J 8.2, 1.0 Hz, 1H, Ar); 7.75 (t, J 8.2 Hz, 1H, Ar); 7.61 (dd, J 8.2, 1.0 Hz, 1H, Ar); 7.39 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.12 (dd, J 3.9, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.9, 2.8 Hz, 1H, Ar); 3.66 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=305.

Compound 13: 1-(6-Bromo-2-cyano-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester

(36) Compound 13 was obtained according to general procedure I(i), starting from 3-bromo-2-fluorobenzonitrile and methyl-2-pyrrole carboxylate. It was isolated as a beige solid in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.13 (dd, J 8.2, 1.3 Hz, 1H, Ar); 7.04 (dd, J 8.2, 1.3 Hz, 1H, Ar); 7.61 (t, J 8.2 Hz, 1H, Ar); 7.32 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.11 (dd, J 3.9, 1.8 Hz, 1H, Ar); 6.47 (dd, J 3.9, 2.8 Hz, 1H, Ar); 3.64 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=305.

Compound 14: 1-(4-Bromo-2-cyano-phenyl)-4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester

(37) Compound 14 was obtained according to general procedure I(ii), starting from 5-bromo-2-fluorobenzonitrile and 4-phenyl-1H-pyrrole-2-carboxylic acid methyl ester. It was isolated as a beige solid in 64% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.37 (d, J 2.2 Hz, 1H, Ar); 8.08 (d, J 8.5, 2.2 Hz, 1H, Ar); 7.89 (d, J 2.0 Hz, 1H, Ar); 7.70 (m, 2H, Ar); 7.65 (d, J 8.5 Hz, 1H, Ar); 7.56 (d, J 2.0 Hz, 1H, Ar); 7.39 (m, 2H, Ar); 7.25 (m, 1H, Ar); 3.70 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=381.1.

(38) General Procedure II: Formation of Benzodiazepinone D, D′, D″, Di from Intermediate C, C′, C″, Ci (Scheme 1, 2 and 4).

(39) Under inert and anhydrous conditions, at room temperature, ethylmagnesium bromide (1M solution in THF, 2.0 equiv.) was added dropwise to a solution of intermediate C, C′, C″, Ci (1.0 equiv.) and titanium isopropoxide (1.0 equiv.) in CH.sub.2Cl.sub.2 (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. more of ethylmagnesium bromide (1M solution in THF) was added and the reaction mixture further stirred for 1 hour at room temperature. After cooling at 0° C., the reaction mixture was hydrolysed with HCl (1N in water) 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) to afford the product.

Compound 15: 9-Bromo-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(40) Compound 15 was obtained according to general procedure II, starting from compound 1. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 15 was isolated as a brown solid in 62% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.62 (s, 1H, NH); 7.76 (d, J 1.9 Hz, 1H, Ar); 7.58 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.51 (dd, J 8.2, 1.9 Hz, 1H, Ar); 7.38 (d, J 8.2 Hz, 1H, Ar); 6.90 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.50 (m, 1H, cyclopropyl); 1.20 (m, 1H, cyclopropyl); 0.79 (m, 1H, cyclopropyl); 0.47 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=303.

Compound 16: 2,9-Dibromo-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(41) Compound 16 was obtained according to general procedure II, starting from compound 2. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 16 was isolated as a white solid in 49% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (s, 1H, NH); 7.82 (d, J 1.9 Hz, 1H, Ar); 7.80 (d, J 1.9 Hz, 1H, Ar); 7.55 (dd, J 8.1, 1.9 Hz, 1H, Ar); 7.39 (d, J 8.1 Hz, 1H, Ar); 6.91 (d, J 1.9 Hz, 1H, Ar); 1.53 (m, 1H, cyclopropyl); 1.22 (m, 1H, cyclopropyl); 0.85 (m, 1H, cyclopropyl); 0.51 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br][.sup.81Br]+H).sup.+=383.

Compound 17: 9-Bromo-2-chloro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(42) Compound 17 was obtained according to general procedure II, starting from compound 3, as a white solid in 57% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (s, 1H, NH); 7.82 (d, J 1.9 Hz, 1H, Ar); 7.78 (d, J 2.0 Hz, 1H, Ar); 7.54 (dd, J 8.1, 1.9 Hz, 1H, Ar); 7.38 (d, J 8.1 Hz, 1H, Ar); 6.86 (d, J 2.0 Hz, 1H, Ar); 1.52 (m, 1H, cyclopropyl); 1.21 (m, 1H, cyclopropyl); 0.85 (m, 1H, cyclopropyl); 0.51 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+=337.

Compound 18: 9-Bromo-3-chloro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(43) Compound 18 was obtained according to general procedure II, starting from compound 4. Ethylmagnesium bromide (1M solution in THF, 2.0 equiv.) was added 2 times more, each time after 1 hour stirring in order to have a complete conversion. Compound 18 was isolated as a beige solid in 62% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.73 (s, 1H, NH); 7.70 (d, J 2.0 Hz, 1H, Ar); 7.46 (m, 2H, Ar); 7.28 (d, J 8.2 Hz, 1H, Ar); 6.43 (d, J 3.1 Hz, 1H, Ar); 1.43 (m, 1H, cyclopropyl); 1.09 (m, 1H, cyclopropyl); 0.75 (m, 1H, cyclopropyl); 0.42 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+=337.

Compound 19: 9-Bromo-7-fluoro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(44) Compound 19 was obtained according to general procedure II, starting from compound 5. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 2.0 equiv.). Compound 19 was isolated as a brown solid in 42% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (s, 1H, NH); 7.64 (m, 1H, Ar); 7.61 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.55 (dd, J 9.8, 1.9 Hz, 1H, Ar); 7.38 (d, J 8.2 Hz, 1H, Ar); 6.90 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.51 (m, 1H, cyclopropyl); 1.40 (m, 1H, cyclopropyl); 0.71 (m, 1H, cyclopropyl); 0.51 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=321.

Compound 20: 9-Bromo-10-fluoro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(45) Compound 20 was obtained according to general procedure II, starting from compound 6. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 2.0 equiv.). Compound 20 was isolated as a brown solid in 57% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (s, 1H, NH); 7.67 (dd, J 8.5, 6.5 Hz, 1H, Ar); 7.44 (m, 1H, Ar); 7.25 (dd, J 8.5, 1.5 Hz, 1H, Ar); 6.86 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.50 (m, 1H, cyclopropyl); 1.21 (m, 1H, cyclopropyl); 0.76 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=321.

Compound 21: 9-Bromo-8-fluoro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(46) Compound 21 was obtained according to general procedure II, starting from compound 7. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.5 equiv.). Compound 21 was isolated as a beige solid in 41% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.63 (s, 1H, NH); 7.90 (d, J 6.3 Hz, 1H, Ar); 7.55 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.49 (d, J 8.8 Hz, 1H, Ar); 6.88 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.58 (m, 1H, cyclopropyl); 1.21 (m, 1H, cyclopropyl); 0.79 (m, 1H, cyclopropyl); 0.53 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=321.

Compound 22: 9-Bromo-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(47) Compound 22 was obtained according to general procedure II, starting from compound 8. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 22 was isolated as a white solid in 64% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.70 (s, 1H, NH); 8.12 (d, J 2.0 Hz, 1H, Ar); 7.93 (d, J 1.9 Hz, 1H, Ar); 7.78 (m, 2H, Ar); 7.54 (dd, J 8.1, 1.9 Hz, 1H, Ar); 7.40 (m, 3H, Ar); 7.33 (d, J 2.0 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 1.54 (m, 1H, cyclopropyl); 1.24 (m, 1H, cyclopropyl); 0.88 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=379.

Compound 23: 9-bromo-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(48) Compound 23 was obtained according to general procedure II, starting from compound 9 (mixture of isomers). The reaction mixture was stirred for 16 hours at room temperature before addition of 2.0 more equiv. of ethylmagnesium bromide (1M solution in THF) in order to complete the reaction. Compound 23 was isolated, as a white solid in 53% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.20 (s, 1H, NH); 8.05 (m, 3H, Ar); 7.61 (dd, J 8.2, 2.0 Hz, 1H, Ar); 7.58 (s, 1H, Ar); 7.52-7.40 (m, 4H, Ar); 1.62 (m, 1H, cyclopropyl); 1.24 (m, 1H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.61 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=380.0.

Compound 24: 9-bromo-2-phenyl-spiro[benzo[f]imidazo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(49) Compound 24 was obtained according to general procedure II, starting from compound 10. The reaction mixture was stirred for 16 hours at room temperature. Compound 24 was isolated as a white solid in 14% yield. M/Z (M[.sup.79Br]+H).sup.+=380.0.

Compound 25: 8-Bromo-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(50) Compound 25 was obtained according to general procedure II, starting from compound 11. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 25 was isolated as a beige solid in 60% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.62 (s, 1H, NH); 7.65 (dd, J 8.4, 2.4 Hz, 1H, Ar); 7.60 (d, J 2.4 Hz, 1H, Ar); 7.49 (m, 2H, Ar); 6.90 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.62 (m, 1H, cyclopropyl); 1.22 (m, 1H, cyclopropyl); 0.80 (m, 1H, cyclopropyl); 0.50 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=303.

Compound 26: 7-Bromo-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(51) Compound 26 was obtained according to general procedure II, starting from compound 12. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 26 was isolated as a brown solid in 25% yield. M/Z (M[.sup.79Br]+H).sup.+=303.

Compound 27: 10-Bromo-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(52) Compound 27 was obtained according to general procedure II, starting from compound 13. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 27 was isolated as a yellow solid in 61% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.65 (s, 1H, NH); 7.78 (dd, J 8.2, 1.3 Hz, 1H, Ar); 7.45 (dd, J 8.2, 1.3 Hz, 1H, Ar); 7.42 (dd, J 2.8, 1.8 Hz, 1H, Ar); 729 (t, J 8.2 Hz, 1H, Ar); 6.77 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.36 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.48 (m, 1H, cyclopropyl); 1.17 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl); 0.45 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=303.

Compound 28: 8-Bromo-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(53) Compound 28 was obtained according to general procedure II, starting from compound 14. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.5 equiv.). Compound 28 was isolated as a brown solid in 60% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.71 (s, 1H, NH); 8.02 (d, J 2.0 Hz, 1H, Ar); 7.76 (m, 2H, Ar); 7.70 (dd, J 8.4, 2.2 Hz, 1H, Ar); 7.63 (m, 2H, Ar); 7.40 (m, 2H, Ar); 7.33 (d, J 2.0 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 1.64 (m, 1H, cyclopropyl); 1.23 (m, 1H, cyclopropyl); 0.88 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=379.

(54) General Procedure III: Formation of N-Substituted Benzodiazepinone F, F′, F″ and Fi from Benzodiazepinone D, D′, D″ and Di with Electrophile E (Scheme 1, 2, 3 and 4).

(55) Under anhydrous conditions, to a solution of benzodiazepinone D, D′, D″ or Di (1.0 equiv.) in DMF (c=0.1 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 the electrophile E (2.0 equiv.) was added. The ice bath was removed, and the reaction mixture was stirred at room temperature. When the reaction is completed, the mixture was hydrolysed with an aqueous HCl solution (1N) and the product was collected by filtration or extracted with EtOAc. When the product was extracted, 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

9-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(56) ##STR00029##

(57) Example 1 was obtained according to general procedure III, starting from compound 15 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by flash column chromatography on silica gel (MeOH in dichloromethane, 0% to 5%) afforded the product as a beige solid in 80% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.78 (d, J 1.9 Hz 1H, Ar); 7.53 (m, 2H, Ar); 7.45 (d, J 8.2 Hz, 1H, Ar); 6.85 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.40 (t, J 3.0 Hz, 1H, Ar); 2.89 (s, 3H, CH.sub.3); 1.43 (m, 2H, cyclopropyl); 0.88 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=317.

Example 2

9-Bromo-5-methoxymethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(58) ##STR00030##

(59) Example 2 was obtained according to general procedure III, starting from compound 15 in presence of chloromethyl methyl ether. The reaction mixture was stirred at room temperature for 1 hour. Purification by filtration after hydrolysis afforded the product as a beige solid in 70% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.79 (d, J 1.8 Hz 1H, Ar); 7.60 (dd, J 2.9, 1.8 Hz, 1H, Ar); 7.52 (dd, J 8.0, 1.8 Hz, 1H, Ar); 7.44 (d, J 8.0 Hz, 1H, Ar); 6.96 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.45 (dd, J 3.7, 2.9 Hz, 1H, Ar); 4.98 (d, J 10.1 Hz, 1H, CH); 4.66 (d, J 10.1 Hz, 1H, CH); 2.93 (s, 3H, CH.sub.3); 1.66 (m, 1H, cyclopropyl); 1.48 (m, 1H, cyclopropyl); 0.86 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=347.

Example 3

9-Bromo-5-(methyl-d.SUB.3.)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(60) ##STR00031##

(61) Example 3 was obtained according to general procedure III, starting from compound 15 in presence of iodomethane-d.sub.3. The reaction mixture was stirred at room temperature for 2 hours. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 50% to 100%) afforded the product as a beige solid in 99% yield. M/Z (M[.sup.79Br]+H).sup.+=320.

Example 4

2,9-Dibromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(62) ##STR00032##

(63) Example 4 was obtained according to general procedure III, starting from compound 16 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 50% to 100%) afforded the product as a yellow solid in 70% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.84 (d, J 1.9 Hz, 1H, Ar); 7.76 (d, J 1.9 Hz 1H, Ar); 7.56 (dd, J 8.2, 1.9 Hz, 1H, Ar); 7.47 (d, J 8.2 Hz, 1H, Ar); 6.88 (d, J 1.9 Hz, 1H, Ar); 2.89 (s, 3H, CH.sub.3); 1.44 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br][.sup.81Br]+H).sup.+=397.

Example 5

9-Bromo-2-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(64) ##STR00033##

(65) Example 5 was obtained according to general procedure III, starting from compound 17 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 50% to 100%) afforded the product as a beige solid in 93% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.83 (d, J 1.9 Hz, 1H, Ar); 7.74 (d, J 2.0 Hz, 1H, Ar); 7.56 (dd, J 8.1, 1.9 Hz, 1H, Ar); 7.47 (d, J 8.1 Hz, 1H, Ar); 6.84 (d, J 2.0 Hz, 1H, Ar); 2.89 (s, 3H, CH.sub.3); 1.45 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+=351.

Example 6

9-Bromo-3-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(66) ##STR00034##

(67) Example 6 was obtained according to general procedure III, starting from compound 18 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by filtration after hydrolysis afforded the product as a beige solid in 92% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.82 (d, J 1.9 Hz, 1H, Ar); 7.56 (dd, J 8.1, 1.9 Hz 1H, Ar); 7.52 (d, J 3.1 Hz, 1H, Ar); 7.46 (d, J 8.1 Hz, 1H, Ar); 6.51 (d, J 3.1 Hz, 1H, Ar); 2.88 (s, 3H, CH.sub.3); 1.44 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+=351.

Example 7

9-Bromo-7-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(68) ##STR00035##

(69) Example 7 was obtained according to general procedure III, starting from compound 19 in presence of iodomethane. The reaction mixture was stirred at room temperature for 30 minutes. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 60%) afforded the product as a beige solid in 76% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.68 (m, 1H, Ar); 7.58 (m, 2H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.62 (m, 1H, cyclopropyl); 1.45 (m, 1H, cyclopropyl); 0.86 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=335.

Example 8

9-Bromo-10-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(70) ##STR00036##

(71) Example 8 was obtained according to general procedure III, starting from compound 20 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 50%) afforded the product as a beige solid in 72% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.69 (dd, J 8.4, 6.6 Hz, 1H, Ar); 7.42 (m, 1H, Ar); 7.34 (dd, J 8.4, 1.4 Hz, 1H, Ar); 6.83 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.88 (s, 3H, CH.sub.3); 1.44 (m, 2H, cyclopropyl); 0.86 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=335.

Example 9

9-Bromo-8-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(72) ##STR00037##

(73) Example 9 was obtained according to general procedure III, starting from compound 21 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by filtration after hydrolysis afforded the product as a beige solid in 89% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.93 (d, J 5.6 Hz, 1H, Ar); 7.61 (d, J 8.5 Hz, 1H, Ar); 7.51 (s, 1H, Ar); 6.84 (s, 1H, Ar); 6.40 (s, 1H, Ar); 2.90 (s, 3H, CH.sub.3); 1.46 (m, 2H, cyclopropyl); 0.89 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=335.

Example 10

9-Bromo-2-phenyl-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(74) ##STR00038##

(75) Example 10 was obtained according to general procedure III, starting from compound 22 in presence of iodomethane. The reaction mixture was stirred at room temperature for 3 hours. Purification by filtration after hydrolysis afforded the product as a beige solid in 91% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.10 (d, J 2.0 Hz, 1H, Ar); 7.90 (d, J 1.9 Hz, 1H, Ar); 7.79 (m, 2H, Ar); 7.52 (dd, J 8.1, 1.9 Hz, 1H, Ar); 7.40 (m, 3H, Ar); 7.31 (d, J 2.0 Hz, 1H, Ar); 7.22 (m, 1H, Ar); 2.90 (s, 3H, CH.sub.3); 1.40 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=393.

Example 11

9-Bromo-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(76) ##STR00039##

(77) Example 11 was obtained according to general procedure III, starting from compound 23 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by filtration after hydrolysis afforded the product as a beige solid in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.04 (m, 3H, Ar); 7.63 (dd, J 8.0, 1.8 Hz, 1H, Ar); 7.56 (s, 1H, Ar); 7.53 (d, J 8.0 Hz, 1H, Ar); 7.49 (m, 2H, Ar); 7.41 (m, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.07 (m, 1H, cyclopropyl); 0.62 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=394.0.

Example 12

9-Bromo-6,6-spirocyclopropyl-5-methyl-2-phenyl-5,6-dihydro-3,5,10b-triaza-benzo[e]azulen-4-one

(78) ##STR00040##

(79) Example 12 was obtained according to general procedure III, starting from compound 24 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by filtration after hydrolysis afforded the product as a yellow solid in 91% yield. M/Z (M[.sup.79Br]+H).sup.+=394.0.

Example 13

8-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(80) ##STR00041##

(81) Example 13 was obtained according to general procedure III, starting from compound 25 in presence of iodomethane. The reaction mixture was stirred at room temperature for 16 hours. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 20%) afforded the product as as a beige solid in 68% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.74 (d, J 2.3 Hz, 1H, Ar); 7.68 (dd, J 8.4, 2.3 Hz, 1H, Ar); 7.52 (d, J 8.4 Hz, 1H, Ar); 7.46 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.86 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 1.53 (m, 1H, cyclopropyl); 1.42 (m, 1H, cyclopropyl); 0.90 (m, 1H, cyclopropyl); 0.54 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=317.

Example 14

7-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(82) ##STR00042##

(83) Example 14 was obtained according to general procedure III, starting from compound 26 in presence of iodomethane. The reaction mixture was stirred at room temperature for 16 hours. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 50%) afforded the product as a brown solid in 74% yield. M/Z (M[.sup.79Br]+H).sup.+=317.

Example 15

10-Bromo-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(84) ##STR00043##

(85) Example 15 was obtained according to general procedure III, starting from compound 27 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 50%) afforded the product as a beige solid in 73% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.80 (dd, J 8.2, 1.3 Hz, 1H, Ar); 7.54 (dd, J 8.2, 1.3 Hz, 1H, Ar); 7.42 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.31 (t, J 8.2 Hz, 1H, Ar); 6.74 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.36 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.85 (s, 3H, CH.sub.3); 1.42 (m, 2H, cyclopropyl); 0.77 (m, 1H, cyclopropyl); 0.50 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=317.

Example 16

8-Bromo-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(86) ##STR00044##

(87) Example 16 was obtained according to general procedure III, starting from compound 28 in presence of iodomethane. The reaction mixture was stirred at room temperature for 16 hours. Purification by flash column chromatography on silica gel (MeOH in dichloromethane, 0% to 1%) afforded the product as as a brown solid in 83% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.98 (d, J 2.0 Hz, 1H, Ar); 7.75 (m, 3H, Ar); 7.72 (dd, J 8.5, 2.2 Hz, 1H, Ar); 7.64 (d, J 8.5 Hz, 1H, Ar); 7.38 (m, 2H, Ar); 7.29 (d, J 2.0 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.56 (m, 1H, cyclopropyl); 1.44 (m, 1H, cyclopropyl); 0.97 (m, 1H, cyclopropyl); 0.62 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=393.

(88) General Procedure IV: Formation of Benzodiazepinone Boronic Ester J, Ji from Benzodiazepinone F, Fi (Scheme 1 and 4)

(89) Under inert atmosphere, a mixture of halide F, Fi (1.0 equiv.), bis(pinacolato)diboran (2.0 equiv.), sodium acetate (2.5 equiv.) and PdCl.sub.2(dppf).sub.2 (0.2 equiv.) in DMF (0.10 mol.Math.L.sup.−1) was heated at 80° C. for 3 days. 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 and concentrated to afford the product.

Compound 29: 9-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(90) Compound 29 was obtained according to general procedure IV, starting from example 10. Compound 29 was obtained as a brown solid in 91% yield and contained one third of boronic acid analogue according to LC/MS analysis. It was taken crude to the next step without purification. M/Z (M+H).sup.+=441.4 (boronic ester). M/Z (M+H).sup.+=359.3 (boronic acid).

Compound 30: 9-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-methyl-2-phenyl-spiro[benzo[f]imidazo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(91) Compound 30 was obtained according to general procedure IV, starting from example 11. Compound 30 was obtained as a brown solid in quantitative yield and contained one third of boronic acid analogue according to LC/MS analysis. It was taken crude to the next step without purification. M/Z (M+H).sup.+=442.1 (boronic ester). M/Z (M+H).sup.+=360.1 (boronic acid).

Compound 31: 5-Methyl-9-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(92) Compound 31 was obtained according to general procedure IV starting from example 1. Trituration in Et.sub.2O afforded the crude product as a beige solid in 80% yield. It was taken crude to the next step without purification. M/Z (M+H).sup.+=365.3.

Compound 32: 5-(Methyl-d.SUB.3.)-9-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(93) Compound 32 was obtained according to general procedure IV starting from example 3. Trituration in Et.sub.2O afforded the crude product as a brown solid in quantitative yield. It was taken crude to the next step without purification. M/Z (M+H).sup.+=368.4.

(94) General Procedure V: Formation of R1-Substituted Intermediate Ci from Dibromo-Substituted Intermediate C (Scheme 4)

(95) Under inert atmosphere, a mixture of dibromo-intermediate C (1.0 equiv.), boronic acid or ester G (1.1 equiv.), cesium fluoride (3.0 equiv.) and tetrakis(triphenylphosphine)palladium (0.10 equiv.) in THF (0.15 mol.Math.L.sup.−1) was heated at 70° C. for 24 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 by flash column chromatography (using a gradient of EtOAc in cyclohexane as eluent) to afford the product.

Compound 33: 1-[2-Cyano-5-(2-methyl-pyridin-3-yl)-phenyl]-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

(96) Compound 33 was obtained according to general procedure V, starting from compound 2 and 2-methylpyridine-3-boronic acid pinacol ester. It was isolated as a beige solid in 78% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.53 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.09 (d, J 7.9 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.72 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.69 (d, J 1.9 Hz, 1H, Ar); 7.36 (dd, J 7.9, 4.8 Hz, 1H, Ar); 7.17 (d, J 1.9 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3); 2.47 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=396.

Compound 34: 2-Bromo-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(97) Compound 34 was obtained according to general procedure II, starting from compound 33. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 34 was isolated as a white solid in 55% yield. M/Z (M[.sup.79Br]+H).sup.+=394.

Example 17

2-Bromo-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(98) ##STR00045##

(99) Example 17 was obtained according to general procedure III, starting from compound 34 in presence of iodomethane. The reaction mixture was stirred at room temperature for 3 hours. Purification by filtration after hydrolysis afforded the product as a yellow solid in 88% yield. M/Z (M[.sup.79Br]+H).sup.+=408.0.

Compound 35: 1-[2-Cyano-5-(6-methyl-pyridin-3-yl)-phenyl]-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

(100) Compound 35 was obtained according to general procedure V, starting from compound 2 and 2-methylpyridine-5-boronic acid. It was isolated as a white solid in 54% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.94 (d, J 2.4 Hz, 1H, Ar); 8.17 (dd, J 8.1, 2.4 Hz, 1H, Ar); 8.08 (m, 3H, Ar); 7.71 (d, J 1.9 Hz, 1H, Ar); 7.41 (d, J 8.1 Hz, 1H, Ar); 7.20 (d, J 1.9 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3); 2.54 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=396.

Compound 36: 2-Bromo-9-(6-methyl-pyridin-3-yl)-6,6-spirocyclopropyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(101) Compound 36 was obtained according to general procedure II, starting from compound 35. The reaction was completed by the addition of more ethylmagnesium bromide (1M solution in THF, 1.0 equiv.). Compound 36 was isolated as a grey solid in 65% yield. M/Z (M[.sup.79Br]+H).sup.+=394.

Example 18

2-Bromo-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(102) ##STR00046##

(103) Example 18 was obtained according to general procedure III, starting from compound 36 in presence of iodomethane. The reaction mixture was stirred at room temperature for 1 hour. Purification by filtration after hydrolysis afforded the product as a yellow solid in 97% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.88 (d, J 2.4 Hz, 1H, Ar); 8.11 (dd, J 8.1, 2.4 Hz, 1H, Ar); 7.93 (d, J 2.0 Hz, 1H, Ar); 7.88 (d, J 1.7 Hz, 1H, Ar); 7.69 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.61 (d, J 7.8 Hz, 1H, Ar); 7.37 (d, J 8.1 Hz, 1H, Ar); 6.89 (d, J 2.0 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 2.52 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.62 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=408.0.

Compound 37: 1-[2-Cyano-5-(2-ethyl-pyridin-3-yl)-phenyl]-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester

(104) Compound 37 was obtained according to general procedure V, starting from compound 2 and 2-ethylpyridine-3-boronic acid. It was isolated as a white solid in 70% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.59 (d, J 4.9 Hz, 1H, Ar); 8.09 (d, J 8.3 Hz, 1H, Ar); 7.69 (m, 3H, Ar); 7.67 (dd, J 7.8, 1.8 Hz, 1H, Ar); 7.35 (dd, J 8.3, 4.9 Hz, 1H, Ar); 7.18 (d, J 1.9 Hz, 1H, Ar); 3.67 (s, 3H, CH.sub.3); 2.74 (q, J 7.7 Hz, 2H, CH.sub.2—CH.sub.3); 1.14 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=410.

Compound 38: 2-Bromo-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(105) Compound 38 was obtained according to general procedure II, starting from compound 37, as a brown solid in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (s, 1H, NH); 8.55 (dd, J 4.8, 1.6 Hz, 1H, Ar); 7.80 (d, J 2.0 Hz 1H, Ar); 7.69 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.56 (d, J 1.7 Hz, 1H, Ar); 7.51 (d, J 7.8 Hz, 1H, Ar); 7.34 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.31 (dd, J 7.8, 4.8 Hz, 1H, Ar); 6.91 (d, J 2.0 Hz, 1H, Ar); 2.74 (q, J 7.5 Hz, 2H, CH.sub.2—CH.sub.3); 1.59 (m, 1H, cyclopropyl); 1.23 (m, 1H, cyclopropyl); 1.14 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 0.88 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=408.

Example 19

2-Bromo-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(106) ##STR00047##

(107) Example 19 was obtained according to general procedure III, starting from compound 38 in presence of iodomethane. The reaction mixture was stirred at room temperature for 4 hours. Purification by filtration after hydrolysis afforded the product as a beige solid in 97% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.55 (dd, J 4.8, 1.3 Hz, 1H, Ar); 7.78 (d, J 2.0 Hz, 1H, Ar); 7.70 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.59 (m, 2H, Ar); 7.37 (dd, J 7.7, 1.3 Hz, 1H, Ar); 7.31 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.89 (d, J 2.0 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.74 (q, J 7.6 Hz, 2H, CH.sub.2—CH.sub.3); 1.50 (m, 2H, cyclopropyl); 1.16 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.00 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=422.0.

(108) General Procedure VI: Formation of Benzodiazepinone K, K′ and K″ from Benzodiazepinone F, F′, F″, Fi and Boronic Acid Derivatives G or from Benzodiazepinone J, Ji and Halide Derivative I (Scheme 1, 2, 3 and 4). Formation of R.sub.1-Substituted Benzodiazepinone U, U′, U″, U.sub.1, U.sub.2, U.sub.3 and U.sub.4 from Intermediate T, T′, T″, T.sub.1, T.sub.2, T.sub.3 and T.sub.4 (Scheme 6, 7 and 8).

(109) Method (i): Under Microwave Irradiation:

(110) Under inert atmosphere, a mixture of halide F, F′, F″, Fi, I, T, T′, T″, T.sub.1, T.sub.2, T.sub.3 or T.sub.4 (1.0 equiv.), boronic acid derivative G or J, Ji (1.5 equiv.) and PdCl.sub.2(dppf).sub.2 (0.10 equiv.) in a mixture of DMF or DMA (0.10 mol.Math.L.sup.−1) and aqueous Na.sub.2CO.sub.3 (1.2 mol.Math.L.sup.−1) was submitted to microwave irradiation at 150° C. for 15 minutes. 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.

(111) Method (ii): Under Oil Bath Heating:

(112) Under inert atmosphere, a mixture of halide F, F′, F″, Fi, I, or T, T′, T″, T.sub.1, T.sub.2, T.sub.3, T.sub.4 (1.0 equiv.), boronic acid derivative G or J, Ji (1.5 equiv.) and PdCl.sub.2(dppf).sub.2 (0.10 equiv.) in a mixture of DMF or DMA (0.10 mol.Math.L.sup.−1) and aqueous Na.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.

(113) General Procedure VII: Formation of HCl Salt

(114) Method (i): in DCM:

(115) To a solution of the free base in dichloromethane, HCl (2N solution in Et2O, 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.

(116) Method (ii): Concentration from MeOH:

(117) 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.

(118) Method (iii): Filtration from MeOH:

(119) The free base was suspended in MeOH and HCl in methanol (1.25N solution in MeOH, 5 equiv.) was added. The suspension was vigorously stirred, and then the solid was collected, washed with Et.sub.2O and dried at 50° C. under reduced pressure with P.sub.2O.sub.5.

Example 20

5-Methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(120) ##STR00048##

(121) Example 20 was obtained according to general procedure VI(ii) starting from example 1 in presence of 2-methylpyridine-3-boronic pinacol ester. Purification by flash column chromatography on silica gel (MeOH in CH.sub.2Cl.sub.2, 1% to 5%) afforded the product as a grey solid in 62% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.50 (dd, J 4.8, 1.6 Hz, 1H, Ar); 7.73 (dd, J 7.6, 1.6 Hz, 1H, Ar); 7.60 (d, J 7.6 Hz, 1H, Ar); 7.58 (d, J 1.6 Hz, 1H, Ar); 7.56 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.38 (dd, J 7.7, 1.6 Hz, 1H, Ar); 7.33 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.40 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.95 (s, 3H, CH.sub.3); 2.69 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=330.0. MP: 200-210° C.

Example 21

5-Methoxymethyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(122) ##STR00049##

(123) Example 21 was obtained according to general procedure VI(ii) starting from example 2 in presence of 2-methylpyridine-3-boronic pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 20% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.42 (dd, J 4.8, 1.6 Hz, 1H, Ar); 7.65 (dd, J 7.7, 1.6 Hz, 1H, Ar); 7.54 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.51 (d, J 7.8 Hz, 1H, Ar); 7.50 (d, J 1.7 Hz, 1H, Ar); 7.30 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.25 (dd, J 7.7, 4.8 Hz, 1H, Ar); 6.90 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.37 (dd, J 3.7, 2.8 Hz, 1H, Ar); 4.92 (d, J 10.3 Hz, 1H, CH); 4.65 (d, J 10.3 Hz, 1H, CH); 2.91 (s, 3H, CH.sub.3); 2.38 (s, 3H, CH.sub.3); 1.64 (m, 1H, cyclopropyl); 1.48 (m, 1H, cyclopropyl); 0.84 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=360.0. MP: 138-142° C.

Example 22

5-Methyl-9-(pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(124) ##STR00050##

(125) Example 22 was obtained according to general procedure VI(i) starting from example 1 in presence of 4-pyridineboronic acid. Purification by preparative HPLC afforded the product as a grey solid in 43% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.97 (bs, 2H, Ar); 8.43 (d, J 5.8 Hz, 2H, Ar); 8.11 (d, J 1.7 Hz, 1H, Ar); 7.95 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.76 (m, 1H, Ar); 7.74 (d, J 7.9 Hz, 1H, Ar); 6.90 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.47 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=316.3. MP>250° C.

Example 23

5-Methyl-9-(pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(126) ##STR00051##

(127) Example 23 was obtained according to general procedure VI(i) starting from example 1 in presence of 3-pyridineboronic acid. Purification by preparative HPLC afforded the product as a grey solid in 50% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 9.28 (s, 1H, Ar); 8.83 (d, J 5.2 Hz, 1H, Ar); 8.74 (d, J 8.0 Hz, 1H, Ar); 8.00 (d, J 1.7 Hz, 1H, Ar); 7.96 (dd, J 8.0, 5.2 Hz, 1H, Ar); 7.80 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.73 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.69 (d, J 7.9 Hz, 1H, Ar); 6.89 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.46 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=316.3. MP>250° C.

Example 24

5-Methyl-9-(2-ethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(128) ##STR00052##

(129) Example 24 was obtained according to general procedure VI(i) starting from example 1 in presence of 2-ethylpyridine-3-boronic acid. Purification by preparative HPLC afforded the product as a grey solid in 23% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 5.1 Hz, 1H, Ar); 8.26 (bs, 1H, Ar); 7.78 (bs, 1H, Ar); 7.66 (m, 2H, Ar); 7.53 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.42 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.94 (q, J 7.4 Hz, 2H, CH.sub.2—CH.sub.3); 1.51 (m, 2H, cyclopropyl); 1.19 (t, J 7.4 Hz, 3H, CH.sub.2—CH.sub.3); 0.95 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=344.4. MP: 136-143° C.

Example 25

5-Methyl-9-(6-methylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(130) ##STR00053##

(131) Example 25 was obtained according to general procedure VI(i) starting from example 1 in presence of 2-methylpyridine-5-boronic acid. Purification preparative HPLC afforded the product as a white solid in 69% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.99 (d, J 1.3 Hz, 1H, Ar); 8.57 (dd, J 8.5, 1.3 Hz, 1H, Ar); 7.78 (d, J 1.7 Hz, 1H, Ar); 7.72 (d, J 8.5 Hz, 1H, Ar); 7.59 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.51 (dd, J 2.8, 1.8 Hz, Ar); 7.46 (d, J 7.8 Hz, 1H, Ar); 6.66 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.23 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.71 (s, 3H, CH.sub.3); 2.55 (s, 3H, CH.sub.3); 1.29 (m, 2H, cyclopropyl); 0.74 (m, 1H, cyclopropyl); 0.34 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=330.4. MP: 205-215° C.

Example 26

5-Methyl-9-(2-methylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(132) ##STR00054##

(133) Example 26 was obtained according to general procedure VI(i) starting from example 1 in presence of 2-methylpyridine-4-boronic acid. Purification by preparative HPLC afforded the product as a grey solid in 34% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (d, J 6.1 Hz, 1H, Ar); 8.35 (bs, 1H, Ar); 8.25 (d, J 6.1 Hz, 1H, Ar); 8.09 (d, J 1.6 Hz, 1H, Ar); 7.93 (dd, J 8.0, 1.6 Hz, 1H, Ar); 7.73 (m, 2H, Ar); 6.90 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.47 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.76 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.97 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=330.4. MP: 183-193° C.

Example 27

5-Methyl-9-(3,5-dimethyl-1H-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(134) ##STR00055##

(135) Example 27 was obtained according to general procedure VI(i) starting from example 1 in presence of 3,5-dimethylpyrazole-4-boronic pinacol ester. Purification by preparative HPLC afforded the product as a grey solid in 44% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.52 (d, J 7.8 Hz, 1H, Ar); 7.47 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.42 (d, J 1.6 Hz, 1H, Ar); 7.26 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.84 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.39 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 2.25 (s, 6H, 2CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.90 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=333.4. MP: 115-125° C.

Example 28

5-Methyl-9-(3-trifluoromethyl-1H-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(136) ##STR00056##

(137) Example 28 was obtained according to general procedure VI(i) starting from example 1 in presence of 3-trifluoromethyl-1H-pyrazole-4-boronic pinacol ester. Purification by preparative HPLC afforded the product as a yellow solid in 54% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 13.83 (bs, 1H, NH); 8.34 (s, 1H, Ar); 7.56 (m, 2H, Ar); 7.51 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.37 (d, J 7.8 Hz, 1H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.92 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=373.4. MP>250° C.

Example 29

5-Methyl-9-(1-methyl-pyrazol-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(138) ##STR00057##

(139) Example 29 was obtained according to general procedure VI(i) starting from example 1 in presence of 1-methylpyrazole-4-boronic pinacol ester. Purification by preparative HPLC afforded the product as a yellow solid in 58% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.24 (s, 1H, Ar); 7.96 (s, 1H, Ar); 7.70 (d, J 1.6 Hz, 1H, Ar); 7.56 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.50 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.45 (d, J 7.8 Hz, 1H, Ar); 6.84 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 3.87 (s, 3H, CH.sub.3); 2.90 (s, 3H, CH.sub.3); 1.43 (m, 2H, cyclopropyl); 0.88 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=319.3. MP: 75-83° C.

Example 30

5-Methyl-9-(1-methyl-pyrazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(140) ##STR00058##

(141) Example 30 was obtained according to general procedure VI(i) starting from example 1 in presence of 1-methylpyrazole-5-boronic pinacol ester. Purification by preparative HPLC afforded the product as a grey solid in 52% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.67 (s, 1H, Ar); 7.60 (m, 2H, Ar); 7.49 (m, 2H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.53 (d, J 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 3.90 (s, 3H, CH.sub.3); 2.93 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=319.4. MP: 214-220° C.

Example 31

5-Methyl-9-(6-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(142) ##STR00059##

(143) Example 31 was obtained according to general procedure VI(i) starting from example 1 in presence of 2-fluoro-5-pyridinylboronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a white solid in 43% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.73 (d, J 2.4 Hz, 1H, Ar); 8.46 (dt, J 8.3, 2.6 Hz, 1H, Ar); 7.91 (d, J 1.6 Hz, 1H, Ar); 7.74 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.73 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.67 (d, J 7.8 Hz, 1H, Ar); 7.37 (dd, J 8.3, 2.6 Hz, 1H, Ar); 6.92 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.48 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=334.3. MP: 171-176° C.

Example 32

5-Methyl-9-(6-fluoro-2-methylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(144) ##STR00060##

(145) Example 32 was obtained according to general procedure VI(i) starting from example 1 in presence of 2-fluoro-6-picoline-5-boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 64% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.95 (t, J 8.2 Hz, 1H, Ar); 7.60 (d, J 7.8 Hz, 1H, Ar); 7.59 (d, J 1.6 Hz, 1H, Ar); 7.56 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.38 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.11 (dd, J 8.2, 3.0 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.43 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=348.3. MP: 198-202° C.

Example 33

5-Methyl-9-(2-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(146) ##STR00061##

(147) Example 33 was obtained according to general procedure VI(i), starting from example 1 in presence of 2-fluoro-3-pyridineboronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 60%) afforded the product as a white solid in 70% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.28 (m, 2H, Ar); 7.77 (s, 1H, Ar); 7.64 (d, J 7.8 Hz, 1H, Ar); 7.59 (m, 2H, Ar); 7.51 (m, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.51 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=334.3. MP: 158-162° C.

Example 34

5-Methyl-9-(2-fluoropyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(148) ##STR00062##

(149) Example 34 was obtained according to general procedure VI(i), starting from example 1 in presence of 2-fluoro-4-pyridineboronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 60%) afforded the product as a beige solid in 76% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.33 (d, J 5.3 Hz, 1H, Ar); 7.97 (d, J 1.8 Hz, 1H, Ar); 7.81 (m, 2H, Ar); 7.72 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.69 (m, 1H, Ar); 7.65 (d, J 8.0 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=334.3. MP: 197-201° C.

Example 35

5-Methyl-9-(2-trifluoromethylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(150) ##STR00063##

(151) Example 35 was obtained according to general procedure VI(i), starting from example 1 in presence of 2-trifluoromethylpyridine-4-boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 20% to 80%) afforded the product as a white solid in 89% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.86 (d, J 5.1 Hz, 1H, Ar); 8.35 (d, J 1.3 Hz, 1H, Ar); 8.17 (dd, J 5.1, 1.3 Hz, 1H, Ar); 8.05 (d, J 1.6 Hz, 1H, Ar); 7.87 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.75 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.68 (d, J 7.9 Hz, 1H, Ar); 6.89 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.45 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.51 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=384.3. MP: 169-174° C.

Example 36

5-Methyl-9-(2-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(152) ##STR00064##

(153) Example 36 was obtained according to general procedure VI(i), starting from example 1 in presence of 2-trifluoromethylpyridine-3-boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 60%) afforded the product as a white solid in 41% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.80 (dd, J 4.7, 1.0 Hz, 1H, Ar); 8.06 (dd, J 7.9, 1.0 Hz, 1H, Ar); 7.81 (dd, J 7.9, 4.7 Hz, 1H, Ar); 7.61 (d, J 7.8 Hz, 1H, Ar); 7.60 (d, J 1.6 Hz, 1H, Ar); 7.48 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.33 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.40 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=384.3. MP: 160-165° C.

Example 37

5-Methyl-9-(4-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(154) ##STR00065##

(155) Example 37 was obtained according to general procedure VI(i), starting from example 1 in presence of 4-trifluoromethylpyridine-3-boronic pinacol ester. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 60%) afforded the product as a beige solid in 53% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.92 (d, J 5.2 Hz, 1H, Ar); 8.82 (s, 1H, Ar); 7.89 (d, J 5.2 Hz, 1H, Ar); 7.64 (m, 2H, Ar); 7.51 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.37 (d, J 7.8 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.95 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=384.3. MP: 67-78° C.

Example 38

5-Methyl-9-(3-methylpyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(156) ##STR00066##

(157) Example 38 was obtained according to general procedure VI(i), starting from example 1 in presence of 3-methylpyridine-4-boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a brown solid in 36% yield. Salt formation was performed by method (i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.90 (s, 1H, Ar); 8.82 (d, J 5.8 Hz, 1H, Ar); 7.97 (d, J 5.8 Hz, 1H, Ar); 7.71 (d, J 1.7 Hz, 1H, Ar); 7.69 (d, J 7.9 Hz, 1H, Ar); 7.57 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.51 (dd, J 7.9, 1.7 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.44 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=330.4. MP>250° C.

Example 39

5-Methyl-9-(3,4-dimethoxy-phenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(158) ##STR00067##

(159) Example 39 was obtained according to general procedure VI(i), starting from example 1 in presence of 3,4-dimethoxyphenylboronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 72% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.72 (d, J 1.6 Hz, 1H, Ar); 7.66 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.58 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.53 (d, J 7.9 Hz, 1H, Ar); 7.29 (m, 2H, Ar); 7.05 (d, J 8.2 Hz, 1H, Ar); 6.85 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 3.85 (s, 3H, OCH.sub.3); 3.80 (s, 3H, OCH.sub.3); 2.92 (s, 3H, CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.53 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=375.2. MP: 150-154° C.

Example 40

5-Methyl-9-(6-amino-5-trifluoromethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(160) ##STR00068##

(161) Example 40 was obtained according to general procedure VI(i), starting from example 1 in presence of 2-amino-3-trifluoromethylpyridine-5-boronic pinacol ester. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 30% to 80%) afforded the product as a beige solid in 64% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.67 (s, 1H, Ar); 8.27 (s, 1H, Ar); 7.80 (d, J 1.5 Hz, 1H, Ar); 7.68 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.62 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.55 (d, J 7.8 Hz, 1H, Ar); 7.15 (bs, 2H, NH.sub.2); 6.85 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.91 (s, 3H, CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=399.3. MP>250° C.

Example 41

5-Methyl-9-(imidazo[1,2-a]pyridin-6-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(162) ##STR00069##

(163) Example 41 was obtained according to general procedure VI(i), starting from example 1 in presence of imidazo[1,2-a]pyridine-6-boronic acid. Purification by flash column chromatography on silica gel (MeOH in CH.sub.2Cl.sub.2, 0% to 5%) afforded the product as a yellow solid in 59% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 9.45 (s, 1H, Ar); 8.42 (dd, J 9.4, 1.3 Hz, 1H, Ar); 8.32 (s, 1H, Ar); 8.25 (d, J 1.7 Hz, 1H, Ar); 8.08 (d, J 9.4 Hz, 1H, Ar); 7.96 (d, J 1.3 Hz, 1H, Ar); 7.76 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.71 (d, J 7.8 Hz, 1H, Ar); 7.69 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.90 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.47 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.95 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.97 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=355.2. MP>250° C.

Example 42

5-Methyl-9-(6-morpholin-4-yl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(164) ##STR00070##

(165) Example 42 was obtained according to general procedure VI(i), starting from example 1 in presence of 6-(morpholin-4-yl)pyridine-3-boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 30% to 80%) afforded the product as a yellow solid in 57% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.50 (s, 1H, Ar); 8.27 (d, J 8.7 Hz, 1H, Ar); 7.80 (d, J 1.3 Hz, 1H, Ar); 7.69 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.63 (dd, J 7.8, 1.3 Hz, 1H, Ar); 7.58 (d, J 7.8 Hz, 1H, Ar); 7.25 (d, J 8.7 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 3.76 (m, 4H, 2CH.sub.2); 3.65 (m, 4H, 2CH.sub.2); 2.93 (s, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.54 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=401.3. MP: 191-199° C.

Example 43

5-Methyl-9-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(166) ##STR00071##

(167) Example 43 was obtained according to general procedure VI(i), starting from example 1 in presence of 6-(piperidin-1-yl)pyridine-3-boronic pinacol ester. Purification by preparative HPLC afforded the product as a beige solid in 42% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.37 (s, 1H, Ar); 8.31 (d, J 8.7 Hz, 1H, Ar); 7.80 (d, J 1.4 Hz, 1H, Ar); 7.69 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.62 (dd, J 7.9, 1.4 Hz, 1H, Ar); 7.58 (d, J 7.9 Hz, 1H, Ar); 7.37 (d, J 8.7 Hz, 1H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 3.73 (m, 4H, 2CH.sub.2); 2.92 (m, 3H, CH.sub.3); 1.64 (m, 6H, 3CH.sub.2); 1.48 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.53 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=399.3. MP: 188-193° C.

Example 44

5-Methyl-9-(3-cyanophenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(168) ##STR00072##

(169) Example 44 was obtained according to general procedure VI(i), starting from example 1 in presence of 3-cyanophenylboronic acid. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 70%) afforded the product as a yellow solid in 90% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.35 (s, 1H, Ar); 8.14 (d, J 7.9 Hz, 1H, Ar); 7.87 (m, 2H, Ar); 7.73 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.69 (m, 2H, Ar); 7.61 (d, J 7.9 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (m, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.92 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=340.3. MP: 189-194° C.

Example 45

5-Methyl-9-(3-(1H-tetrazol-5-yl)-phenyl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(170) ##STR00073##

(171) Under inert and anhydrous conditions, to a solution of example 44 (1.0 equiv.) in DMF (0.05 mol.Math.L.sup.−1), sodium azide (5.0 equiv.) and ammonium chloride (5.0 equiv.) were added portionwise. The reaction mixture was heated at 80° C. for 3 days to give a yellow suspension. The solvent was removed under vacuum and the crude product was purified by preparative HPLC to afford example 45 as a white solid in 27% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.40 (s, 1H, Ar); 8.08 (d, J 7.8 Hz, 1H, Ar); 8.01 (d, J 7.8 Hz, 1H, Ar); 7.88 (d, J 1.6 Hz, 1H, Ar); 7.71 (m, 3H, Ar); 7.65 (d, J 7.8 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (m, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for NH not observed. M/Z (M+H).sup.+=383.3. MP>250° C.

Example 46

5-Methyl-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(172) ##STR00074##

(173) Example 46 was obtained according to general procedure VI(i), starting from example 1 in presence of N-boc-1,2,3,6-tetrahydropyridine-4-boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 80%) afforded a yellow oil which was taken in a 1:1 mixture (0.10 mol.Math.L.sup.−1) of CH.sub.2Cl.sub.2 and HCl (2N in Et.sub.2O) for 4 hours at room temperature. The yellow precipitate was collected by filtration and dried under vacuum to afford example 46 as a beige solid in 89% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.26 (bs, 2H, NH+HCl); 7.58 (d, J 1.6 Hz, 1H, Ar); 7.57 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.51 (d, J 7.9 Hz, 1H, Ar); 7.43 (dd, J 7.9, 1.6 Hz, 1H, Ar); 6.85 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 6.36 (m, 1H, ═CH); 3.77 (m, 2H, CH.sub.2); 3.31 (m, 2H, CH.sub.2); 2.91 (m, 3H, CH.sub.3); 2.75 (m, 2H, CH.sub.2); 1.45 (m, 2H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.51 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=320.4. MP: 208-215° C.

Example 47

5-Methyl-9-(1-pyrimidin-4-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(174) ##STR00075##

(175) A suspension of example 46 (1.0 equiv.), 4-bromopyrimidine hydrochloride (2.0 equiv.) and diisopropylethylamine (4.0 equiv.) in EtOH (0.15 mol.Math.L.sup.−1) was stirred at room temperature for 16 hours to give a yellow solution. EtOH was removed under vacuum and the crude orange oil was purified by preparative HPLC to afford example 47 as a yellow solid in 25% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.85 (s, 1H, Ar); 8.37 (m, 1H, Ar); 7.58 (d, J 1.4 Hz, 1H, Ar); 7.56 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.49 (d, J 7.9 Hz, 1H, Ar); 7.43 (dd, J 7.9, 1.4 Hz, 1H, Ar); 7.26 (m, 1H, Ar); 6.84 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (m, 2H, ═CH+Ar); 4.48 (m, 2H, CH.sub.2); 4.10 (m, 2H, CH.sub.2); 2.90 (m, 3H, CH.sub.3); 2.73 (m, 2H, CH.sub.2); 1.44 (m, 2H, cyclopropyl); 0.89 (m, 1H, cyclopropyl); 0.50 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=398.4. MP: 210-220° C.

Example 48

5-Methyl-9-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(176) ##STR00076##

(177) A suspension of example 46 (1.0 equiv.), acetyl chloride (1.2 equiv.) and triethylamine (2.2 equiv.) in CH.sub.2Cl.sub.2 (0.20 mol.Math.L.sup.−1) was stirred at room temperature for 16 hours. CH.sub.2Cl.sub.2 was removed under vacuum and the crude orange oil was purified by preparative HPLC to afford example 48 as a grey solid in 29% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.54 (m, 2H, Ar); 7.46 (d, J 7.8 Hz, 1H, Ar); 7.39 (m, 1H, Ar); 6.83 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.39 (dd, J 3.7, 2.8 Hz, 1H, Ar); 6.30 (m, 1H, ═CH); 4.13 (m, 2H, CH.sub.2); 3.64 (m, 2H, CH.sub.2); 2.89 (m, 3H, CH.sub.3); 2.60 (m, 2H, CH.sub.2); 2.05 (s, 3H, CH.sub.3); 1.43 (m, 2H, cyclopropyl); 0.89 (m, 1H, cyclopropyl); 0.50 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=362.3. MP: 101-110° C.

Example 49

5-Methyl-9-(4-methyl-oxazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(178) ##STR00077##

(179) Under inert atmosphere, a mixture of example 1 (1.0 equiv.), 4-methyloxazole-5-carboxylic acid (2.0 equiv.), cesium carbonate (1.5 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (0.05 equiv.) in DMA (0.05 mol.Math.L.sup.−1) was subjected to microwave irradiation for 10 minutes at 170° C. The mixture was hydrolysed and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. The crude yellow oil was purified by preparative HPLC to afford example 49 as a white solid in 24% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.39 (s, 1H, Ar); 7.67 (d, J 1.6 Hz, 1H, Ar); 7.62 (d, J 7.9 Hz, 1H, Ar); 7.59 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.56 (dd, J 7.9, 1.6 Hz, 1H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.92 (m, 3H, CH.sub.3); 2.40 (m, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.92 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=320.3. MP: 120-128° C.

Example 50

5-Methyl-9-(4-methylthiazol-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(180) ##STR00078##

(181) Under inert atmosphere, a mixture of example 1 (1.0 equiv.), 4-methylthiazole-5-carboxylic acid (2.0 equiv.), cesium carbonate (1.5 equiv.) and bis(triphenylphosphine)palladium(II) dichloride (0.05 equiv.) in DMA (0.05 mol.Math.L.sup.−1) was subjected to microwave irradiation for 10 minutes at 170° C. The mixture was hydrolysed and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. The crude yellow oil was purified by preparative HPLC to afford example 50 as a white solid in 55% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.04 (s, 1H, Ar); 7.61 (d, J 1.6 Hz, 1H, Ar); 7.59 (d, J 7.9 Hz, 1H, Ar); 7.55 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.45 (dd, J 7.9, 1.6 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (m, 3H, CH.sub.3); 2.49 (m, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=336.4. MP: 205-212° C.

Example 51

5-Methyl-9-acetonitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(182) ##STR00079##

(183) Under inert atmosphere, in a sealed reactor, a mixture of example 1 (1.0 equiv.), cyanoacetic acid (5.0 equiv.), sodium tertbutoxide (5.0 equiv.), RuPhos ligand (0.20 equiv.) and allylpalladium (II) chloride dimer (0.10 equiv.) in xylene (0.10 mol.Math.L.sup.−1) was heated at 120° C. for 2 days. The mixture was hydrolysed and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. The crude yellow oil was purified by preparative HPLC to afford example 51 as a white solid in 15% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.53 (m, 2H, Ar); 7.43 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.33 (dd, J 7.9, 1.7 Hz, 1H, Ar); 6.85 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 4.09 (s, 2H, CH.sub.2); 2.89 (m, 3H, CH.sub.3); 1.44 (m, 2H, cyclopropyl); 0.90 (m, 1H, cyclopropyl); 0.51 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=278.3. MP: 60-69° C.

Example 52

5-Methyl-9-actylonitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(184) ##STR00080##

(185) Under inert atmosphere, in a sealed reactor, a mixture of example 1 (1.0 equiv.), acrylonitrile (1.5 equiv.), potassium carbonate (2.0 equiv.), triphenylphosphine (0.20 equiv.) and palladium acetate (0.10 equiv.) in DMF (0.10 mol.Math.L.sup.−1) was heated at 110° C. for 16 hours. The mixture was hydrolysed with a saturated aqueous solution of K.sub.2CO.sub.3 and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. The crude yellow oil was purified by preparative HPLC to afford example 52 as a white solid in 55% yield. A mixture of Z and E diastereoisomers was obtained in a 3:7 ratio. .sup.1H-NMR (400 MHz, DMSO-D6) of the E isomer: 7.88 (d, J 1.4 Hz, 1H, Ar); 7.71 (d, J 16.7 Hz, 1H, ═CH); 7.61 (dd, J 7.9, 1.4 Hz, 1H, Ar); 7.57 (d, J 7.9 Hz, 1H, Ar); 7.52 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.65 (d, J 16.7 Hz, 1H, ═CH); 6.44 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.91 (m, 3H, CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.53 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=290.2. MP: 130-138° C.

Example 53

5-Methyl-9-propionitrile-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(186) ##STR00081##

(187) A mixture of example 52 (1.0 equiv.) and palladium on activated charcoal (10%, 0.20 equiv.) in MeOH (0.10 mol.Math.L.sup.−1) was placed under hydrogen atmosphere (1 bar) for 3 days at room temperature. The mixture was filtered through celite with ethanol and the filtrate was concentrated under vacuum. The crude yellow oil was purified by preparative HPLC to afford example 53 as a white solid in 60% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.51 (d, J 1.6 Hz, 1H, Ar); 7.45 (m, 2H, Ar); 7.26 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.85 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (m, 2H, CH.sub.2); 2.90 (m, 3H, CH.sub.3); 2.88 (m, 2H, CH.sub.2); 1.44 (m, 2H, cyclopropyl); 0.89 (m, 1H, cyclopropyl); 0.50 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=292.3. MP: 59-64° C.

Example 54

5-Methyl-9-(6-chloropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(188) ##STR00082##

(189) Example 54 was obtained according to general procedure VI(i), starting from example 1 in presence of 6-chloro-3-pyridinyl boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 15% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.85 (d, J 2.5 Hz, 1H, Ar); 8.29 (dd, J 8.3, 2.5 Hz, 1H, Ar); 7.87 (d, J 1.7 Hz, 1H, Ar); 7.69 (m, 2H, Ar); 7.64 (d, J 8.3 Hz, 1H, Ar); 7.62 (d, J 7.9 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=350.2. MP: 192-198° C.

Example 55

5-(Methyl-d.SUB.3.)-9-(6-fluoropyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(190) ##STR00083##

(191) Example 55 was obtained according to general procedure VI(i), starting from example 3 in presence of 2-fluoro-5-pyridinylboronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 82% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.67 (d, J 2.6 Hz, 1H, Ar); 8.41 (dt, J 8.2, 2.6 Hz, 1H, Ar); 7.85 (d, J 1.7 Hz, 1H, Ar); 7.69 (dd, J 3.8, 2.8 Hz, 1H, Ar); 7.67 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.61 (d, J 7.9 Hz, 1H, Ar); 7.32 (dd, J 8.5, 2.6 Hz, 1H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 1.48 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=337.2. MP: 166-178° C.

Example 56

5-Methyl-9-(2,6-dimethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(192) ##STR00084##

(193) Example 56 was obtained according to general procedure VI(i) starting from compound 31 in presence of 3-bromo-2,6-dimethylpyridine. Purification by preparative HPLC afforded the product as a beige solid in 47% yield. Salt formation was performed by method (ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.34 (bs, 1H, Ar); 7.76 (bs, 1H, Ar); 7.65 (m, 2H, Ar); 7.54 (m, 1H, Ar); 7.46 (d, J 7.8 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.1, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.77 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.51 (m, 2H, cyclopropyl); 0.95 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=344.3. MP>250° C.

Example 57

5-Methyl-9-(4-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(194) ##STR00085##

(195) Example 57 was obtained according to general procedure VI(i), starting from compound 31 in presence of 2-bromo-4-fluoropyridine. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 27% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.74 (dd, J 8.9, 5.6 Hz, 1H, Ar); 8.20 (d, J 1.7 Hz, 1H, Ar); 8.15 (dd, J 11.0, 2.4 Hz, 1H, Ar); 8.09 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.66 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.64 (d, J 7.9 Hz, 1H, Ar); 7.37 (ddd, J 11.0, 5.6, 2.4 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=344.4. MP: 198-202° C.

Example 58

5-Methyl-9-(3-methyl-pyrazin-2-yl)-5,6-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(196) ##STR00086##

(197) Example 58 was obtained according to general procedure VI(i), starting from compound 31 in presence of 2-bromo-3-methylpyrazine. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a yellow solid in 24% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.56 (d, J 8.5 Hz, 2H, Ar); 7.78 (s, 1H, Ar); 7.60 (m, 2H, Ar); 7.49 (s, 1H, Ar); 6.87 (s, 1H, Ar); 6.40 (s, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.60 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=331.4. MP: 123-129° C.

Example 59

5-Methyl-9-(4-methyl-pyrimidin-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(198) ##STR00087##

(199) Example 59 was obtained according to general procedure VI(i), starting from compound 31 in presence of 5-bromo-4-methylpyrimidine. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a yellow solid in 24% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.07 (s, 1H, Ar); 8.72 (s, 1H, Ar); 7.67 (d, J 1.6 Hz, 1H, Ar); 7.63 (d, J 7.8 Hz, 1H, Ar); 7.56 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.45 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=331.4. MP: 140-147° C.

Example 60

5-Methyl-9-(6-trifluoromethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(200) ##STR00088##

(201) Example 60 was obtained according to general procedure VI(i), starting from compound 31 in presence of 5-bromo-2-trifluoromethylpyridine. Purification by preparative HPLC afforded the product as a beige solid in 33% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.20 (d, J 1.9 Hz, 1H, Ar); 8.50 (dd, J 8.1, 1.9 Hz, 1H, Ar); 8.02 (d, J 8.1 Hz, 1H, Ar); 7.96 (d, J 1.6 Hz, 1H, Ar); 7.77 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.71 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.67 (d, J 7.9 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=384.4. MP: 88-97° C.

Compound 39: 3-bromo-2-propylpyridine

(202) Under inert atmosphere, to a solution of 2,3-dibromopyridine (1.0 equiv.) and tetrakistriphenylphosphine palladium (0.05 equiv.) in THF (0.10 mol.Math.L.sup.−1), a solution of propylzinc bromide (0.5M in THF, 1.5 equiv.) was added dropwise. The reaction mixture was heated at 65° C. for 1 hour, before being neutralized by addition of a saturated aqueous solution of K.sub.2CO.sub.3 and extracted twice with Et.sub.2O. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. The crude yellow oil was purified by flash column chromatography on silica gel (EtOAc in cyclohexane, 0 to 10%) to afford compound 39 as a colorless oil in 77% yield. M/Z (M[.sup.79Br]+H).sup.+=200.0.

Example 61

5-Methyl-9-(2-propylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(203) ##STR00089##

(204) Example 61 was obtained according to general procedure VI(i), starting from compound 31 in presence of compound 39. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 30% to 80%) afforded the product as a yellow solid in 18% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 4.9 Hz, 1H, Ar); 8.30 (m, 1H, Ar); 7.81 (m, 1H, Ar); 7.66 (m, 2H, Ar); 7.51 (m, 1H, Ar); 7.42 (d, J 7.9 Hz, 1H, Ar); 6.88 (m, 1H, Ar); 6.42 (m, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.92 (m, 2H, CH.sub.2); 1.63 (m, 2H, CH.sub.2); 1.51 (m, 2H, cyclopropyl); 0.95 (m, 1H, cyclopropyl); 0.78 (t, J 7.1 Hz, 3H, CH.sub.3); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=358.3. MP: 150-157° C.

Compound 40: 3-Bromo-2-cyclopropylpyridine

(205) Under inert atmosphere, to a solution of 2,3-dibromopyridine (1.0 equiv.) and tetrakistriphenylphosphine palladium (0.05 equiv.) in THF (0.10 mol.Math.L.sup.−1), a solution of cyclopropylzinc bromide (0.5M in THF, 1.5 equiv.) was added dropwise. The reaction mixture was heated at 65° C. for 1 hour, before being neutralized by addition of a saturated aqueous solution of K.sub.2CO.sub.3 and extracted twice with Et.sub.2O. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Compound 40 was obtained as a crude yellow oil and taken to the next step without purification. M/Z (M[.sup.79Br]+H).sup.+=198.0.

Example 62

5-Methyl-9-(2-cyclopropylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(206) ##STR00090##

(207) Example 62 was obtained according to general procedure VI(i), starting from compound 31 in presence of compound 40. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a yellow solid in 9% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.52 (d, J 4.7 Hz, 1H, Ar); 7.98 (m, 1H, Ar); 7.67 (d, J 1.4 Hz, 1H, Ar); 7.64 (d, J 7.8 Hz, 1H, Ar); 7.56 (m, 1H, Ar); 7.46 (m, 2H, Ar); 6.87 (m, 1H, Ar); 6.41 (m, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.16 (m, 1H, cyclopropyl); 1.50 (m, 2H, cyclopropyl); 1.15 (m, 2H, cyclopropyl); 1.00 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=356.3. MP: 160-180° C.

Example 63

5-Methyl-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(208) ##STR00091##

(209) Example 63 was obtained according to general procedure VI(i), starting from compound 31 in presence of 2-bromo-5-fluoropyridine. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 60% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 2.9 Hz, 1H, Ar); 8.20 (dd, J 8.9, 4.2 Hz, 1H, Ar); 8.13 (d, J 1.6 Hz, 1H, Ar); 8.01 (dd, J 8.0, 1.6 Hz, 1H, Ar); 7.87 (dt, J 8.9, 2.9 Hz, 1H, Ar); 7.62 (m, 2H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=334.3. MP: 148-156° C.

Example 64

5-(Methyl-d.SUB.3.)-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(210) ##STR00092##

(211) Example 64 was obtained according to general procedure VI(i), starting from compound 32 in presence of 2-bromo-5-fluoropyridine. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 62% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 2.9 Hz, 1H, Ar); 8.20 (dd, J 8.9, 4.5 Hz, 1H, Ar); 8.13 (d, J 1.7 Hz, 1H, Ar); 8.01 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.87 (dt, J 8.9, 2.9 Hz, 1H, Ar); 7.62 (m, 2H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 1.48 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=337.2. MP: 138-142° C.

Example 65

5-Methyl-9-(2,4-dimethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(212) ##STR00093##

(213) Example 65 was obtained according to general procedure VI(i), starting from compound 31 in presence of 3-bromo-2,4-dimethylpyridine. Purification by preparative HPLC, afforded the product as a white solid in 11% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.70 (m, 1H, Ar); 7.91 (m, 1H, Ar); 7.69 (d, J 7.9 Hz, 1H, Ar); 7.56 (m, 1H, Ar); 7.50 (m, 1H, Ar); 7.30 (m, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (m, 1H, Ar); 2.95 (s, 3H, CH.sub.3); 2.32 (s, 3H, CH.sub.3); 2.27 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=344.3. MP: 200-208° C.

Example 66

5-Methyl-9-(3-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(214) ##STR00094##

(215) Example 66 was obtained according to general procedure VI(i), starting from compound 31 in presence of 2-chloro-3-fluoropyridine. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a beige solid in 44% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.58 (m, 1H, Ar); 8.01 (m, 1H, Ar); 7.87 (m, 2H, Ar); 7.65 (d, J 7.9 Hz, 1H, Ar); 7.53 (m, 2H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=334.3. MP: 102-118° C.

Example 67

5-Methyl-9-(6-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(216) ##STR00095##

(217) Example 67 was obtained according to general procedure VI(i), starting from compound 31 in presence of 2-bromo-6-fluoropyridine. Purification by preparative HPLC afforded the product as a beige solid in 35% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.15-8.08 (m, 3H, Ar); 8.02 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.64 (m, 2H, Ar); 7.19 (m, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=334.3. MP: 106-117° C.

Example 68

5-Methyl-9-(2-hydroxypyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(218) ##STR00096##

(219) Example 68 was obtained according to general procedure VI(i), starting from compound 31 in presence of 4-bromo-2-hydroxypyridine. Purification by flash column chromatography on silica gel (MeOH in CH.sub.2Cl.sub.2, 0% to 5%) afforded the product as a brown solid in 38% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.63 (bs, 1H, NH); 7.79 (d, J 1.7 Hz, 1H, Ar); 7.72 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.64 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.60 (d, J 7.9 Hz, 1H, Ar); 7.47 (d, J 6.8 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.75 (d, J 1.7 Hz, 1H, Ar); 6.61 (dd, J 6.8, 1.7 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=332.3. MP: 183-197° C.

Example 69

5-Methyl-9-(5-trifluoromethylpyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(220) ##STR00097##

(221) Example 69 was obtained according to general procedure VI(i), starting from compound 31 in presence of 2-bromo-5-trifluoromethylpyridine. Purification by preparative HPLC, afforded the product as a beige solid in 18% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.08 (m, 1H, Ar); 8.37 (d, J 8.4 Hz, 1H, Ar); 8.34 (m, 1H, Ar); 8.24 (d, J 1.6 Hz, 1H, Ar); 8.13 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.67 (d, J 7.8 Hz, 1H, Ar); 7.65 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.45 (d, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.51 (m, 2H, cyclopropyl); 0.95 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=384.3. MP: 78-89° C.

Example 70

5-Methyl-9-(pyridazin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(222) ##STR00098##

(223) Example 70 was obtained according to general procedure VI(i), starting from compound 31 in presence of 3-chloro-pyridazine. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 50% to 90%), afforded the product as a beige solid in 67% yield. M/Z (M+H).sup.+=317.1.

Example 71

5-Methyl-9-(2-methoxycarbonylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(224) ##STR00099##

(225) Example 71 was obtained according to general procedure VI(i), starting from compound 31 in presence of methyl 3-bromopicolinate. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 0% to 50%) afforded the product as a white solid in 63% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.67 (dd, J 4.6, 1.5 Hz, 1H, Ar); 8.10 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.69 (dd, J 7.8, 4.6 Hz, 1H, Ar); 7.60 (m, 2H, Ar); 7.53 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.30 (dd, J 7.9, 1.6 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.7, 2.8 Hz, 1H, Ar); 3.71 (s, 3H, CH.sub.3); 2.94 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 0.95 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=374.3. MP: 198-203° C.

Example 72

5-Methyl-9-(2-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(226) ##STR00100##

(227) Under inert atmosphere, to a solution of example 71 (1.0 equiv.) in THF (0.10 mol.Math.L.sup.−1) cooled at −10° C., a solution of methylmagnesium bromide (3.0M in Et.sub.2O, 2.2 equiv.) was added dropwise. The reaction mixture was stirred at −10° C. for 1 hour before being hydrolysed by saturated aqueous ammonium chloride and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 40% to 100%) afforded example 72 as a white solid in 46% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.54 (m, 1H, Ar); 7.55 (m, 1H, Ar); 7.48 (m, 2H, Ar); 7.43 (m, 1H, Ar); 7.34 (dd, J 7.5, 4.8 Hz, 1H, Ar); 7.23 (d, J 7.5 Hz, 1H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.39 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.95 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 1.39 (s, 3H, CH.sub.3); 1.35 (s, 3H, CH.sub.3); 0.93 (m, 1H, cyclopropyl); 0.54 (m, 1H, cyclopropyl). Proton for OH not observed. M/Z (M+H).sup.+=374.3. MP: 220-228° C.

Example 73

7-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(228) ##STR00101##

(229) Example 73 was obtained according to general procedure VI(ii) starting from example 7 in presence of 2-methylpyridine-3-boronic pinacol ester. Purification by flash column chromatography on silica gel (10 to 70% EtOAc in cyclohexane) afforded the product as a beige solid in 59% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 5.8 Hz, 1H, Ar); 8.36 (d, J 7.6 Hz, 1H, Ar); 7.85 (dd, J 7.6, 5.8 Hz, 1H, Ar); 7.57 (m, 2H, Ar); 7.46 (dd, J 10.5, 1.5 Hz, 1H, Ar); 6.89 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.89 (s, 3H, CH.sub.3); 2.69 (s, 3H, CH.sub.3); 1.68 (m, 1H, cyclopropyl); 1.53 (m, 1H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=348.0. MP: 174-188° C.

Example 74

7-Fluoro-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(230) ##STR00102##

(231) Example 74 was obtained according to general procedure VI(ii) starting from example 7 in presence of 6-fluoro-3-pyridinyl boronic acid. Purification by flash column chromatography on silica gel (10 to 100% EtOAc in cyclohexane) afforded the product as a white solid in 41% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.72 (d, J 2.6 Hz, 1H, Ar); 8.45 (ddd, J 8.4, 7.9, 2.6 Hz, 1H, Ar); 7.74 (m, 2H, Ar); 7.66 (dd, J 11.0, 1.6 Hz, 1H, Ar); 7.33 (dd, J 8.4, 2.8 Hz, 1H, Ar); 6.88 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.44 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.67 (m, 1H, cyclopropyl); 1.51 (m, 1H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.62 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=352.0. MP: 220-225° C.

Example 75

10-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(232) ##STR00103##

(233) Example 75 was obtained according to general procedure VI(ii) starting from example 8 in presence of 2-methylpyridine-3-boronic pinacol ester. Purification by flash column chromatography on silica gel (10 to 70% EtOAc in cyclohexane) afforded the product as a brown solid in 29% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (d, J 5.6 Hz, 1H, Ar); 8.35 (d, J 7.5 Hz, 1H, Ar); 7.84 (dd, J 7.5, 5.6 Hz, 1H, Ar); 7.54 (d, J 7.8 Hz, 1H, Ar); 7.45 (m, 2H, Ar); 6.85 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.59 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.64 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=348.0. MP: 166-184° C.

Example 76

10-Fluoro-5-Methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(234) ##STR00104##

(235) Example 76 was obtained according to general procedure VI(ii) starting from example 8 in presence of 6-fluoro-3-pyridinyl boronic acid. Purification by preparative HPLC afforded the product as a white solid in 14% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.42 (s, 1H, Ar); 8.18 (m, 1H, Ar); 7.51-7.44 (m, 3H, Ar); 7.20 (dd, J 8.5, 2.6 Hz, 1H, Ar); 6.98 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.45 (dd, J 3.7, 2.8 Hz, 1H, Ar); 3.04 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.69 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=352.0. MP: 153-157° C.

Example 77

8-Fluoro-5-methyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(236) ##STR00105##

(237) Example 77 was obtained according to general procedure VI(ii) starting from example 9 in presence of 2-methylpyridine-3-boronic pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a beige solid in 56% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (d, J 5.6 Hz, 1H, Ar); 8.36 (d, J 7.5 Hz, 1H, Ar); 7.84 (dd, J 7.5, 5.6 Hz, 1H, Ar); 7.71 (d, J 6.6 Hz, 1H, Ar); 7.65 (d, J 9.5 Hz, 1H, Ar); 7.50 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.87 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.58 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 0.96 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=348.0. MP: 200-210° C.

Example 78

8-Fluoro-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(238) ##STR00106##

(239) Example 78 was obtained according to general procedure VI(ii) starting from example 9 in presence of 6-fluoro-3-pyridinyl boronic acid. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 48% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.55 (s, 1H, Ar); 8.30 (m, 1H, Ar); 7.77 (d, J 6.9 Hz, 1H, Ar); 7.64 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.60 (d, J 10.3 Hz, 1H, Ar); 7.36 (d, J 8.5, 2.8 Hz, 1H, Ar); 6.86 (dd, J 3.7, 1.8 Hz, 1H, Ar); 6.41 (dd, J 3.7, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=352.0. MP: 185-192° C.

Example 79

9-Bromo-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(240) ##STR00107##

(241) A mixture of example 1 (1.0 equiv.) and SelectFluor™ (1.0 equiv.) in acetonitrile (0.10 mol.Math.L.sup.−1) was subjected to microwave irradiation at 100° C. for 10 minutes. The reaction mixture was neutralized with an aqueous solution of 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 afford a 3:1 mixture of product and starting material according to LC/MS analysis. The mixture was obtained as a brown solid in quantitative yield and taken crude to the next step without purification. M/Z (M[.sup.79Br]+H).sup.+=335.2.

Example 80

9-Bromo-2-chloro-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(242) ##STR00108##

(243) Example 80 was prepared according to procedure of example 79, starting from example 5. A 3:1 mixture of product and starting material was obtained according to LC/MS analysis. The mixture was obtained as a brown solid in quantitative yield and taken crude to the next step without purification. M/Z (M[.sup.79Br][.sup.35Cl]+H).sup.+=369.

Example 81

9-(2-Methyl-pyridin-3-yl)-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(244) ##STR00109##

(245) Example 81 was obtained according to general procedure VI(i), starting from example 79 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by preparative HPLC afforded the product as a white solid in 25% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (d, J 5.5 Hz, 1H, Ar); 8.37 (d, J 7.5 Hz, 1H, Ar); 7.89 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.55 (dd, J 7.8, 1.4 Hz, 1H, Ar); 6.76 (dd, J 6.1, 4.2 Hz, 1H, Ar); 6.08 (t, J 6.1 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.69 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.76 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=348.3. MP=150-158° C.

Example 82

9-(2-Methyl-pyridin-3-yl)-2-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(246) ##STR00110##

(247) Example 82 was obtained according to general procedure VI(i), starting from example 5 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded the product as a white solid in 46% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 5.5 Hz, 1H, Ar); 8.39 (d, J 7.5 Hz, 1H, Ar); 7.87 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.75 (d, J 2.0 Hz, 1H, Ar); 7.74 (d, J 1.6 Hz, 1H, Ar); 7.68 (d, J 7.8 Hz, 1H, Ar); 7.51 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.87 (d, J 2.0 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.68 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M[.sup.35Cl]+H).sup.+=364.3. MP=210-219° C.

Example 83

9-(2-Methyl-pyridin-3-yl)-2-chloro-1-fluoro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(248) ##STR00111##

(249) Example 83 was obtained according to general procedure VI(i), starting from example 80 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by preparative HPLC afforded the product as a white solid in 12% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (d, J 5.5 Hz, 1H, Ar); 8.33 (d, J 7.5 Hz, 1H, Ar); 7.87 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.84 (dd, J 5.6, 1.6 Hz, 1H, Ar); 7.77 (d, J 7.9 Hz, 1H, Ar); 7.58 (dd, J 7.9, 1.6 Hz, 1H, Ar); 6.89 (d, J 5.6 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.68 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.83 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M[.sup.35Cl]+H).sup.+=382.2. MP>250° C.

Example 84

9-(2-Methyl-pyridin-3-yl)-3-chloro-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(250) ##STR00112##

(251) Example 84 was obtained according to general procedure VI(i), starting from example 6 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by preparative HPLC afforded the product as a beige solid in 29% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 5.5 Hz, 1H, Ar); 8.39 (d, J 7.5 Hz, 1H, Ar); 7.87 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.72 (d, J 1.6 Hz, 1H, Ar); 7.67 (d, J 7.9 Hz, 1H, Ar); 7.52 (m, 2H, Ar); 6.54 (d, J 3.1 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.68 (s, 3H, CH.sub.3); 1.51 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M[.sup.35Cl]+H).sup.+=364.3. MP=191-208° C.

Example 85

1-Bromo-5-methyl-9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(252) ##STR00113##

(253) At 0° C., a solution of N-bromosuccinimide (1.0 equiv.) in DMF (0.2 mol.Math.L.sup.−1) was added dropwise to a solution of example 65 (1.0 equiv.) in DMF (0.2 mol.Math.L.sup.−1). The reaction mixture was stirred for 1 hour at 0° C. before being hydrolysed and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated under vacuum to afford a 6:1 mixture of product and di-brominated byproduct according to LC/MS analysis. The mixture was obtained as a white solid in 83% yield and taken crude to the next step without purification. .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 2.9 Hz, 1H, Ar); 8.31 (d, J 1.7 Hz, 1H, Ar); 8.12 (m, 2H, Ar); 7.86 (dt, J 8.9, 2.9 Hz, 1H, Ar); 7.68 (d, J 8.0 Hz, 1H, Ar); 6.84 (d, J 4.0 Hz, 1H, Ar); 6.62 (d, J 4.0 Hz, 1H, Ar); 2.90 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=412.0.

Example 86

5-Methyl-1-(2-methyl-2H-pyrazol-3-yl)9-(5-fluoropyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(254) ##STR00114##

(255) Example 86 was obtained according to general procedure VI(i) starting from example 85 in presence of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester. Purification by preparative HPLC afforded the product as a beige solid in 12% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.58 (d, J 2.9 Hz, 1H, Ar); 7.97 (dd, J 8.0, 1.7 Hz, 1H, Ar); 7.77 (dt, J 8.7, 2.9 Hz, 1H, Ar); 7.66 (d, J 8.0 Hz, 1H, Ar); 7.53 (dd, J 8.7, 4.2 Hz, 1H, Ar); 7.39 (d, J 1.9 Hz, 1H, Ar); 7.33 (dd, J 1.7 Hz, 1H, Ar); 6.97 (d, J 3.8 Hz, 1H, Ar); 6.69 (d, J 3.8 Hz, 1H, Ar); 6.20 (d, J 1.9 Hz, 1H, Ar); 3.55 (s, 3H, CH.sub.3); 2.93 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.80 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=414.1. MP=143-166° C.

Example 87

5,8-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(256) ##STR00115##

(257) Under inert atmosphere, a mixture of example 13 (1.0 equiv.), dimethyl zinc (2M solution in toluene, 4.0 equiv.) and 1,1′-bis(1,2-diphenylphosphino)ferrocene palladium (II) chloride, complex with dichloromethane (0.2 equiv.) in dioxane (0.15 mol.Math.L.sup.−1) was heated at 90° C. for 16 hours. The reaction mixture was neutralized with aqueous potassium carbonate 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 (20% to 100% EtOAc in cyclohexane) to afford example 87 as a grey solid in 98% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.42 (d, J 8.1 Hz, 1H, Ar); 7.41 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.32 (d, J 1.7 Hz, 1H, Ar); 7.28 (dd, J 8.1, 1.7 Hz, 1H, Ar); 6.82 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.37 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.90 (s, 3H, CH.sub.3); 2.36 (s, 3H, CH.sub.3); 1.44 (m, 2H, cyclopropyl); 0.87 (m, 1H, cyclopropyl); 0.49 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=253.2. MP=143-150° C.

Example 88

8-Morpholin-4-yl-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(258) ##STR00116##

(259) Under inert atmosphere, a mixture of example 13 (1.0 equiv.), morpholine (1.2 equiv.), sodium tert-butoxide (1.2 equiv.) and bis(tri-tert-butylphosphine)palladium (0.3 equiv.) in toluene (0.2 mol.Math.L.sup.−1) was heated at 100° C. for 3 hours. 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 by preparative HPLC to afford example 88 as a white solid in 41% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.38 (d, J 8.6 Hz, 1H, Ar); 7.35 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.04 (d, J 2.6 Hz, 1H, Ar); 7.00 (dd, J 8.6, 2.6 Hz, 1H, Ar); 6.78 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.33 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.76 (m, 4H, 2CH.sub.2); 3.19 (m, 4H, 2CH.sub.2); 2.91 (s, 3H, CH.sub.3); 1.52 (m, 1H, cyclopropyl); 1.37 (m, 1H, cyclopropyl); 0.86 (m, 1H, cyclopropyl); 0.49 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=324.2. MP=140-146° C.

Example 89

5,7-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(260) ##STR00117##

(261) Example 89 was obtained according to the procedure of example 87, starting from example 14 (1.0 equiv.). Purification by preparative HPLC afforded example 89 as a white solid in 37% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.44 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.33 (m, 2H, Ar); 7.19 (m, 1H, Ar); 6.79 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.37 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 2.56 (s, 3H, CH.sub.3); 1.65 (m, 1H, cyclopropyl); 1.44 (m, 1H, cyclopropyl); 0.77 (m, 1H, cyclopropyl); 0.47 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=253.2. MP=126-134° C.

Example 90

5,10-Dimethyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(262) ##STR00118##

(263) Example 90 was obtained according to the procedure of example 87, starting from example 15 (1.0 equiv.). Purification by flash column chromatography on silica gel (0% to 50% EtOAc in cyclohexane) afforded example 90 as a white solid in 47% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.38-7.26 (m, 4H, Ar); 6.70 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.34 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.83 (s, 3H, CH.sub.3); 2.32 (s, 3H, CH.sub.3); 1.36 (m, 2H, cyclopropyl); 0.75 (m, 1H, cyclopropyl); 0.45 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=253.2. MP=200-207° C.

Example 91

10-Cyano-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(264) ##STR00119##

(265) Under inert atmosphere, a mixture of example 15 (1.0 equiv.), zinc cyanide (1.6 equiv.), and tetrakis(triphenylphosphine)palladium (0.1 equiv.) in DMF (0.10 mol.Math.L.sup.−1) was subjected to microwave irradiation at 130° C. for 10 minutes. The reaction mixture was poured into water and the grey precipitate was collected by filtration. Purification by flash column chromatography on silica gel (0% to 70% EtOAc in cyclohexane) afforded example 91 as a beige solid in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.99 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.87 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.59 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.54 (t, J 7.8 Hz, 1H, Ar); 6.87 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.48 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.88 (s, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.86 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=264.2. MP=250° C.

Example 92

10-(2-Methyl-pyridin-3-yl)-5-methyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(266) ##STR00120##

(267) Example 92 was obtained according to general procedure VI(i), starting from example 15 and 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (0% to 100% EtOAc in cyclohexane) afforded the product as a beige solid in 37% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 5.6 Hz, 1H, Ar); 8.43 (d, J 7.7 Hz, 1H, Ar); 7.87 (dd, J 7.7, 5.6 Hz, 1H, Ar); 7.72 (dd, J 7.5, 1.5 Hz, 1H, Ar); 7.56 (t, J 7.5 Hz, 1H, Ar); 7.48 (dd, J 7.5, 1.5 Hz, 1H, Ar); 6.70 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.25 (dd, J 2.8, 1.8 Hz, 1H, Ar); 6.09 (dd, J 3.8, 2.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.67 (s, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.85 (m, 1H, cyclopropyl); 0.53 (m, 1H, cyclopropyl). Proton for HCl not observed. M/Z (M+H).sup.+=330.2. MP=250° C.

Example 93

5-Methyl-2-phenyl-9-pyridin-3-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(268) ##STR00121##

(269) Example 93 was obtained according to general procedure VI(i) starting from example 10 in presence of 3-pyridineboronic acid. Purification by flash column chromatography on silica gel (MeOH in CH.sub.2Cl.sub.2, 0% to 5%) afforded the product as a grey solid in 50% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.33 (d, J 1.7 Hz, 1H, Ar); 8.86 (d, J 5.4 Hz, 1H, Ar); 8.80 (d, J 7.9 Hz, 1H, Ar); 8.23 (d, J 1.9 Hz, 1H, Ar); 8.14 (d, J 1.7 Hz, 1H, Ar); 7.99 (dd, J 7.9, 5.4 Hz, 1H, Ar); 7.88 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.78 (m, 2H, Ar); 7.72 (d, J 7.8 Hz, 1H, Ar); 7.42 (m, 2H, Ar); 7.33 (d, J 1.9 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl not observed. M/Z (M+H).sup.+=392.2. MP: 218-222° C.

Example 94

3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzoic acid

(270) ##STR00122##

(271) Example 94 was obtained according to general procedure VI(i) starting from example 10 in presence of 3-carboxyphenylboronic acid. Purification by flash column chromatography on silica gel (MeOH in CH.sub.2Cl.sub.2, 0% to 5%) afforded the product as a beige solid in 41% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 13.1 (s, 1H, COOH), 8.29 (s, 1H, Ar); 8.22 (d, J 1.9 Hz, 1H, Ar); 8.08 (d, J 7.7 Hz, 1H, Ar); 7.98 (m, 2H, Ar); 7.78 (m, 2H, Ar); 7.65 (m, 3H, Ar); 7.39 (m, 2H, Ar); 7.30 (d, J 1.8 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 1.51 (m, 2H, cyclopropyl); 1.01 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=435.1. MP>250° C.

Example 95

5-Methyl-2-phenyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(272) ##STR00123##

(273) Example 95 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 58% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (dd, J 5.5, 1.3 Hz, 1H, Ar); 8.40 (d, J 7.5 Hz, 1H, Ar); 8.06 (d, J 2.0 Hz, 1H, Ar); 7.87 (m, 1H, Ar); 7.83 (d, J 1.7 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.69 (d, J 7.9 Hz, 1H, Ar); 7.50 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.38 (m, 2H, Ar); 7.32 (d, J 2.0 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=406.1. MP=174-180° C.

Example 96

5-Methyl-2-phenyl-9-(6-amino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(274) ##STR00124##

(275) Example 96 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-aminopyridine-5-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a yellow solid in 36% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 14.2 (bs, 1H, HCl salt); 8.45 (m, 2H, Ar); 8.16 (d, J 1.9 Hz, 1H, Ar); 8.16 (bs, 2H, NH.sub.2); 7.94 (d, J 1.2 Hz, 1H, Ar); 7.77 (m, 2H, Ar); 7.65 (dd, J 8.0, 1.5 Hz, 1H, Ar); 7.62 (d, J 8.0 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.30 (d, J 1.9 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 7.13 (d, J 9.0 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 1.01 (m, 1H, cyclopropyl); 0.62 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=407.2. MP>250° C.

Example 97

5-Methyl-2-phenyl-9-(2,6-dimethyl-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(276) ##STR00125##

(277) Example 97 was obtained according to general procedure VI(i) starting from example 10 in presence of 2,6-dimethylpyridine-4-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a beige solid in 59% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 15.8 (bs, 1H, HCl salt); 8.22 (m, 3H, Ar); 8.20 (d, J 2.0 Hz, 1H, Ar); 7.96 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.78 (m, 3H, Ar); 7.42 (m, 2H, Ar); 7.34 (d, J 2.0 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 2.77 (s, 6H, 2CH.sub.3); 1.56 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=420.2. MP=227-234° C.

Example 98

5-Methyl-2-phenyl-9-(5-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(278) ##STR00126##

(279) Example 98 was obtained according to general procedure VI(i) starting from example 10 in presence of 5-methylpyridine-3-boronic acid. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a beige solid in 55% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.18 (s, 1H, Ar); 8.74 (m, 2H, Ar); 8.20 (d, J 1.9 Hz, 1H, Ar); 8.13 (d, J 1.6 Hz, 1H, Ar); 7.84 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.78 (m, 2H, Ar); 7.71 (d, J 7.9 Hz, 1H, Ar); 7.41 (m, 2H, Ar); 7.32 (d, J 1.9 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 2.54 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.64 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=406.2. MP=212-220° C.

Example 99

5-Methyl-2-phenyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(280) ##STR00127##

(281) Example 99 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-ethylpyridine-3-boronic acid. Purification by flash column chromatography on silica gel (80% EtOAc in cyclohexane to 100% EtOAc) afforded the product as a beige solid in 56% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (d, J 5.5 Hz, 1H, Ar); 8.31 (s, 1H, Ar); 8.06 (d, J 2.0 Hz, 1H, Ar); 7.85 (m, 2H, Ar); 7.74 (m, 2H, Ar); 7.68 (d, J 7.9 Hz, 1H, Ar); 7.45 (dd, J 7.7, 1.5 Hz, 1H, Ar); 7.38 (m, 2H, Ar); 7.32 (d, J 2.0 Hz, 1H, Ar); 7.22 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 2.97 (q, J 8.0 Hz, 2H, CH.sub.2CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.21 (t, J 8.0 Hz, 3H, CH.sub.2CH.sub.3); 1.05 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=420.2. MP=179-183° C.

Example 100

5-Methyl-2-phenyl-9-(2-trifluoromethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(282) ##STR00128##

(283) Example 100 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-(trifluoromethyl)pyridine-3-boronic acid. Purification by flash column chromatography on silica gel (0% to 60% EtOAc in cyclohexane) afforded the product as a white solid in 29% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (d, J 5.4 Hz, 1H, Ar); 8.08 (d, J 7.8 Hz, 1H, Ar); 8.05 (d, J 2.0 Hz, 1H, Ar); 7.83 (dd, J 7.8, 5.4 Hz, 1H, Ar); 7.74 (m, 3H, Ar); 7.63 (d, J 7.8 Hz, 1H, Ar); 7.36 (m, 3H, Ar); 7.31 (d, J 2.0 Hz, 1H, Ar); 7.21 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=460.3. MP=199-204° C.

Example 101

5-Methyl-2-phenyl-9-(4-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(284) ##STR00129##

(285) Example 101 was obtained according to general procedure VI(i) starting from example 10 in presence of 4-methylpyridine-3-boronic acid. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a beige solid in 48% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.86 (s, 1H, Ar); 8.78 (d, J 5.7 Hz, 1H, Ar); 8.09 (d, J 2.0 Hz, 1H, Ar); 7.96 (d, J 5.7 Hz, 1H, Ar); 7.85 (d, J 1.6 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.70 (d, J 7.8 Hz, 1H, Ar); 7.52 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.39 (m, 2H, Ar); 7.33 (d, J 2.0 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 2.55 (s, 3H, CH.sub.3); 1.56 (m, 2H, cyclopropyl); 1.06 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=406.3. MP=205-217° C.

Example 102

5-Methyl-2-phenyl-9-(pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(286) ##STR00130##

(287) Example 102 was obtained according to general procedure VI(i) starting from example 10 in presence of 4-pyridineboronic acid. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cycloheaxane) afforded the product as a white solid in 70% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.99 (d, J 6.2 Hz, 2H, Ar); 8.46 (d, J 6.2 Hz, 2H, Ar); 8.26 (d, J 2.0 Hz, 1H, Ar); 8.24 (d, J 1.7 Hz, 1H, Ar); 7.98 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.78 (m, 3H, Ar); 7.42 (m, 2H, Ar); 7.34 (d, J 2.0 Hz, 1H, Ar); 7.26 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.56 (m, 2H, cyclopropyl); 1.06 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=392.4. MP=220-230° C.

Example 103

5-Methyl-2-phenyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(288) ##STR00131##

(289) Example 103 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-methylpyridine-5-boronic acid. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 71% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.23 (d, J 1.5 Hz, 1H, Ar); 8.81 (dd, J 8.1, 1.5 Hz, 1H, Ar); 8.23 (d, J 2.0 Hz, 1H, Ar); 8.13 (d, J 1.7 Hz, 1H, Ar); 7.95 (d, J 8.1 Hz, 1H, Ar); 7.84 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.78 (m, 2H, Ar); 7.71 (d, J 7.8 Hz, 1H, Ar); 7.42 (m, 2H, Ar); 7.33 (d, J 2.0 Hz, 1H, Ar); 7.26 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 2.77 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=406.3. MP=200-215° C.

Example 104

5-Methyl-2-phenyl-9-(pyrimidin-5-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(290) ##STR00132##

(291) Example 104 was obtained according to general procedure VI(i) starting from example 10 in presence of 5-pyrimidine boronic acid pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 60% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.31 (s, 2H, Ar); 9.25 (s, 1H, Ar); 8.23 (d, J 2.0 Hz, 1H, Ar); 8.11 (d, J 1.7 Hz, 1H, Ar); 7.81 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.79 (m, 2H, Ar); 7.69 (d, J 7.8 Hz, 1H, Ar); 7.41 (m, 2H, Ar); 7.32 (d, J 2.0 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=393.1. MP=168-173° C.

Example 105

5-Methyl-2-phenyl-9-(2-methyl-pyridin-4-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(292) ##STR00133##

(293) Example 105 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-methylpyridine-4-boronic acid. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded the product as a white solid in 57% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.85 (d, J 6.0 Hz, 1H, Ar); 8.39 (s, 1H, Ar); 8.30 (d, J 6.0 Hz, 1H, Ar); 8.22 (m, 2H, Ar); 7.97 (dd, J 7.9, 1.4 Hz, 1H, Ar); 7.79 (m, 3H, Ar); 7.42 (m, 2H, Ar); 7.34 (d, J 2.0 Hz, 1H, Ar); 7.27 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 2.78 (s, 3H, CH.sub.3); 1.56 (m, 2H, cyclopropyl); 1.07 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=406.2. MP=225-235° C.

Example 106

5-Methyl-2-phenyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(294) ##STR00134##

(295) Example 106 was obtained according to general procedure VI(i) starting from example 10 in presence of 6-fluoropyridine-3-boronic acid. Purification by flash column chromatography on silica gel (50% EtOAc in cyclohexane to 100% EtOAc) afforded the product as a beige solid in 22% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.72 (d, J 2.4 Hz, 1H, Ar); 8.44 (dt, J 8.4, 2.6 Hz, 1H, Ar); 8.19 (d, J 2.0 Hz, 1H, Ar); 7.99 (d, J 1.6 Hz, 1H, Ar); 7.77 (m, 2H, Ar); 7.69 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.63 (d, J 7.8 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.32 (dd, J 8.4, 2.6 Hz, 1H, Ar); 7.30 (d, J 2.0 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 1.02 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=410.3. MP=177-184° C.

Example 107

5-Methyl-2-phenyl-9-(2,6-dimethyl-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(296) ##STR00135##

(297) Example 107 was obtained according to general procedure VI(i) starting from compound 29 in presence of 3-bromo-2,6-dimethylpyridine. Purification by flash column chromatography on silica gel (50% EtOAc in cyclohexane to 100% EtOAc) afforded the product as a yellow solid in 60% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.42 (d, J 7.9 Hz, 1H, Ar); 8.05 (d, J 2.0 Hz, 1H, Ar); 7.82 (m, 2H, Ar); 7.74 (m, 2H, Ar); 7.69 (d, J 7.8 Hz, 1H, Ar); 7.49 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.39 (m, 2H, Ar); 7.32 (d, J 2.0 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 2.80 (s, 3H, CH.sub.3); 2.75 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=420.3. MP=206-214° C.

Example 108

5-Methyl-2-phenyl-9-pyrazin-2-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(298) ##STR00136##

(299) Example 108 was obtained according to general procedure VI(i) starting from compound 29 in presence of chloropyrazine. Purification by flash column chromatography on silica gel (50% EtOAc in cyclohexane to 100% EtOAc) afforded the product as a beige solid in 39% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.46 (d, J 1.4 Hz, 1H, Ar); 8.78 (dd, 2.3, 1.4, 1H, Ar); 8.69 (d, J 2.3 Hz, 1H, Ar); 8.37 (d, J 1.5 Hz, 1H, Ar); 8.21 (d, J 2.0 Hz, 1H, Ar); 8.13 (dd, J 7.9, 1.5 Hz, 1H, Ar); 7.80 (m, 2H, Ar); 7.70 (d, J 7.9 Hz, 1H, Ar); 7.41 (m, 2H, Ar); 7.33 (d, J 2.0 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=393.3. MP=130-141° C.

Example 109

5-Methyl-2-phenyl-9-pyridazin-3-yl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(300) ##STR00137##

(301) Example 109 was obtained according to general procedure VI(i) starting from compound 29 in presence of 3-chloropyridazine. Purification by flash column chromatography on silica gel (50% EtOAc in cyclohexane to 100% EtOAc) afforded the product as a brown solid in 40% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.27 (dd, J 4.8, 1.3 Hz, 1H, Ar); 8.42 (dd, J 8.5, 1.3 Hz, 1H, Ar); 8.35 (d, J 1.4 Hz, 1H, Ar); 8.20 (d, J 1.9 Hz, 1H, Ar); 8.17 (dd, J 7.8, 1.4 Hz, 1H, Ar); 7.85 (dd, J 8.5, 4.8 Hz, 1H, Ar); 7.80 (m, 2H, Ar); 7.72 (d, J 7.8 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.32 (d, J 1.9 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=393.3.

Example 110

5-Methyl-2-phenyl-9-(5-fluoro-pyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(302) ##STR00138##

(303) Example 110 was obtained according to general procedure VI(i) starting from compound 29 in presence of 2-bromo-5-fluoropyridine. Purification by flash column chromatography on silica gel (0% to 50% EtOAc in cyclohexane) afforded the product as a yellow solid in 57% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.70 (d, J 2.8 Hz, 1H, Ar); 8.24 (m, 2H, Ar); 8.17 (d, J 2.0 Hz, 1H, Ar); 8.04 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.89 (dt, J 8.7, 2.8 Hz, 1H, Ar); 7.79 (m, 2H, Ar); 7.64 (d, J 7.9 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.30 (d, J 2.0 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 2.95 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 1.01 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=410.2. MP=140-151° C.

Example 111

5-Methyl-2-phenyl-9-(pyridin-2-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(304) ##STR00139##

(305) Example 111 was obtained according to general procedure VI(i) starting from compound 29 in presence of 2-bromopyridine. Purification by flash column chromatography on silica gel (0% to 80% EtOAc in cyclohexane) afforded the product as a yellow solid in 57% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (m, 1H, Ar); 8.34 (d, J 1.7 Hz, 1H, Ar); 8.30 (d, J 8.1 Hz, 1H, Ar); 8.26 (d, J 2.0 Hz, 1H, Ar); 8.18 (m, 1H, Ar); 8.07 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.80 (m, 2H, Ar); 7.70 (d, J 7.9 Hz, 1H, Ar); 7.62 (m, 1H, Ar); 7.41 (m, 2H, Ar); 7.31 (d, J 2.0 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=392.3. MP=185-198° C.

Example 112

5-methyl-2-phenyl-9-(6-ethylpyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(306) ##STR00140##

(307) Example 112 was obtained according to general procedure VI(i) starting from compound 29 in presence of 5-bromo-2-ethylpyridine. Purification by flash column chromatography on silica gel (40% to 100% EtOAc in cyclohexane) afforded the product as a yellow solid in 46% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 9.18 (s, 1H, Ar); 8.73 (d, J 7.8 Hz, 1H, Ar); 8.22 (d, J 2.0 Hz, 1H, Ar); 8.11 (d, J 1.4 Hz, 1H, Ar); 7.90 (d, J 7.8 Hz, 1H, Ar); 7.82-7.77 (m, 3H, Ar); 7.70 (d, J 7.9 Hz, 1H, Ar); 7.42 (m, 2H, Ar); 7.33 (d, J 2.0 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 3.03 (q, J 7.7 Hz, 2H, CH.sub.2—CH.sub.3); 2.97 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.35 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3); 1.04 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=420.4. MP=209-212° C.

Example 113

5-Methyl-2-phenyl-9-(2-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(308) ##STR00141##

(309) Example 113 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-fluoro-3-pyridineboronic acid. Purification by flash column chromatography on silica gel (0% to 70% EtOAc in cyclohexane) afforded the product as a beige solid in 59% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.29 (m, 2H, Ar); 8.12 (d, J 1.9 Hz, 1H, Ar); 7.91 (s, 1H, Ar); 7.76 (m, 2H, Ar); 7.65 (d, J 7.8 Hz, 1H, Ar); 7.60 (m, 1H, Ar); 7.52 (m, 1H, Ar); 7.38 (m, 2H, Ar); 7.31 (d, J 1.9 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.02 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=410.2. MP=143-149° C.

Example 114

5-Methyl-2-phenyl-9-(6-dimethylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(310) ##STR00142##

(311) Example 114 was obtained according to general procedure VI(i) starting from example 10 in presence of 6-fluoropyridine-3-boronic acid and dimethylamine (2M in THF, 2 equiv.). Purification by flash column chromatography on silica gel (0% to 60% EtOAc in cyclohexane) afforded the product as a yellow solid in 53% yield. Salt formation was performed by method (ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.39 (s, 2H, Ar); 8.19 (d, J 2.0 Hz, 1H, Ar); 7.95 (d, J 1.5 Hz, 1H, Ar); 7.77 (m, 2H, Ar); 7.66 (dd, J 7.9, 1.5 Hz, 1H, Ar); 7.61 (d, J 7.9 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.30 (d, J 2.0 Hz, 1H, Ar); 7.24 (m, 2H, Ar); 3.26 (s, 6H, 2CH.sub.3); 2.95 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 1.01 (m, 1H, cyclopropyl); 0.62 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=435.3. MP=200-208° C.

Example 115

9-Dimethylamino-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(312) ##STR00143##

(313) Under inert atmosphere, a mixture of example 10 (1.0 equiv.), dimethylamine (2M solution in THF, 1.2 equiv.), sodium tertbutoxide (1.2 equiv.) and bis(tri-tert-butylphosphine)palladium (0.1 equiv.) in toluene (0.2 mol.Math.L.sup.−1) was heated at 100° C. for 16 hours. The reaction mixture was neutralized with aqueous potassium carbonate 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 (0% to 50% EtOAc in cyclohexane) to afford example 115 as a beige solid in 53% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.01 (d, J 2.0 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.38 (m, 2H, Ar); 7.33 (d, J 8.4 Hz, 1H, Ar); 7.22 (m, 2H, Ar); 7.02 (s, 1H, Ar); 6.78 (m, 1H, Ar); 3.00 (s, 6H, 2CH.sub.3); 2.90 (s, 3H, CH.sub.3); 1.39 (m, 2H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.52 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=358.3. MP=160-170° C.

Example 116

5-Methyl-2-phenyl-9-(2-methoxy-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(314) ##STR00144##

(315) Example 116 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-methoxy-3-pyridineboronic acid. Purification by flash column chromatography on silica gel (0% to 40% EtOAc in cyclohexane) afforded the product as a white solid in 59% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.23 (dd, J 5.0, 1.8 Hz, 1H, Ar); 8.09 (d, J 1.9 Hz, 1H, Ar); 7.91 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.81 (s, 1H, Ar); 7.76 (m, 2H, Ar); 7.57 (m, 2H, Ar); 7.38 (m, 2H, Ar); 7.29 (d, J 1.9 Hz, 1H, Ar); 7.22 (m, 1H, Ar); 7.14 (dd, J 7.2, 5.0 Hz, 1H, Ar); 3.97 (s, 3H, OCH.sub.3); 2.96 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 1.00 (m, 1H, cyclopropyl); 0.64 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=422.2. MP=183-186° C.

Example 117

5-Methyl-2-phenyl-9-(6-cyano-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(316) ##STR00145##

(317) A solution of example 106 (1.0 equiv.) and tetraethylammonium cyanide (8.0 equiv.) in DMA (0.10 mol.Math.L.sup.−1) was subjected to microwave irradiation for 40 minutes at 120° C. The reaction mixture was neutralized with aqueous potassium carbonate 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 (0% to 50% EtOAc in cyclohexane) to afford example 117 as a white solid in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.28 (d, J 2.3 Hz, 1H, Ar); 8.53 (dd, J 8.2, 2.3 Hz, 1H, Ar); 8.24 (d, J 2.0 Hz, 1H, Ar); 8.20 (d, J 8.2 Hz, 1H, Ar); 8.11 (d, J 1.7 Hz, 1H, Ar); 7.83 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.78 (m, 2H, Ar); 7.70 (d, J 7.9 Hz, 1H, Ar); 7.41 (m, 2H, Ar); 7.32 (d, J 2.0 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=417.3. MP=200-204° C.

Example 118

5-Methyl-2-phenyl-9-(6-methylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(318) ##STR00146##

(319) Example 118 was obtained according to general procedure VI(i) starting from example 10 in presence of 6-(methylamino)-3-pyridinylboronic acid pinacol ester. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded the product as a yellow solid in 33% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (bs, 1H, NH); 8.35 (m, 2H, Ar); 8.18 (d, J 1.9 Hz, 1H, Ar); 7.94 (s, 1H, Ar); 7.76 (m, 2H, Ar); 7.65 (dd, J 7.9, 1.5 Hz, 1H, Ar); 7.61 (d, J 7.9 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.30 (d, J 1.9 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 7.15 (d, J 9.2 Hz, 1H, Ar); 3.01 (s, 3H, CH.sub.3); 2.94 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 1.01 (m, 1H, cyclopropyl); 0.62 (m, 1H, cyclopropyl). HCl proton not observed. M/Z (M+H).sup.+=421.3. MP>250° C.

Example 119

5-Methyl-2-phenyl-9-(2-dimethylamino-pyridin-3-yl)-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(320) ##STR00147##

(321) Example 119 was obtained according to general procedure VI(i) starting from example 10 in presence of 2-fluoro-3-pyridine boronic acid and dimethylamine (2M in THF, 6 equiv.). The reaction mixture was subjected to microwave irradiation for 3 hours at 150° C. Purification by flash column chromatography on silica gel (0% to 50% EtOAc in cyclohexane) afforded the product as a yellow solid in 28% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.16 (dd, J 5.6, 1.7 Hz, 1H, Ar); 8.08 (d, J 1.8 Hz, 1H, Ar); 7.95 (m, 1H, Ar); 7.79 (s, 1H, Ar); 7.75 (m, 2H, Ar); 7.61 (d, J 7.8 Hz, 1H, Ar); 7.44 (dd, J 7.8, 1.4 Hz, 1H, Ar); 7.38 (m, 2H, Ar); 7.31 (d, J 1.8 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 7.09 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 2.82 (s, 6H, 2CH.sub.3); 1.51 (m, 2H, cyclopropyl); 1.02 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=435.3. MP=209-213° C.

Example 120

8-Morpholin-4-yl-5-methyl-2-phenyl-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(322) ##STR00148##

(323) Under inert atmosphere, a mixture of example 16 (1.0 equiv.), morpholine (1.2 equiv.), sodium tert-butoxide (1.2 equiv.) and bis(tri-tert-butylphosphine)palladium (0.3 equiv.) in toluene (0.25 mol.Math.L.sup.−1) was heated at 100° C. for 3 hours. 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 by preparative HPLC to afford example 120 as a white solid in 23% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.86 (d, J 2.0 Hz, 1H, Ar); 7.72 (m, 2H, Ar); 7.50 (dd, J 8.3, 1.6 Hz, 1H, Ar); 7.37 (m, 2H, Ar); 7.20 (m, 2H, Ar); 7.04 (m, 2H, Ar); 3.76 (m, 4H, 2CH.sub.2); 3.20 (m, 4H, 2CH.sub.2); 2.92 (s, 3H, CH.sub.3); 1.53 (m, 1H, cyclopropyl); 1.39 (m, 1H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.56 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=400.4. MP=117-123° C.

Example 121

9-(2,6-Dimethyl-pyridin-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(324) ##STR00149##

(325) Example 121 was obtained according to general procedure VI(i) starting from example 11 in presence of 2,6-dimethylpyridine-4-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (50% to 80% EtOAc in cyclohexane) afforded the product as a white solid in 48% yield. Salt formation was performed by method VII(iii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.37 (s, 1H, Ar); 8.13-8.00 (m, 4H, Ar); 7.98 (d, J 8.0 Hz, 1H, Ar); 7.81 (d, J 8.0 Hz, 1H, Ar); 7.60 (s, 1H, Ar); 7.51 (m, 2H, Ar); 7.43 (m, 1H, Ar); 3.03 (s, 3H, CH.sub.3); 2.72 (s, 6H, 2CH.sub.3); 1.64 (m, 2H, cyclopropyl); 1.14 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=421.1. MP>250° C.

Example 122

9-(2-Methyl-pyridin-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(326) ##STR00150##

(327) Example 122 was obtained according to general procedure VI(i) starting from example 11 in presence of 2-methylpyridine-4-boronic acid. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded the product as a white solid in 65% yield. Salt formation was performed by method VII(iii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.83 (d, J 6.2 Hz, 1H, Ar); 8.41 (d, J 1.8 Hz, 1H, Ar); 8.34 (s, 1H, Ar); 8.24 (d, J 6.2 Hz, 1H, Ar); 8.08 (m, 2H, Ar); 8.03 (dd, J 8.0, 1.8 Hz, 1H, Ar); 7.83 (d, J 8.0 Hz, 1H, Ar); 7.61 (s, 1H, Ar); 7.51 (m, 2H, Ar); 7.43 (m, 1H, Ar); 3.04 (s, 3H, CH.sub.3); 2.79 (s, 3H, CH.sub.3); 1.64 (m, 2H, cyclopropyl); 1.15 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=407.2. MP>250° C.

Example 123

2,9-Diphenyl-5-methyl-2-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(328) ##STR00151##

(329) Example 123 was obtained according to general procedure VI(i) starting from example 11 in presence of phenyl boronic acid. Purification by flash column chromatography on silica gel (40% to 80% EtOAc in cyclohexane) afforded the product as a white solid in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.12 (d, J 1.7 Hz, 1H, Ar); 8.05 (m, 2H, Ar); 7.76 (m, 2H, Ar); 7.72 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.66 (d, J 7.8 Hz, 1H, Ar); 7.56 (s, 1H, Ar); 7.54-7.42 (m, 6H, Ar); 3.03 (s, 3H, CH.sub.3); 1.59 (m, 2H, cyclopropyl); 1.10 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=392.1. MP=133-140° C.

Example 124

9-(4-Amino-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(330) ##STR00152##

(331) Example 124 was obtained according to general procedure VI(i) starting from example 11 in presence of 4-aminophenyl boronic acid pinacol ester. Purification by flash column chromatography on silica gel (40% to 80% EtOAc in cyclohexane) afforded the product as a white solid in 45% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.07 (m, 3H, Ar); 7.72 (m, 2H, Ar); 7.68 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.63 (d, J 7.8 Hz, 1H, Ar); 7.55 (s, 1H, Ar); 7.49 (m, 2H, Ar); 7.42 (m, 1H, Ar); 7.19 (d, J 8.0 Hz, 2H, Ar); 3.02 (s, 3H, CH.sub.3); 1.59 (m, 2H, cyclopropyl); 1.10 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). Protons for NH.sub.2 not observed. M/Z (M+H).sup.+=407.2. MP=195-209° C.

Example 125

9-(2-Methyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(332) ##STR00153##

(333) Example 125 was obtained according to general procedure VI(i) starting from example 11 in presence of 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (40% to 100% EtOAc in cyclohexane) afforded the product as a beige solid in 65% yield. Salt formation was performed by method VII(iii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (d, J 5.6 Hz, 1H, Ar); 8.36 (d, J 6.8 Hz, 1H, Ar); 8.03 (m, 2H, Ar); 8.00 (d, J 1.7 Hz, 1H, Ar); 7.86 (dd, J 6.8, 5.6 Hz, 1H, Ar); 7.75 (d, J 7.9 Hz, 1H, Ar); 7.59 (s, 1H, Ar); 7.57 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.48 (m, 2H, Ar); 7.40 (m, 1H, Ar); 3.43 (s, 3H, CH.sub.3); 2.67 (s, 3H, CH.sub.3); 1.63 (m, 2H, cyclopropyl); 1.14 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=407.1. MP=185-206° C.

Example 126

9-(2,6-Dimethyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(334) ##STR00154##

(335) Example 126 was obtained according to general procedure VI(i) starting from compound 30 in presence of 3-bromo-2,6-dimethylpyridine. Purification by flash column chromatography on silica gel (60% to 100% EtOAc in cyclohexane) afforded the product as a beige solid in 27% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.37 (bs, 1H, Ar); 8.02 (m, 2H, Ar); 7.98 (d, J 1.7 Hz, 1H, Ar); 7.77 (bs, 1H, Ar); 7.74 (d, J 7.9 Hz, 1H, Ar); 7.59 (s, 1H, Ar); 7.55 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.48 (m, 2H, Ar); 7.41 (m, 1H, Ar); 3.04 (s, 3H, CH.sub.3); 2.77 (s, 3H, CH.sub.3); 2.68 (s, 3H, CH.sub.3); 1.63 (m, 2H, cyclopropyl); 1.13 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=421.1. MP>250° C.

Example 127

9-(6-Amino-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(336) ##STR00155##

(337) Example 127 was obtained according to general procedure VI(i) starting from example 11 in presence of 2-aminopyridine-5-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a beige solid in 54% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.41 (d, J 2.0 Hz, 1H, Ar); 8.34 (dd, J 9.2, 2.0 Hz, 1H, Ar); 8.11 (d, J 1.5 Hz, 1H, Ar); 8.05 (m, 4H, Ar+NH.sub.2); 7.71 (dd, J 7.9, 1.5 Hz, 1H, Ar); 7.67 (d, J 7.9 Hz, 1H, Ar); 7.57 (s, 1H, Ar); 7.48 (m, 2H, Ar); 7.41 (m, 1H, Ar); 7.09 (d, J 9.2 Hz, 1H, Ar); 3.00 (s, 3H, CH.sub.3); 1.59 (m, 2H, cyclopropyl); 1.10 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=408.1. MP>250° C.

Example 128

9-(4-Methoxy-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(338) ##STR00156##

(339) Example 128 was obtained according to general procedure VI(i) starting from example 11 in presence of 4-methoxyphenyl boronic acid. Purification by flash column chromatography on silica gel (40% to 80% EtOAc in cyclohexane) afforded the product as a white solid in 47% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.06 (m, 3H, Ar); 7.70 (m, 2H, Ar); 7.67 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.62 (d, J 7.8 Hz, 1H, Ar); 7.55 (s, 1H, Ar); 7.49 (m, 2H, Ar); 7.42 (m, 1H, Ar); 7.08 (d, J 8.8 Hz, 2H, Ar); 3.82 (s, 3H, O—CH.sub.3); 3.02 (s, 3H, CH.sub.3); 1.58 (m, 2H, cyclopropyl); 1.10 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=422.1. MP>250° C.

Example 129

9-(3-Cyano-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(340) ##STR00157##

(341) Example 129 was obtained according to general procedure VI(i) starting from example 11 in presence of 3-cyanophenyl boronic acid. Purification by flash column chromatography on silica gel (40% to 80% EtOAc in cyclohexane) afforded the product as a white solid in 64% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.28 (s, 1H, Ar); 8.21 (d, J 1.8 Hz, 1H, Ar); 8.13 (d, J 7.9 Hz, 1H, Ar); 8.07 (m, 2H, Ar); 7.90 (d, J 7.9 Hz, 1H, Ar); 7.81 (dd, J 8.0, 1.8 Hz, 1H, Ar); 7.73 (t, J 7.9 Hz, 1H, Ar); 7.70 (d, J 8.0 Hz, 1H, Ar); 7.57 (s, 1H, Ar); 7.49 (m, 2H, Ar); 7.42 (m, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 1.61 (m, 2H, cyclopropyl); 1.12 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=417.1. MP=185-190° C.

Example 130

9-(3-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(342) ##STR00158##

(343) Example 130 was obtained according to general procedure VI(i) starting from example 11 in presence of 3-chlorophenyl boronic acid. Purification by flash column chromatography on silica gel (40% to 80% EtOAc in cyclohexane) afforded the product as a white solid in 59% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.14 (d, J 1.7 Hz, 1H, Ar); 8.06 (m, 2H, Ar); 7.83 (m, 1H, Ar); 7.75 (m, 2H, Ar); 7.67 (d, J 7.9 Hz, 1H, Ar); 7.57 (s, 1H, Ar); 7.55-7.47 (m, 4H, Ar); 7.42 (m, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 1.59 (m, 2H, cyclopropyl); 1.09 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=426.1. MP=177-182° C.

Example 131

9-(2-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(344) ##STR00159##

(345) Example 131 was obtained according to general procedure VI(i) starting from example 11 in presence of 2-chlorophenyl boronic acid. Purification by flash column chromatography on silica gel (40% to 80% EtOAc in cyclohexane) afforded the product as a white solid in 37% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.02 (m, 2H, Ar); 7.93 (d, J 1.7 Hz, 1H, Ar); 7.68 (d, J 8.0 Hz, 1H, Ar); 7.62 (m, 1H, Ar); 7.57 (s, 1H, Ar); 7.55-7.45 (m, 6H, Ar); 7.40 (m, 1H, Ar); 3.04 (s, 3H, CH.sub.3); 1.61 (m, 2H, cyclopropyl); 1.11 (m, 1H, cyclopropyl); 0.69 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=426.1. MP=163-170° C.

Example 132

9-(Oxazol-5-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(346) ##STR00160##

(347) Under inert atmosphere, a mixture of example 11 (1.0 equiv.), oxazole (2.0 equiv.), potassium carbonate (3.0 equiv.), pivalic acid (0.4 equiv.), palladium acetate (0.05 equiv.) and di(1-adamantyl)-n-butylphosphine hydriodide (0.1 equiv.) in dimethylacetamide (0.15 mol.Math.L.sup.−1) was heated at 110° C. for 4 hours. The reaction mixture was neutralized with aqueous HCl (1 N) 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 (40% to 100% EtOAc in cyclohexane) to afford example 132 as a white solid in 32% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.52 (s, 1H, Ar); 8.19 (d, J 1.7 Hz, 1H, Ar); 8.06 (m, 2H, Ar); 7.91 (s, 1H, Ar); 7.80 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.69 (d, J 7.9 Hz, 1H, Ar); 7.57 (s, 1H, Ar); 7.51 (m, 2H, Ar); 7.43 (m, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 1.60 (m, 2H, cyclopropyl); 1.10 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=383.1. MP=214-220° C.

Example 133

3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzoic acid

(348) ##STR00161##

(349) Example 133 was obtained according to general procedure VI(i) starting from example 11 in presence of 3-carboxyphenyl boronic acid. Purification by precipitation from water and colletion by filtration afforded the product as a beige solid in 74% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 13.12 (bs, 1H, COOH); 8.24 (s, 1H, Ar); 8.13 (d, J 1.7 Hz, 1H, Ar); 8.06-7.99 (m, 3H, Ar); 7.96 (s, 1H, Ar); 7.76 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.68 (d, J 7.9 Hz, 1H, Ar); 7.64 (t, J 7.8 Hz, 1H, Ar); 7.56 (s, 1H, Ar); 7.49 (m, 2H, Ar); 7.41 (m, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 1.61 (m, 2H, cyclopropyl); 1.11 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=436.1. MP=211-217° C.

Example 134

9-(1H-pyrazol-4-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(350) ##STR00162##

(351) Example 134 was obtained according to general procedure VI(i) starting from example 11 in presence of 1H-pyrazole-4-boronic acid. Purification by flash column chromatography on silica gel (40% to 100% EtOAc in cyclohexane) afforded the product as a white solid in 45% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 13.06 (bs, 1H, NH); 8.36 (s, 1H, Ar); 8.07 (m, 3H, Ar); 8.04 (s, 1H, Ar); 7.66 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.54 (d, J 7.9 Hz, 1H, Ar); 7.53 (s, 1H, Ar); 7.50 (m, 2H, Ar); 7.42 (m, 1H, Ar); 3.00 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.06 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=382.0. MP=199-208° C.

Example 135

9-(4-Chloro-phenyl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(352) ##STR00163##

(353) Example 135 was obtained according to general procedure VI(i) starting from example 11 in presence of potassium 4-chlorophenyltrifluoroborate. Purification by flash column chromatography on silica gel (0% to 60% EtOAc in cyclohexane) afforded the product as a white solid in 53% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.12 (d, J 1.7 Hz, 1H, Ar); 8.06 (m, 2H, Ar); 7.80 (m, 2H, Ar); 7.73 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.66 (d, J 7.9 Hz, 1H, Ar); 7.57 (m, 3H, Ar); 7.50 (m, 2H, Ar); 7.42 (m, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 1.59 (m, 2H, cyclopropyl); 1.10 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=426.1. MP=248-255° C.

Example 136

9-(1H-pyrazol-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(354) ##STR00164##

(355) Example 136 was obtained according to general procedure VI(i) starting from example 11 in presence of potassium 1H-pyrazole-3-trifluoroborate. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a beige solid in 45% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 13.02 (bs, 1H, NH); 8.31 (s, 1H, Ar); 8.06 (m, 2H, Ar); 7.85 (m, 2H, Ar); 7.59 (d, J 8.0 Hz, 1H, Ar); 7.55 (s, 1H, Ar); 7.50 (m, 2H, Ar); 7.42 (m, 1H, Ar); 6.85 (s, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 1.58 (m, 2H, cyclopropyl); 1.09 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=382.0. MP=218-224° C.

Example 137

9-Cyano-5-methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(356) ##STR00165##

(357) Under inert atmosphere, a mixture of example 11 (1.0 equiv.), zinc cyanide (1.6 equiv.), and tetrakis(triphenylphosphine)palladium (0.1 equiv.) in DMF (0.1 mol.Math.L.sup.−1) was subjected to microwave irradiation at 120° C. for 10 minutes. The reaction mixture was poured into water and the grey precipitate was collected by filtration. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded example 137 as a white solid in 51% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.33 (d, J 1.6 Hz, 1H, Ar); 8.06 (m, 2H, Ar); 7.91 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.79 (d, J 7.9 Hz, 1H, Ar); 7.60 (s, 1H, Ar); 7.50 (m, 2H, Ar); 7.42 (m, 1H, Ar); 3.00 (s, 3H, CH.sub.3); 1.61 (m, 2H, cyclopropyl); 1.11 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=341.1. MP=196-200° C.

Example 138

5-Methyl-2-phenyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(358) ##STR00166##

(359) Under hydrogen atmosphere (1 bar), a mixture of example 11 (1.0 equiv.), and palladium 10% on charcoal (0.2 equiv.) in a 1:1 mixture of MeOH and DMF (0.1 mol.Math.L.sup.−1) was stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give a colorless oil. Trituration in water afforded example 138 as a white solid in 45% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.02 (d, J 7.2 Hz, 2H, Ar); 7.89 (d, J 8.0 Hz, 1H, Ar); 7.58-7.40 (m, 7H, Ar); 2.99 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.06 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=316.1. MP=212-218° C.

Example 139

5-Methyl-2-phenyl-9-(pyrrolidin-1-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(360) ##STR00167##

(361) Under inert atmosphere, a mixture of example 11 (1.0 equiv.), pyrrolidine (1.5 equiv.), sodium tert-butoxide (3.0 equiv.), BINAP (0.2 equiv.) and palladium acetate (0.1 equiv.) in toluene (0.06 mol.Math.L.sup.−1) was heated at 120° C. for 2 hours. The reaction mixture was neutralized with aqueous HCl (1 N) 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 (0% to 30% EtOAc in cyclohexane) to afford example 139 as a white solid in 27% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.94 (m, 2H, Ar); 7.46 (m, 2H, Ar); 7.37 (m, 2H, Ar); 7.27 (m, 1H, Ar); 6.90 (s, 1H, Ar); 6.52 (m, 1H, Ar); 3.23 (m, 4H, 2 N—CH.sub.2); 2.92 (s, 3H, CH.sub.3); 1.93 (m, 4H, 2 CH.sub.2); 1.42 (m, 2H, cyclopropyl); 0.94 (m, 1H, cyclopropyl); 0.42 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=385.1. MP=226-230° C.

Example 140

9-(2-Methyl-pyridin-3-yl)-5-methyl-2-phenyl-spiro[benzo[f]imidazo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(362) ##STR00168##

(363) Example 140 was obtained according to general procedure VI(i) starting from example 12 in presence of 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a yellow solid in 57% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.84 (d, J 5.6 Hz, 1H, Ar); 8.51 (d, J 7.8 Hz, 1H, Ar); 8.48 (s, 1H, Ar); 8.00-7.93 (m, 4H, Ar); 7.78 (d, J 7.8 Hz, 1H, Ar); 7.63 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.46 (m, 2H, Ar); 7.32 (m, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 2.77 (s, 3H, CH.sub.3); 1.59 (m, 2H, cyclopropyl); 1.10 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=407.1. MP=235-240° C.

Compound 41: N,N-dimethyl-3-(4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide

(364) Compound 41 was obtained according to general procedure VI(i) starting from compound 22 in presence of N,N-dimethyl-3-boronobenzene sulfonamide. Purification by flash column chromatography on silica gel (50% to 70% EtOAc in cyclohexane) afforded the product as an orange solid in 96% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.71 (s, 1H, NH); 8.25 (d, J 1.9 Hz, 1H, Ar); 8.18 (m, 1H, Ar); 8.03 (s, 1H, Ar); 7.96 (d, J 1.6 Hz, 1H, Ar); 7.88 (m, 4H, Ar); 7.68 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.56 (d, J 7.8 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.33 (d, J 1.9 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 2.66 (s, 6H, 2CH.sub.3); 1.60 (m, 1H, cyclopropyl); 1.27 (m, 1H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=484.0. MP>250° C.

Example 141

N,N-dimethyl-3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide

(365) ##STR00169##

(366) Example 141 was obtained according to general procedure III, starting from compound 41 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by preparative HPLC afforded the product as a white solid in 35% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.22 (d, J 1.9 Hz, 1H, Ar); 8.17 (m, 1H, Ar); 8.03 (s, 1H, Ar); 7.97 (d, J 1.4 Hz, 1H, Ar); 7.79 (m, 4H, Ar); 7.70 (dd, J 7.8, 1.4 Hz, 1H, Ar); 7.65 (d, J 7.8 Hz, 1H, Ar); 7.40 (m, 2H, Ar); 7.30 (d, J 1.9 Hz, 1H, Ar); 7.23 (m, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 2.66 (s, 6H, 2CH.sub.3); 1.52 (m, 2H, cyclopropyl); 1.02 (m, 1H, cyclopropyl); 0.64 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=498.2. MP=198-205° C.

Compound 42: N,N-dimethyl-3-(4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide

(367) Compound 42 was obtained according to general procedure VI(i) starting from compound 23 in presence of N,N-dimethyl-3-boronobenzene sulfonamide. Purification by flash column chromatography on silica gel (50% to 70% EtOAc in cyclohexane) afforded the product as an orange solid in 98% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.23 (s, 1H, NH); 8.16 (s, 1H, Ar); 8.12 (m, 1H, Ar); 8.03 (m, 2H, Ar); 7.99 (s, 1H, Ar); 7.81 (m, 2H, Ar); 7.76 (d, J 7.8 Hz, 1H, Ar); 7.62 (d, J 7.8 Hz, 1H, Ar); 7.58 (s, 1H, Ar); 7.49 (m, 2H, Ar); 7.42 (m, 1H, Ar); 2.67 (s, 6H, 2CH.sub.3); 1.60 (m, 1H, cyclopropyl); 1.27 (m, 1H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=485.0. MP=234-240° C.

Example 142

N,N-dimethyl-3-(5-methyl-4-oxo-2-phenyl-4,5-dihydrospiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-9-yl)benzenesulfonamide

(368) ##STR00170##

(369) Example 142 was obtained according to general procedure III, starting from compound 42 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by preparative HPLC afforded the product as a white solid in 23% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.15 (d, J 1.8 Hz, 1H, Ar); 8.11 (m, 1H, Ar); 8.04 (m, 2H, Ar); 7.99 (s, 1H, Ar); 7.78 (m, 3H, Ar); 7.70 (d, J 7.9 Hz, 1H, Ar); 7.57 (s, 1H, Ar); 7.48 (m, 2H, Ar); 7.40 (m, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 2.66 (s, 6H, 2CH.sub.3); 1.60 (m, 2H, cyclopropyl); 1.11 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=499.1. MP=182-189° C.

Example 143

5-Methyl-2-(pyridine-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(370) ##STR00171##

(371) Example 143 was obtained according to general procedure VI(i) starting from example 17 in presence of 3-pyridine-boronic acid. Purification by preparative HPLC afforded the product as a yellow solid in 16% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 9.34 (m, 1H, Ar); 8.81 (m, 2H, Ar); 8.72 (m, 1H, Ar); 8.49 (d, J 1.9 Hz, 1H, Ar); 8.45 (m, 1H, Ar); 7.98 (m, 1H, Ar); 7.91 (m, 1H, Ar); 7.86 (d, J 1.4 Hz, 1H, Ar); 7.73 (d, J 7.8 Hz, 1H, Ar); 7.62 (d, J 1.9 Hz, 1H, Ar); 7.56 (dd, J 7.8, 1.4 Hz, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 2.75 (s, 3H, CH.sub.3); 1.56 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=407.2. MP>250° C.

Example 144

2,5-Dimethyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(372) ##STR00172##

(373) Under inert atmosphere, a mixture of example 17 (1.0 equiv.), dimethyl zinc (2M solution in toluene, 4.0 equiv.) and 1,1′-bis(1,2-diphenylphosphino)ferrocene palladium (II) chloride, complex with dichloromethane (0.2 equiv.) in dioxane (0.15 mol.Math.L.sup.−1) was heated at 90° C. for 16 hours. The reaction mixture was neutralized with aqueous potassium carbonate 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 (0% to 5% MeOH in dichloromethane) to afford example 144 as a white solid in 78% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (d, J 5.7 Hz, 1H, Ar); 8.43 (d, J 7.5 Hz, 1H, Ar); 7.91 (dd, J 7.5, 5.7 Hz, 1H, Ar); 7.69 (m, 2H, Ar); 7.49 (dd, J 7.8, 1.4 Hz, 1H, Ar); 7.39 (d, J 1.4 Hz, 1H, Ar); 6.79 (d, J 1.7 Hz, 1H, Ar); 2.99 (s, 3H, CH.sub.3); 2.73 (s, 3H, CH.sub.3); 2.19 (s, 3H, CH.sub.3); 1.56 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=344.2. MP=162-175° C.

Example 145

5-Methyl-2-(pyridine-4-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(374) ##STR00173##

(375) Example 145 was obtained according to general procedure VI(i) starting from example 17 in presence of 4-pyridine-boronic acid. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a beige solid in 27% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.84 (d, J 6.7 Hz, 2H, Ar); 8.79 (d, J 5.3 Hz, 1H, Ar); 8.75 (d, J 1.8 Hz, 1H, Ar); 8.39 (m, 3H, Ar); 7.89 (m, 2H, Ar); 7.75 (m, 2H, Ar); 7.60 (dd, J 7.8, 1.4 Hz, 1H, Ar); 3.00 (s, 3H, CH.sub.3); 2.74 (s, 3H, CH.sub.3); 1.58 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.71 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=407.2. MP>250° C.

Example 146

5-Methyl-2-(1H-pyrazol-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(376) ##STR00174##

(377) Example 146 was obtained according to general procedure VI(i) starting from example 17 in presence of potassium 1H-pyrazole-3-trifluoroborate. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a beige solid in 24% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (dd, J 5.8, 1.4 Hz, 1H, Ar); 8.54 (dd, J 7.9, 1.4 Hz, 1H, Ar); 7.99 (m, 2H, Ar); 7.79 (d, J 1.6 Hz, 1H, Ar); 7.73 (d, J 2.1 Hz, 1H, Ar); 7.71 (d, J 7.8 Hz, 1H, Ar); 7.52 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.28 (d, J 1.9 Hz, 1H, Ar); 6.62 (d, J 2.1 Hz, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 2.76 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=396.3. MP=240-250° C.

Example 147

5-Methyl-2-(2-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(378) ##STR00175##

(379) Example 147 was obtained according to general procedure VI(i) starting from example 17 in presence of 2-chlorophenyl boronic acid. Purification by preparative HPLC afforded the product as a yellow solid in 23% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.74 (d, J 5.1 Hz, 1H, Ar); 8.34 (d, J 7.5 Hz, 1H, Ar); 7.96 (d, J 2.0 Hz, 1H, Ar); 7.81 (m, 2H, Ar); 7.74 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.69 (d, J 7.9 Hz, 1H, Ar); 7.51 (m, 2H, Ar); 7.38 (m, 1H, Ar); 7.30 (m, 2H, Ar); 2.98 (s, 3H, CH.sub.3); 2.68 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M[.sup.35Cl]+H).sup.+=440.3. MP=192-200° C.

Example 148

5-Methyl-2-(3-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(380) ##STR00176##

(381) Example 148 was obtained according to general procedure VI(i) starting from example 17 in presence of 3-chlorophenyl boronic acid. Purification by preparative HPLC afforded the product as a yellow solid in 25% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 5.1 Hz, 1H, Ar); 8.37 (d, J 7.5 Hz, 1H, Ar); 8.14 (d, J 1.9 Hz, 1H, Ar); 7.83 (m, 3H, Ar); 7.70 (m, 2H, Ar); 7.50 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.40 (t, J 8.0 Hz, 1H, Ar); 7.36 (d, J 1.9 Hz, 1H, Ar); 7.27 (d, J 8.0 Hz, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M[.sup.35Cl]+H).sup.+=440.3. MP=211-220° C.

Example 149

5-Methyl-2-(4-chlorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(382) ##STR00177##

(383) Example 149 was obtained according to general procedure VI(i) starting from example 17 in presence of potassium 4-chlorophenyltrifluoroborate. Purification by preparative HPLC afforded the product as a yellow solid in 23% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 5.1 Hz, 1H, Ar); 8.38 (d, J 7.5 Hz, 1H, Ar); 8.09 (d, J 1.9 Hz, 1H, Ar); 7.87 (dd, J 7.5, 5.1 Hz, 1H, Ar); 7.82 (d, J 1.3 Hz, 1H, Ar); 7.78 (d, J 8.4 Hz, 2H, Ar); 7.69 (d, J 7.8 Hz, 1H, Ar); 7.50 (dd, J 7.8, 1.3 Hz, 1H, Ar); 7.43 (d, J 8.4 Hz, 2H, Ar); 7.33 (d, J 1.9 Hz, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 2.71 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M[.sup.35Cl]+H).sup.+=440.3. MP=214-231° C.

Example 150

5-Methyl-2-(4-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(384) ##STR00178##

(385) Example 150 was obtained according to general procedure VI(i) starting from example 17 in presence of potassium 4-fluorophenylboronic acid. Purification by preparative HPLC afforded the product as a beige solid in 29% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 5.1 Hz, 1H, Ar); 8.37 (d, J 7.5 Hz, 1H, Ar); 8.04 (d, J 2.0 Hz, 1H, Ar); 7.85 (dd, J 7.5, 5.1 Hz, 1H, Ar); 7.79 (m, 3H, Ar); 7.68 (d, J 7.8 Hz, 1H, Ar); 7.49 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.31 (d, J 2.0 Hz, 1H, Ar); 7.21 (t, J 8.9 Hz, 2H, Ar); 2.97 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.65 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=424.2. MP=226-230° C.

Example 151

5-Methyl-2-(2-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(386) ##STR00179##

(387) Example 151 was obtained according to general procedure VI(i) starting from example 17 in presence of 2-fluorophenyl boronic acid. Purification by preparative HPLC afforded the product as a yellow solid in 20% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 5.1 Hz, 1H, Ar); 8.40 (d, J 7.5 Hz, 1H, Ar); 7.99 (s, 1H, Ar); 7.86 (m, 3H, Ar); 7.70 (d, J 7.9, 1H, Ar); 7.51 (d, J 7.9 Hz, 1H, Ar); 7.33 (s, 1H, Ar); 7.26 (m, 3H, Ar); 2.97 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=424.3. MP=185-190° C.

Example 152

5-Methyl-2-(3-fluorophenyl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(388) ##STR00180##

(389) Example 152 was obtained according to general procedure VI(i) starting from example 17 in presence of 3-fluorophenyl boronic acid. Purification by flash column chromatography on silica gel (EtOAc in cylohexane, 50% to 100%) afforded the product as a yellow solid in 35% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 5.4 Hz, 1H, Ar); 8.39 (d, J 7.5 Hz, 1H, Ar); 8.13 (d, J 2.0 Hz, 1H, Ar); 7.87 (dd, J 7.5, 5.4 Hz, 1H, Ar); 7.83 (d, J 1.5 Hz, 1H, Ar); 7.70 (d, J 7.8 Hz, 1H, Ar); 7.60 (m, 2H, Ar); 7.51 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.42 (m, 1H, Ar); 7.37 (d, J 2.0 Hz, 1H, Ar); 7.04 (m, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 2.72 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=424.3. MP=183-190° C.

Example 153

5-Methyl-2-cyano-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(390) ##STR00181##

(391) Under inert atmosphere, a mixture of example 17 (1.0 equiv.), zinc cyanide (3.2 equiv.), and tetrakis(triphenylphosphine)palladium (0.2 equiv.) in DMF (0.1 mol.Math.L.sup.−1) was subjected to microwave irradiation at 130° C. for 30 minutes. The reaction mixture was poured into water and the grey precipitate was collected by filtration. Purification by flash column chromatography on silica gel (80% to 100% EtOAc in cyclohexane) afforded example 153 as a white solid in 35% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.50 (dd, J 4.9, 1.7 Hz, 1H, Ar); 8.41 (d, J 1.9 Hz, 1H, Ar); 7.73 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.71 (d, J 1.7 Hz, 1H, Ar); 7.64 (d, J 7.8 Hz, 1H, Ar); 7.49 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.33 (dd, J 7.8, 4.9 Hz, 1H, Ar); 7.25 (d, J 1.9 Hz, 1H, Ar); 2.95 (s, 3H, CH.sub.3); 2.48 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 0.98 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=355.3. MP>250° C.

Example 154

5-Methyl-2-dimethylamino-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(392) ##STR00182##

(393) Under inert atmosphere, a mixture of example 17 (1.0 equiv.), dimethylamine (2M solution in THF, 2.4 equiv.), sodium tertbutoxide (1.2 equiv.) and bis(tri-tert-butylphosphine)palladium (0.2 equiv.) in toluene (0.2 mol.Math.L.sup.−1) was heated at 90° C. for 2 days. The reaction mixture was neutralized with aqueous potassium carbonate 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 (0% to 5% MeOH in dichloromethane) to afford example 154 as a yellow solid in 11% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (d, J 5.1 Hz, 1H, Ar); 8.43 (d, J 7.5 Hz, 1H, Ar); 7.91 (dd, J 7.5, 5.1 Hz, 1H, Ar); 7.72 (d, J 1.2 Hz, 1H, Ar); 7.68 (d, J 7.8 Hz, 1H, Ar); 7.58 (s, 1H, Ar); 7.50 (dd, J 7.8, 1.2 Hz, 1H, Ar); 7.00 (s, 1H, Ar); 3.01 (s, 6H, 2CH.sub.3); 2.95 (s, 3H, CH.sub.3); 2.69 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.00 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=373.3. MP=120-134° C.

Example 155

5-Methyl-2-cyclopropyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(394) ##STR00183##

(395) Under inert atmosphere, a mixture of example 17 (1.0 equiv.), cyclopropylzinc bromide (0.5M solution in THF, 0.1 mol.Math.L.sup.−1), copper iodide (0.2 equiv.) and bis(tri-tert-butylphosphine)palladium (0.2 equiv.) was heated at 80° C. for 1 hour. The reaction mixture was neutralized with aqueous potassium carbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by preparative HPLC to afford example 155 as a beige solid in 15% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (d, J 5.1 Hz, 1H, Ar); 8.41 (d, J 7.5 Hz, 1H, Ar); 7.90 (dd, J 7.5, 5.1 Hz, 1H, Ar); 7.64 (m, 2H, Ar); 7.44 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.34 (d, J 2.0 Hz, 1H, Ar); 6.65 (d, J 2.0 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.80 (m, 1H, cyclopropyl); 1.51 (m, 2H, cyclopropyl); 0.98 (m, 1H, cyclopropyl); 0.86 (m, 2H, cyclopropyl); 0.60 (m, 3H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=370.3. MP=190-198° C.

Example 156

5-Methyl-2-cyclopentyl-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(396) ##STR00184##

(397) Under inert atmosphere, a mixture of example 17 (1 equiv.), cyclopentylzinc bromide (0.5M solution in THF, 2.2 equiv.) and bis(tri-tert-butylphosphine)palladium (0.2 equiv.) in dioxane (0.2 mol.Math.L.sup.−1) was heated at 100° C. for 1 hour. The reaction mixture was neutralized with aqueous potassium carbonate 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 (0% to 5% MeOH in dichloromethane) to afford example 156 as a yellow solid in 43% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (d, J 5.5 Hz, 1H, Ar); 8.40 (d, J 7.4 Hz, 1H, Ar); 7.88 (dd, J 7.4, 5.5 Hz, 1H, Ar); 7.67 (d, J 1.6 Hz, 1H, Ar); 7.65 (d, J 7.8 Hz, 1H, Ar); 7.43 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.35 (d, J 1.9 Hz, 1H, Ar); 6.78 (d, J 1.9 Hz, 1H, Ar); 2.95 (m, 1H, CH); 2.93 (s, 3H, CH.sub.3); 2.68 (s, 3H, CH.sub.3); 2.02 (m, 2H, 2CH); 1.74 (m, 2H, 2CH); 1.56 (m, 6H, 2cyclopropyl+4CH); 0.97 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=398.4. MP=230-235° C.

Example 157

5-Methyl-2-(thiazol-2-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(398) ##STR00185##

(399) Under inert atmosphere, a mixture of example 17 (1.0 equiv.), 2-thiazolzinc bromide (0.5M solution in THF, 0.1 mol.Math.L.sup.−1) copper iodide (0.4 equiv.) and bis(tri-tert-butylphosphine)palladium (0.2 equiv.) was heated at 80° C. for 8 hours. The reaction mixture was neutralized with aqueous potassium carbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by preparative HPLC to afford example 157 as a beige solid in 15% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.68 (d, J 5.5 Hz, 1H, Ar); 8.37 (d, J 7.5 Hz, 1H, Ar); 8.06 (d, J 1.9 Hz, 1H, Ar); 7.81 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.76 (d, J 1.5 Hz, 1H, Ar); 7.70 (d, J 3.3 Hz, 1H, Ar); 7.59 (d, J 7.8 Hz, 1H, Ar); 7.53 (d, J 3.3 Hz, 1H, Ar); 7.42 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.13 (d, J 1.9 Hz, 1H, Ar); 2.85 (s, 3H, CH.sub.3); 2.59 (s, 3H, CH.sub.3); 1.42 (m, 2H, cyclopropyl); 0.93 (m, 1H, cyclopropyl); 0.57 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=413.3. MP=240-245° C.

Example 158

5-Methyl-2-(thiazol-2-yl)-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(400) ##STR00186##

(401) Example 158 was prepared according to the procedure of example 157, starting from example 18. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded example 158 as a brown solid in 18% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.29 (s, 1H, Ar); 8.93 (d, J 8.5 Hz, 1H, Ar); 8.39 (d, J 1.9 Hz, 1H, Ar); 8.19 (d, J 1.7 Hz, 1H, Ar); 8.02 (d, J 8.5 Hz, 1H, Ar); 7.89 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.85 (d, J 3.3 Hz, 1H, Ar); 7.73 (d, J 7.8 Hz, 1H, Ar); 7.68 (d, J 3.3 Hz, 1H, Ar); 7.27 (d, J 1.9 Hz, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 2.80 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=413.2. MP=228-239° C.

Example 159

5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(402) ##STR00187##

(403) Example 159 was obtained according to general procedure VI(i) starting from example 18 in presence of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a greenish solid in 33% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 9.26 (d, J 1.6 Hz, 1H, Ar); 8.85 (dd, J 8.3, 1.6 Hz, 1H, Ar); 8.16 (d, J 1.5 Hz, 1H, Ar); 8.06 (d, J 2.0 Hz, 1H, Ar); 7.99 (d, J 8.3 Hz, 1H, Ar); 7.87 (dd, J 7.9, 1.5 Hz, 1H, Ar); 7.73 (d, J 7.9 Hz, 1H, Ar); 7.45 (d, J 1.8 Hz, 1H, Ar); 7.19 (d, J 2.0 Hz, 1H, Ar); 6.55 (d, J 1.8 Hz, 1H, Ar); 4.03 (s, 3H, CH.sub.3); 2.97 (s, 3H, CH.sub.3); 2.79 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=410.4. MP=187-194° C.

Example 160

5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(2-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(404) ##STR00188##

(405) Example 160 was obtained according to general procedure VI(i) starting from example 17 in presence of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) afforded the product as a yellow solid in 31% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.81 (d, J 5.5 Hz, 1H, Ar); 8.49 (d, J 7.5 Hz, 1H, Ar); 7.95 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.86 (m, 2H, Ar); 7.72 (d, J 7.8 Hz, 1H, Ar); 7.54 (dd, J 7.8, 1.3 Hz, 1H, Ar); 7.41 (d, J 1.8 Hz, 1H, Ar); 7.18 (d, J 2.0 Hz, 1H, Ar); 6.52 (d, J 1.8 Hz, 1H, Ar); 3.99 (s, 3H, CH.sub.3); 2.97 (s, 3H, CH.sub.3); 2.74 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=410.3. MP=229-237° C.

Example 161

5-Methyl-2-dimethylamino-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(406) ##STR00189##

(407) Under inert atmosphere, a mixture of example 18 (1.0 equiv.), dimethylamine (2M solution in THF, 2.4 equiv.), sodium tertbutoxide (1.2 equiv.) and bis(tri-tert-butylphosphine)palladium (0.2 equiv.) in toluene (0.2 mol.Math.L.sup.−1) was heated at 90° C. for 16 hours. The reaction mixture was neutralized with aqueous potassium carbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4, concentrated and purified by preparative HPLC to afford example 161 as a yellow solid in 20% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 9.19 (s, 1H, Ar); 8.73 (d, J 8.2 Hz, 1H, Ar); 8.00 (s, 1H, Ar); 7.90 (d, J 8.2 Hz, 1H, Ar); 7.80 (d, J 8.0 Hz, 1H, Ar); 7.76 (s, 1H, Ar); 7.68 (d, J 8.0 Hz, 1H, Ar); 6.97 (s, 1H, Ar); 3.03 (s, 6H, 2CH.sub.3); 2.93 (s, 3H, CH.sub.3); 2.74 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=373.3. MP=183-190° C.

Example 162

5-Methyl-2-(2-fluorophenyl)-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(408) ##STR00190##

(409) Example 162 was obtained according to general procedure VI(i) starting from example 19 in presence of 2-fluoroboronic acid. Purification by preparative HPLC afforded the product as a white solid in 17% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (m, 1H, Ar); 8.36 (m, 1H, Ar); 7.97 (s, 1H, Ar); 7.86 (m, 2H, Ar); 7.80 (s, 1H, Ar); 7.69 (m, 1H, Ar); 7.46 (m, 1H, Ar); 7.33 (s, 1H, Ar); 7.26 (m, 3H, Ar); 2.97 (m, 5H, CH.sub.3+CH.sub.2—CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.21 (t, J 6.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.02 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=438.3. MP=189-195° C.

Example 163

5-Methyl-2-(2-methyl-2H-pyrazol-3-yl)-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(410) ##STR00191##

(411) Example 163 was obtained according to general procedure VI(i) starting from example 19 in presence of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester. Purification by preparative HPLC afforded the product as a white solid in 13% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (d, J 4.8 Hz, 1H, Ar); 8.41 (d, J 7.2 Hz, 1H, Ar); 7.90 (dd, J 7.2, 4.8 Hz, 1H, Ar); 7.86 (d, J 1.9 Hz, 1H, Ar); 7.84 (d, J 1.5 Hz, 1H, Ar); 7.71 (d, J 7.8 Hz, 1H, Ar); 7.49 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.41 (d, J 1.8 Hz, 1H, Ar); 7.18 (d, J 1.9 Hz, 1H, Ar); 6.52 (d, J 1.8 Hz, 1H, Ar); 3.98 (s, 3H, CH.sub.3); 2.97 (m, 5H, CH.sub.3+CH.sub.2—CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.22 (t, J 7.6 Hz, 3H, CH.sub.2—CH.sub.3); 1.04 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=424.4. MP=187-192° C.

(412) General Procedure VIII: Reductive Cyclization of Intermediate C, C″ into Benzodiazepinone L, L″ (Scheme 3).

(413) At 0° C., sodium borohydrate (10 equiv.) was slowly added to a mixture of intermediate C, C″ (1.0 equiv.) and cobalt chloride hexahydrate (2.0 equiv.) in methanol (0.15 mol.Math.L.sup.−1). The reaction mixture was heated for 24 hours at 85° C. The reaction mixture was neutralized with an aqueous solution of ammonium chloride 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 (unsing a gradient of EtOAc in cyclohexane as eluent) to afford the product.

Compound 43: 9-Bromo-2-phenyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(414) Compound 43 was prepared according to procedure VIII starting from compound 8. It was obtained as a white solid in 38% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.40 (m, 1H, NH); 8.10 (d, J 2.0 Hz, 1H, Ar); 7.91 (d, J 1.9 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.55 (dd, J 8.0, 1.9 Hz, 1H, Ar); 7.45 (d, J 8.0 Hz, 1H, Ar); 7.39 (m, 2H, Ar); 7.32 (d, J 2.0 Hz, 1H, Ar); 7.24 (m, 1H, Ar); 4.13 (s, 2H, CH.sub.2). M/Z (M[.sup.79Br]+H).sup.+=353.0.

Example 164

9-Bromo-5-methyl-2-phenyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(415) ##STR00192##

(416) Example 164 was prepared according to general procedure III, starting from compound 43 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by filtration after hydrolysis afforded the product as a white solid in 97% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.10 (s, 1H, Ar); 7.94 (s, 1H, Ar); 7.75 (m, 2H, Ar); 7.60 (m, 2H, Ar); 7.39 (m, 2H, Ar); 7.32-7.24 (m, 2H, Ar); 4.39 (s, 2H, CH.sub.2); 3.08 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=367.0. MP=76-84° C.

Example 165

9-(6-Amino-pyridin-3-yl)-5-methyl-2-phenyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one, hydrochloride

(417) ##STR00193##

(418) Example 165 was obtained according to general procedure VI(i) starting from example 164 in presence of 2-aminopyridine-5-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 44% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 14.30 (bs, 1H, HCl salt); 8.50 (d, J 1.9 Hz, 1H, Ar); 8.45 (dd, J 9.3, 2.0 Hz, 1H, Ar); 8.17 (d, J 2.0 Hz, 1H, Ar); 8.11 (bs, 2H, NH.sub.2); 7.94 (d, J 1.6 Hz, 1H, Ar); 7.74 (m, 3H, Ar); 7.68 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.41 (m, 2H, Ar); 7.32 (d, J 1.9 Hz, 1H, Ar); 7.25 (m, 1H, Ar); 7.12 (d, J 9.3 Hz, 1H, Ar); 4.44 (s, 2H, CH.sub.2); 3.10 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=381.1. MP>250° C.

Compound 44: 1-[2-Cyano-5-(2-methyl-pyridin-3-yl)-phenyl]-4-phenyl-1H-imidazole-2-carboxylic acid ethyl ester

(419) Compound 44 was obtained according to general procedure V, starting from compound 10 and 2-methylpyridine-3-boronic acid pinacol ester. It was isolated as a yellow oil in 98% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.55 (dd, J 4.8, 1.7 Hz, 1H, Ar); 8.37 (s, 1H, Ar); 8.20 (d, J 7.9 Hz, 1H, Ar); 7.96 (d, J 1.6 Hz, 1H, Ar); 7.90 (m, 2H, Ar); 7.82 (dd, J 8.0, 1.7 Hz, 1H, Ar); 7.75 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.46 (m, 2H, Ar); 7.39 (dd, J 8.0, 4.8 Hz, 1H, Ar); 7.34 (m, 1H, Ar); 4.23 (q, J 7.0 Hz, 2H, CH.sub.2—CH.sub.3); 2.51 (s, 3H, CH.sub.3); 1.18 (t, J 7.0 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M+H).sup.+=409.1.

Compound 45: 9-(2-Methylpyridin-3-yl)-2-phenyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one

(420) Compound 45 was obtained according to general procedure VIII starting from compound 44. It was obtained as a white solid in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.98 (m, 1H, NH); 8.86 (d, J 5.5 Hz, 1H, Ar); 8.56 (d, J 7.9 Hz, 1H, Ar); 8.51 (s, 1H, Ar); 8.02 (dd, J 7.9, 5.5 Hz, 1H, Ar); 7.93 (m, 3H, Ar); 7.76 (d, J 7.8 Hz, 1H, Ar); 7.63 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.46 (m, 2H, Ar); 7.33 (m, 1H, Ar); 4.32 (s, 2H, CH.sub.2); 2.78 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=367.1. MP=240-250° C.

Example 166

5-Methyl-9-(2-methylpyridin-3-yl)-2-phenyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one, hydrochloride

(421) ##STR00194##

(422) Example 166 was prepared according to general procedure III, starting from compound 45 in presence of iodomethane. The reaction mixture was stirred at room temperature for 3 hours. Purification by filtration after hydrolysis afforded the product as a white solid in 95% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 5.5 Hz, 1H, Ar); 8.45 (d, J 7.5 Hz, 1H, Ar); 8.40 (s, 1H, Ar); 7.91 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.84 (m, 3H, Ar); 7.80 (d, J 7.8 Hz, 1H, Ar); 7.56 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.37 (m, 2H, Ar); 7.24 (m, 1H, Ar); 4.50 (s, 2H, CH.sub.2); 3.07 (s, 3H, CH.sub.3); 2.69 (s, 3H, CH.sub.3). Proton for HCl salt not observed. M/Z (M+H).sup.+=381.1. MP=240-245° C.

Example 167

5-Ethyl-9-(2-methylpyridin-3-yl)-2-phenyl-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one, hydrochloride

(423) ##STR00195##

(424) Example 167 was prepared according to general procedure III, starting from compound 45 in presence of iodoethane. The reaction mixture was stirred at room temperature for 3 hours. Purification by filtration after hydrolysis afforded the product as a white solid in 61% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.85 (d, J 5.5 Hz, 1H, Ar); 8.56 (d, J 7.5 Hz, 1H, Ar); 8.50 (s, 1H, Ar); 8.01 (dd, J 7.5, 5.5 Hz, 1H, Ar); 7.93 (m, 3H, Ar); 7.91 (d, J 7.8 Hz, 1H, Ar); 7.65 (dd, J 7.8, 1.4 Hz, 1H, Ar); 7.46 (m, 2H, Ar); 7.33 (m, 1H, Ar); 4.60 (s, 2H, CH.sub.2); 3.62 (q, J 6.8 Hz, 2H, CH.sub.2—CH.sub.3); 2.78 (s, 3H, CH.sub.3); 1.18 (t, J 6.8 Hz, 3H, CH.sub.2—CH.sub.3). Proton for HCl salt not observed. M/Z (M+H).sup.+=395.1. MP=200-220° C.

(425) General Procedure IX: Formylation of Benzodiazepinone K into Carboxaldehyde K.sub.3 (Scheme 5).

(426) At 0° C., to a solution of benzodiazepinone K (1.0 equiv.) and dichloromethylmethyl ether (2.2 equiv.) in a mixture of 1,2-dichloroethane (0.30 mol.Math.L.sup.−1) and nitromethane (0.30 mol.Math.L.sup.−1), aluminium chloride (2.2 equiv.) was slowly added. The reaction mixture was stirred for 1 hour and allowed to reach room temperature. Aluminium chloride (2.2 equiv.) was added again and the reaction mixture was stirred for one more hour at room temperature. The reaction mixture was neutralized with aqueous potassium carbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated to dryness to afford the product. No purification, otherwise specified.

Example 168

5-Methyl-9-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(427) ##STR00196##

(428) Example 168 was obtained according to general procedure IX, starting from the free base of example 20. It was isolated as a brown oil in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.87 (s, 1H, COH); 8.51 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.43 (d, J 1.9 Hz, 1H, Ar); 7.75 (m, 2H, Ar); 7.65 (d, J 7.9 Hz, 1H, Ar); 7.49 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.34 (dd, J 7.9, 4.8 Hz, 1H, Ar); 7.19 (d, J 1.9 Hz, 1H, Ar); 3.32 (s, 3H, CH.sub.3); 2.97 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.01 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=358.3.

Example 169

5-Methyl-9-(2-ethyl-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(429) ##STR00197##

(430) Example 169 was obtained according to general procedure IX starting from the free base of example 24. Purification by flash column chromatography (40% to 100% EtOAc in cyclohexane) afforded example 169 as a white solid in 56% yield. M/Z (M+H).sup.+=372.2.

Example 170

5-Methyl-9-(6-methyl-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(431) ##STR00198##

(432) Example 170 was obtained according to general procedure IX, starting from the free base of example 25. It was isolated as a brown oil in quantitative yield. M/Z (M+H).sup.+=358.2.

Example 171

5-Methyl-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(433) ##STR00199##

(434) Example 171 was obtained according to general procedure IX, starting from example 31. It was isolated as a brown oil in quantitative yield. M/Z (M+H).sup.+=362.3.

Example 172

5-(Methyl-d.SUB.3.)-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(435) ##STR00200##

(436) Example 172 was obtained according to general procedure IX starting from example 55. It was isolated as a brown oil in 82% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.89 (s, 1H, COH); 8.72 (d, J 2.6 Hz, 1H, Ar); 8.54 (d, J 1.9 Hz, 1H, Ar); 8.45 (dt, J 8.4, 2.6 Hz, 1H, Ar); 8.04 (d, J 1.6 Hz, 1H, Ar); 7.78 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.67 (d, J 7.8 Hz, 1H, Ar); 7.34 (dd, J 8.4, 2.6 Hz, 1H, Ar); 7.20 (d, J 1.9 Hz, 1H, Ar); 1.50 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.64 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=365.2.

Example 173

5-Methyl-9-bromo-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(437) ##STR00201##

(438) Example 173 was prepared according to general procedure IX starting from example 1. It was obtained as a yellow solid in quantitative yield. M/Z (M[.sup.79Br]+H).sup.+=345.0.

Example 174

5-Methyl-9-(3-cyanophenyl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(439) ##STR00202##

(440) Example 174 was prepared according to general procedure IX starting from example 44. It was obtained as a yellow solid in quantitative yield. M/Z (M+H).sup.+=368.2.

Example 175

5-Methyl-9-(pyridazin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carbaldehyde

(441) ##STR00203##

(442) Example 175 was prepared according to general procedure IX starting from example 70. It was obtained as a brown solid in 93% yield. M/Z (M+H).sup.+=345.2.

(443) General Procedure X: Oxydation of Carboxaldehyde K.sub.3 into Carboxylic Acid K.sub.4 (Scheme 5).

(444) To a solution of carboxaldehyde K.sub.3 (1.0 equiv.) and 2-methyl-2-butene (0.13 mol.Math.L.sup.−1) in a mixture of THF (0.10 mol.Math.L.sup.−1) and tert-butanol (0.10 mol.Math.L.sup.−1), a solution of sodium chlorite (3.0 equiv.) and sodium phosphate monobasic (4.5 equiv.) in water (0.10 mol.Math.L.sup.−1) was slowly added. The reaction mixture was stirred for 2 days at room temperature. The reaction mixture was acidified with aqueous hydrogene chloride (0.1N) and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated to dryness to afford the product. No purification, otherwise specified.

Example 176

5-Methyl-9-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid

(445) ##STR00204##

(446) Example 176 was prepared according to general procedure X starting from example 168. It was obtained as a yellow solid in 95% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 12.10 (bs, 1H, COOH); 8.52 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.12 (d, J 1.9 Hz, 1H, Ar); 7.83 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.73 (d, J 1.5 Hz, 1H, Ar); 7.63 (d, J 7.8 Hz, 1H, Ar); 7.46 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.38 (dd, J 7.9, 4.8 Hz, 1H, Ar); 7.09 (d, J 1.9 Hz, 1H, Ar); 3.35 (s, 3H, CH.sub.3); 2.95 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=374.3. MP>250° C.

Example 177

5-Methyl-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid

(447) ##STR00205##

(448) Example 177 was prepared according to general procedure X starting from example 171. It was obtained as an orange solid in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 12.38 (bs, 1H, COOH); 8.79 (d, J 2.5 Hz, 1H, Ar); 8.53 (dt, J 8.4, 2.5 Hz, 1H, Ar); 8.36 (d, J 1.9 Hz, 1H, Ar); 8.07 (d, J 1.6 Hz, 1H, Ar); 7.80 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.71 (d, J 7.8 Hz, 1H, Ar); 7.38 (dd, J 8.4, 2.5 Hz, 1H, Ar); 7.15 (d, J 1.9 Hz, 1H, Ar); 2.99 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.69 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=378.2. MP>250° C.

Example 178

5-(Methyl-d.SUB.3.)-9-(6-fluoro-pyridin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid

(449) ##STR00206##

(450) Example 178 was prepared according to general procedure X starting from example 172. It was obtained as an orange solid in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 12.23 (bs, 1H, COOH); 8.78 (d, J 2.5 Hz, 1H, Ar); 8.53 (dt, J 8.4, 2.5 Hz, 1H, Ar); 8.35 (d, J 1.9 Hz, 1H, Ar); 8.06 (d, J 1.7 Hz, 1H, Ar); 7.80 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.70 (d, J 7.8 Hz, 1H, Ar); 7.38 (dd, J 8.4, 2.5 Hz, 1H, Ar); 7.15 (d, J 1.9 Hz, 1H, Ar); 1.55 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.68 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=381.2. MP>250° C.

Example 179

5-Methyl-9-bromo-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid

(451) ##STR00207##

(452) Example 179 was prepared according to general procedure X starting from example 173. It was obtained as an orange solid in quantitative yield. M/Z (M[.sup.79Br]+H).sup.+=361.0.

Example 180

5-Methyl-9-(pyridazin-3-yl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid

(453) ##STR00208##

(454) Example 180 was prepared according to general procedure X starting from example 175. It was obtained as a yellow solid in quantitative yield. M/Z (M+H).sup.+=361.1.

Example 181

5-Methyl-9-(3-cyanophenyl)-4-oxo-4,5-dihydrospiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropane]-2-carboxylic acid

(455) ##STR00209##

(456) Example 181 was prepared according to general procedure X starting from example 174. It was obtained as a yellow solid in quantitative yield. M/Z (M+H).sup.+=384.1.

Example 182

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(oxazol-5-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(457) ##STR00210##

(458) A suspension of example 168 (1.0 equiv.), tosylmethylisocyanide (1.2 equiv.) and sodium methoxide (4.2 equiv.) in methanol (0.05 mol.Math.L.sup.−1) was refluxed for 16 hours. Methanol was removed under reduced pressure and the crude mixture was purified by preparative HPLC to afford example 182 as a yellow solid in 66% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.89 (d, J 5.0 Hz, 1H, Ar); 8.56 (d, J 7.6 Hz, 1H, Ar); 8.45 (s, 1H, Ar); 8.05 (d, J 1.9 Hz, 1H, Ar); 8.01 (dd, J 7.6, 5.0 Hz, 1H, Ar); 7.91 (d, J 1.6 Hz, 1H, Ar); 7.79 (d, J 7.9 Hz, 1H, Ar); 7.62 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.53 (s, 1H, Ar); 7.29 (d, J 1.9 Hz, 1H, Ar); 3.05 (s, 3H, CH.sub.3); 2.80 (s, 3H, CH.sub.3); 1.62 (m, 2H, cyclopropyl); 1.11 (m, 1H, cyclopropyl); 0.75 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=397.3. MP=158-168° C.

Example 183

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(3H-imidazol-4-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(459) ##STR00211##

(460) In a sealed vial, a suspension of example 168 (1.0 equiv.), tosylmethylisocyanide (1.2 equiv.), cyanide potassium (0.1 equiv.) and ammonia (7M solution in methanol, 0.05 mol.Math.L.sup.−1) was heated at 110° C. for 16 hours. Methanol was removed under vacuum and the crude mixture was purified by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) to afford example 183 as a dark solid in 15% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 9.17 (d, J 1.3 Hz, 1H, Ar); 8.76 (d, J 5.0 Hz, 1H, Ar); 8.39 (d, J 2.0 Hz, 1H, Ar); 8.35 (d, J 7.5 Hz, 1H, Ar); 7.97 (d, J 1.3 Hz, 1H, Ar); 7.85 (dd, J 7.5, 5.0 Hz, 1H, Ar); 7.73 (m, 2H, Ar); 7.54 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.43 (d, J 2.0 Hz, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 2.74 (s, 3H, CH.sub.3); 1.56 (m, 2H, cyclopropyl); 1.04 (m, 1H, cyclopropyl); 0.69 (m, 1H, cyclopropyl). Proton for HCl salt not observed. Proton for NH not observed. M/Z (M+H).sup.+=396.3. MP>250° C.

Example 184

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(1H-imidazol-2-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(461) ##STR00212##

(462) In a sealed vial, a suspension of example 168 (1.0 equiv.), glyoxal (40% aqueous solution, 0.3 mol.Math.L.sup.−1), ammonium hydroxide (28% aqueous solution, 0.6 mol.Math.L.sup.−1) in ethanol (0.05 mol.Math.L.sup.−1) was heated at 80° C. for 5 days. 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 by preparative HPLC to afford example 184 as a yellow solid in 6% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 14.80 (bs, 1H, NH); 8.71 (m, 2H, Ar); 8.19 (d, J 7.0 Hz, 1H, Ar); 7.76-7.71 (m, 5H, Ar); 7.64 (d, J 2.0 Hz, 1H, Ar); 7.57 (dd, J 7.8, 1.6 Hz, 1H, Ar); 2.99 (s, 3H, CH.sub.3); 2.69 (s, 3H, CH.sub.3); 1.58 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.72 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=396.2. MP>250° C.

Example 185

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(463) ##STR00213##

(464) A solution of example 176 (1.0 equiv.) and isocyanoiminotriphenylphosphorane (2.0 equiv.) in DMF (0.05 mol.Math.L.sup.−1) was heated at 80° C. for 2 days. 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 by flash column chromatography on silica gel (0% to 5% MeOH in dichloromethane) to afford example 185 as a yellow solid in 36% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.27 (s, 1H, Ar); 8.51 (dd, J 4.8, 1.6 Hz, 1H, Ar); 8.39 (d, J 1.9 Hz, 1H, Ar); 7.81 (d, J 1.5 Hz, 1H, Ar); 7.79 (dd, J 7.8, 1.5 Hz, 1H, Ar); 7.65 (d, J 7.8 Hz, 1H, Ar); 7.49 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.34 (dd, J 7.8, 4.8 Hz, 1H, Ar); 7.29 (d, J 1.9 Hz, 1H, Ar); 2.99 (s, 3H, CH.sub.3); 2.52 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.69 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=398.3. MP>250° C.

Example 186

5-Methyl-9-(6-fluoro-pyridin-3-yl)-2-(1H-imidazol-2-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(465) ##STR00214##

(466) Example 186 was obtained according to the procedure of example 184, starting from example 171. Purification by preparative HPLC afforded a beige solid in 16% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 13.60 (bs, 1H, NH); 8.69 (s, 1H, Ar); 8.43 (t, J 8.2 Hz, 1H, Ar); 8.31 (m, 1H, Ar); 7.96 (s, 1H, Ar); 7.75 (d, J 7.8 Hz, 1H, Ar); 7.67 (d, J 7.8 Hz, 1H, Ar); 7.43-7.32 (m, 4H, Ar); 2.96 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 1.02 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=400.3. MP>250° C.

Example 187

5-Methyl-9-(6-fluoro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(467) ##STR00215##

(468) Example 187 was prepared according to the procedure of example 185, starting from example 177. Purification by preparative HPLC afforded a beige solid in 41% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.28 (s, 1H, Ar); 8.75 (d, J 2.6 Hz, 1H, Ar); 8.55 (d, J 1.9 Hz, 1H, Ar); 8.48 (dt, J 8.4, 2.6 Hz, 1H, Ar); 8.08 (d, J 1.6 Hz, 1H, Ar); 7.78 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.68 (d, J 7.8 Hz, 1H, Ar); 7.34 (dd, J 8.4, 2.6 Hz, 1H, Ar); 7.29 (d, J 1.9 Hz, 1H, Ar); 2.97 (s, 3H, CH.sub.3); 1.54 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=402.3. MP=160-175° C.

Example 188

5-(Methyl-d.SUB.3.)-9-(6-fluoro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(469) ##STR00216##

(470) Example 188 was prepared according to the procedure of example 185, starting from example 178. Purification by preparative HPLC afforded a white solid in 25% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.28 (s, 1H, Ar); 8.75 (d, J 2.6 Hz, 1H, Ar); 8.55 (d, J 1.9 Hz, 1H, Ar); 8.48 (dt, J 8.4, 2.6 Hz, 1H, Ar); 8.08 (d, J 1.6 Hz, 1H, Ar); 7.77 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.68 (d, J 7.8 Hz, 1H, Ar); 7.34 (dd, J 8.4, 2.6 Hz, 1H, Ar); 7.29 (d, J 1.9 Hz, 1H, Ar); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.67 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=405.3. MP>250° C.

Example 189

5-Methyl-9-bromo-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(471) ##STR00217##

(472) Example 189 was prepared according to the procedure of example 185, starting from example 179. Purification by preparative HPLC afforded a white solid in 36% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.26 (s, 1H, Ar); 8.34 (d, J 1.7 Hz, 1H, Ar); 8.02 (d, J 1.6 Hz, 1H, Ar); 7.62 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.51 (d, J 7.9 Hz, 1H, Ar); 7.26 (d, J 1.7 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 1.48 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.61 (m, 1H, cyclopropyl). M/Z (M[.sup.79Br]+H).sup.+=385.0. MP=246-252° C.

Example 190

5-Methyl-9-(6-dimethylamino-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(473) ##STR00218##

(474) Example 190 was prepared according to general procedure VI(i) starting from example 189 in presence of 6-fluoropyridine-3-boronic acid and dimethylamine (2M in THF, 2 equiv.). Purification by preparative HPLC afforded the product as a beige solid in 10% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.26 (s, 1H, Ar); 8.59 (s, 1H, Ar); 8.49 (s, 1H, Ar); 8.00 (d, J 8.5 Hz, 1H, Ar); 7.92 (s, 1H, Ar); 7.64 (d, J 7.8 Hz, 1H, Ar); 7.57 (d, J 7.8 Hz, 1H, Ar); 7.26 (s, 1H, Ar); 6.73 (d, J 8.5 Hz, 1H, Ar); 3.08 (s, 6H, 2CH.sub.3); 2.95 (s, 3H, CH.sub.3); 1.49 (m, 2H, cyclopropyl); 1.00 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=427.3. MP>250° C.

Example 191

5-Methyl-9-(6-chloro-pyridin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(475) ##STR00219##

(476) Example 191 was prepared according to general procedure VI(i) starting from example 189 in presence of 6-chloropyridine-3-boronic acid. Purification by preparative HPLC afforded the product as a white solid in 10% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.27 (s, 1H, Ar); 8.92 (d, J 2.5 Hz, 1H, Ar); 8.55 (d, J 1.9 Hz, 1H, Ar); 8.35 (dd, J 8.3, 2.5 Hz, 1H, Ar); 8.09 (d, J 1.7 Hz, 1H, Ar); 7.79 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.68 (d, J 7.8 Hz, 1H, Ar); 7.66 (d, J 8.3 Hz, 1H, Ar); 7.28 (d, J 1.9 Hz, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M[.sup.35Cl]+H).sup.+=418.1. MP>250° C.

Example 192

5-Methyl-9-(3-cyanophenyl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(477) ##STR00220##

(478) Example 192 was prepared according to the procedure of example 185, starting from example 181. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 0% to 50%) afforded the product as a white solid in 19% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.27 (s, 1H, Ar); 8.55 (d, J 1.9 Hz, 1H, Ar); 8.40 (m, 1H, Ar); 8.19 (m, 1H, Ar); 8.08 (d, J 1.7 Hz, 1H, Ar); 7.87 (m, 1H, Ar); 7.80 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.69 (m, 2H, Ar); 7.28 (d, J 1.9 Hz, 1H, Ar); 2.96 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=408.2. MP>250° C.

Example 193

5-Methyl-9-(pyridazin-3-yl)-2-[1,3,4]oxadiazol-2-yl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(479) ##STR00221##

(480) Example 193 was prepared according to the procedure of example 185, starting from example 180. Purification by preparative HPLC afforded the product as a brown solid in 22% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 9.27 (m, 2H, Ar); 8.50 (d, J 1.9 Hz, 1H, Ar); 8.46 (dd, J 8.6, 1.5 Hz, 1H, Ar); 8.40 (d, J 1.7 Hz, 1H, Ar); 8.25 (dd, J 8.0, 1.7 Hz, 1H, Ar); 7.85 (dd, J 8.6, 4.8 Hz, 1H, Ar); 7.75 (d, J 8.0 Hz, 1H, Ar); 7.30 (d, J 1.9 Hz, 1H, Ar); 2.98 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.05 (m, 1H, cyclopropyl); 0.69 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=385.2. MP>250° C.

(481) General Procedure XI: Acylation of Benzodiazepinone K from Alcyl Chloride Derivatives (Scheme 5).

(482) At 0° C., to a solution of benzodiazepinone K (1.0 equiv.) in a mixture of 1,2-dichloroethane (0.30 mol.Math.L.sup.−1) and nitromethane (0.30 mol.Math.L.sup.−1), aluminium chloride (2.5 equiv.) was slowly added. After 10 minutes of vigorous stirring, acyl chloride (2.5 equiv.) was added dropwise and the reaction mixture was stirred for 1 hour and allowed to reach room temperature. At 0° C., Aluminium chloride (2.2 equiv.) and acyl chloride (2.5 equiv.) were added again and the reaction mixture was stirred for one more hour at room temperature. The reaction mixture was neutralized with aqueous potassium carbonate 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 194

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(cyclopentanecarbonyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(483) ##STR00222##

(484) Example 194 was prepared according to procedure XI starting from the free base of example 20 in presence of cyclopentane carbonyl chloride. Purification by flash column chromatography on silica gel (MeOH in dichloromethane, 0% to 5%) afforded the product as a white solid in 92% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (d, J 5.5 Hz, 1H, Ar); 8.40 (d, J 7.9 Hz, 1H, Ar); 8.29 (d, J 1.9 Hz, 1H, Ar); 7.87 (m, 2H, Ar); 7.71 (d, J 7.9 Hz, 1H, Ar); 7.56 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.20 (d, J 1.9 Hz, 1H, Ar); 3.63 (quint, J 7.4 Hz, 1H, CH); 2.97 (s, 3H, CH.sub.3); 2.69 (s, 3H, CH.sub.3); 1.90 (m, 2H, 2CH); 1.81-1.50 (m, 8H, 6CH+2cyclopropyl); 1.02 (m, 1H, cyclopropyl); 0.66 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=426.2. MP=177-190° C.

Example 195

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-acetyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(485) ##STR00223##

(486) Example 195 was prepared according to procedure XI starting from the free base of example 20 in presence of acetyl chloride. Purification by flash column chromatography on silica gel (MeOH in dichloromethane, 0% to 5%) afforded the product as a white solid in 92% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.84 (d, J 5.5 Hz, 1H, Ar); 8.47 (d, J 7.5 Hz, 1H, Ar); 8.35 (d, J 1.9 Hz, 1H, Ar); 7.93 (m, 2H, Ar); 7.77 (d, J 7.9 Hz, 1H, Ar); 7.62 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.24 (d, J 1.9 Hz, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 2.75 (s, 3H, CH.sub.3); 2.52 (s, 3H, CH.sub.3); 1.60 (m, 2H, cyclopropyl); 1.07 (m, 1H, cyclopropyl); 0.71 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=372.3. MP=200-220° C.

(487) General Procedure XII: Reduction of Benzodiazepinone K.sub.1 or K.sub.3 into Benzodiazepinone K.sub.2 (Scheme 5).

(488) A solution of benzodiazepinone K.sub.1 or K.sub.3 (1.0 equiv.) and triethylsilane (4.0 equiv.) in trifluoroacetic acid (0.15 mol.Math.L.sup.−1) was stirred for 16 hours at room temperature. The reaction mixture was neutralized with aqueous sodium hydroxide (1N) 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 196

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(cyclopentylmethyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(489) ##STR00224##

(490) Example 196 was obtained according to procedure XII starting from example 194. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as as a white solid in 25% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 5.4 Hz, 1H, Ar); 8.38 (d, J 7.5 Hz, 1H, Ar); 7.87 (dd, J 7.5, 5.4 Hz, 1H, Ar); 7.64 (m, 2H, Ar); 7.43 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.33 (d, J 1.7 Hz, 1H, Ar); 6.74 (d, J 1.9 Hz, 1H, Ar); 2.93 (s, 3H, CH.sub.3); 2.67 (s, 3H, CH.sub.3); 2.48 (m, 2H, CH.sub.2); 2.12 (m, 1H, CH); 1.75 (m, 2H, 2CH); 1.60 (m, 2H, 2CH); 1.51 (m, 4H, 2CH+2cyclopropyl); 1.23 (m, 2H, 2CH); 0.97 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=412.3. MP=165-176° C.

Example 197

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-ethyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(491) ##STR00225##

(492) Example 197 was obtained according to procedure XII starting from example 195. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 81% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (d, J 5.4 Hz, 1H, Ar); 8.42 (d, J 7.5 Hz, 1H, Ar); 7.89 (dd, J 7.5, 5.4 Hz, 1H, Ar); 7.65 (m, 2H, Ar); 7.44 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.35 (d, J 1.7 Hz, 1H, Ar); 6.78 (d, J 1.8 Hz, 1H, Ar); 2.94 (s, 3H, CH.sub.3); 2.70 (s, 3H, CH.sub.3); 2.55 (q, J 7.5 Hz, 2H, CH.sub.2—CH.sub.3); 1.51 (m, 2H, cyclopropyl); 1.23 (t, J 7.5 Hz, 3H, CH.sub.2—CH.sub.3); 0.98 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=358.3. MP=165-175° C.

Example 198

2,5-Dimethyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(493) ##STR00226##

(494) Example 198 was obtained according to procedure XII starting from example 170. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 31% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.18 (s, 1H, Ar); 8.76 (d, J 8.2 Hz, 1H, Ar); 7.95 (d, J 1.7 Hz, 1H, Ar); 7.91 (d, J 8.2 Hz, 1H, Ar); 7.77 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.66 (d, J 7.9 Hz, 1H, Ar); 7.51 (m, 1H, Ar); 6.74 (d, J 1.8 Hz, 1H, Ar); 2.92 (s, 3H, CH.sub.3); 2.76 (s, 3H, CH.sub.3); 2.18 (s, 3H, CH.sub.3); 1.51 (m, 2H, cyclopropyl); 0.97 (m, 1H, cyclopropyl); 0.58 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=344.3.

Example 199

2,5-Dimethyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(495) ##STR00227##

(496) Example 199 was obtained according to procedure XII starting from example 169. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a yellow solid in 22% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (s, 1H, Ar); 8.33 (m, 1H, Ar); 7.84 (m, 1H, Ar); 7.61 (m, 2H, Ar); 7.39 (d, J 6.9 Hz, 1H, Ar); 7.31 (s, 1H, Ar); 6.72 (s, 1H, Ar); 2.95 (q, J 7.2 Hz, 2H, CH.sub.2—CH.sub.3); 2.92 (s, 3H, CH.sub.3); 2.12 (s, 3H, CH.sub.3); 1.50 (m, 2H, cyclopropyl); 1.19 (t, J 7.2 Hz, 3H, CH.sub.2—CH.sub.3); 0.96 (m, 1H, cyclopropyl); 0.59 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=358.2. MP=179-184° C.

Example 200

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-(morpholin-4-ylmethyl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(497) ##STR00228##

(498) At 0° C., sodium triacetoxyborohydride (2.2 equiv.) was added in one portion to a solution of example 168 (1.0 equiv.) and morpholine (2.0 equiv.) in THF (0.1 mol.Math.L.sup.−1). The reaction mixture was stirred for 6 hours at room temperature before being hydrolyzed 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 (0% to 5% MeOH in dichloromethane) to afford example 200 as a yellow solid in 65% yield. Salt formation was performed by method (i). .sup.1H-NMR (400 MHz, DMSO-D6): 11.39 (bs, 1H, HCl salt); 8.79 (d, J 5.4 Hz, 1H, Ar); 8.39 (d, J 7.5 Hz, 1H, Ar); 7.89 (dd, J 7.5, 5.4 Hz, 1H, Ar); 7.79 (d, J 1.9 Hz, 1H, Ar); 7.75 (d, J 1.6 Hz, 1H, Ar); 7.71 (d, J 7.8 Hz, 1H, Ar); 7.53 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.10 (d, J 1.9 Hz, 1H, Ar); 4.26 (m, 2H, CH.sub.2); 3.96 (m, 2H, 2CH); 3.83 (m, 2H, 2CH); 3.31 (m, 2H, 2CH); 3.06 (m, 2H, 2CH); 2.96 (s, 3H, CH.sub.3); 2.73 (s, 3H, CH.sub.3); 1.53 (m, 2H, cyclopropyl); 0.99 (m, 1H, cyclopropyl); 0.64 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=342.2. MP=242-250° C.

Example 201

5-Methyl-9-(2-methyl-pyridin-3-yl)-2-difluoromethyl-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(499) ##STR00229##

(500) A solution of example 168 (1.0 equiv.) and Deoxofluor™ (50% solution in toluene, 0.25 mol.Math.L.sup.−1) in dichloromethane (0.10 mol.Math.L.sup.−1) was stirred for 36 hours at room temperature before being hydrolyzed 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 (0% to 10% MeOH in dichloromethane) to afford example 201 as a white solid in 16% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.69 (d, J 5.4 Hz, 1H, Ar); 8.31 (d, J 7.5 Hz, 1H, Ar); 7.82 (d, J 1.9 Hz, 1H, Ar); 7.78 (dd, J 7.5, 5.4 Hz, 1H, Ar); 7.68 (d, J 1.6 Hz, 1H, Ar); 7.61 (d, J 7.8 Hz, 1H, Ar); 7.44 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.97 (t, J 56.0 Hz, 1H, CF.sub.2H); 6.92 (d, J 1.9 Hz, 1H, Ar); 2.87 (s, 3H, CH.sub.3); 2.60 (s, 3H, CH.sub.3); 1.45 (m, 2H, cyclopropyl); 0.91 (m, 1H, cyclopropyl); 0.55 (m, 1H, cyclopropyl). Proton for HCl salt not observed. M/Z (M+H).sup.+=380.3. MP=240-250° C.

(501) General Procedure XIII: Reduction of Carboxaldehyde K.sub.3 into the Corresponding Alcohol K.sub.6 (Scheme 5).

(502) At 0° C., sodium borohydride (1.1 equiv.) was added in one portion to a solution of carboxaldehyde K.sub.3 (1.0 equiv.) in THF (0.10 mol.Math.L.sup.−1). The reaction mixture was stirred for 16 hours at room temperature before being neutralized with aqueous ammonium chloride 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 202

2-Hydroxymethyl-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(503) ##STR00230##

(504) Example 202 was obtained according to procedure XIII starting from example 170. Purification by preparative HPLC to afford the product as a white solid in 42% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.93 (d, J 1.9 Hz, 1H, Ar); 8.76 (dd, J 8.2, 2.4 Hz, 1H, Ar); 7.84 (d, J 1.6 Hz, 1H, Ar); 7.69 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.65 (m, 2H, Ar); 7.45 (d, J 8.2 Hz, 1H, Ar); 6.89 (d, J 1.9 Hz, 1H, Ar); 4.99 (bs, 1H, OH); 4.52 (s, 2H, CH.sub.2); 2.98 (s, 3H, CH.sub.3); 2.59 (s, 3H, CH.sub.3); 1.52 (m, 2H, cyclopropyl); 1.01 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=360.3. MP=144-154° C.

Example 203

2-Hydroxymethyl-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(505) ##STR00231##

(506) Example 203 was obtained according to procedure XIII starting from example 169. Purification by flash column chromatography on silica gel (80% to 100% EtOAc in cyclohexane) afforded the product as a white solid in 29% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.75 (s, 1H, Ar); 8.24 (m, 1H, Ar); 7.76 (m, 1H, Ar); 7.65 (m, 3H, Ar); 7.42 (d, J 7.8 Hz, 1H, Ar); 6.91 (s, 1H, Ar); 4.75 (s, 2H, CH.sub.2); 2.94 (s, 3H, CH.sub.3); 2.91 (q, J 7.3 Hz, 2H, CH.sub.2—CH.sub.3); 1.51 (m, 2H, cyclopropyl); 1.18 (t, J 7.3 Hz, 3H, CH.sub.2—CH.sub.3); 0.98 (m, 1H, cyclopropyl); 0.61 (m, 1H, cyclopropyl). Protons for HCl salt and OH were not observed. M/Z (M+H).sup.+=374.3. MP>250° C.

Example 204

2-Hydroxymethyl-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(507) ##STR00232##

(508) Example 204 was obtained according to procedure XIII starting from example 171. It was obtained as a yellow solid in 71% yield and was taken crude to the next step. M/Z (M+H).sup.+=364.3.

(509) General Procedure XIV: Alkylation of Alcohol K.sub.6 into the Corresponding Alkyloxy K.sub.7 (Scheme 5).

(510) At 0° C., sodium hydride (60% dispersion in oil, 2.0 equiv.) was added in one portion to a solution of alcohol K.sub.6 (1.0 equiv.) in THF (0.10 mol.Math.L.sup.−1). After 10 minutes, iodomethane (3.0 equiv.) was added dropwise and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was neutralized with aqueous ammonium chloride 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 205

2-Methoxymethyl-5-methyl-9-(6-methyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one, hydrochloride

(511) ##STR00233##

(512) Example 205 was obtained according to procedure XIV starting from example 202. Purification by flash column chromatography on silica gel (100% EtOAc) afforded the product as a white solid in 27% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 9.22 (s, 1H, Ar); 8.78 (d, J 8.2 Hz, 1H, Ar); 8.03 (d, J 1.6 Hz, 1H, Ar); 7.93 (d, J 8.2 Hz, 1H, Ar); 7.84 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.74 (m, 2H, Ar); 6.90 (d, J 1.8 Hz, 1H, Ar); 4.45 (s, 2H, CH.sub.2); 3.38 (s, 3H, OCH.sub.3); 2.98 (s, 3H, CH.sub.3); 2.79 (s, 3H, CH.sub.3); 1.55 (m, 2H, cyclopropyl); 1.03 (m, 1H, cyclopropyl); 0.63 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=374.3. MP=113-123° C.

Example 206

2-Methoxymethyl-5-methyl-9-(2-ethyl-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(513) ##STR00234##

(514) Example 206 was prepared according to procedure XIV starting from the free base of example 203. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded the product as a white solid in 39% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.76 (d, J 5.5 Hz, 1H, Ar); 8.26 (d, J 6.4 Hz, 1H, Ar); 7.77 (dd, J 6.4, 5.5 Hz, 1H, Ar); 7.64 (m, 2H, Ar); 7.53 (d, J 1.6 Hz, 1H, Ar); 7.41 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.83 (d, J 1.8 Hz, 1H, Ar); 4.34 (s, 2H, CH.sub.2); 3.28 (s, 3H, OCH.sub.3); 2.94 (s, 3H, CH.sub.3); 2.92 (q, J 7.7 Hz, 2H, CH.sub.2—CH.sub.3); 1.51 (m, 2H, cyclopropyl); 1.18 (t, J 7.7 Hz, 3H, CH.sub.2—CH.sub.3); 0.98 (m, 1H, cyclopropyl); 0.60 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=388.3. MP=206-121° C.

Example 207

2-Methoxymethyl-5-methyl-9-(6-fluoro-pyridin-3-yl)-spiro[benzo[f]pyrazolo[1,5-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(515) ##STR00235##

(516) Example 207 was prepared according to procedure XIV starting from example 204. Purification by flash column chromatography on silica gel (50% to 100% EtOAc in cyclohexane) afforded the product as a beige solid in 44% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.59 (s, 1H, Ar); 8.33 (m, 1H, Ar); 7.77 (s, 1H, Ar); 7.61 (m, 3H, Ar); 7.26 (d, J 8.5 Hz, 1H, Ar); 6.83 (s, 1H, Ar); 4.35 (s, 2H, CH.sub.2); 3.27 (s, 3H, CH.sub.3); 2.90 (s, 3H, CH.sub.3); 1.47 (m, 2H, cyclopropyl); 0.92 (m, 1H, cyclopropyl); 0.54 (m, 1H, cyclopropyl). M/Z (M+H).sup.+=378.3. MP=71-80° C.

Compound 46: 1-(5-Bromo-2-cyano-phenyl)-pyrrolidine-2-carboxylic acid

(517) A mixture of 4-bromo-2-fluorobenzonitrile (1.0 equiv.), I-proline methyl ester hydrochloride (2.0 equiv.), potassium carbonate (2.0 equiv.) in anhydrous DMSO (0.5 mol.Math.L.sup.−1) was heated at 100° C. for 20 hours. The mixture was poured into an aqueous solution of potassium hydroxide (6 N) and washed twice with Et.sub.2O. The aqueous phase was acidified to pH=1-2 with aqueous HCl (6N). The resulting white precipitate was collected by filtration and dried under reduced pressure to afford the product as a white solid in 68% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 12.88 (bs, 1H, COOH); 7.45 (d, J 8.3 Hz, 1H, Ar); 6.91 (dd, J 8.3, 1.8 Hz, 1H, Ar); 6.86 (d, J 1.8 Hz, 1H, Ar); 4.75 (m, 1H, CH); 3.69 (m, 1H, CH); 3.63 (m, 1H, CH); 2.30 (m, 1H, CH); 2.07 (m, 1H, CH); 1.96 (m, 2H, 2CH). M/Z (M[.sup.79Br]+H).sup.+=295.2.

Compound 47: 1-(5-Bromo-2-cyano-phenyl)-pyrrolidine-2-carboxylic acid methyl ester

(518) At 0° C., thionyl chloride (2.0 equiv.) was added dropwise to a solution of compound 46 (1.0 equiv.) in anhydrous methanol (0.15 mol.Math.L.sup.−1). The reaction mixture was stirred at room temperature for 16 hours. MeOH and excess of thionyl chloride were removed under vacuum. The crude mixture was hydrolyzed and extracted twice with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated under vacuum to afford the product as a thick yellow oil in 93% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.45 (d, J 8.3 Hz, 1H, Ar); 6.93 (dd, J 8.3, 1.8 Hz, 1H, Ar); 6.91 (d, J 1.8 Hz, 1H, Ar); 4.90 (m, 1H, CH); 3.67 (m, 4H, CH+CH.sub.3); 3.59 (m, 1H, CH); 2.32 (m, 1H, CH); 2.10 (m, 1H, CH); 1.99 (m, 1H, CH); 1.90 (m, 1H, CH). M/Z (M[.sup.79Br]+H).sup.+=309.2.

Compound 48: 9-Bromol-1,2,3,3a-tetrahydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(519) Compound 48 was obtained according to general procedure II, starting from compound 47, as a white solid in 42% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.37 (s, 1H, NH); 6.86 (d, J 8.3 Hz 1H, Ar); 6.62 (dd, J 8.3, 1.8 Hz, 1H, Ar); 6.59 (d, J 1.8 Hz, 1H, Ar); 5.21 (m, 1H, CH); 3.28 (m, 2H, 2CH); 2.37 (m, 1H, CH); 1.90 (m, 3H, 3CH); 1.74 (m, 1H, CH); 1.12 (m, 1H, CH); 1.02 (m, 1H, CH); 0.97 (m, 1H, CH). M/Z (M[.sup.79Br]+H).sup.+=307.2.

Example 208

9-Bromo-5-methyl-1,2,3,3a-tetrahydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(520) ##STR00236##

(521) Example 208 was obtained according to general procedure III, starting from compound 48 in presence of iodomethane. The reaction mixture was stirred at room temperature for 2 hours. Purification by flash column chromatography on silica gel (EtOAc in cyclohexane, 10% to 60%) afforded the product as as a yellow solid in 81% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 6.94 (d, J 8.3 Hz 1H, Ar); 6.63 (dd, J 8.3, 1.8 Hz, 1H, Ar); 6.57 (d, J 1.8 Hz, 1H, Ar); 5.44 (m, 1H, CH); 3.26 (m, 2H, 2CH); 2.77 (s, 3H, CH.sub.3); 2.38 (m, 1H, CH); 1.92 (m, 3H, 3CH); 1.68 (m, 1H, CH); 1.33 (m, 1H, CH); 1.27 (m, 1H, CH); 1.19 (m, 1H, CH). M/Z (M[.sup.79Br]+H).sup.+=321.2.

Example 209

5-Methyl-9-(2-methylpyridin-3-yl)-1,2,3,3a-tetrahydro-spiro[benzo[f]pyrrolo[1,2-a][1,4]diazepine-6,1′-cyclopropan]-4(5H)-one

(522) ##STR00237##

(523) Example 209 was obtained according to general procedure VI(ii) starting from example 208 in presence of 2-methylpyridine-3-boronic pinacol ester. Purification by preparative HPLC afforded the product as a green solid in 22% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.63 (d, J 5.1 Hz, 1H, Ar); 8.07 (d, J 7.2 Hz, 1H, Ar); 7.65 (dd, J 7.2, 5.1 Hz, 1H, Ar); 7.14 (d, J 7.8 Hz, 1H, Ar); 6.56 (dd, J 7.8, 1.6 Hz, 1H, Ar); 6.48 (d, J 1.6 Hz, 1H, Ar); 5.50 (m, 1H, CH); 3.34 (m, 2H, 2CH); 2.82 (s, 3H, CH.sub.3); 2.58 (s, 3H, CH.sub.3); 2.41 (m, 1H, CH); 1.95 (m, 3H, 3CH); 1.78 (m, 1H, CH); 1.39 (m, 1H, CH); 1.27 (m, 1H, CH); 1.24 (m, 1H, CH). M/Z (M+H).sup.+=334.3.

Compound 49: (4-Bromo-2-fluoro-benzyl)-methyl-amine

(524) A mixture of 4-bromo-2-fluorobenzoic acid (1.0 equiv.), methylamine hydrochloride (1.1 equiv.), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.1 equiv.) and diisopropylethylamine (3.3 equiv.) in dichloromethane (0.20 mol.Math.L.sup.−1) was stirred for 2 hours at room temperature. The reaction mixture was hydrolyzed 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 (10% to 50% EtOAc in cyclohexane) to afford the intermediate methylamide as a white solid in quantitative yield. The white solid was dissolved in a solution of borane-THF complex (1M, 0.15 mol.Math.L.sup.−1) and heated at 60° C. for 16 hours. The reaction mixture was neutralized with methanol (gas evolution!) and the solvent was removed under vacuum. The crude mixture was taken in HCl (1N, 0.05 mol.Math.L.sup.−1) and heated at 100° C. for 1 hour, cooled to 0° C. and basified with NaOH (6N) to pH=12. The milky mixture was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated to afford the product as a pale yellow oil in 46% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.48 (m, 1H, Ar); 7.40 (m, 2H, Ar); 3.63 (s, 2H, CH.sub.2); 2.25 (s, 3H, CH.sub.3); Proton for NH not observed. M/Z (M[.sup.79Br]+H).sup.+=319.2.

Compound 50: [1-(4-Bromo-2-fluoro-phenyl)-ethyl]-methyl-amine

(525) A solution of 4-bromo-2-fluoroacetophenone (1.0 equiv.), methylamine (2M solution in THF, 1.2 equiv.) and titanium isopropoxide (0.6 equiv.) was stirred for 16 hours at room temperature. Sodium borohydride (4.3 equiv.) was slowly added and the reaction mixture was stirred for 2 hours at room temperature. The mixture was treated with ammonia (28% aqueous) and stirred for 1 hour at room temperature before being filtered through celite with ethyl acetate. The filtrate was extracted twice with EtOAc, dried with brine and MgSO.sub.4, filtered and concentrated to dryness to afford compound 50 as a yellow oil in 94% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.48-7.38 (m, 4H, NH+4Ar); 3.83 (q, J 6.2 Hz, 1H, CH—CH.sub.3); 2.11 (s, 3H, N—CH.sub.3); 1.21 (d, J 6.2 Hz, 3H, CH—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=232.

Compound 51: 1-(4-Bromo-2-fluoro-phenyl)-propan-1-one

(526) A solution of 4-bromo-2-fluorobenzoic acid (1.0 equiv.), N,O-dimethylhydroxylamine (1.2 equiv.), HOBt (1.2 equiv.), EDAC (1.2 equiv.) and diisopropylethylamine (4 equiv.) in DMA (0.40 mol.Math.L.sup.−1) was stirred at room temperature for 16 hours. The reaction mixture was hydrolyzed with aqueous sodium carbonate and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated to dryness to give the Weinreb amide as a thick colorless oil. The amide was dissolved in dichloromethane (0.5 mol.Math.L.sup.−1) and cooled to 0° C. Ethylmagnesium bromide (1M solution in THF, 1.3 equiv.) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with citric acid (0.5 M) and extracted twice with diethyl ether. The organic layers were combined, washed with brine, dried over MgSO.sub.4 and concentrated. Purification by flash column chromatography on silica gel (0% to 20% EtOAc in cyclohexane) afforded the product as a colorless oil in 44% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.77 (t, J 8.3 Hz, 1H, Ar); 7.73 (dd, J 10.7, 1.7 Hz, 1H, Ar); 7.56 (dd, J 8.3, 1.7 Hz, 1H, Ar); 2.96 (q, J 7.2 Hz, 2H, CH.sub.2—CH.sub.3); 1.07 (t, J 7.2 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=231.

Compound 52: [1-(4-Bromo-2-fluoro-phenyl)-propyl]-methyl-amine

(527) Compound 52 was prepared according to the procedure of compound 50, starting from compound 51. It was isolated as a colorless oil in quantitative yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.45-7.40 (m, 4H, NH+4Ar); 3.66 (t, J 6.7 Hz, 1H, CH—CH.sub.2); 2.09 (s, 3H, N—CH.sub.3); 1.60 (m, 2H, CH—CH.sub.2—CH.sub.3); 0.76 (m, 3H, CH.sub.2—CH.sub.3); M/Z (M[.sup.79Br]+H).sup.+=246.

Compound 53: 1-(4-Chloro-2-fluoro-phenyl)-1-methyl-ethylamine, hydrochloride

(528) Under inert and anhydrous conditions, a mixture of 4-chloro-2-fluorobenzonitrile (1.0 equiv.) and methylmagnesium bromide (3M solution in Et.sub.2O, 3.5 equiv.) in THF (0.20 mol.Math.L.sup.−1) was subjected to microwave irradiation at 100° C. for 10 minutes. Titanium isopropoxide (3.5 equiv.) was added dropwise and the reaction mixture was again subjected to microwave irradiation at 50° C. for 1 hour, then stirred at room temperature overnight. The mixture was treated with brine and extracted twice with dichloromethane. The combined organic extracts were dried over sodium sulfate and filtered through celite with dichloromethane. The filtrate was acidified by addition of HCl (2M solution in Et.sub.2O, 2.5 equiv.) and concentrated to dryness. Trituration in Et.sub.2O afforded the product as a greenish solid in 60% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.81 (bs, 3H, NH.sub.2+HCl); 7.55 (dd, J 12.4, 2.2 Hz, 1H, Ar); 7.47 (t, J 8.6 Hz, 1H, Ar); 7.40 (dd, J 8.6, 2.2 Hz, 1H, Ar); 1.67 (s, 6H, 2CH.sub.3).

(529) M/Z (M[.sup.35Cl]+H).sup.+=188.

(530) General Procedure XV: Preparation of Intermediate S, S′, S″, S.sub.1, S.sub.2, S.sub.4 from Benzylamine Q, Q.sub.1, Q.sub.2, Q.sub.4 and Carboxylic Acid R, R′, R″, R.sub.1 (Scheme 6, 7 and 8).

(531) A mixture of benzylamine Q, Q.sub.1, Q.sub.2 or Q.sub.4 (1.0 equiv.), carboxylic acid R, R′, R″ or R.sub.1 (1.0 equiv.), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.5 equiv.) and diisopropylethylamine (3.0 equiv.) in DMF (0.20 mol.Math.L.sup.−1) was stirred for 16 hours at 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 by flash column chromatography on silica gel (using a gradient of MeOH in dichloromethane as eluent) to afford the product.

Compound 54: 3H-Imidazole-4-carboxylic acid (4-bromo-2-fluoro-benzyl)-methyl-amide

(532) Compound 54 was prepared according to procedure XV starting from compound 49 and 4-imidazolecarboxylic acid. It was obtained as a white solid in 51% yield. M/Z (M[.sup.79Br]+H).sup.+=312.2.

Compound 55: 1H-Imidazole-2-carboxylic acid (4-bromo-2-fluoro-benzyl)-methyl-amide

(533) Compound 55 was prepared according to procedure XV starting from compound 49 and 2-imidazolecarboxylic acid. It was obtained as a white solid in 54% yield. M/Z (M[.sup.79Br]+H).sup.+=312.1.

Compound 56: 2H-Pyrazole-3-carboxylic acid (4-bromo-2-fluoro-benzyl)-methyl-amide

(534) Compound 56 was prepared according to procedure XV starting from compound 49 and 3-pyrazolecarboxylic acid. It was obtained as a brown solid in 87% yield. M/Z (M[.sup.79Br]+H).sup.+=312.1.

Compound 57: 1H-Pyrrole-2-carboxylic acid [1-(4-bromo-2-fluoro-phenyl)-ethyl]-methyl-amide

(535) Compound 57 was prepared according to procedure XV starting from compound 50 and pyrrole-2-carboxylic acid. It was obtained as a yellow oil in 50% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.44 (bs, 1H, NH); 7.51 (m, 1H, Ar); 7.43 (m, 2H, Ar); 6.89 (m, 1H, Ar); 6.51 (m, 1H, Ar); 6.11 (m, 1H, Ar); 5.92 (q, J 7.0 Hz, 1H, CH—CH.sub.3); 2.89 (s, 3H, N—CH.sub.3); 1.52 (d, J 7.0 Hz, 3H, CH—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=325.

Compound 58: 1H-Pyrrole-2-carboxylic acid [1-(4-bromo-2-fluoro-phenyl)-propyl]-methyl-amide

(536) Compound 58 was prepared according to procedure XV starting from compound 52 and pyrrole-2-carboxylic acid. It was obtained as a beige solid in 29% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.44 (bs, 1H, NH); 7.53-7.42 (m, 3H, Ar); 6.89 (m, 1H, Ar); 6.52 (m, 1H, Ar); 6.11 (m, 1H, Ar); 5.77 (t, J 7.7 Hz, 1H, CH—CH.sub.2); 2.94 (s, 3H, N—CH.sub.3); 1.99 (m, 2H, CH—CH.sub.2—CH.sub.3); 0.89 (t, J 7.2 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=339.

Compound 59: 1H-Pyrrole-2-carboxylic acid [1-(2-fluoro-phenyl)-1-methyl-ethyl]-amide

(537) Compound 59 was prepared according to procedure XV starting from 2-(2-fluorophenyl)propan-2-amine and pyrrole-2-carboxylic acid. It was obtained as a white solid in 62% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.26 (bs, 1H, NH); 7.90 (s, 1H, NH); 7.35 (m, 1H, Ar); 7.23 (m, 1H, Ar); 7.08 (m, 2H, Ar); 6.88 (m, 1H, Ar); 6.83 (m, 1H, Ar); 6.07 (m, 1H, Ar); 1.72 (s, 6H, 2CH.sub.3). M/Z (M+H).sup.+=247.3.

Compound 60: 1H-Pyrrole-2-carboxylic acid [1-(4-chloro-2-fluoro-phenyl)-1-methyl-ethyl]-amide

(538) Compound 60 was prepared according to procedure XV starting from compound 53 and pyrrole-2-carboxylic acid. It was obtained as a yellow solid in 32% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 11.26 (bs, 1H, NH); 7.97 (s, 1H, NH); 7.37 (t, J 8.5 Hz, 1H, Ar); 7.27 (dd, J 12.2, 2.2 Hz, 1H, Ar); 7.20 (dd, J 8.5, 2.2 Hz, 1H, Ar); 6.88 (m, 1H, Ar); 6.83 (m, 1H, Ar); 6.07 (m, 1H, Ar); 1.69 (s, 6H, 2CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=281.

(539) General Procedure XVI: Preparation of Benzodiazepinone T, T′, T″, T.sub.1, T.sub.2, T.sub.3 and T.sub.4 from Intermediate S, S′, S″, S.sub.1, S.sub.2, S.sub.3 and S.sub.4 (Scheme 6, 7 and 8).

(540) Method (i):

(541) A mixture of intermediate S, S′ or S″ (1.0 equiv.) and potassium carbonate (3.0 equiv.) in DMA (0.20 mol.Math.L.sup.−1) was heated at 170° C. for 16 hours. 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 to afford the product. No purification, otherwise specified.

(542) Method (ii):

(543) At room temperature, sodium hydride (1.2 equiv.) was added to a solution of compound S.sub.1, S.sub.2 or S.sub.3 in dry DMA (0.15 mol.Math.L.sup.−1). After 10 minutes stirring, the reaction mixture was heated at 100° C. for 2 hours before being 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 210

5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-4-one

(544) ##STR00238##

(545) Example 210 was prepared according to procedure XVI(i) starting from compound 54. It was obtained as a white solid in 71% yield and taken to the next step without purification. .sup.1H-NMR (400 MHz, DMSO-D6): 8.45 (s, 1H, Ar); 8.00 (d, J 1.7 Hz, 1H, Ar); 7.67 (dd, J 7.9, 1.7 Hz, 1H, Ar); 7.62 (m, 2H, Ar); 4.37 (s, 2H, CH.sub.2); 3.06 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=292.2.

Example 211

5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one

(546) ##STR00239##

(547) Example 211 was prepared according to procedure XVI(i) starting from compound 55. It was obtained as a yellow solid in 55% yield and taken to the next step without purification. .sup.1H-NMR (400 MHz, DMSO-D6): 7.83 (d, J 1.3 Hz, 1H, Ar); 7.80 (d, J 1.6 Hz, 1H, Ar); 7.55 (dd, J 7.9, 1.6 Hz, 1H, Ar); 7.51 (d, J 7.9 Hz, 1H, Ar); 7.18 (d, J 1.3 Hz, 1H, Ar); 4.26 (s, 2H, CH.sub.2); 2.95 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=292.2.

Example 212

5-Methyl-9-bromo-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,4]diazepin-4-one

(548) ##STR00240##

(549) Example 212 was prepared according to procedure XVI(i) starting from compound 56. Purification by flash column chromatography on silica gel (MeOH in dichloromethane, 0% to 4%) afforded the product as a white solid in 73% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.96 (m, 2H, Ar); 7.71 (dd, J 7.8, 1.7 Hz, 1H, Ar); 7.67 (d, J 7.8 Hz, 1H, Ar); 7.09 (d, J 1.9 Hz, 1H, Ar); 4.48 (s, 2H, CH.sub.2); 3.16 (s, 3H, CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=292.2.

Example 213

9-Bromo-5,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(550) ##STR00241##

(551) Example 213 was prepared according to procedure XVI(ii) starting from compound 57. Purification by flash column chromatography on silica gel (0% to 50% EtOAc in cyclohexane) afforded the product as a beige solid in 85% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.76 (d, J 1.7 Hz, 1H, Ar); 7.53 (m, 2H, Ar); 7.47 (d, J 8.0 Hz, 1H, Ar); 6.85 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.39 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.69 (q, J 7.2 Hz, 1H, CH—CH.sub.3); 3.10 (s, 3H, N—CH.sub.3); 1.05 (d, J 7.2 Hz, 3H, CH—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=305.

Example 214

9-Bromo-5-methyl-6-ethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(552) ##STR00242##

(553) Example 214 was prepared according to procedure XVI(ii) starting from compound 58. Purification by flash column chromatography on silica gel (0% to 50% EtOAc in cyclohexane) afforded the product as a colorless oil in 63% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.75 (d, J 1.8 Hz, 1H, Ar); 7.53 (m, 2H, Ar); 7.46 (d, J 8.0 Hz, 1H, Ar); 6.84 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.37 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.43 (t, J 8.0 Hz, 1H, CH—CH.sub.2); 3.12 (s, 3H, N—CH.sub.3); 1.30 (m, 2H, CH—CH.sub.2—CH.sub.3); 0.70 (t, J 7.4 Hz, 3H, CH.sub.2—CH.sub.3). M/Z (M[.sup.79Br]+H).sup.+=319.

Example 215

5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-4-one, hydrochloride

(554) ##STR00243##

(555) Example 215 was prepared according to general procedure VI(i) starting from example 210 in presence of 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (MeOH in dichloromethane, 0% to 10%) afforded the product as a brown solid in 69% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.88 (s, 1H, Ar); 8.82 (d, J 5.4 Hz, 1H, Ar); 8.45 (d, J 7.6 Hz, 1H, Ar); 7.92 (m, 3H, Ar); 7.87 (d, J 7.8 Hz, 1H, Ar); 7.66 (dd, J 7.8, 1.6 Hz, 1H, Ar); 4.53 (s, 2H, CH.sub.2); 3.12 (s, 3H, CH.sub.3); 2.73 (s, 3H, CH.sub.3). Proton for HCl salt not observed. M/Z (M+H).sup.+=305.2. MP=158-170° C.

Example 216

5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-one, hydrochloride

(556) ##STR00244##

(557) Example 216 was prepared according to general procedure VI(i) starting from example 211 in presence of 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (MeOH in dichloromethane, 0% to 4%) afforded the product as a brown solid in 43% yield. Salt formation was performed by method VII(ii). .sup.1H-NMR (400 MHz, DMSO-D6): 8.84 (d, J 5.4 Hz, 1H, Ar); 8.51 (d, J 7.5 Hz, 1H, Ar); 8.26 (s, 1H, Ar); 7.99 (dd, J 7.5, 5.4 Hz, 1H, Ar); 7.95 (d, J 1.4 Hz, 1H, Ar); 7.92 (d, J 7.8 Hz, 1H, Ar); 7.77 (s, 1H, Ar); 7.72 (d, J 7.8, 1.4 Hz, 1H, Ar); 4.66 (s, 2H, CH.sub.2); 3.18 (s, 3H, CH.sub.3); 2.75 (s, 3H, CH.sub.3). Proton for HCl salt not observed. M/Z (M+H).sup.+=305.3. MP=210-230° C.

Example 217

5-Methyl-9-(2-methylpyridin-3-yl)-5,6-dihydro-4H-benzo[f]pyrazolo[1,5-a][1,4]diazepin-4-one, hydrochloride

(558) ##STR00245##

(559) Example 217 was prepared according to general procedure VI(i) starting from example 212 in presence of 2-methylpyridine-3-boronic acid pinacol ester. It was purified by preparative HPLC to afford the product as a yellow solid in 32% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.77 (d, J 4.2 Hz, 1H, Ar); 8.35 (d, J 6.8 Hz, 1H, Ar); 7.90-7.81 (m, 4H, Ar); 7.57 (d, J 7.4 Hz, 1H, Ar); 7.05 (s, 1H, Ar); 4.53 (s, 2H, CH.sub.2); 3.15 (s, 3H, CH.sub.3); 2.66 (s, 3H, CH.sub.3). Proton for HCl salt not observed. M/Z (M+H).sup.+=305.3. MP=120-140° C.

Example 218

5,6-Dimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one, hydrochloride

(560) ##STR00246##

(561) Example 218 was prepared according to general procedure VI(i) starting from example 213 in presence of 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (0% to 4% MeOH in dichloromethane) afforded example 218 as a white solid in 84% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.79 (d, J 5.6 Hz, 1H, Ar); 8.47 (d, J 7.8 Hz, 1H, Ar); 7.93 (dd, J 7.8, 5.6 Hz, 1H, Ar); 7.68 (m, 2H, Ar); 7.55 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.48 (dd, J 7.9, 1.3 Hz, 1H, Ar); 6.87 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.79 (q, J 7.2 Hz, 1H, CH—CH.sub.3); 2.72 (s, 3H, N—CH.sub.3); 1.12 (d, J 7.2 Hz, 3H, CH—CH.sub.3); Proton for HCl salt not observed. M/Z (M+H).sup.+=318.3. MP=140-156° C.

Example 219

9-(6-Dimethylamino-pyridin-3-yl)-5,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one, hydrochloride

(562) ##STR00247##

(563) Example 219 was prepared according to general procedure VI(i) starting from example 213 in presence of 6-fluoropyridine-3-boronic acid and DMF as solvent. Purification by flash column chromatography on silica gel (0% to 10% MeOH in dichloromethane) afforded example 219 as a white solid in 62% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.39 (m, 2H, Ar); 7.80 (dd, J 5.6, 1.4 Hz, 1H, Ar); 7.71 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.65 (dd, J 7.8, 1.6 Hz, 1H, Ar); 7.61 (d, J 7.8 Hz, 1H, Ar); 7.28 (d, J 9.1 Hz, 1H, Ar); 6.86 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.43 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.73 (q, J 7.3 Hz, 1H, CH—CH.sub.3); 3.26 (s, 6H, N—(CH.sub.3).sub.2); 3.13 (s, 3H, N—CH.sub.3); 1.09 (d, J 7.3 Hz, 3H, CH—CH.sub.3); Proton for HCl salt not observed. M/Z (M+H).sup.+=347.3. MP=145-162° C.

Example 220

6-Ethyl-5-methyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one, hydrochloride

(564) ##STR00248##

(565) Example 220 was prepared according to general procedure VI(i) starting from example 214 in presence of 2-methylpyridine-3-boronic acid pinacol ester. Purification by flash column chromatography on silica gel (30% to 100% EtOAc in cyclohexane) afforded example 220 as a beige solid in 35% yield. Salt formation was performed by method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.78 (d, J 5.6 Hz, 1H, Ar); 8.44 (d, J 7.8 Hz, 1H, Ar); 7.90 (dd, J 7.8, 5.6 Hz, 1H, Ar); 7.67 (m, 2H, Ar); 7.53 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.48 (dd, J 7.8, 1.4 Hz, 1H, Ar); 6.86 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.40 (dd, J 3.8, 2.8 Hz, 1H, Ar); 4.53 (t, J 8.0 Hz, 1H, CH—CH.sub.2); 3.17 (s, 3H, N—CH.sub.3); 2.70 (s, 3H, CH.sub.3); 1.40 (m, 2H, CH—CH.sub.2—CH.sub.3); 0.77 (t, J 7.4 Hz, 3H, CH.sub.2—CH.sub.3); Proton for HCl salt not observed. M/Z (M+H).sup.+=332.3. MP=160-170° C.

Compound 61: 6,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(566) A suspension of compound 59 (1.0 equiv.) and potassium carbonate (3.0 equiv.) in DMA (0.20 mol.Math.L.sup.−1) was heated at 180° C. for 36 hours. As the reaction was not complete, the mixture was subjected to microwave irradiation at 220° C. for 1 hour, before being hydrolyzed 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 (50% to 90% EtOAc in cyclohexane) to afford the product as a brown solid in 58% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.10 (s, 1H, NH); 7.52-7.43 (m, 4H, Ar); 7.36 (m, 1H, Ar); 6.85 (dd, J 3.8, 1.9 Hz, 1H, Ar); 6.40 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.39 (bs, 6H, 2CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=227.3.

Compound 62: 9-Chloro-6,6-dimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(567) A suspension of compound 60 (1.0 equiv.) and potassium carbonate (3.0 equiv.) in DMA (0.20 mol.Math.L.sup.−1) was subjected to microwave irradiation at 220° C. for 1 hour. The mixture was hydrolyzed 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 (0% to 90% EtOAc in cyclohexane) to afford the product as a brown solid in 49% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 8.16 (s, 1H, NH); 7.59 (d, J 2.2 Hz, 1H, Ar); 7.56 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.52 (d, J 8.6 Hz, 1H, Ar); 7.42 (dd, J 8.6, 2.2 Hz, 1H, Ar); 6.87 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 1.37 (bs, 6H, 2CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=261.

Example 221

5,6,6-Trimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(568) ##STR00249##

(569) Example 221 was obtained according to general procedure III, starting from compound 61 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 100% EtOAc in cyclohexane) afforded the product as a yellow solid in 86% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.60 (dd, J 7.9, 1.3 Hz, 1H, Ar); 7.50 (m, 2H, Ar); 7.43 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.38 (m, 1H, Ar); 6.80 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.40 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.02 (s, 3H, CH.sub.3); 1.92 (s, 3H, CH.sub.3); 1.09 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=241.1. MP=127-130° C.

Example 222

9-Chloro-5,6,6-trimethyl-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one

(570) ##STR00250##

(571) Example 222 was obtained according to general procedure III, starting from compound 62 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 100% EtOAc in cyclohexane) afforded the product as a yellow solid in 72% yield. .sup.1H-NMR (400 MHz, DMSO-D6): 7.63 (d, J 2.2 Hz, 1H, Ar); 7.60 (d, J 8.5 Hz, 1H, Ar); 7.53 (dd, J 2.8, 1.8 Hz, 1H, Ar); 7.44 (dd, J 8.5, 2.2 Hz, 1H, Ar); 6.82 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.42 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.01 (s, 3H, CH.sub.3); 1.90 (s, 3H, CH.sub.3); 1.08 (s, 3H, CH.sub.3). M/Z (M[.sup.35Cl]+H).sup.+=275.

Example 223

5,6,6-Trimethyl-9-(2-methyl-pyridin-3-yl)-5,6-dihydro-benzo[f]pyrrolo[1,2-a][1,4]diazepin-4-one, hydrochloride

(572) ##STR00251##

(573) Under inert atmosphere, XPhos precatalyst (0.05 equiv.) was added to a mixture of example 222 (1.0 equiv.), 2-methylpyridine-3-boronic acid pinacol ester (2.0 equiv.) and tripotassium phosphate (2.0 equiv.) in dioxane (0.17 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 the resulting precipitate was collected by filtration, washed with water and dried by succion. Purification by preparative HPLC afforded the product as a white solid in 45% yield. Salt formation was performed according to method VII(i). .sup.1H-NMR (400 MHz, DMSO-D6): 8.82 (d, J 5.6 Hz, 1H, Ar); 8.43 (d, J 7.5 Hz, 1H, Ar); 7.90 (dd, J 7.5, 5.6 Hz, 1H, Ar); 7.80 (d, J 8.2 Hz, 1H, Ar); 7.71 (d, J 1.6 Hz, 1H, Ar); 7.58 (m, 2H, Ar); 6.90 (dd, J 3.8, 1.8 Hz, 1H, Ar); 6.49 (dd, J 3.8, 2.8 Hz, 1H, Ar); 3.12 (s, 3H, CH.sub.3); 2.74 (s, 3H, CH.sub.3); 2.04 (s, 3H, CH.sub.3); 1.20 (s, 3H, CH.sub.3). M/Z (M+H).sup.+=332.1. MP=230-250° C.

Example 224

Human mGluR3 Positive Allosteric Modulator Evaluation Using Ca++ Functional Assay

(574) 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.

(575) Cell Culture and Transfection:

(576) 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.

(577) 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.

(578) Calcium Assay EC50 Determination:

(579) Receptor activity was detected by changes in intracellular calcium measured using the fluorescent Ca.sup.2+ sensitive dye, Fluo4AM (Molecular Probes).

(580) 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).

(581) 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.

(582) 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.

(583) 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, more preferably 0.1 μM or less.

(584) The following list represents selected examples of the compounds of the present invention showing mGluR3 positive allosteric modulator activity with an EC50>1.0 μM: Examples: 5, 6, 7, 9, 11, 13, 16, 21, 27, 28, 37, 40, 43, 46, 49, 51, 53, 58, 59, 65, 66, 68, 71, 72, 86, 87, 88, 89, 90, 91, 92, 100, 115, 119, 120, 123, 124, 131, 135, 137, 138, 139, 167, 189, 200, 209, 214, 215, 216, 217, 221 and 222.

(585) The following list represents selected examples of the compounds of the present invention showing mGluR3 positive allosteric modulator activity with 0.1 μM<EC50<1.0 μM: Examples: 1, 17, 19, 20, 22, 23, 24, 26, 29, 30, 33, 34, 35, 36, 38, 39, 42, 45, 47, 48, 50, 52, 57, 60, 62, 67, 69, 75, 77, 78, 84, 96, 97, 98, 99, 101, 104, 105, 108, 109, 113, 116, 117, 121, 122, 128, 129, 130, 132, 134, 136, 141, 142, 147, 148, 149, 150, 153, 154, 156, 165, 166, 176, 193, 194, 195, 196, 203, 218, 220 and 223.

(586) 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: 18, 25, 31, 32, 41, 44, 54, 55, 56, 61, 63, 64, 73, 74, 76, 81, 82, 83, 93, 94, 95, 102, 103, 106, 107, 110, 111, 112, 114, 118, 125, 126, 127, 133, 140, 143, 144, 145, 146, 151, 152, 155, 157, 158, 159, 160, 161, 162, 163, 182, 183, 184, 185, 186, 187, 188, 190, 191, 192, 197, 198, 199, 201, 202, 205, 206, 207 and 219.

Example 225

Neuroprotection of Example 207 on Cortical Primary Neurons

(587) Primary mouse neurons were incubated with vehicle or NMDA (60 μM)+vehicle or example 207 or LY379268 (mixed mGluR2/3 agonist used as positive control) for 24 hours. Tests were performed in triplicate. Neuron viability was measured using a MTT test.

(588) Results:

(589) In FIG. 1, it can be observed that NMDA treatment induced a close to 50% reduction of the neuron viability (black histograms). Example 207 alone, in absence of NMDA challenge, has no toxicity on cortical primary neuron viability at concentrations ranging from 30 nM to 30 μM (hashed histograms). Example 207 reduces in a dose-dependent manner the toxicity induced by NMDA up to 1 μM, this effect tending to disappear at higher concentrations (white histograms). Reference LY379268 (mGluR2/3 agonist) has no toxicity alone and decreases NMDA-induced toxicity at 1 μM (grey histograms).

Example 226

Neuroprotection of Example 63 on Striatal Primary Neurons

(590) Primary mouse neurons were incubated with vehicle or NMDA (60 μM)+vehicle or example 63 or LY379268 (mixed mGluR2/3 agonist used as positive control) for 24 hours. Tests were performed in triplicate. Neuron viability was measured using a MTT test.

(591) Results:

(592) In FIG. 2, it can be observed that NMDA treatment induced a close to 70% reduction of the neuron viability (black histograms). Example 63 alone, in absence of NMDA challenge, has no toxicity on striatal primary neuron viability at concentrations ranging from 30 nM to 30 μM (hashed histograms). Example 63 reduces in a dose-dependent manner the toxicity induced by NMDA up to 10 μM, this effect tending to disappear at 30 μM (white histograms). Reference LY379268 (mGluR2/3 agonist) has no toxicity alone and decreases NMDA-induced toxicity at 1 μM (grey histograms).