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Title:
TRICYCLIC COMPOUNDS AS VASOPRESSIN V1A RECEPTOR ANTAGONISTS
Document Type and Number:
WIPO Patent Application WO/2019/116325
Kind Code:
A1
Abstract:
The present invention relates to 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine derivatives of general formula (I) and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof which are centrally and/or peripherally acting V1a receptor modulators, particularly V1a receptor antagonists. Additional subject of the present invention is the process for the preparation of the compounds and the intermediates of the preparation process as well. The invention also relates to the pharmaceutical compositions containing the compounds or together with one or more other active substances, as well as to the use in the treatment and/or prophylaxis of a disease or condition associated with V1a receptor function.

Inventors:
BATA IMRE (HU)
SZELECZKY ZSOLT (HU)
SZONDINÉ KORDÁS KRISZTINA (HU)
SZÁNTÓ GÁBOR (HU)
Application Number:
PCT/IB2018/060078
Publication Date:
June 20, 2019
Filing Date:
December 14, 2018
Export Citation:
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Assignee:
RICHTER GEDEON NYRT (HU)
International Classes:
C07D223/06; A61K31/55; A61P25/00; A61P25/24; C07D223/10; C07D487/04; C07D487/14
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Claims:
Claims

1. The compound of formula (I)

wherein

ring A is a cycloalkyl or heterocyclyl group;

Y is -0-, -C(O)-, -CH2-, -NH- or bond if ring B is present; or -N(Ci.4alkyl)2, C(0)0Ci-4alkyl, Ci-4alkyl group optionally substituted with halogen, Ci-4alkoxy group or halogen if ring B it not present;

ring B is an optionally substituted aryl, heterocyclyl or heteroaryl group;

or B-Y-A- jointly represents 3H-spiro[2-benzofuran-1 ,4’-piperidin-T-yl]; or group;

R1 is a hydrogen, halogen, C ^alkyl, Ci^alkoxy, CF3 or CN;

R2 is a hydrogen or Ci^alkyl group;

R3 is a (CHalnR4, C(0)R5 or C .4aikyi group optionally substituted with R6;

or R2 and R3 jointly represent -(CHalp-O-iCh jq- or -(Ch jr group;

R4 is a CN, azide or Cy1 group;

R5 is a C1 -4aikyi, C ^alkoxy, OH or NR7R® group;

R6 is a OR9, NR10R1 1 , oxo, -OfCHskO- group or one or more halogen; R7 and R8 is independently a hydrogen, Ci-talkyl, Cy2 or R7 and R8 taken together with the N to which they are attached form a heterocycle;

R9 is a hydrogen; Ci^alkyl optionally substituted with Nh or with optionally substituted aryl group; Si(CH3)3; or C(0)R12 group;

R10 and R11 is independently a hydrogen; Ci^alkyl optionally substituted with Ci-4alkoxy group; Cy3; C(0)R13 or R10 and R11 taken together with the N to which they are attached form an optionally substituted heterocycle;

R12 is a Ci-sa!ky! or NR14R15 group;

R13 is a Ci-4aikyi, Cy1 or NR16R17 group;

R14 and R15 is independently a hydrogen, optionally substituted aryl or R14 and R15 taken together with the N to which they are attached form an optionally substituted heteroeyc!e;

R 16 and R17 is a Chalky! or R16 and R17 taken together with the N to which they are attached form an optionally substituted heterocycle;

Cy1 is an optionally substituted heteroaryl group;

Cy2 is an optionally substituted aryl or heteroaryl group;

Cy3 is an optionally substituted cycloalkyl or heterocyclyl group;

X is a Chalky!, aryl or heteroaryl group;

Z is a Chalky! group;

n is 0 or 1 ;

p is 1 , 2 or 3;

q is 1 , 2 or 3;

r is 4, 5 or 6

and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof

2. The compound according to claim 1 , wherein R1 is hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CF3 or CN.

3. The compound according to any of claims 1 or 2, wherein ring A is a 3- to 6-membered saturated carbocydic or a 4- to 7-membered saturated heterocyde containing 1 or 2 N;

ring B is an optionally substituted 6- or 5-membered mono-heteroaryl group, 6- to 10- membered aromatic carbocycle, or 4- to 7-membered saturated, monocyclic, bicyclic, fused and/or bridged heterocyde containing 1 , 2 or 3 heteroatoms selected from O, S or N;

or B-Y-A- jointly represents a 3/-Aspiro[2-benzofuran-1 ,4’-piperidin-1’-yi]; or group;

X is isopropyl group;

Z is methyl group.

4. The compound according to any of claims 1 to 3, wherein ring B is optionally substituted 6-membered mono-heteroaryi group, phenyl, or 4- to 6-membered saturated, monocyclic heterocyde containing 1 or 2 heteroatoms selected from O, S or N.

5. The compound according to any of claims 1 to 4, wherein Y is -0-, -C(O)-, -CH2-, -NH-, or a single bond if ring B is present.

6. The compound according to any of claims 1 to 5, wherein ring A is a 4- to 6-membered saturated carbocydic group or a 4- to 7-membered saturated heterocyde containing 1 or 2 N attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H- [1 ,2,4]triazo!o[4,3~a][1]benzazepine core.

/. The compound according to any of claims 1 to 6, wherein ring A is cyclohexyi, Y is -0-, ring B is pyridin-2~yl and R1 is chlorine.

8. The compound according to any of claims 1 to 6, wherein ring A is azetidine, piperidine or piperazine, Y is -O- or a single bond, ring B is pyridine, pyrimidine, piperidine and R1 is chlorine.

9. The compound according to any of claims 1 to 3, wherein Y is -N(Ci-4alkyl)2, C(0)0Ci-4alkyl, Chalky! group optionally substituted with halogen, Ci-4alkoxy group and halogen and ring B is not present.

10. The compound according to claim 9, wherein ring A is a 4- to 6-membered saturated carbocyclic group.

1 1. The compound according to claim 10, wherein Y is one group selected from the group consisting of -N(Ci-4alkyl)2, C(0)GCi-4aikyi, Ci^aikyi group optionally substituted with halogen, Ci-4aikoxy group and halogen.

12. The compound according to claim 10, wherein Y is two groups selected from the group consisting of Ci-4aiky! group optionally substituted with halogen, C<-4alkoxy group and halogen.

13. The compound according to any of claims 1 to 12, wherein R2 is a hydrogen or Ci- 4aikyi group, R3 is a (CH2)nR4 group.

14. The compound according to claim 13, wherein R2 is a hydrogen, R3 is a (CH2)nR4 group; R4 is CN, azide or 5-membered mono-heteroaryi group containing 2 N and 1 O or 4 N optionally substituted with Chalky! group.

15. The compound according to any of claims 1 to 12, wherein R2 is a hydrogen or Ci- 4aikyi group, R3 is a C(0)R5 group.

16. The compound according to claim 15, wherein R2 is a hydrogen.

17. The compound according to claim 15, wherein R5 is a methyl, methoxy, OH or NR7R® group, wherein R7 and R® is independently a hydrogen, methyl, ethyl or isopropyl group.

18. The compound according to any of claims 1 to 12, wherein R2 is a hydrogen or Ci-

4aikyi group and R3 is a Ci-4alkyl group optionally substituted with R6.

19. The compound according to claim 18, wherein R2 is a hydrogen or Ci-4alkyl group and R3 is a Ci-4aikyi group.

20. The compound according to claim 19, wherein R2 is a hydrogen or Cvsalkyl group and R3 is Chalky! group.

21. The compound according to claim 18, wherein R3 is a single or multiple branched Ci- 4aikyi group substituted with R6.

22. The compound according to claim 21 , wherein R3 is a -CH2R6 or -CH(R6)CH3 group.

23. The compound according to any of claims 21 or 22, wherein R2 is a hydrogen and R6 is OR9 group.

24. The compound according to claim 23, wherein R9 is a hydrogen, Ci-talkyl group optionally substituted with phenyl group or C(0)R12 group, wherein R12 is methyl group.

25. The compound according to any of claims 21 or 22, wherein R2 is a Ci-4alkyl group and R6 is OR9 group.

28. The compound according to claim 24, wherein R2 is a methyl or ethyl group, R9 is a hydrogen.

27. The compound according to any of claims 21 or 22, wherein R2 is a hydrogen, R6 is NR^R11 group.

28. The compound according to claim 27, wherein R10 and R11 is independently a hydrogen, Chalky! group optionally substituted with Ci-4aikoxy group, Cy3, C(0)R13, or R16 and R17 taken together with the N to which they are attached form an optionally substituted hete recycle.

29. The compound according to any of claims 21 or 22, wherein R2 is a C halky! group and R6 is NR10R11 group.

30. The compound according to any of claims 21 or 22, wherein R2 is a hydrogen and R6 is one or more halogens.

31. The compound according to claim 30, wherein the halogen is fluorine.

32. The compound according to any of claims 21 or 22, wherein R2 is a Chalky! group and R6 is one or more halogens.

33. The compound according to claim 21 , wherein R6 is an oxo or -0(CH2)2G- group.

34. The compound aaccording to any of claims 13 to 33, wherein the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine core is (R).

35. The compound according to any of claims 13 to 33, wherein the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine core is (S).

38. The compound according to any of claims 1 to 12, wherein R2 and R3 jointly represent ~(CH2)p-0-(CH2)q~ group, wherein p is 1 , 2 or 3 and q is 1 , 2 or 3.

37. The compound according to claim 35, wherein the sum of p and q is 3 or 4.

38. The compound according to any of claims 1 to 12, wherein R2 and R3 jointly represent -(Ch jr group, wherein r is 4, 5 or 8.

39. The compound according to any of claims 1 to 38, wherein the compound is selected from the group consisting of:

methyl 8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro~4H-[1 ,2,4]triazolo[4,3~ a][1]benzazepine-5-carboxylate,

8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-[1 ,2,4]triazoio[4,3- a][1]benzazepine-5-carboxy!ic acid,

8-cbloro-1-jYrans-4-{pyridin-2-y!axy)cydohexyi]-5,6-dibydro-4H-[1 ,2,4]triazoio[4,3- a][1]benzazepine- 5-carboxamide,

8-cbloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dibydro-4i4-[1 ,2,4]triazoio[4,3- a][1]benzazepine-5-carbonitrile,

8-chloro-A/,A/-dimethyi-1-[irans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro~4H-

[1 ,2,4]triazoio[4,3-a][1]benzazepine-5-carboxamide,

(5S)-8-chioro-A/ A/-dimethyi-1-[frans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine-5-carboxamide,

(5R)-8-ch!aro-A/,/V-dimethyM-jYra/?s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dibydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine- 5-carboxamide,

8-chloro-A/-(propan-2-yl)-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine- 5-carboxamide,

{8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5 8-d!hydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}(pyrroiidin-1-yl)methanone,

{8-chloro-1-[frans-4-(pyrid!n-2-yioxy)cyclohexyl]-5 6-dihydro-4H-[1 ,2 4]triazolo[4,3- a][1]benzazepin-5-yl}(morphoiin-4-yi)methanone,

{8-chloro-1-[frans-4-{pyridin-2-yloxy)cydohexyij-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yi}(1 ,1-dioxidothiomorpholin-4-yl)methanone, {8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5 6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1 jbenzazepin-5-yl}methanol ,

{(5S)-8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-yl}methano!,

{(5R)-8-cbloro-1-[iAans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}metbanol,

8-cbloro-5-(methoxymethyl)-1-[fra/7s-4-(pyridin-2-yloxy)cyclobexyl]-5,6-dihydro-4H-

[ 2.4]triazolo[4,3-a][1]benzazepine,

{8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- aj[1]benzazepin-5-yl}metbyI-morpholine-4-carboxy!ate,

{8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-y!}metbyl (4-fluoropbenyl)carbamate,

5-(azidomethyl)-8-chloro-1-[frans-4-(pyridjn-2-yloxy)cyclobexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

1-{8-chloro-1-[ira/7S-4-(pyridin-2-yloxy)cyclohexyl]-5>6-dihydro-4H-[1 ,2,4]triazolo[4,3- aj[1]benzazepin-5-yl}methane amine,

8-chloro-5-(morpholin-4-ylmethyl)-1-[i/¾A7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1 ,2,4]triazolo[4,3-a][1]benzazepine,

1-{8-chloro-1-[ira/7s-4-(pyridin-2-yloxy)cyclobexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}-/V,/\/-dimethylmethane amine,

/V-({8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yi}metbyl)propane-2-amine,

methyl 8-chloro-1-[1-(pyrimidin-2-yl)azetidin-3-yl]-5>6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

methyl 8-chloro-1~[frans-4-(dimethyiamino)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]tnazolo[4,3- a][1]benzazepine-5-carboxylate,

methyl 8-chloro-1-[frans-4-(trifluormethyl)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

methyl 8-chloro-1-[fra/7s-4-(morpholin-4-yl)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate, {1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-

5-yl}methanol,

methyl 8-chloro-1-[/rans-4-(pyrrolidin-1-ylcarbonyl)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

{8-chloro-1-[iAaA7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}acetonitrile,

8-chloro-5-[(4-methylpiperazin-1-yl)methyl]-1-[iraA7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine,

8-chloro-5-(fluoromethyl)-1-[f/a/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

8-chloro-5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1-[/rans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepjne,

8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5-(2H-tetrazol-5-yl)-5 6-dihydro-4W-

[1.2.4]triazolo[4,3-a][1]benzazepine,

A/-({8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}methyi)tetrahydro~2H-piran-4-amine,

A/,A/-dimethyl-1-[ira/7s-4-(pyridin-2-yloxy)cyclobexyl]-8-(trifluoromethyl)-5,6-dibydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine- 5-amine,

methyl 8-chloro-1-[i/¾A?s-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-8-yl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

/V-({8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}methyl)acetamide,

A/-({8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}methyl)oxetane-3-amine,

methyl 8~chloro-1-[frans~4~(morpholin~4~ylcarbonyl)cyclohexyl]-5,8-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

methyl 8-chloro-1-[c/s-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-8-yl]-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-aj[1]benzazepine-5-carboxylate,

methyl 8-chloro-1-[1-(pyridin-2-yl)azetidin-3-yl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate, methyl 1~[/fans~4-(azeiidin~1~ylcarbonyl)cyclobexyl]-8-chloro~5,8~dihydro-4H~

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate

8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrrolidin-1-ylmethyl)-5,6-dihydro-4/-/-

[1.2.4]triazolo[4,3-a][1]benzazepine,

A/-({8-chloro-1-[fraA7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}methyl)-2-methyl-A/-(2-methylpropyl)propane-1 -amine,

methyl 8-chloro-1-[fra/7s-4-(piperidin-1-ylcarbonyl)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazo!o[4,3-a][1]benzazepine~5~carboxylate,

methyl 1-(frans~4~{[4-(te/ -butoxycarbonyl)piperazin-1-yl]carbonyl}cyclohexyl)~8~chloro-5,6- dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

methyl 8-chloro-1-[f/a/7s-4-(piperazin-1-ylcarbonyl)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-aj[1]benzazepine-5-carboxylate hydrochloride,

methyl 8-methoxy-1-[fraA7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

methyl 8-methyl-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- aj[1]benzazepine-5-carboxylate,

8-chloro-A/-(4-fluorophenyl)-1-[fra/7s-4-(pyridin-2-yloxy)cyclchexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine- 5- carboxamide,

methyl 8-bromo-1-[/rans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

1-(1 ,4'-bipiperidin-1'-yl)-8-chloro-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5- carboxamide,

methyl 8-chloro-1-[(5r,8r)-1-oxo-2-(propan-2-yl)-2-azaspiro[4.5]dec-8-yl]-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine-5-carboxylate,

1-{8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- aj[1]benzazepin-5-yl}ethanol,

1-{8-chloro-1-[fra/?s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}ethanone,

8-chloro-5-(fluoromethyl)-1-(fraA7s-4-methoxy-4-methylcyclohexyl)-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine, 1-{8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydiO-4H-[1 ,2,4]triazolo[4,3- a][1jbenzazepin-5-yi}-A/-(2-methoxyethyl)ethanamine,

methyl 8-fluoro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

8-chloro-5-(fluoromethyl)-1-[irans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

5-(fluoromethyl)-1-(fra/7s-4-methoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine,

{8-fluoro~1~[/rans-4-(pyndin~2-yloxy)cydohexyl]~5,6~dihydro-4H-[1 ,2,4]triazolo[4,3- aj[1]benzazepin-5-yl}methanol,

8-fluoro-5-(fluoromethyl)-1-[/rans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]Ip3zoIo[4,3-3][1 qhz3ZQrihq,

c/s-(racem)-1-{8-chloro-1-[iAans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yi}ethanol,

fra/7s-(racem)-1-{8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

(IR)-1-{(5R)-8-chloro-1-[frans-4-(pyndin-2-yloxy)cydohexyl]-5,6-d!hydro-4H-

[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

(I S)-1-{(5S)-8-chloro-1-[irans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H- [1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

{1 S)-1-{(5R)-8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cydohexyl]-5,8-dihydro-4H-

[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

(1R)-1-{(5S)-8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

5-(fluoromethyl)-8-methyl-1-[i/¾A7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

(5S)-8-chloro-5-(fluoromethyl)-1-[/rans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-al[1]benzazepine,

(5 ?)-8-chloro-5-(fluoromethyl)-1-[fra/7s-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro-4W-

[1.2.4]triazolo[4,3-a][1]benzazepine, methyl 8~fluoro-1-[frans-4-(trifluoromethyl)cydohexyl]-5,6-dihydro~4H-[1 ,2,4]tnazolo[4,3~ a][1jbenzazepine-5-carboxylate,

8-chloro-1-[4-(2,3-dimethylphenyl)piperazin-1-yl]-5,6-dihydro-4H-[1 2,4]triazolo[4,3- a][1]benzazepine- 5-carboxamide,

{8-fluoro-1-[ffa/?s-4-(trifluoromethyl)cydohexyl]-5,6-dihydro-4H-[1 ,2,4]triazalo[4,3- a][1]benzazepin-5-yi}metbanol,

{8-chloro-5-methyl-1-[fra/?s-4-(pyrldin-2-yioxy)cydobexyl]-5,8-dihydrQ-4H-[1 ,2,4]trlazolo[4,3- a][1]benzazepin-5-yl}methanol,

{8-chloro-5-ethyl-1-[irans-4-(pyridin-2-yloxy)cydohexyi]-5,6-dihydro~4H-[1 ,2,4]triazolo[4,3~ a][1]benzazepin-5-yl}methanol,

(5S)-8-fluoro-5-(fluoromethy!)-1-[frans-4-(pyndin-2-yloxy)cydohexyl]-5 6-dihydro-4H-

[1 ,2,4]triazolo[4,3-a][1]benzazepine,

(5R)-8-fliioro-5-(fluaromethyl)-1-[frans-4-(pyridin-2-yioxy)cyclobexyl]-5,6-dihydro-4H-

[1 ,2,4]triazolo[4,3-a][1]benzazepine,

8-chlQro-1-[4-(3-chiorophenyi)piperazin-1-yl]-5,8-dihydro-4H-[1 ,2,4]iriazolo[4,3- a][1]benzazepine- 5-carboxamide,

8~chloro-1-[4-(pyridin~2~yi)piperazin-1-yl]~5,8~dihydro-4H~[1 ,2,4jjtriazolo[4,3- a][1]benzazepine- 5-carboxamide,

8-chloro-1-[4-(pyrid!n-2-yioxy)piperidin-1-y!]-5,6-dihydro-4H-[1 2,4]triazolo[4,3- a][1]benzazepine- 5-carboxamide,

5-[(benzyloxy)methyi]-8-chloro-1-[/rans-4-(pyridin-2-yioxy)cydohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

methyl 8-chloro-1-(3,3-difiuorocyclobutyi)-5,8-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

methyl 8-chloro~1~[/rans-4-(piperidin-1~ylmethyi)cyclohexyl]-5,8-dihydro-4H-

[1.2.4]triazo!o[4,3-a][1]benzazepine-5-carboxylate,

{8-chloro-1-[frans-4-(pyndin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]tnazolo[4,3- a][1]benzazepin-5-yl}methyl acetate,

8-chloro-1-( H,3H-spiro[2-benzofuran-1 ,4'-piperidin]- -yl)-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine-5-carboxamide, 8-chloro~A/~(pyridin-2-yl)-1-[frans~4~(pyriclin-2-yioxy)cyclohexy!]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine- 5- carboxamide,

8-cbloro-1-( W,3H-spiro[2-benzofuran-1 ,4'-piperidin]- -yl)-5,6-dihydro-4/-/-

[1.2.4]triazoio[4,3-a][1]benzazepine-5-carbonitri!e,

8-chloro-1-[4-(2,3-dimethylphenyl)piperazin-1-yl]-5 6-dihydro-4/-/-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carbonitrile,

8-cbloro-1-[4-(pyridin-2-yl)piperazin-1-yl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carbonitrile,

8-fluoro-5,5-dimethyl-1-[ira/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

8-fluoro-5-(propan-2-yl)-1-[irans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

8'-bromo-1 '-[irans-4-(pyridin-2-yloxy)cyclobexyl]-4,H 6'H-spiro[cyclopentane-1 ,5'-

[1.2.4]triazoio[4,3-a][1]benzazepine],

8-bromo-5-(propan-2-yl)-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

8'-bromo-f-[fran$~4~(pyndin-2-y!oxy)cyciohexy!]-2,3,5,6~tetrahydro-4'H,6'H~spiro[pyran-4,5'~

[1.2.4]triazolo[4,3-a][1]benzazepine],

8-f!uoro-5,5-d!methyl-1-[frans-4-(trifluoromethy!)cyclobexy!]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

(5R)-8-bromo-5-(propan-2-yl)-1-[ira/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

(5S)-8-bromo-5-(propan-2-yl)-1-[ira/is-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

[1 ,2,4jiriazo!o[4,3-a][1jbenzazepine,

8,-bromo- -[ira/7s-4-(pyridin-2-yloxy)cyclohexyl]-4,5-dihydro-4'H,6,H-spiro[furan-3,5'-

[1.2.4]triazoio[4,3-a][1]benzazepine],

8'-chloro-T-[frans-4-(pyr!din-2-y!oxy)cyclohexy!]-2,3,5,8-tetrahydro-4'H,6'H-spiro[pyran-4,5'-

[1.2.4]triazolo[4,3-a][1]benzazepine],

8'-chloro- -[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H 4'H 6'H-spiro[pyran-3,5'-

[1 ,2,4]triazolo[4,3-a][1]benzazepine], 8’-ch!oro~1'~[ffans-4-(pyridin~2~yioxy)cydobexyi]~4,5~dihydro-4'H,6'H~spiro[furan~3,5'~

[1 ,2,4]triazolo[4,3-a][1]benzazepine],

8'-chloro-1'-[/rans-4-(trifluoromethyl)cyclobexyl]-2,3,5,6-tetrahydro-4,H,6,H-spiro[pyran-4,5'-

[1 ,2,4]triazolo[4,3-a][1]benzazepine],

(3R)-8'-bromo-1'-[fraA7s-4-(pyridin-2-yloxy)cyclohexyl]-4,5-dihydro-4'H,6'H-spiro[furan-3,5'-

[1.2.4]triazolo[4,3-a][1]benzazepine],

(3S)-8'-bromo- -[frar?s-4-(pyridin-2-yloxy)cyclohexyl]-4 5-dibydro-4'H,6'H-spiro[furan-3,5'-

[ 2.4]friazolo[4,3-a][1]benzazepine],

(3S)-8'-chloro-T-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H,4'H,6,H-spiro[pyran-

3,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

(3R)-8'-chloro-T-[frans-4-(pyndin-2-y!oxy)cydohexy!]-5,6-dihydro-4H,4'H,6'H-spiro[pyran-

3,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

8-fluoro-1-(frans-4-methoxy-4-methylcyclahexyl)-5,5-dimethyl-5,6-dihydra-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine,

8-fluoro-1-(cis-4-methoxy-4-metbylcyclohexyl)-5,5-dimetbyl-5,6-dibydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

8'-chloro~T-(trans-4-metboxy-4-methylcydobexyl)-2,3,5,6~tetrahydro-4'H,6'H~spiro[pyran-

4,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

8,-chloro-T-(ds-4-methoxy-4-methylcydohexyl)-2,3,5,6-tetrabydro-4'H,6'H-spiro[pyran-4,5'-

[1.2.4]triazolo[4,3-a][1]benzazepine], and

methyl 8-chloro-1-[frans-4-(pyridin-2-ylamino)cyclohexyl]-5 6-dihydro-4/-/-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate.

40. A pharmaceutical composition comprising therapeutically effective amount of a compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 39 as active substance and a pharmaceutically acceptable excipient.

41. A combinational composition comprising therapeutically effective amount of a compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 39 and one or more other active substances.

42. The combinational composition according to claim 41 , wherein the one or more other active substances are selected from the group consisting of psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents.

43. The composition of any of claims 40 to 42 for use in the treatment and/or prophylaxis of a disease or condition associated with the central and/or peripheral antagonisation of Via receptor.

44. A process for the preparation of a pharmaceutical composition having Via receptor antagonist activity comprising a therapeutically effective amount of a compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 39 as active substance with pharmaceutically acceptable excipients

45. The compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 39 for use in the treatment and/or prophylaxis of a disease or condition associated with the central and/or peripheral antagonisation of Via receptor.

46. The compound for use according to claim 45, wherein the disease or condition associated with the central and/or peripheral antagonisation of Via receptor is selected from the group consisting of various pathological conditions of the female sex organs, long- standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.

47. Use of a compound of general formula (!) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 39 for the treatment and/or prophylaxis of a disease or condition associated with the central and/or peripheral antagonisation of Via receptor.

48. The use according to claim 47, wherein the disease or condition associated with the central and/or peripheral antagonisation of Vi a receptor is selected from the group consisting of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.

49. Method for treating and/or preventing a disease or condition associated with Vi a receptor function comprising administering, to the mammal to be treated, of a therapeutically effective amount of a compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 39 alone or with pharmaceutically acceptable excipients.

50. The method according to claim 49, wherein the disease or condition associated with the central and/or peripheral antagonisation of Via receptor is selected from the group consisting of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.

51. The compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any of claims 1 to 39 and one or more other active substances for use in the treatment and/or prophylaxis of a disease or condition associated with the central and/or peripheral antagonisation of Via receptor.

52 The combination for use according to claim 51 , wherein the one or more other active substances are selected from the group consisting of psychoieptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents.

53. The compound of formula (lll-a) wherein R1 is chlorine, bromine, fluorine, methyl or methoxy group.

(lll-a)

54 The compound of formula (X) wherein R1 is chlorine, bromine, fluorine, methyl or methoxy group.

55. The compound of formula (XLM), the methyl 1-bromo-8-chloro-5,6-dihydro-4H- [1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate

56. The compound of formula (LI) wherein R1 is as defined for formula (I), R2 and R3 taken together are -(CH2)P-0~(CH2)q- or -(Ch group

57. The compound of formula (LIV) wherein R1 is chlorine, fluorine or methyl group.

Description:
TRICYCLIC COMPOUNDS AS VASOPRESSIN V1 RECEPTOR ANTAGONISTS

THE FIELD OF THE INVENTION

The present invention relates to 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine derivatives of the general formula (I) and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof which are centrally and/or peripherally acting Via receptor modulators, particularly Via receptor antagonists. Additional subject of the present invention is the process for the preparation of the compounds and the intermediates of the preparation process as well. The invention also relates to the pharmaceutical compositions containing the compounds and to the use thereof in the treatment and/or prophylaxis of a disease or condition associated with Via receptor function

THE BACKGROUND OF THE INVENTION

The vasopressin (antidiuretic hormone, ADH, CYIQNCPRG) is a 9-amino acid peptide hormone produced by the magnoceliular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus and secreted directly into the posterior lobe of the pituitary gland where the hormone is stored until entering into the bloodstream in the periphery, the major role of vasopressin is in the contraction of blood vessels, as well as in glucose metabolism and in the regulation of excretion.

For this reason, the conditions due to inappropriate secretion of vasopressin thus the lack of vasopressin may lead to pathological changes in the body, such as the central form of diabetes insipidus or abnormally low blood pressure (hypotension), while in the case of elevated levels of vasopressin or exogenous administration various forms of strengthening of the aggressive behaviour can be observed (Ferris et ai., BMC Neuroscience 2008, 9:111).

Oxytocin (OXT, CY!QNGPLG) is a vasopressin-related peptide hormone, differing from that in one amino acid and its receptor is also related to vasopressin receptors. The effects of compounds on the oxytocin receptor show species-specific differences, but the oxytocin hormone itself is identical in the different mammalian species. Similarly, the vasopressin peptide is the same in ail mammals (except marsupials and pigs) and the effects exerted through its receptors may also show species-specific differences. The anxiolytic effect of oxytocin exerted in the central nervous system is well-known (Neumann ID. J Neuroendocrinal 2008, 20(6): 858-65), therefore the inhibition of the oxytocin receptor in the central nervous system can trigger anxiety as undesirable side effect.

Three vasopressin receptors are distinguished, all of them are G-protein coupled receptors. The Via receptor (V1aR) is expressed centrally in the cerebral cortex, hippocampus and pituitary gland, furthermore peripherally in the liver, vascular smooth muscle, lung, uterus and testes (Frank et a! , Eur J Pharmacol 2008, 583:226-42) The V1 b receptors (V1bR) are also can be found in the cortex, hippocampus and pituitary gland, and in the periphery they play an important role in the regulation of the pancreas and the adrenal glands. In contrast to this, the V2 receptor (V2R) is mainly localised on the periphery, in the kidneys where it increases water reabsorption, thereby exerting the antidiuretic effect of vasopressin (Robben et a! , Am J Physiol Renal Physiol 2007, 292(1): F253-60). Thus, due to changes in the regulation of water balance the effect on the V2 receptor may cause undesirable side effect.

The secondary signalling pathway of Via and V1b receptors include the change of intracellular Ca 2 * concentration through phosphatidylinositol, whereas the V2 receptors activate adenylate cyclase enzyme and influence cAMP levels (Gouzenes et a!., J Physiol 1999, 517(Pt3):771-9; Tahara et al., Pf!ugers Arch 1999, 437(2):219-26).

An important role is attached to the Via receptors in the regulation of the circadian rhythm. One-third of the neurons in the suprachiasmatic nucleus (SCN) express vasopressin and the mRNA of Via receptors exhibit daily fluctuations in this brain region of which the highest values can be observed during night hours (de Vries and Miller, Prog Brain Res 1998, 119:3-20). Vasopressin shows sexual dimorphism in inducing behavioural effects, despite the fact that distribution and amount of the V1aR mRNAs do not differ in men and women (Szot et al., Brain Res Mol Brain Res 1994, 24(1-4):1-10) Experiments in mice have shown that the increased water absorption prior to their sleep period was triggered by their internal clock and not their physiological necessities (Gizowski et al., Nature 2016, 537(7622):685- 8). Sleep disorder is a major accompanying symptom of autism (Giickman, Neuroses Blobehav Rev 2010, 34(5): 755-68).

Vasopressin acts as a neuromodulator in the brain, its elevated level can be detected in the amygdala under stress (Ebner et al., Eur J Neuroses 2002, 15(2):384-8) Such stressful life situations are well known to increase the likelihood of developing depression and anxiety (Kendier et al., Arch Gen Psychiatry 2003, 60(8):789-96; Simon et al., Recent Pat CNS Drug Discov, 2008, 3(2):77-93; Egashira et al., J Pharmacol Sci 2009, 109(1):44-9; Bielsky et al., Neuropsychopharmacology 2004, 29(3):483-93). The expression of V1aR is high in the brain, especially in certain parts of the limbic system, such as the amygdala, the lateral septum and the hippocampus which play an important role in the development of anxiety Male V1aR gene knocked out mice exhibited reduced anxiety in the elevated plus maze, the open field and the light-dark box tests, but these differences could not be detected in females (Bielsky et al , Behav Brain Res 2005, 164(1): 132-6).

The male V1 aR knockout mice did not show any phenotypic difference in motor performances. In normal light-dark-cycle experiments, V1aR KO mice showed no difference compared to their wild-type littermates, however, in the experiments carried out in continuous darkness the diurnal rhythm of Vi a knockout mice was shifted significantly (Egashira et al., Behav Brain Res 2007, 178(1): 123-7).

The V1 aR KO mice showed modified activity in the prepu!se inhibition test, in the test which is accepted as animal model of sensory motor deficiency observed in most schizophrenic patients Egashira et al have shown decreased function in the social interaction test, which is suitable to measure socio-cognitive behaviour of the V1 aR KO mice in both sexes, but it was not observed after the treatment with antagonist (Bleickard et al , Psychopharmacology (Berl) , 2009, 202:71 1-18).

Two microsateliite polymorphisms associated with autism could be determined in the case of variants of the AVPR1A gene encoding the Via receptor (Kim et al., Mol Psychiatry 2002, 7:503-7; Yirmiya et al., Mol Psychiatry 2006, 11 :488-94; Yang et al., Psychiatry Res, 2010, 178(1): 199~201 ; Yang et al., Neurosci Lett 2010, 479(3): 197-200) It also refers to a genetic connection that altered activation of amygdala could be detected in patients carrying two risk alleles in the V1aR gene. These modified receptors have been shown to be able to alter the activation threshold of amygdala during emotional facial recognition process (Meyer- Lindenberg et al., Mol Psychiatry 2009, 14:968-75).

Preclinical data also support the efficacy of V1aR antagonists in autism. A widely used and accepted animal model of autism is to study the behaviour of rats exposed to valproate (VPA) treatment in utero. The reduced social behaviour of VPA-treated animals could be reversed by the V1 aR antagonist compound to the normal level in a functional magnetic resonance imaging study it was also found that decreased perfusion values were restored by the V1 aR antagonist in different brain regions of prenata!iy VPA-treated animals. The decreased function of the cortex, the inferior colliculus, the hippocampus and the hypothalamus was increased by treatment with the V1 aR antagonist, whereas in the ventral tegmentum, the striatum and the colliculus superior, the augmented perfusion was normalised by the V1aR antagonist (Grundschober et al , Poster presented at Annual Meeting of the American College of Neuropsychopharmacology, 2014, Phoenix, USA). For this reason, V1aR antagonist compounds showing favourable blood-brain barrier penetration are expected to be advantageous.

Influencing V1aR with small molecule antagonists is a promising strategy for the treatment of various pathological conditions of the female sex organs (such as, but not limited to, dysmenorrhea, sexual dysfunction), long-lasting pathological conditions in blood pressure control (such as, but not limited to, hypertension and/or chronic heart failure), conditions resulting from inappropriate secretion of vasopressin (such as, but not limited to, diabetes insipidus, renal failure, nephrotic syndrome and cirrhosis). It can be considered another promising strategy in the treatment of anxiety, depression, aggression, and disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to the latter three diseases or show comorbidity with them. These include, but not limited to, autistic spectrum disorder (well-functioning autism, Asperger's syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD) and its various syndromic forms: fragile X syndrome, Prader-Willi syndrome, Reft syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD). V1aR antagonists are also suitable for the treatment of aggressive behavioural disorders and/or irritability (such as, but not limited to, patients with ASD, or suffering from Huntington's disease (HD) or various forms of schizophrenia), behavioural hyperactivity disorders (such as, but not limited to, attention deficit hyperactivity disorder (ADHD)), cognitive disorders (such as, but not limited to, dementia, mild cognitive disorders (MCI), cognitive impairment associated with schizophrenia (CIAS), and Alzheimer's disease), and other neuropsychiatric disorders (such as, but not limited to, schizophrenia and associated diseases).

Many patent applications deal with Via receptor antagonists, for example, Otsuka discloses benzoheterocyclic derivatives (WO 95/034540 A1 , WO 2009/001968 A1 , WO 2011/052519 A1), Astellas Pharma (Yamanouchi) discloses condensed benzodiazepine and triazo!e derivatives (WO 95/03305 A1 , WO 01/87855 A1 , WO 02/44179 A1), AbbVie discloses oxindole derivatives (WO 2006/072458 A2, WO 2006/100082 A2), Bayer Pharma discloses aryl- or heteroaryltriazole derivatives (WO 2017/191102 A1 , WO 2017/191107 A1 , WO 2017/191114 A1). Various benzoazulene core containing derivatives (WO 2005/068466 A1 , WO 2006/021213 A2, WO 2006/021882 A1 , WO 2011/114109 A1 , WO 2011/128265 A1 , WO 2011/141396 A1 , WO 2014/127350 A1), spiroindoiinone and indolylcarbonyl derivatives (WO 97/15556 A1 , WO 2007/009906 A1 , WO 2007/014851 A2) are also described as Via receptor antagonists. The first clinical developments considered the Via receptor as peripheral target, the poor brain penetration was therefore beneficial in the development of compounds. Such was Sanofi’s indoline core compound, relcovaptan (SR-49059, WO 93/03013 A1), which was developed until the Phase 2 clinical trial. Among the indications studied were premature birth, pelvic pain observed during the menstruation, dysmenorrhea (Brouard et a!., Br J Obstetr Gynaeco! 2000, 107:614-9), heart failure, hypertension, and coronary spasm, but it was also tested as an antineoplastic agent in small-cell lung carcinoma until the last clinical trial was stopped in 2003 (Serradeil-Le Gal et al., Prog Brain Res 2002, 139:197-210; Adis!nsight: Relcovaptan - Latest Information Update: 03 Oct

2006 http://adisinsiaht.sprinaer.eom/druas/800004942). Relcovaptan has been in clinical development since 1993 and it is the most frequently used in vitro tool in the V1aR research (Tahara et al., Br J Pharmacol 2000, 129:131-9).

Pfizer studied its triazole derivative PF 00738245 (WO 2005/063754 A1) and compound PF-184583 of triazolobenzodiazepine core (WO 2004/074291 A1) in preciinicai development for dysmenorrhea, based on measured data these are efficient V1aR antagonists (Russell et al., Eur. J Pharmacol, 2011 , 670(2): 347-355; Johnson et al., Bioorg Med Chem Lett 2011 , 21 :5684-7) but their development was terminated.

By the examination of effects exerted on the central nervous system, the treatment of depression and anxiety has also been raised as a novel therapeutic area. Johnson & Johnson’s compound JNJ-17308618 of spirobenzazepine core was one of the first central nervous system acting V1aR antagonist compound (Bleickard et al., Psychopharmacology ( Beil.), 2009, 202:711-18; WO 02/02531 A1) which demonstrated efficacy in a variety of different animal models used for anxiety research: significantly reduced anxiety behaviour in the elevated plus maze test, marble burying test, and in the separation-induced ultrasonic vocalisation of rat pups. Although it proved to be effective in influencing the elevated G- labyrinth and the conditioned lick response, due to its poor metabolic stability measured in rodents, its efficacy was not good and was measurable only at high doses and therefore it was difficult to test.

Azevan’s V1aR antagonist azetidone derivatives, SRX246 and SRX251 (also known as API246 or API251 , WO 03/031407 A2) also reached the clinical trial phase. Clinical trials of SRX246 are also currently ongoing for the treatment of aggression, and intermittent explosive disorder and irritability in Huntington's Disease and post-traumatic stress disorder, as well as in the human behavioural models of anxiety and fear (Adislnsight: SRX 246 - Latest information Update: 16 Feb 2017 http://adisinsiqht.sprinqer.com/drugs/800023656). Clinical trial was conducted with SRX251 to treat dysmenorrhea but both Phase 1 studies were discontinued in 2016 and similarly to SRX246 it was also investigated for aggression in the preciinicai development (Adis!nsight: SRX 251 - Latest information Update: 04 Nov 2017 http://adisinsight.springer.com/drugs/800025117). SRX-246 and SRX-251 are active on the human Via receptor and in rats both compounds were detectable in the brain at approximately 100-fold of the effective concentrations detected in the binding assay (Guilion et a!., Bioorg Med Chem 2007, 15:2054-80; Fabio et a!., J Pharm Sci 2013, 102(6):2033-43).

Vantia’s V1aR antagonist compound, VA 11 1913 of pyrazoiobenzodiazepine core (WO 2010/097576 A1 ; Adislnsight: VA 111913 - Latest information Update: 25 Aug 2015 http://adisinsiaht.springer.com/drugs/800028777) was tested in Phase 2 clinical trial for the treatment of dysmenorrhea but there is no information about its development since 2015.

Otsuka’s V1 aR antagonist, the quinolinone derivative OPC 21268 (EPG382185A2; Adislnsight: OPC 21268 - Latest Information Update: 06 Oct

2006 http://adisinsight.springer.com/drugs/800000284) was tested for the indication of gastric mucosal damage indication in the preciinicai phase, whereas in Phase 2 clinical trials it was studied for heart failure and hypertension but there is no information on its development since 2015 (Yamamura et al. , Science 1991 , 252:572; Serradeil-Le Gal et ai. , J Clin invest 1993, 92(1):224).

When examining the brainstem in post mortem human samples selective localisation of Vi a receptors unrelated to oxytocin receptors could be detected in the nucleus prepositus, which plays a role in eye gaze stabilisation (Freeman et al., Soc Neurosci 2017, 12(2): 113- 123). A fundamental skill required for human social behaviour is the recognition and eye tracking of biologically relevant information (Klin et al., Nature 2009, 459:257-63, Simion et al., PNAS 2008, 105(2): 809- 13). The most active V1 aR researcher Hoffmann-La Roche reached Phase 1 study with their indole derivative RO5028442 (RG-7713; WO 2007/006688 A1), where positive effect on the orientation of eye-gaze pattern could be detected in humans (Umbricht et ai., Neuropsychopharmacology 2017 , 42 (9): 1914-1923; Adislnsight: RG 7713 - Latest Information Update: 05 Nov 2015 http://adisinsight.springer.com/drugs/800043668). Phase 2 clinical trials for the treatment of autism are currently ongoing with ba!ovaptan of the triazo!obenzodiazepine core (RG-7314, R05285119; WO 2010/060836 A1 ; Adislnsight: RG 7314 - Latest information Update: 10 Sep

2017 http://adisinsight.springer.com/drugs/800035102).

Despite the numerous V1 aR antagonist compounds and clinical studies, unmet medical need still persists to develop a V1 aR antagonist that is suitable for the treatment and/or prophylaxis of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.

SUMMARY OF THE INVENTION

Our aim was to synthetize novel structured Via receptor antagonists whose physical- chemical (e.g. kinetic or thermodynamic solubility, ionisation, iipophilicity or permeability) or pharmaceutical properties (e.g. metabolic stability, GYP-450 enzyme inhibition) provide the favorable bioavailability, ADME (absorption, distribution, metabolism, excretion), membrane penetration or blood-brain barrier penetration.

Surprisingly, such novel 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine derivatives of general formula (I) have been prepared which show Vi a receptor antagonistic activity profile.

The present invention relates to compounds of general formula (I)

wherein

ring A is a cycloaikyl or heterocyclyl group;

Y is -0-, -C(O)-, -GH2-, -NH- or bond if ring B is present; or -N(Ci- 4 aikyi) 2 , C(0)0Ci- 4 alkyl, Ci-4alkyl group optionally substituted with halogen, Ci.4alkoxy group or halogen if ring B is not present;

ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group;

or B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1 ,4’~piperidin-Y-y!]; or group;

R 1 is a hydrogen, halogen, C h alky!, Ci- 4 alkoxy, CF 3 or CN;

R 2 is a hydrogen or Gi^a!ky! group;

R 3 is a (CHzj n R 4 , C(0)R 5 group or C-^alkyl optionally substituted with R 6 ;

or R 2 and R 3 jointly represent -{CHzjp-CMCHsj c r or ~{CH 2 )r group;

R 4 is a CN, azide or Cy 1 group;

R 5 is a Ci -4 alkyl, Ci- 4 alkoxy, OH or NR 7 R 8 group;

R 6 is an OR 9 , NR 10 R 11 , oxo, -G(CH 2 ) 2 0- group or one or more halogens;

R 7 and R 8 is independently a hydrogen, C^alkyl, Cy 2 or R 7 and R 8 taken together with the N to which they are attached form a heterocycle;

R 9 is a hydrogen; C h alky! optionally substituted with NH 2 or with optionally substituted aryl group; SiCCHsja; or C(Q)R 12 group;

R 10 and R 11 is independently a hydrogen; Ci -4 alkyl optionally substituted with C^alkoxy group; Cy 3 ; C(G)R 13 or R 10 and R 11 taken together with the N to which they are attached form an optionally substituted heterocycle;

R 12 is a C h alky! or NR 14 R 15 group;

R 13 is a Ci- 4 alkyl, Cy 1 or NR 16 R 17 group;

R 14 and R 15 is independently a hydrogen, optionally substituted aryl or R 14 and R 15 taken together with the N to which they are attached form an optionally substituted heterocycle;

R 16 and R 17 is a C h alky! or R 16 and R 17 taken together with the N to which they are attached form an optionally substituted heterocycle;

Cy 1 is an optionally substituted heteroaryl group;

Cy 2 is an optionally substituted aryl or heteroaryl group;

Cy 3 is an optionally substituted cydoalkyl or heterocyciyl group;

X is a Ci- 4 alkyl, aryl or heteroaryi group;

Z is a C h alky! group;

n is 0 or 1 ; p is 1 , 2 or 3;

q is 1 , 2 or 3;

r is 4, 5 or 6;

and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof.

The present invention also relates to pharmaceutical compositions containing the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof as active substances.

In addition, the present invention also relates to the preparation of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof, to the intermediates of the preparation process and to the chemical and pharmaceutical preparation of pharmaceutical compositions containing the compounds.

The invention also relates to a method for treating a mammal, including humans suffering from a central and/or peripheral disease, where modulation, preferably antagonism of the Via receptor may have therapeutic benefits wherein the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof or a therapeutically effective amount thereof In a composition is administered.

The invention also relates to the use of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with Via receptor function. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to Via receptor modulators, in particular Via receptor antagonists. It is a further objective of the invention to provide selective Via receptor inhibitor compounds since selectivity is less likely to cause undesirable side effects. Another aspect of the invention is to provide compounds with favourable physicochemical properties as favourable physical-chemical properties are expected to result in beneficial bioavailability, ADME (absorption, distribution, metabolism, excretion), membrane penetration or blood- brain barrier penetration of the compounds.

The compounds of general formula (I) of the present invention are thus Vi a receptor antagonists which are centrally and/or peripherally acting therapeutic agents in the treatment and/or prophylaxis of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.

The present invention relates to compounds of general formula (I)

wherein

ring A is a cycloalkyl or heterocyclyl group;

Y is -0-, -C(O)-, -CH2-, -NH- or bond if ring B is present; or -N(Ci- 4 aikyi) 2 , C(0)0Ci-4alkyl, Ci-4alkyl group optionally substituted with halogen, C^alkoxy group or halogen if ring B is not present;

ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group; or B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1 ,4’-piperidin-1’-yl]; or group;

R 1 is a hydrogen, halogen, C h alky!, Ci- 4 alkoxy, CF 3 or CN;

R 2 is a hydrogen or C^alkyl group;

R 3 is a (CHzj n R 4 , C(0)R 5 group or C-^alkyl optionally substituted with R 6 ;

or R 2 and R 3 jointly represent -(CHzjp-O-CCHsjq- or ~{CH 2 )r group;

R 4 is a CN, azide or Cy 1 group;

R 5 is a Ci -4 alkyl, Ci- 4 alkoxy, OH or NR 7 R 8 group;

R 6 is an OR 9 , NR 10 R 11 , oxo, -G(CH 2 ) 2 0- group or one or more halogen;

R 7 and R 8 is independently a hydrogen, Ci^aikyi, Cy 2 or R 7 and R 8 taken together with the N to which they are attached form a heterocycle;

R 9 is a hydrogen; C h alky! optionally substituted with NH 2 or with optionally substituted aryl group; S CHsb; or C(Q)R 12 group;

R 10 and R 11 is Independently a hydrogen; Ci^alkyl optionally substituted with Ci- 4 alkoxy group; Cy 3 ; C(G)R 13 or R 10 and 11 taken together with the N to which they are attached form an optionally subsituted heterocycle;

R 12 is a C h alky! or NR 14 R 15 group;

R 13 is a Ci- 4 alkyl, Cy 1 or NR 16 R 17 group;

R 14 and R 15 is independently a hydrogen, optionally substituted aryl or R 14 and R 15 taken together with the N to which they are attached form an optionally substituted heterocycle;

R 16 and R 17 is a C h alky! or R 16 and R 17 taken together with the N to which they are attached form an optionally substituted heterocycle;

Cy 1 is an optionally substituted heteroaryl group;

Cy 2 Is an optionally substituted aryl or heteroaryl group;

Cy 3 is an optionally substituted cycloalkyl or heterocyclyl group;

X is a Ci- 4 alkyl, aryl or heteroaryl group;

Z is a C h alky! group; n is 0 or 1 :

p is 1 , 2 or 3;

q is 1 , 2 or 3;

r is 4, 5 or 6;

and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof.

Definition of the general terms used herein, whether or not the terms in question are presented individually or in combination with other groups are described below.

The term "cycloalkyl group" refers alone or in combination with other groups to 3~ to 8-membered, preferably 3- to 6-membered, saturated or unsaturated, preferably saturated carbocyciic groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In ring A and Cy 3 , the term "cycloalkyl group" refers preferably to a 4- to 6-membered saturated carbocyciic group. Examples include cyclobutyl, cyclopentyl or cyclohexyl. Preferably cyclobutyl or eydobexy! group. Particularly preferred is the cyclohexyl group. The term "substituted cycloaikyi group" refers preferably to a cycloalkyl group having gemina! halogen substitution.

The term“aryl group” refers alone or in combination with other groups to a 6- to 14- membered, preferably 6- to 10-membered aromatic carbocyciic moiety comprising at least one aromatic ring or a condensed ring system containing at least one aromatic ring. Examples include, but are not limited to, phenyl, benzyl, naphthyl, biphenyl, antbryi, azulenyi or indany!. Particularly preferred is the phenyl group.

The term "heterocyclyl group" refers alone or in combination with other groups to 3- to 8-membered, preferably 4~ to 7-membered, saturated or unsaturated, preferably saturated, monocyclic, bicyclic, condensed and/or bridged ring cycle containing 1 , 2, 3 or 4 heteroatoms selected from O, S or N. Preferred 4- to 7-member monocyclic heterocycle contains 1 N, 2 N, 1 O, 1 N and 1 O or 1 N and 1 S. Examples include, but are not limited to, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, piperazine, morpholine, 1 ,3-oxazolidine, 1 ,3-thiazoiidine, thiomorpho!ine-1 , 1-dioxide and the like. The term "substituted heterocyclyl group” refers preferably to a heterocycie substituted with Ci - 4 aikyi. When ring A is heterocycly!, then heterocyclyi refers preferably to a 4- to 7-membered saturated heterocyclyi group containing 1 N or 2 N, wherein ring A is attached via a ring nitrogen to Y or to the triazoie ring of the 5 6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core. Examples include, but are not limited to, azetidinyi, 1 ,3-diazetidinyl, pyrroiidinyi, pyrazolidinyl, imidazolidinyl, piperidinyi, piperazinyi, azepanyl, 1 ,3- or 1 ,4-diazepanyl. Preferably azetidinyi, piperidinyi or piperazinyi.

In the case of Cy 3 , the heterocyde refers preferably to a 4- to 7-membered saturated heterocyclyi group containing 1 O, more preferably oxetane or tefrabydropyran.

When ring B is heterocyclyi, then heterocyclyi refers preferably a 4- to 7-membered saturated heterocyclyi group containing 1 N or 1 N and 1 O. Examples include, but are not limited to, azetidinyi, pyrroiidinyi, piperidinyi, piperazinyi or morpboiiny!.

When R 7 and R 8 , R 10 and R 11 , R 14 and R 15 or R 16 and R 17 „taken together with the N to which they are attached form an optionally substituted heterocyde", the heterocyde refers preferably to 4- to 7-membered saturated ring containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S. Examples include, but are not limited to, morpholine, 4-meihyi-piperazinyl, pyrroiidinyi, piperidinyi, piperazinyi, 1 ,3-oxazolidine, 1 ,3-thiazoiidine or thiomorpholine-1 , 1-dioxide.

The term "heteroaryl group" refers alone or in combination with other groups to a cyclic aromatic group containing a single 5- to 6-membered ring containing 1 , 2, 3 or 4 heferoatoms in which group at least one heterocyclic ring is aromatic. The "6-membered mono-heteroaryl group" refers to a monocyclic aromatic group which is a single 6-membered ring containing 1 , 2, or 3 heteroatoms selected from O, S or N. Examples include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl and the like. Preferred single 6-membered mono-heteroaryl groups contain 1 or 2 N. A preferred 6- membered ring is pyridinyl, more preferably pyridin-2-yl and pyridin-3-yl. Particularly preferred is pyridine-2-yl. The term "5-membered mono-heteroaryl" means a monocyclic aromatic group which is a single 5-membered ring containing 1 , 2, 3 or 4 heteroatoms selected from O, S or N. Preferred single 5-membered mono-heteroaryl groups contain 2 N and 1 O, 2 N and 1 S, 4 N, 3 N, 2 N, 1 N or 1 S or 1 N and 1 O. Examples include, but are not limited to, thiophenyl, furanyl, pyrrolyi, tetrazoiyl, triazolyi, imidazoiy!, thiazoiy!, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, 1H-pyrazo!yl and the like. Preferred are isoxazol-3-yl, tetrazoiyl and 1 ,2,4-oxadiazol-5-yl. The term "substituted heteroaryl group" refers preferably to a heteroaryl group substituted with Ci^alkyl or halogen. In Cy\ the optionally substituted heteroaryl refers preferably to a C^alkyl, more preferably a methyl-substituted single 5-membered mono-heteroaryl group containing 2 N and 1 O or 4 N. Preferred are tefrazo!yl or 3-metbyi-1 ,2,4-oxadiazol-5-yi.

When ring B is an optionally substituted beferoary! group, heteroaryl refers to a 5- or 6-membered mono-heteroaryl group containing 1 N, 2 N or 1 N and 1 O optionally substituted with halogen, preferably chlorine or C h alky!, preferably methyl. Examples include, but are not limited to, pyridin-2-yl, 3-chioro-pyridin-2-yl, 3-methyl-pyridin-2~yl, pyridin-3-yl, pyrimidin- 2-y! or 5-methyl-isoxazol-3-yi.

The term "bond” refers to a single bond, in which one pair of electrons is shared between two atoms.

The term "Ci^alkyl group" or“Ci-salkyl group” refers alone or in combination with other groups to a straight or branched, single or multiple branched, hydrocarbon radical and consists of 1 to 4 or 1 to 5 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, i-propyl (isopropyl), /7-butyl, 2-butyl (sec-butyl), /-butyl (teri- butyl), /7-pentyl-, t- pentyi-, neopentyl·, isopentyl·, 2-pentyl· (sec-pentyl-) or 3-pentyl group. Preferred alkyl groups are those having 1 to 3 carbon atoms. Preferred are methyl, ethyl, isopropyl, /-butyl and /-pentyl groups. Particularly preferred is the methyl group.

The term "Ci- 4 alkoxy group” refers alone or in combination with other groups to -O- Ci-4alkyl group, wherein the C h alky! group is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy or /-butoxy. Preferred alkoxy groups are methoxy, propoxy or t-butoxy. Particularly preferred are the methoxy and /-butoxy groups.

The term "Boc” refers alone or in combination with other groups to /-butoxycarbonyl group.

The term "halogen" refers alone or in combination with other groups to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. In W and R 6 , preferred are fluorine, chlorine or bromine in R\ more preferred are chlorine or bromine, even more preferred is the chlorine. In R 6 , more preferred is the fluorine.

The term "optionally substituted" on any atom of the relevant group refers to the substitution by one or more Ci-4alkyl groups or halogens. Here, "one or more" means from one to the highest possible number of substitution, that is, from replacing one hydrogen to replacing all hydrogens. One, two or three substituents on a given atom are thus preferred. Even more preferred are one or two, or one substitution. Particularly preferred is one substitution for the optionally substituted cycloalkyl, aryl, heterocyciy! or heteroaryl group. The expression "C h alky! optinai!y substituted with halogen" refers preferably to a Ci- 4 aikyi group having one, two or three halogen substituents on any atom of the Ci -4 alkyl group, more preferably to a methyl group having three halogen substituents. Particularly preferred is the CFs group.

The Ci. 4 alkyl group in the meaning of “C h alky! substituted with R 6' is as defined above. The substituted C h alky! group in the meaning of “C h alky! substituted with R 6“ is preferably a branched, single or multiple branched, hydrocarbon radical consisting of 1 to 4 carbon atoms. The term“substituted” in the meaning of“Ci^alkyl substituted with R 6 refers to the substitution by one or more R 6 groups on any atom of the relevant group. The "one or more" means from one to the highest possible number of substitution, that is, from replacing one hydrogen to replacing all hydrogens. When R 6 is OR 9 or NR^R 11 group, “C h alky! substituted with R 6 ” is for example, but is not limited to, -CH2R 6 or -CH(R 6 )CH3, preferably - CH2R 6 . When R 6 is oxo or -0(CH 2 ) 2 0- group,“Ci -4 alkyl substituted with R 6 is for example, but is not limited to, ~C(R 6 )CH3. When R 6 is one or more halogens, the terms“C h alky! substituted with R 6 ”,“one or more” and“halogen” are as defined above in this case“C h alky! substituted with R 6 ” is for example, but not limited to, -Chhhalagen, -CH(halogen)CH3 or -Cfba!ogen^Chh, preferably -CHahalogen.

The term "salt" refers to pharmaceutically acceptable and/or pharmaceutically non- acceptable salts. The pharmaceutically acceptable salt refers to a conventional acid addition and base addition salts which preserve the biological efficacy and properties of the compounds of general formula (I) and which can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include salts derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulphamic acid, phosphoric acid, nitric acid and perchloric acid and derived from various organic acids, such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like. Examples of base addition salts are salts derived from ammonium-, potassium-, sodium- and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. These salts often exhibit more favourable solubility properties than the compounds used for their preparation and are therefore more suitable for use in the preparation for example of liquid or emulsion formulations. The pharmaceutically non-acceptable salts may be preferred for the purification and isolation of the compounds of general formula (I) and therefore also fall within the scope of the invention. The term “prodrug” refers to derivatives of compounds of genera! formula (!) according to the invention which themselves have no therapeutic effect but containing such groups which, after in vivo chemical or metabolic degradation (biotransformation) become “biologically active metabolites” which are responsible for the therapeutic effect. Such decomposing groups associated with the compounds of general formula (I) of the present invention, in particular those suitable for prodrugs, are known in the art and may also be applied for the compounds of the present invention (Rautio et a!., Nat Rev Drug Discov 2003, 7:255-270).

The compounds of genera! formula (I) may exist in various geometric isomeric forms. In addition, certain compounds of genera! formula (!) may contain one or more asymmetric centers, thus exist in the form of stereoisomers and diastereomers. All of these compounds, such as cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers also fail within the scope of the invention. The substantially pure enantiomers contain up to 5 wt%, preferably 2 wt%, most preferably 1 wt%, of the corresponding opposite enantiomer.

Optical isomers can be prepared by resolving the racemic mixtures by known methods, for example, by using an optically active acid or base to form diastereoisomeric salts or by forming covalent diastereomers. Suitable acids include, for example, tartaric acid, diacetyltartaric acid, dibenzoy!tartaric acid, dito!uoyltartaric acid and camphorsulfonic acid. Diastereoisomeric mixtures can be separated into individual diastereomers based on their physical and/or chemical differences, by methods known to those skilled in the art, such as chromatography or fractional crystallization. Subsequently, the optically active bases or acids are liberated from the separated diastereoisomeric salts. Various methods of separating optical isomers include chiral chromatography (e.g., chiral HPLC columns) optionally used by derivatization with the aim to maximize the separation of enantiomers. Appropriate chiral HPLC columns are Diacel columns, such as CHIRALPAK or CHIRALCEL columns, which can be routinely chosen as desired. Where applicable, enzymatic separations carried out by derivatization may also be used. The optically active compounds of general formula (!) can also be prepared using optically active starting materials using chiral synthesis without racemization reaction conditions.

The absolute configuration of the chiral compounds was determined by VCD (vibrational circular dichroism spectroscopy) method described in the literature (Freedman et al. , Chirality 2003, f5(9):743-58; Stephens et a! , Chirality 2008, 20:643-663) and/or by 1 H NMR spectroscopic assays of the diastereomeric pair of compounds produced from chiral compounds (Seco et al., J Org Chem 1999, 64: 4869-4675; Seco et ai , Tetrahedron Asymmetry 2001 , 12: 2915-2925; Latypov et al , JAm.Chem.Soc. 1998, 120, 4741-4751).

The compounds of genera! formula (!) may exist in various polymorphic forms. As is known in the art, polymorphism is the ability of a compound to crystallize in more than one crystalline form, i.e. in polymorphic form. Polymorphic forms of a particular compound can be defined by identical chemical formula or composition and differ in their chemical structure like the crystalline structures of two different chemical compounds.

The compounds of general formula (I) and salts thereof may also be present as solvates or hydrates, which also fall within the scope of the invention. The term "solvate” refers to non-covalent combinations of solvent and solute. The term "hydrate" refers to non- covaient combinations of water and solute.

The present invention further relates to pharmaceutical compositions containing the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.

The present invention also relates to the chemical and pharmaceutical preparation of pharmaceutical compositions containing the compound of general formula (!) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.

The pharmaceutical compositions of the present invention may be formulated in various pharmaceutical formulations, such as, but not limited to, solid ora! dosage forms such as tablets (e.g. buccal, sublingual, effervescent, chewable, orally dispersible), capsules, pills, piiuias, orally dispersible films, granules, powders; liquid formulations such as solutions, emulsions, suspensions, syrups, elixirs, drops; parenteral dosage forms such as intravenous injections, intramuscular injections, subcutaneous injections; other forms of medicine such as eye drops, semi-solid ophthalmic preparations, semi-solid derma! preparations (such as ointments, creams, pastes), transdermai therapeutic systems, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.

One embodiment of the invention relates to pharmaceutical compositions for paediatric use, such as, but not limited to, solutions, syrups, elixirs, suspensions, powders for the preparation of suspensions, dispersible or effervescent tablets, chewable tablets, orodispersible tablets, tablets or coated tablets, orally sparkling powders or granules, capsules.

The pharmaceutical compositions of the present invention may be prepared by methods known perse, such as conventional mixing, dissolution, emulsification, suspending, microencapsulation, lyophilisation, extrusion and spheronisation, lamination, film coating, granulation, encapsulation, drageeing or pressing.

The pharmaceutical compositions of the present invention may be formulated in the usual way using one or more physiologically acceptable excipients, including binders, which promote the incorporation of the active substance into pharmaceutically acceptable pharmaceutical forms. The proper formulation depends on the mode of administration chosen. Any of the techniques and excipients well known in the art can be used.

The excipients applicable in the preparation may be selected from the following categories, such as, but not limited to, fillers of tablets and capsules, binders of tablets and capsules, modified drug release agents, disintegrants, glidants, lubricants, sweeteners, taste-masking agents, flavourants, coating materials, surfactants, stabilisers, preservatives or antioxidants, buffering agents, complexing agents, wetting or emulsifying agents, salts for adjusting the osmotic pressure, lyophilisation excipients, microencapsulating agents, ointment materials, penetration enhancers, solubilisers, solvents, suppository materials, suspending agents . Suitable pharmaceutical excipients can be for example: starch, microcrystalline cellulose, talc, glucose, lactose, gelatin, silica, talc, magnesium stearate, sodium stearate, glycerol monostearate, cellulose derivatives, sodium chloride, glycerol, propylene glycol, water, ethanol and the like.

Another embodiment of the present invention relates to the use of special binders that can improve the solubility, dissolution, penetration, absorption or bioavai!abi!ity of the active substance(s), such as, but not limited to, hydrophilic polymers, hot melting extruding excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization excipients, disintegrants, microencapsulating agents, penetration promoters, solubilisers, cosolvents, suspending agents.

The excipients described above and the various methods of preparation are only representative examples. Other materials and process techniques known in the art may also be used.

The terms "disease or condition associated with Vi a receptor function" or "disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of the Via receptor" refer to a disease or condition selected from the group consisting of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.

The various pathological conditions of the female sex organs include, but not limited to, dysmenorrhea (primary and/or secondary) or sexual dysfunction.

The long-standing conditions in blood pressure control include, but not limited to, hypertension and/or chronic heart failure.

The conditions resulting from inappropriate secretion of vasopressin include, but not limited to, diabetes insipidus, renal failure, nephrotic syndrome or cirrhosis.

The disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them include, but not limited to, autistic spectrum disorder (well-functioning autism, Asperger's syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD) and its various syndrome forms: fragile X syndrome, Prader-Willi syndrome, Rett syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD).

The aggressive behavioral disorders and/or irritability include, but not limited to, ASD, Huntington's disease or different forms of schizophrenia.

The behavioral hyperactivity disorders include, but not limited to, attention deficit hyperactivity disorder.

The cognitive disorders include, but not limited to, dementia, mild cognitive disorders, cognitive impairment associated with schizophrenia or Alzheimer's disease.

The other neuropsychiatric disorders include, but not limited to, schizophrenia and associated diseases. In one embodiment, the disease or condition associated with Via receptor function or disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of Via receptor refers to autistic spectrum disorder.

The present invention relates to a method for treating and/or preventing a disease or condition associated with Vi a receptor function, comprising the administration to a subject in need of treatment and/or prophylaxis, preferably a mammal, more preferably a human being, of a therapeutically effective amount of a compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof alone or with at least one pharmaceutically acceptable excipient in the form of a pharmaceutical formulation.

The present invention relates to a method for the treatment of a subject, preferably a mammal, more preferably a human being, suffering from a disease or condition selected from the group consisting of various pathological conditions of the female sex organs, long- standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders, or combination of the these diseases. This method of treatment comprises the administration to a subject in need of such treatment, preferably a mammal, more preferably a human being, the therapeutically effective amount of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof. The method of treatment may include the administration to a subject in need of such treatment, preferably a mammal, more preferably a human being, of a therapeutically effective amount of a pharmaceutical composition comprising the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof. The present invention relates to the use of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with Via receptor function.

The term "treatment" refers to the alleviation of a specific pathological condition, the elimination or reduction of one or more of the symptoms of the condition, the slowing or elimination of the progression of the disease state, and the prevention or delay of recurrence of the pathological condition of a patient or subject already suffering from or diagnosed with the disease "Prevention" (or prophylaxis or delay of occurence of the disease) is typically performed by administering the drug in the same or similar way as if it were given to a patient with a disease or condition already developed.

The term "therapeutically effective amount" refers to the amount of active substance resulting in the treatment, cure, prevention or improvement of the disease or pathological condition or side effect, and reduces the progression of the disease or pathological condition in comparison with the corresponding subject who did not receive such amount. The term also includes effective amounts to enhance normal physiological functioning. For use in therapy the compound of general formula (1) and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof as well as any pharmaceutically acceptable salt thereof may be administered in a therapeutically effective amount as a raw chemical. In addition, the active substance can be made available as a pharmaceutical formulation. The exact therapeutically effective amount of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof depends on a number of factors including, but not limited to, the age and body weight of the subject (patient) treated, the precise type of disease requiring treatment and its seriousness, the nature of the medicinal product and the route of administration.

The term "mammal" refers to any member of the "Mammalia" class, including, but not limited to, humans. The present invention also relates to pharmaceutical compositions comprising the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof suitable for the treatment of a disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of the Vi a receptor.

The compound of the invention may also be used in combination with one or more of the compounds of the invention or with one or more other active substance (e.g., psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents) in a mammal, including, but not limited to, humans, suffering from a central and/or peripheral disease, where the central and/or peripheral modulation, preferably antagonisation of Via receptor has therapeutic benefits.

Psycholeptics include, but not limited to, antipsychotics, anxiolytics, and sedatohipnotics or narcotics.

Antipsychotics include, but not limited to, typical and atypical antipsychotics, such as phenofhiazines with aliphatic side chains (chlorpromazine, promazine, levomepromazine, acepromazine, trifluproazine, ciamemazine, chlorproethazine, protipendyl), piperazine- derived phenothiazines (dixyrazine, fiufenazine, perazine, perfenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine), piperidine-derived phenothiazines (periciazine, thioridazine, mesoridazine, pipofhiazine), thioxanthenes (chiorprothixene, ciopenthixoie, flupentixol, thiothixene, zudopenthixol), butyrophenone derivatives (haloperidol, trif!upidol, melperone, moperone, pipamperone, bromperidoi, benperidoi, droperidol, timiperone, fluanisone), diphenyibutyipiperidine derivatives (fluspirilene, penfluridol, pimozide), diazepine-, oxazepine- or thiazepine derivatives (clozapine, olanzapine, dotiapine, quetiapine, loxapine, azenapine), indole derivatives (sertindole, ziprasidone, lurazidone, molindone, oxipertine), benzamide derivatives (sulpiride, sultropride, tiapride, remoxipride, amisulpride, veralipride, nemonapride, verasulpiride) or other agents (risperidone, aripiprazole, cariprazine, brexpiprazole, metodopramide, mosapramine, iloperidone, paliperidone, amoxapine, amperoside, perospirone, carpipramine, docapramine, tetrabenazine, lithium).

Anxiolytics include, but not limited to, benzodiazepines (diazepam, chlorodiazepoxide, medazepam, oxazepam, potassium chlorazepate, iorazepam, adinazo!am, bromazepam, ciobazam, kefazoiam, prazepam, alprazolam, ha!azepam, pinazepam, camazepam, nordazepam, fludiazepam, ethyl ioflazepate, etizolam, ciotiazepam, coxazolam, tophizopam), diphenylmethane derivatives (hydroxyzine, eaptodiame), carbamates (meprobamate, emiicamate, mebutamate), dibenzobicydooctadiene derivatives (benzoquinone), azaspirode-diones (buspirone), other agents (mefenoxalone, gedocarnii, etifoxine, fabomotizole, trimethosine), derivatives acting by increasing GABA A -mediated inhibition or compounds acting on a serotonin receptor, and other GABAergic agents (such as GABA A a5 NAMS, e.g. basmisanil, GABA A a5 PAMS, e.g. RG7816).

Sedative hypnotics or narcotics include, but not limited to, barbiturates (pentobarbital, amobarbital, butobarbitai, barbital, aprobarbitai, secobarbital, talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbita!, reposal, methohexitol, hexobarbital, thiopental, etha!iobarbitai, aliobarbitoi, proxibarbital), aldehydes (chloral hydrate, chioralodol, acetylglycinamide chloral hydrate, dichloralphenazone, paraldehyde), benzodiazepines (fiurazepam, nitrazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam, loprazolam, doxefazepam, cino!azepam), piperidindione derivatives (glutethimide, methyprylon, pyrithyldione), cydopyrrolone benzodiazepine derivatives (zopiclone, zolpidem, zaleplon, eszopiclone), melatonin receptor agonists (melatonin, ramelteon) or other hypnotics and sedatives (methaqualone, ciomethiazoie, bromisoval, carbromal, scopolamine, propiomazine, thdofos, etbchlorvynoi, Valerianae Radix, hexapropymate, bromides, apronal, valnoctamide, methylpentynoi, niaprazine, dexmedetomidine).

Psychoanaleptics include, but not limited to, psychostimulants or antidepressants.

Psychostimulants include, but not limited to, centrally acting sympathomimetics (amphetamine, dexamphetamine, methamphetamine, methylphenidate, pemoline, fencamfamine, modafinil, phenozolone, atomoxetine, phenetiiline, dexmethylphenidate, lysdexamfetamine), nootropics or other psychostimulants (caffeine, propentofylline, meclofenoxate, pyhtinol, piracetam, deanol, fipexide, citoco!ine, oxiracetam, pirisudanol, linopirdine, nizofenone, aniracetam, acetylcarnitine, idebenone, proiintane, pipradrol, pramiracetam, adrafinil, vinpocetine, tacrine, donepezil, rivastigmine, ga!antamine, ipidachrine, memantine, mebicar, phenibut).

Antidepressants include, but not limited to, non-selective monoamine reuptake inhibitors (desipramine, imipramine, imipramine oxide, clomipramine, opipramoi, trimipramine, lofepramine, dibenzepine, amitriptyline, nortriptyline, protriptyline, doxepin, iprindole, melitracene, butripty!ine, dosu!epin, amoxapine, dimetacrine, amineptin, maprotiline, quinupramine), serotonin modulator and stimulators (vilazodone, vortioxetine), selective serotonin reuptake inhibitors (zimeldine, fluoxetine, paroxetine, sertraline, aiaprodate, fluvoxamine, etoperidone, cita!opram, escitalopram), non-selective hydrazide- derived monoamine oxidase inhibitors (isocarboxazide, nialamide, phenelzine, tranylcypromine, iproniazid, iprocloside), non-hydrazide monoamine oxidase inhibitors (modobemide, toloxatone) or other agents (oxitriptan, tryptophan, mianserin, nomifensin, trazodone, nefazodone, minaprine, bifemelane, viloxazine, oxaflozane, mirtazapine, medifoxamine, tianeptine, pivagabine, veniafaxine, miinacipran, reboxetine, pyrazidol, duloxetine, agomeiatine, desvenlafaxine, bupropion, gepirone, Hyperici herba extractum).

Antihypertensives indude, but not limited to, b receptor blockers, thiazide diuretics, angiotensin-converting-enzyme inhibitors, calcium antagonists, angiotensin receptor antagonists (losartan), auwo!fia alkaloids (rescinnamine, reserpine, deserpidine, methoserpidine, bietaserpine), methyidopa, imidazoline receptor agonists (donidine, guanfacine, tolonidine, moxonidine, riimenidine), ganglion blocking antiadrenergic agents (su!fonium derivative trimetapban, secondary and tertiary amine mecamylamine), peripherally acting antiadrenergic agents, alpha-adrenoreceptor blockers (prazosin, indoramin, trimazosin, doxazosin, urapidii), guanidine derivatives (betanidine, guanethidine, guanoxane, debrisoquine, guanoclor, guanazodine, guanoxabenz), agents acting on arteriolar smooth muscle, the thiazide derivative diazoxide, hydrazinophthaiazine derivatives (dihydralazine, hydralazine, endralazine, cadraiazine), the pyrimidine derivative minoxidil, the nitroferricyanide derivative nitroprusside, the guanidine derivative pinacidil, the non- Rauwoifia alkaloid veratrum, the tyrosine hydroxylase inhibitory metyrosine, the MAO inhibitor pargyline, the serotonin antagonist ketanserin, or other antihypertensives (bosentan, ampbrisentan, sitaxentan, macitentan, riociguat) and a combination of these substances with a diuretic.

Spasmolytics or antispasmodics include, but not limited to, peripheral muscle relaxants, curare alkaloids, choline derivatives, other quaternary ammonium muscle relaxants (pancuronium, gailamine, vecuronium, atracurium, hexafluronium, pipecuronium bromide, doxacurium chloride, fazadinium bromide, rocuronium bromide, mivacurium bromide, cisatracurium, botulinum toxin), centra! nervous system muscle relaxants, carbamic acid esters (phenprobamate, carisoprodol, metocarbamoi, styramate, febarbamate), oxazole-, thiazine- and triazine derivatives (ch!ormezanone, chlorzoxazone), ethers related to antihistamines (orphenadrine, guaifenesin) and other histaminergic agents (such as histamine Hs receptor antagonists/inverse agonists e.g. ciproxifan, thioperamide, pitoiisant, ciobenpropit, ABT-239, conessine, A-349,821 , betahistine), other centrally acting agents (baclofen, arbaclofen, tizanidine, pridinol, tolperisone, thiocolchicoside, mephenesin, tertazepam, cyc!obenzaprine, phenyramidol), the directly acting muscle relaxant dantrolene and Its derivatives, compounds acting by increasing GABA A -mediated inhibition or decreasing conduction of Na ÷ (phenytoin, carbamazepine, iamotrigine, VPA), gamma- aminobutyric acid derivatives (vigabatrin, gabapentin), other GABAergic agents (such as GABA B PAMs, e.g. ADX71441), esters with a tertiary amino group (oxyphencydimine, camylofin, mebeverine, trimebutine, rociverine, dicydoverine, dihexyverine, difemerine, piperidoiate), quaternary ammonium compounds (benziione, glycopyrronium, oxyphenonium, penthienate, propantheline, otilonium bromide, methantheline, tridihexethyl, isopropamide, hexocyclium, poldine, mepenzolate, bevonium, pipenzolate, diphemanii, e etonium iodide, tiemoniu iodide, prifinium bromide, timepidium bromide and fenpiverinium), amides with tertiary amines (astra 1397, nicofetamide, tiropramide), papaverine and its derivatives (drotaverine, moxaverine, etaverine), agents acting on serotonin receptors (alosetron, tegaserod, cilansteron, prucaiopride), other agents of functional gastrointestinal disorders (fenpiprane, diisopromine, chlorbenzoxamine, pinaverium, fenoverine, idanpramine, proxazole, alverine, trepibutone, isometheptene, caroverine, phioroglucinol, silicones, trimethyldipheny!propy!amine), succinimide derivative (ethosuximide, phensuximide, mesuximide) or Belladonna alkaloids and their derivatives (atropine, hyoscyamine, butylscopolamine, methylatropine, methylseopoiamine, fentonium, cimetropium bromide).

Antiepileptics include, but not limited to, barbiturates and their derivatives (methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbitai), hydantoin derivatives (ethotion, phenytoin, amino(diphenylhydantoin) valeric acid, mepbenytoin, fosphenytoin), oxazoiidine derivatives (paramethadione, trimethadione, ethadion), succinimide derivatives (ethosuximide, phensuximide, mesuximide), benzodiazepine derivative clonazepam, carboxamide derivatives (carbamazepine, oxcarbazepine, rufinamide), fatty acid derivatives (valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine) and other antiepileptics (sultiame, phenacemide, Iamotrigine, feibamate, topiramate, gabapentin, pheneturide, !evetiracetam, zonisamide, pregabaiin, stiripentol, lacosamide, carisbamate, retigabine, brivaracetam, beclamide).

Other agents include, but not limited to, medicinal products (probiotics, digestive aids/digestives, herbal extracts), vitamins (both water soluble and fat soluble, such as, but not limited to, vitamin A, D3, E, K, B1 , B5, B6, B12, C or their derivatives) and nutritional supplements (coenzymes e.g. Q10, flavonoids e.g. resveratrol, lecithin, unsaturafed fatty acids, including fatty acids w-3 and w-6). The compounds of the invention may also be used in combination with phosphodiesterase 5 isoenzyme inhibitors (PDE5), nitric oxide donors, cyclooxygenase inhibitors, other Via receptor antagonists (such as balovaptan) or L-arginine for the treatment and/or prophylaxis of a disease or condition associated with Via receptor function.

The combinational composition may comprise the compound of the invention together with another active substance in a single dosage form or separately. The combinational composition may be administered simultaneously, separately or sequentially.

Suitable dosage forms include oral, rectal, mucous, transdermai or intestinal administration; parenteral administration including intramuscular, subcutaneous, intravenous, intramedullary injections as well as intraarticuiar, intrathecal, direct intraventricular, intraperitoneal, intranasai or intraocular injections and eye drops.

Alternatively, the compounds may be administered locally and not systemicaily, for example by direct injection of the compound to the kidney or the heart, often in a modified release formulation in addition, the drug may be administered in a targeted carrier system, for example in a tissue-specific antibody encapsulated liposome. The liposomes transfer the active substance selectively to the target organ, which absorbs it.

The pharmaceutical composition may be administered in various ways and in pharmaceutical forms. The compound of the invention may be administered alone or in combination with pharmaceutically acceptable excipients, in single or multiple doses. The dose required to achieve the appropriate therapeutic effect may vary widely and must always be adapted to individual needs with regard to the stage of disease, the condition and weight of the patient to be treated, and the sensitivity to the active substance, the way of dosage regimen, and the numbers of daily treatments.

For simple administration, it is preferred that the pharmaceutical compositions consist of dosage units that contain the amount of drug to be administered once, or a small number of its multiple, or half, one third, one quarter. Such dosage units are, for example, tablets that can be provided with a half or quarter groove to facilitate halving or quarter-splitting of the tablet in order to measure the required amount of drug.

Pharmaceutical compositions containing the active substance according to the invention generally contain from 0.01 to 500 mg of active substance per dosage unit it is of course also possible that the amount of active substance in each formulation exceeds the above limit either up or down. Further preferred groups of compounds of general formula (I) are those wherein each embodiments of ring A, ring B, X, Y, Z, R'-R 17 , Cy 1 -Cy 3 , n, p, q and r described below are optionally combined. Any combination of the preferred, more preferred or most preferred embodiments of ring A, ring B, X, Y, Z, R 1 -R 17 , Cy 1 -Cy 3 , n, p, q and r as defined below are also preferred, more preferred and most preferred groups of compounds of general formula

(I).

In certain embodiments of the invention, ring A in the compounds of general formula (I) is a 4 to 0-membered saturated carbocycle.

In certain preferred embodiments of the invention, ring A in the compounds of general formula (I) is cyclobutyl or cyc!ohexyi.

In certain more preferred embodiments of the invention, ring A in the compounds of general formula (I) is cyclohexyl.

In certain embodiments of the invention, ring A in the compounds of general formula (I) is a 4- to 7-membered saturated heterocyciyi group containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to Y.

In certain embodiments of the invention, ring A in the compounds of general formula (I) is a 4- to 7-membered saturated heterocyciyi group containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine core.

In certain embodiments of the invention, ring A in the compounds of general formula (I) is azetidinyl, 1 ,3-diazetidinyi, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyi, 1 ,3- or 1 ,4-diazepanyl, wherein ring A is attached via a ring nitrogen to Y.

In certain embodiments of the invention, ring A in the compounds of general formula (I) is azetidinyl, 1 ,3-diazetidinyi, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyi, 1 ,3- or 1 ,4-diazepanyl, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,8-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core.

In certain preferred embodiments of the invention, ring A in compounds of general formula (I) Is azetidin-1 ,3-diyl, piperidin~1 ,4~dly! or piperazine-1 , 4-diyl, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H- [1 ,2,4]triazo!o[4,3-a][1]benzazepine core.

In certain embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted heteroaryl group. In certain preferred embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted 5- or 6-membered mono-heteroaryl group containing 1 N, 2 N or 1 N and 1 O.

In certain more preferred embodiments of the invention, ring B in the compounds of general formula (I) is pyrdin-2-yi, 3-chioro-pyridin-2-yi, 3-methyl-pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl or 5-methyl~isoxazol-3-yl.

In certain most preferred embodiments of the invention, ring B in the compounds of genera! formula (I) is pyridin-2-yi.

In certain embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted aryl group.

In certain preferred embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted phenyl.

In certain embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted heterocyclyl group.

In certain preferred embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted 4- to 7-membered heterocyclyl group containing 1 N or 1 N and 1 O.

In certain more preferred embodiments of the invention, ring B in the compounds of general formula (!) is azetidin-1-yl, pyrrolidin-1-yl, piperidinyl, piperazinyl or morpholin-4-yl.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -0-, if ring B is present.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -C(O)-, if ring B is present.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -CH2-, if ring B is present.

In certain embodiments of the invention, Y in the compounds of general formula (I) is -NH-, if ring B is present.

In certain embodiments of the invention, Y in the compounds of formula (I) is a single bond, if ring B is present. In certain embodiments of the invention, Y in the compounds of general formula (I) is -N(Ci-4alkyl)2, C h alky! group optionally substituted with halogen, Ci- 4 alkoxy group, C(0)0Ci- 4 alkyl or halogen, if ring B is not present.

In certain embodiments of the invention, Y in the compounds of general formula (I) is Ci -4 alkyl optionally substituted with halogen or Ci. 4 aikoxy group, if ring B is not present.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I) is Ci-salkyl group, if ring B is not present.

In certain more preferred embodiments of the invention, Y in the compounds of general formula (!) is methyl or ethyl group, if ring B is not present.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I) is Ch-aalkoxy group, if ring B is not present.

In certain more preferred embodiments of the invention, Y in the compounds of general formula (I) is methoxy or ethoxy group, if ring B is not present.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I) is CFs group, if ring B is not present.

In certain embodiments of the invention, Y in the compounds of general formula (I), if ring B is not present, refers to one group selected from the group consisting of -N(Ci -4 alkyl)2, C(0)OCi -4 alkyl, C h alky! optionally substituted with halogen, Ci -4 alkoxy group and halogen.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I), if ring B is not present, refers to one group selected from the group consisting of dimethylamine and CF 3 group.

In certain embodiments of the invention, Y in the compounds of general formula (I), if ring B is not present, refers to two groups selected from the group consisting of Ci -4 alkyl group optionally substituted with halogen, Ci- 4 aikoxy group and halogen.

In certain preferred embodiments of the invention, Y in the compounds of general formula (I), if ring B is not present, refers to two groups selected from the group consisting of Ci-salkyl, Ci^aikoxy and fluorine.

In certain more preferred embodiments of the invention, Y in the compounds of general formula (I), if ring B is not present, refers to two groups selected from the group consisting of methyl, ethyl, methoxy, ethoxy group and fluorine. In certain even more preferred embodiments of the invention, Y in the compounds of genera! formula (I), if ring B is not present, refers to two groups selected from the group consisting of methyl and methoxy group.

In certain preferred embodiments of the invention, in the compounds of genera! formula (I), ring A is cyclobutyl or cyclohexyl, Y refers to one group selected from the group consisting of -N(Ci- 4 alkyl) 2 , CFs and halogen and ring B is not present.

In certain preferred embodiments of the invention, in the compounds of genera! formula (I), ring A is eyc!obutyl or cyclohexyi, Y refers to two groups selected from the group consisting of C^alkyl group optionally substituted with halogen, Ci- 4 alkoxy group and halogen and ring B is not present.

In certain preferred embodiments of the invention, in the compounds of general formula (I), ring A is cyclobutyl or cyclohexyi, Y is -O- or a single bond and B is phenyl, 2- methyl-phenyl, azetidin-1-yi, pyrrol idin- 1 -y I , morpholin-4-yl, pyrdin-2-yl, 3-ch!oro-pyridin-2-yl, 3-methy!-pyridin-2-yi, pyridin-3-yl, pyrimidin-2-ly or 5-methyl-isoxazol-3-yi.

in certain more preferred embodiments of the invention, in the compounds of general formula (I), ring A is cyclohexyi, Y is -O- and B is pyridin-2-yl, pyridin-3-yi, 3-chioro-pyridin-2- yl, 3-methy!pyridin-2~yi, pyrimidin-2-yl or 5-mefhy!isoxazo!~3~yl.

in certain most preferred embodiments of the invention, in the compounds of genera! formula (I), ring A is cyclohexyi, Y is -O- and B is pyridin-2-yi.

in certain preferred embodiments of the invention, in the compounds of general formula (I), ring A is cyclohexyi, Y is a single bond and ring B is morpholin-4-yl.

in certain embodiments of the invention, in the compounds of general formula (I), ring A is cyc!obutyl or cyclohexyi, Y is -C(O)- and ring B is azetidin-1-yl, pyrrolidin-1-yl or morpholin-4-yi.

In certain embodiments of the invention, in the compounds of general formula (I), ring A is cyclobutyi or cyclohexyi, Y is -Chh- and ring B is an optionally substituted aryl, heterocyciyi or heteroaryl group.

In certain embodiments of the invention, in the compounds of general formula (I), ring A is cyclobutyi or cyclohexyi, Y is -CH 2 - and ring B is optionally substituted 4- to 7-membered heterocyciyi group containing 1 N or 1 N and 1 O.

In certain preferred embodiments of the invention, in the compounds of genera! formula (I), ring A is azetidin-1 ,3-diyi, piperidin-1 ,4-diyl or piperazin-1 ,4-diyi, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H~ [1 ,2,4]triazolo[4,3-a][1]benzazepine core, Y is -O- or a single bond and ring B is phenyl, 2- methy!-pbenyi, azetidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, pyrdin-2-yi, 3-chloro-pyridin-2-yl, 3-methyl-pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl or 5-methyl-isoxazol-3-yl.

in certain more preferred embodiments of the invention, in the compounds of general formula (I), ring A is azetidin-1 ,3-diyl, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dibydro-4H-[1 ,2,4]triazoio[4,3-a][1]benzazepine core, Y is a single bond and ring B is pyrdin-2-yl, pyrimidin-2-yi, piperidinyl or optionally substituted phenyl. in certain embodiments of the invention, B-Y-A- in the compounds of general formula (I) jointly represents 3H-spiro[2-benzofuran-1 ,4'-piperidin-1’-yl], 1-oxa-3-azaspiro[4.5]decan- 2-on-8-yi substituted at 3-position by Ci -4 a!ky! or 2-azaspiro[4.5]decan-1-on-8-yl substituted at 2-position by C h alky!, aryl or heteroaryl.

In certain embodiments of the invention, B-Y-A- in the compounds of formula (I) jointly represents 3W-spiro[2-benzofuran-1 ,4'-piperidin-1’-yl], (5S,8S)-3-methyl-1-oxa-3- azaspiro[4.5]decan-2-on-8-yl, (5R,8R)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-on-8-yl, (5 ,8 )-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one or (5S,8S)-2-(propan-2-yl)-2- azaspiro[4 5]decan-1-one.

in certain embodiments of the invention, R 1 in the compounds of general formula (I) is a hydrogen.

In certain embodiments of the invention, R 1 in the compounds of general formula (I) is a halogen.

In certain preferred embodiments of the invention, R 1 in the compounds of general formula (I) is a chlorine, bromine or fluorine.

In certain more preferred embodiments of the invention, R 1 in the compounds of general formula (I) is a chlorine.

In certain embodiments of the invention, R 1 in the compounds of general formula (I) is a Ci- 4 alkyl group.

In certain preferred embodiments of the invention, R 1 in the compounds of general formula (I) is a methyl group.

In certain embodiments of the invention, R 1 in the compounds of general formula (I) is a Ci- 4 aikoxy group. In certain preferred embodiments of the invention, R 1 in the compounds of general formula (I) is a methoxy group.

In certain embodiments of the invention, 1 in the compounds of general formula (I) is a CF3 group.

In certain embodiments of the invention, R 1 in the compounds of general formula (I) is a CN group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen or Ci-4alkyl group, R 3 is a (CH 2 ) n R 4 , C(0)R 5 or Ci-4alkyl group optionally substituted with R 6 .

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a (CH2) n R 4 , C(0)R 5 or Ci^alkyl group optionally substituted with R 6 .

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a (CH 2 ) n R 4 group, wherein R 4 is CN, azide or optionally substituted 5- membered mono-heteroaryl group containing 2 N and 1 O or 4 N and n is 0 or 1.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a (ChhJ n R 4 group, wherein R 4 is CN and n is 0 or 1

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a (CHz) n R 4 group, wherein R 4 is tetrazolyl or 3-methyl- 1 ,2, 4-oxadiazol- 5-yi and n is 0 or 1.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is Ci-4alkyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is methyl-, ethyl-, isopropyi- or /-butyl group.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R s is methyl-group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is C^alkoxy group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is methoxy-, ethoxy-, propoxy- or f-butoxy group. In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(G)R 5 group, wherein R 5 is methoxy group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C{0)R 5 group, wherein R 5 is OH group.

In certain embodiments of the invention, in the compounds of general formula (i), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, wherein R 7 and R 8 are independently hydrogen, C h alky! or Cy 2 .

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are hydrogen.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 is hydrogen, R 8 is methyl-, ethyl-, isopropyl- or f-butyi-group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are independently methyl-, ethyl-, isopropyl- or f-butyl-group.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are methyl-groups.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 is hydrogen, R 8 is optionally substituted aryl or heteroaryl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(Q)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are taken together with the N to which they are attached form an optionally substituted heterocycle.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C(Q)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are taken together with the N to which they are attached form an optionally substituted 4- to 7~membered saturated heterocycle containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S. In certain embodiments of the invention, in the compounds of general formula (i), R 2 is a hydrogen, R 3 is a C h alky! group optionally substituted with R 6 , wherein R 6 is OR 9 , NR 10 R 11 , oxo, -0(CH 2 ) m 0- group or one or more halogens.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a methyl, ethyl or isopropyl group.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is an isopropyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a single or multiple branched Ci^alkyl substituted with R 6 , wherein R 6 is OR 9 , NR 10 R 11 group or one or more halogens.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a single or multiple branched C ^alkyl substituted with R 6 , wherein R 6 is one or more halogens.

In certain embodiments of the invention, in the compounds of general formula (i), R 2 is a hydrogen, R 3 is a -Chhhalogen, -CH(halogen)CH 3 or -C(halogen) 2 CH 3 group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CHzhalogen group.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -ChhF group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C h alky! group substituted with R 6 , wherein R 6 is oxo or -GiChh^O- 9 roup.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a single or multiple branched Ci^alkyl group substituted with R 6 , wherein R 6 is OR 9 or NR !0 R 11 group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, wherein R 6 is OR 9 or NR^R 11 group.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CHzR 6 group, wherein R 6 is OR 9 or NR '°R 11 group.

In certain embodiments of the invention, in the compounds of general formula (i), R 2 is a hydrogen, R 3 is a C h alky! group substituted with R 6 , wherein R 6 is OR 9 . In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or ~CH( 6 )CH 3 group, 6 is OR 9 , wherein R 9 is hydrogen.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is Ci- 4 alkyl optionally substituted with NH 2 or with optionally substituted aryl group .

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is NH 2 substituted ethyl or isopropyl .

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is ethyl or isopropyl.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -GH(R 6 )CH3 group, R 6 is OR 9 , wherein R 9 is Si(CH 3 ) 3 .

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is Ci-salkyl.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is C(G)R 12 group, R 12 is methyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 isa -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is C{0)R 12 group, R 12 is NR 1 4 R 15 group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or ~CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is G(0)R 12 group, R 12 is NR 14 R 1 5 group, wherein R 14 and R 15 is hydrogen.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is NR 14 R 15 group, wherein R 14 and R 15 are independently hydrogen or optionally substituted aryl. In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 group, R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is NR 14 R 15 group, wherein one of R 14 is hydrogen, R 15 is 4-f!uoro-phenyl.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 or -CH(R 6 )CH3 group, R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is NR 14 R 15 group, wherein R 14 and R 15 taken together with the N to which they are attached form an optionally substituted 4- to 7-membered saturated heterocycle containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is -CH2R 6 group, R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is NR 14 R 15 group, wherein R 14 and R 15 taken together with the N to which they are attached form a morpholine.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C h alky! group substituted with R 6 , wherein R 6 is NR '°R 11 group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 or -CH(R 6 )CH3 group, R 6 is NR 10 R 1 1 group, wherein R 10 and R 11 is hydrogen.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 or -CH(R 6 )CH3 group, R 6 is NR '°R 11 group, wherein R 10 and R 11 are independently hydrogen or Ci -4 a!ky! optionally substituted with Ci- 4 alkoxy group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 or -CH(R 6 )CH3 group, R 6 is NR^R 11 group, wherein R 10 and R 11 are independently hydrogen, methyl, ethyl, isopropyl, s-butyl or f-butyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 or -CH(R 6 )CH3 group, R 6 is NR 10 R 1 1 group, wherein R 1 0 and R 11 are independently hydrogen and methyl, ethyl or isopropyl substituted with methoxy or ethoxy group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 or -CH(R 6 )CH3 group, R 6 is NR 10 R 1 1 group, wherein R 10 and R 11 are independently hydrogen or Cy 3 .

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH2R 6 or -CH(R 6 )CH3 group, R 6 is NR^R 11 group, wherein R 10 is hydrogen, R 11 is a 4- to 7-membered saturated heterocydyi group containing 1 O or C 4-6 cycloalkyl group having geminal halogen substitution.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C h alky! group substituted with R 6 , R 6 is NR^R 11 group, wherein R 10 and R 11 are independently hydrogen or C(0)R 13 .

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is NR^'R 11 group, wherein R 10 is hydrogen, R 11 is C(0)R 13 , R 13 is C h alky!

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a -CH 2 R 6 group, R 6 is NR 10 R" group, wherein R 10 is hydrogen, R 11 is C(0)R 13 , R 13 is methyl group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C h alky! group substituted with R 6 , R 6 is NR^R 11 group, wherein R 10 and R 11 are independently hydrogen or C(0)R 13 , wherein R 13 is Cy 1

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a hydrogen, R 3 is a C h alky! group substituted with R 6 , R 6 is NR^R 11 group, wherein R 10 and R 11 are independently hydrogen or C(0)R 13 , wherein R 13 is NR 16 R 17 group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a Ci- 4 alkyl group, R 3 is a (Ch l n R 4 , C(0)R 5 or Ci- 4 alkyl group optionally substituted with R 6 .

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a Ci- 4 alkyl group, R 3 is a (CH 2 ) n 4 group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a Ci- 4 alkyl group, R 3 is a C(0)R s group.

In certain embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 are C h alky! groups.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 are C h alky! groups.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 is independently a methyl, ethyl or isopropyl group.

In certain even more preferred embodiments of the invention, in the compounds of formula (I), R 2 and R 3 are methyl groups. In certain embodiments of the invention, in the compounds of general formula (i), R 2 is a Ci- 4 alkyl group, R 3 is a Ci- 4 aikyi group substituted with R 6 , wherein R 6 is OR 9 .

In certain embodiments of the invention, in the compounds of general formula (I), R 2 is a C h alky! group, R 3 is a Ci -4 a!ky! group substituted with R 6 , R 6 is OR 9 , wherein R 9 is Ci- 4 alkyl group.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 is a methyl or ethyl group, R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, R 6 is OR 9 , wherein R 9 is hydrogen.

In certain embodiments of the invention, in the compounds of general formula (!), R 2 is a C h alky! group, R 3 is a Ci- 4 aikyi group optionally substituted with R 6 , wherein R 6 is N I °R " , OXO -0(GH 2 ) m O- group or one or more halogen.

In certain embodiments of the invention, in the compounds of general formula (i), R 2 and R 3 jointly represent -(CH 2 ) P -0-(CH 2 )q- group, wherein p is 1 , 2 or 3 and q is 1 , 2 or 3.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 jointly represent -(CH 2 ) P -0-(CH 2 )q- group, wherein the sum of p and q is 3.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 jointly represent -(CH 2 ) p -0-(GH 2 ) q - group, wherein the sum of p and q is 4.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 jointly represent -(Chhjp-G-iGh jq- group, wherein p is 1 and q is 2.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 jointly represent -(CH 2 ) p -0-{CH 2 ) q - group, wherein p is 1 and q is 3.

In certain more preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 jointly represent -(CH 2 ) p -0-(CH 2 ) q - group, wherein p is 2 and q is 2.

In certain embodiments of the invention, in the compounds of general formula (i), R 2 and R 3 jointly represent ~(CH 2 ) r group, wherein r is 4, 5 or 6.

In certain preferred embodiments of the invention, in the compounds of general formula (I), R 2 and R 3 jointly represent ~(CH 2 ) r group, wherein r is 4

While the invention has been described in connection with certain embodiments, certain preferred, more preferred or most preferred embodiments, it is not intended to limit the scope of the invention to the particular form set forth, but on the contrary, it is intended to cover such alternatives, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the statements of inventions. Examples of alternative claims directed to the compounds of the present invention may include:

(1) The compounds of general formula (I) as described above or in any other embodiment.

(2) The compound as described in (1), or in any other embodiment, wherein R 1 is a hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CFs or CN.

(3) The compound as described in any of (1) to (2), or in any other embodiment, wherein

ring A is a 3- to 6-membered saturated carbocydic or a 4- to 7-membered saturated beterocyde containing 1 or 2 N;

ring B is an optionally substituted 6- or 5-membered mono-beteroaryi group, 6- to 10- membered aromatic carbocyde, or 4- to 7-membered saturated, monocyclic, bicyclic, fused and/or bridged heterocycle containing 1 , 2 or 3 heteroatoms selected from O, S or N;

or B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1 ,4’-piperidin-T-yl]; or group;

X is isopropyl group;

Z is methyl group.

(4) The compound as described in any of (1) to (3), or in any other embodiment, wherein ring B is optionally substituted 6-membered mono-heteroaryi group, phenyl, or 4- to 6-membered saturated, monocyclic heterocycie containing 1 or 2 heteroatoms selected from O, S or N.

(5) The compound as described in any of (1) to (4), or in any other embodiment, wherein Y is -0-, -C(O)-, -CH2-, -NH-, or a single bond if ring B is present.

(6) The compound as described in any of (1) to (5), or in any other embodiment, wherein ring A is a 4- to 6-membered saturated carbocydic group or a 4- to 7-membered saturated heterocycie containing 1 or 2 N attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dibydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core. (7) The compound as described in any of (1) to (6), or in any other embodiment, wherein ring A is cyclohexyl, Y is -0-, ring B is pyridin-2-yl and R 1 is chlorine.

(8) The compound as described in any of (1) to (6), or in any other embodiment, wherein ring A is azetidine, piperidine or piperazine, Y is -O- or a single bond, ring B is pyridine, pyrimidine, piperidine and R 1 is chlorine.

(9) The compound as described in any of (1) to (3), or in any other embodiment, wherein Y is -N(Ci-4alkyl)2, C(0)OCi- 4 alkyl, C h alky! group optionally substituted with halogen, Ci- 4 alkoxy group and halogen and ring B is not present.

(10) The compound as described in (9), or in any other embodiment, wherein ring A is a 4- to d-membered saturated carbocyclic group.

(1 1) The compound as described in (10), or in any other embodiment, wherein Y is one group selected from the group consisting of -N(Ci.4aikyi)2, C(0)OCi- 4 alkyl, C h alky! group optionally substituted with halogen, Ci-4aikoxy group and halogen.

(12) The compound as described in (10), or in any other embodiment, wherein Y is two groups selected from the group consisting of Ci- 4 alkyl group optionally substituted with halogen, Ci-4alkoxy group and halogen.

(13) The compound as described in any of (1) to (12), or in any other embodiment, wherein R 2 is a hydrogen or Ci^alkyl group, R 3 is a (CH2) n R 4 group.

(14) The compound as described in (13), or in any other embodiment, wherein R 2 is a hydrogen, R 3 is a (CH 2 ) n R 4 group, R 4 is CN, azide or 5-membered mono-heteroaryl group containing 2 N and 1 O or 4 N optionally substituted with Ci -4 aikyi group.

(15) The compound as described in any of (1) to (12), or in any other embodiment, wherein R 2 is a hydrogen or Ci- 4 alkyl group, R 3 is a C(G)R 5 group.

(16) The compound as described in (15), or in any other embodiment, wherein R 2 is a hydrogen.

(17) The compound as described in (16), or in any other embodiment, wherein R 5 is a methyl, methoxy, OH or NR 7 R 8 group wherein R 7 and R 8 are independently hydrogen, methyl, ethyl or isopropyl group.

(18) The compound as described in any of (1) to (12), or in any other embodiment, wherein R 2 is a hydrogen or C h alky! group, R 3 is a C h alky! group optionally substituted with R 6 . (19) The compound as described in (18), or in any other embodiment, wherein R 2 is a hydrogen or Gi^a!ky! group, R 3 is a Gi^aikyi group.

(20) The compound as described in (19), or in any other embodiment, wherein R 2 is a hydrogen or C -aalkyl group and R 3 is a C h alky! group.

(21) The compound as described in (18), or in any other embodiment, wherein R 2 is a hydrogen or C h alky! group, R 3 is a single or multiple branched C^alkyl group substituted with R 6 ,

(22) The compound as described in (21), or in any other embodiment, R 3 is a -CH 2 R 6 or -CH(R 6 )CH3 group.

(23) The compound as described in any of (21) or (22), or in any other embodiment, wherein R 2 is a hydrogen, R 6 is an OR 9 group.

(24) The compound as described in (23), or in any other embodiment, wherein R 9 is a hydrogen, C ^alkyl group optionally substituted with phenyl group or C(0)R 12 group, wherein R 12 is methyl group.

(25) The compound as described in any of (21) or (22), or in any other embodiment, wherein R 2 is a G^alkyl group, R 6 is an OR 9 group.

(26) The compound as described in (25), or in any other embodiment, wherein R 2 is a methyl or ethyl group, R 9 is a hydrogen.

(27) The compound as described in any of (21) or (22), or in any other embodiment, wherein R 2 is a hydrogen, R 6 is a NR 10 R 11 group.

(28) The compound as described in (27), or in any other embodiment, wherein R 10 and R 11 is independently a hydrogen, C h alky! group optionally substituted with C^alkoxy group, Gy 3 , C(G)R 13 , or R 16 and R 17 taken together with the N to which they are attached form an optionally substituted heterocycle.

(29) The compound as described in any of (21) or (22), or in any other embodiment, wherein R 2 is a Ci- 4 aikyi group, R 6 is a NR 10 R 11 group.

(30) The compound as described in any of (21) or (22), or in any other embodiment, wherein R 2 is a hydrogen, R 6 is one or more halogens.

(31) The compound as described in (30), or in any other embodiment, wherein, the halogen is fluorine. (32) The compound as described in any of (21) or (22), or in any other embodiment, wherein R 2 is a Gi^a!ky! group, R 6 is one or more halogens

(33) The compound as described in (21), or in any other embodiment, wherein R 6 is an oxo or -OfCHz O- group.

(34) The compound as described in any of (13) to (33), or in any other embodiment, wherein the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H- [1 ,2,4]triazo!o[4,3-a][1]benzazepine core is (R)

(35) The compound as described in any of (13) to (33), or in any other embodiment, wherein the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H- [1 ,2,4]triazo!o[4,3-a][1]benzazepine core is (S).

(36) The compound as described in any of (1) to (12), or in any other embodiment, wherein R 2 and R 3 jointly represent -(CH 2 ) P -0-(CH 2 ) q - group, wherein p is 1 , 2 or 3 and q is 1 , 2 or 3

(37) The compound as described in (36), or in any other embodiment, wherein the sum of p and q is 3 or 4

(38) The compound as described in any of (1) to (12), or in any other embodiment, wherein R 2 and R 3 jointly represent -(Chhjr group, wherein r is 4, 5 or 6.

A preferred group of compounds of general formula (I) of the present invention are, for example, the following compounds and/or salts and/or solvates and/or hydrates and/or polymorphs and/or biologically active metabolites and/or prodrugs thereof:

1. methyl 8-ch!oro~1~[ifans-4-(pyridin~2~yioxy)cydohexyl]~5,6~dihydro- 4H~

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

2. 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylic acid,

3. 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine- 5-carboxamide,

4 8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydr o-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carbonitrile,

5 8-chloro-A/,/\/-dimethyl-1-[fra/7S-4-(pyridin-2-yloxy)cycloh exyl]-5,6-dihydro-4/-/-

[1.2.4]triazoio[4,3-a][1]benzazepine-5-carboxamide,

6 (5S)-8-chioro~A ,A/-dimethyl~1~[frans-4-(pyridin-2-yloxy)cyclohexyi]~5,6~dih ydro-4H~

[1.2.4]triazolo[4,3-a][1]benzazepine-5- carboxamide, 7. (5R)-8-chloro-A/,/V-dimethyl-1-[irans-4-(pyridin-2-yloxy)cyc lohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3~a][1]benzazepine- 5-carboxamide,

8 8-cbloro-A/-(propan-2-yl)-1-[ira/is-4-(pyridin-2-yloxy)cyclo hexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxamide,

9. {8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihyd ro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}(pyrrolidin-1-yl)methanone,

10. {8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihyd ro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin~5-yl}(morphoiin-4-yi)methanone,

1 1 . {8-chloro-1-jYrans-4-(pyridin-2-yloxy)cyclohexyi]-5 6-dihydro4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}(1 , 1-dioxidothiomorpholin-4-yl)methanone,

12. {8-chloro-1-[frans-4-(pyridin-2-y!oxy)cyclohexyl]-5 6-d!hydro-4H-[1 ,2,4]triazoio[4,3- a][1]benzazepin-5-yi}metbanoi,

13. {(5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-d ihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine-5-yi}metbanoi,

14. {(5R)-8-chloro-1-[f/a/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine-5-y!}metbanoi,

15. 8-cbloro-5-(methoxymethyl)-1-[fra/is-4-(pyridin-2-yloxy)cycl obexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

16. {8-eh!orG-1-[frans~4~(pyridin-2-yioxy)cyc!ohexyl]-5 6-dihydrG-4H-[1 ,2 4]triazGiG[4,3- a][1lbenzazepin-5-yi}metby!-morpho!ine-4-carboxylate

17. {8-chloro-1-[fraA7s-4-(pyridin-2-yloxy)cyclohexyl]-5 6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-y!}metbyi (4-fluoropbenyl)carbamate,

18. 5-(azidomethyl)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclobe xyl]-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-a][1]benzazepine,

19. 1-{8-chloro-1-[f/a/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dih ydro-4H-[1 ,2,4]triazolo[4,3- aj[1]benzazepin-5-yi}metbane amine,

20. 8-chloro-5-(morpholin-4-ylmethyl)-1-[fraA7s-4-(pyridin-2-ylo xy)cyclohexyl]-5,6- dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine >

21. 1-{8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dih ydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yi}-A/,A/-dimethyimetbane amine,

22. A/-({8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-d ihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}methyl)propane-2 -amine,

23. methyl 8-chloro-1-[1-(pyrimidin-2-yl)azetidin-3-yl]-5,6-dihydro-4H- [1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate, 24. methyl 8-ehloro-1-[frans-4-(dimethylamino)cyclohexyl]-5,6-dihydro-4 H-

[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

25. methyl 8-chloro-1-[ira/is-4-(trifluoromethyl)cyclohexyl]-5,6-dihydr o-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

26. methyl 8-chloro-1-[ira/7s-4-(morpholin-4-yl)cyclohexyl]-5,6-dihydro -4H-

[1.2.4]triazolo[4,3-al[1]benzazepine-5-carboxylate,

27. {1-[i/¾A7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazep!n~5-yl}methanoi,

28. methyl 8-chloro-1-[frans-4-(pyrrolidin-1-ylcarbonyl)cydobexy!]-5,8- dihydrc>-4H-

[1.2.4]triazolo[4,3-al[1]benzazepine-5-carboxylate,

29. {8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5 6-d!hydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}acetonitrile,

30. 8-chloro-5-[(4-methylpiperazin-1-yl)methyl]-1-[fra/7s-4-(pyr idin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine,

31. 8-chloro-5-(fluoromethyl)-1-[f/a/7s-4-(pyridin-2-yloxy)cyclo hexyl]-5,6-dihydro-4H-

[l ^^jtriazolo^.S-ajnjbenzazepine,

32. 8-chloro-5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1-[fra/is-4-(pyridin-2-yloxy)cyclohexyl ]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine,

33. 8-chloro-1-[irans-4-(pyridin-2-yloxy)cyclohexyl]-5-(2H-tetra zol-5-yl)-5,6-dihydro-4H-

[1 2.4]triazolo[4,3-a][1]benzazepine,

34. A/-({8-chloro-1-[frans-4-(pyridin-2-yioxy)cyclohexyl]-5,8-di hydro-4H-

[1.2.4]tr!azolo[4,3-a][1]benzazepin-5-yl}methyl)tetrahydr o~2H-pyran-4-amine,

35. /V,/V-dimethyl-1-[fraA7S-4-(pyridin-2-yloxy)cyclohexyl]-8-(t rifluoromethyl)-5,6-dihydiO- 4H-[1 , 2, 4]triazolo[4,3-a][1]benzazepine- 5-amine,

36. methyl 8-chloro-1-[/rar?s-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-8 -yl]-5,6-dihydro- 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

37. /V-({8-chloro-1-[fraA7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-d ihydrc>-4H-

[1.2.4]triazolo[4,3-al[1]benzazepin-5-yi}methyl)acetamide ,

38. A/-({8-chioro-1-[frans~4~(pyridin-2-yioxy)cyclohexyl]-5,8-di hydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}methyl)oxetane- 3-amine,

39. methyl 8-chloro-1-[ira/is-4-(morpholin-4-ylcarbonyl)cyclohexyl]-5,6 -dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

40. methyl 8-chloro-1-[c/s-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-8-yl ]-5,6-dihydro- 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate, 41. methyl 8-chloro-1-[1-(pyridin-2-yl)azetidin-3-yl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

42. methyl 1-[frans-4-(azetidin-1-ylcarbonyl)cyclohexyl]-8-chloro-5,6-d ihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

43. 8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrroli din-1-ylmethyl)-5,6-dihydro- 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine,

44. A/-({8-chloro-1-[ira/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-d ihydro-4H-

[12.4]triazolo[4,3-a][1]benzazepin-5-yl}methy!)-2-methyl- A/-(2- methylpropyl)propane-1-amine,

45. methyl 8-chloro-1-[fra/7s-4-(piperidin-1-ylGarbonyl)cyclohexyl]-5,6 -dihydro-4/7-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

46. methyl 1-(/rans-4-{[4-(fe/f-butoxycarbonyl)piperazin-1-yl]carbonyl} cyclohexyl)-8- chloro-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

47. methyl 8-chloro-1-[ira/7s-4-(piperazin-1-ylcarbonyl)cyclohexyl]-5,6 -dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate hydrochloride,

48. methyl 8-methoxy-1-[/rans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydr o-4H-

[1.2.4]triazolo[4,3-al[1]benzazepine-5-carboxylate,

49. methyl 8-methyl-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydr o-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

50. 8-cbloro-A/-(4-fliioraphenyl)-1-[frans-4-(pyridin-2-yloxy)cy clohexyi]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxamide,

51. methyl 8-bromo-1-[frans~4~(pyridin-2-yioxy)cyclobexyl]-5,8-dihydro~ 4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

52. 1-(1 ,4'-bipiperidin-1'-yi)-8-chloro-5 6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxamide,

53. methyl 8-chloro-1-[(5r,8r)-1-oxo-2-(propan-2-y!)-2-azaspiro[4 5]dec-8-y!]-5,6-dihydro- 4H- [ 1 , 2 , 4]tri azo I o[4 , 3-a] [ 1 ] be nzaze pi n e- 5- carboxyl ate ,

54. 1-{8-chloro-1-[irans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihy dro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}ethanol,

55. 1-{8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dih ydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}ethanone,

56. 8-chloro-5-(fluoromethyl)-1-(ira/7s-4-methoxy-4-methylcycloh exyl)-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

57. 1-{8-chloro-1-[ira/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dih ydro-4W-[1 ,2,4]triazolo[4,3- a][1lbenzazepin-5-yl}-A/-(2-methoxyethyl)ethanamine, 58. methyl 8-fluoro-1-[fraA7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydr o-4H-

[1 2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

59. 8-chloro-5-(fluoromethyl)-1-[ira/7s-4-(trifluoromethyl)cyclo hexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

60. 5-(fluoromethyl)-1-(/rans-4-methoxy-4-methylcyclohexyl)-5,6- dihydro-4H-

[1.2.4]triazolo[4,3-al[1]benzazepine,

61. {8-fluoro-1-[/rar?s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihyd ro-4H-[1 ,2,4]triazolo[4 3- a][1]benzazepin~5-yi}methanoi,

62. 8-fluoro-5-(fluoromethyl)-1-[frans-4-(pyridin-2-yloxy)cycloh exyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

63. c/s-(racem)-1-{8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohe xyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

64. irans-(racem)-1-{8-chloro-1-[frans-4-(pyridjn-2-yloxy)cycloh exyl]-5,6-dihydro-4H- [1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

65. (1fi)-1-{(5fi)-8-chlorc>-1-[fra/7S-4-(pyridin-2-yloxy)cyc lohexyl]-5,6-dihydiO-4H- [1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

66. (1 S)-1-{(5S)-8-chloro-1-[ira/7S-4-(pyridin-2-yloxy)cyclohexyl] -5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol,

67. (1 S)~1~{(5/ )~8~chloro-1-[frans~4~(pyridin-2-y!oxy)cydobexyl]-5,8-dihydr o~4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}etbanol,

68. (1R)-1-{(5S)-8~chloro-1-[frans~4~(pyridin-2-yioxy)cyclohexyl ]-5,8-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin-5-yl}etbanoi,

69. 5-(fiuoromeihyl)-8-methyi-1-[fra/7S-4-(pyridin-2-yloxy)cycio bexyl]-5,8-dihydrQ-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

70. (5S)-8-chioro~5-(fluoromethyl)~1-[frans-4-(pyridin-2-yloxy)c ydobexyl]~5,6~dihydro-

4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine,

71. (5R)-8-cbloro-5-(fluoromethyl)-1-[irans-4-(pyridin-2-yloxy)c yclohexyl]-5,6-dibydro- 4/7-[1 ,2,4]triazolo[4,3-a][1]benzazepine,

72. methyl 8-fluoro-1-[frans~4~(trifluoromethyi)cyclohexyl]-5,6-dihydro -4H-

[1 2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

73. 8-chloro-1-[4-(2,3-dimethylphenyl)piperazin-1-yl]-5,6-dihydr o-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxamide,

74. {8-fluoro-1-[frans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydr o-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepin-5-yl}methanol, 75. {8-eh!oro-5-methy!-1-[frans-4~(pyridin-2-yloxy)cyc!obexyI]-5 ,6-dihydro~4H- [1 2,4]triazolo[4,3-a][1]benzazepin-5-y!}methanoI,

76. {8-chloro-5-ethyl-1-[ira/7S-4-(pyridin-2-yloxy)cyclohexyl]-5 ,6-dibyclro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepin~5-yl}meihanol,

77. (5S)-8-fluoro-5-(fluoromethyl)-1-[irans-4-(pyridin-2-yloxy)c yclohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-al[1]benzazepine,

78. (5 )-8-fluoro-5-(fluoromethyl)-1-[ira/?s-4-(pyridin-2-yloxy)cyc lobexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

79. 8-cbloro-1-[4-(3-chlorophenyl)piperazin-1-yl]-5,6-dihydro-4H -[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxamide,

80. 8-cbloro-1-[4-(pyridin-2-yl)piperazin-1-yl]-5,6-dihydro-4H-[ 1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxamide,

81. 8-chloro1-[4-(pyridin-2-yloxy)piperidin-1-yl]-5,6-dihydiO-4H -[1 ,2,4]triazolo[4,3- a][1lbenzazepine-5-carboxamide,

82. 5-[(benzyloxy)metbyl]~8-chloro-1-[frans~4~(pyridin-2-yioxy)c yclobexyl]-5,8-dihydro-

4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine,

83. methyl 8-chloro-1-(3,3-difluorocyclobutyl)-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxylate,

84. methyl 8-chloro-1-[frans-4-(piperidin-1-ylmethy!)cyclobexyl]-5,6-di hydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxylate,

85. {8-chloro-1-[fraA7s-4-(pyridin-2-yloxy)cyclohexyl]-5 6-dihydro-4H-[1 ,2,4]triazolo[4,3- aj [ 1 ] benzazepi n-5-y !}m ethyl acetate ,

86. 8-chloro-1-( H,3H-spiro[2-benzofuran-1 ,4'-pjperidin]-1 '-yl)-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxamide,

87. 8-chloro-A/-(pyridin~2-yl)~1-[frans-4-(pyridin-2-yloxy)cydoh exyl]~5,6~dihydro-4H~

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carboxamide,

88. 8-chloro-1-( W,3W-spiro[2-benzofuran-1 ,4'-piperidin]-1 '-yl)-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine-5-carbonitrile,

89. 8-chloro-1-[4-(2,3-dimethylphenyl)piperazin-1-yl]-5,6-dihydr o-4H-[1 ,2,4]triazolc[4,3- a][1]benzazepine-5-carbonitrile,

90. 8-chloro-1-[4-(pyridin-2-yl)piperazin-1-yl]-5,6-dihydro-4H-[ 1 ,2,4]triazolo[4,3- aj[1]benzazepine-5-carbonitrile,

91. 8-fluoro-5,5-dimethyl-1-[irans-4-(pyridin-2-yloxy)cyclohexyl ]-5,6-dihydro-4H-

[1.2.4]triazoio[4,3-al[1]benzazepine, 92. 8-fluoro-5-(propan-2-yl)-1-[fra/7S-4-(pyridin-2-yloxy)cycloh exyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

93. 8'-bromo-1'-[ffans-4-(pyridin-2-yloxy)cyclohexyl]-4 , H 6 , H-spiro[cydopentane-1 ,5'-

[1.2.4]triazolo[4,3-a][1]benzazepine],

94. 8-bromo-5-(propan-2-yl)-1-[ira/7s-4-(pyridin-2-yloxy)cyclobe xyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-al[1]benzazepine,

95. 8'-bro o-1'-[frans-4-(pyrid!n-2-yloxy)cyclobexyl]-2,3,5,8-tetrahydr o-4’H,6’H- spiro[pyran~4,5 , ~[1 ,2,4]triazolo[4,3-a][1jbenzazepinej,

96. 8-fluoro-5,5-dimethyl-1-[frans-4-(trifluoromethyl)cyclohexyl ]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

97. (5R)-8-bromo-5-(propan-2-yl)-1-[f/a/7S-4-(pyridin-2-yloxy)cy clohexyl]-5,6-dihydro-4H-

[1 ,2,4]triazolo[4,3-a][1]benzazepine,

98. (5S)-8-bromo-5-(propan-2-yl)-1-[fra/7s-4-(pyridin-2-yloxy)cy clohexyl]-5,6-dihydro-4H-

[1.2.4]triazolo[4,3-a][1]benzazepine,

99. 8'~bro o~T-[frans-4-(pyrid!n-2-yloxy)cyclobexyl]-4,5~dihydro-4'H,6' H-3piro[furan~ S.S -f Z^jtriazoloj I.S-aJjdjbenzazepine],

100. 8 , -chioro-1'-[fra/7S-4-(pyridin-2-yloxy)cydohexyl]-2,3,5 ,8-tetrahydro-4 , i4 6 , i4- spiro[pyran-4 5 , -[1 ,2 4]triazolo[4,3-a][1]benzazepine] >

101. 8'-chloro-T-[/rans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydr o-4H,4'H,6'H-spiro[pyran- 3,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

102. 8'-chloro~T-[frans-4-(pyridin-2-yloxy)cyc!ohexyl]~4,5~dihydr o-4'H,8'H~spiro[furan~3,5'~

[1.2.4]triazolo[4,3-a][1]benzazepine],

103. 8'-chloro- -[frans-4-(trifluoromethyl)cyclohexyl]-2,3 5,6-tetrahydro-4'H,6'H- spiro[pyran-4,5 , -[1 2,4]triazolo[4,3-a][1]benzazepine],

104. (3R)-8'-bromo-T-[ira/7S-4-(pyridin-2-yloxy)cyclobexyl]-4,5-d ihydro-4 , H,6'H- spiro[furan-3,5'-[1 ,2,4]triazoio[4,3-a][1]benzazepine],

105 (3S)-8'-bromo-1 '-[fAa/7S-4-(pyridin-2-yloxy)cyclohexyl]-4 5-dibydro-4'H,6'H- spiro[furan-3,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

106. (3S)-8'-chloro-T-[frans-4-(pyridin-2-y!oxy)cyclohexyl]-5 6-d!hydro-4H,4’H,6’H- spiro[pyran-3,5'-[1 ,2 4]triazo!o[4,3-a][1jbenzazepinej,

107. (3R)-8'-chloro-T-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H,4'H > 6'H- spiro[pyran-3,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

108 8-fluoro-1-(trans-4-methoxy-4-methylcyclobexyl)-5,5-dimethyl -5,6-dihydro-4H-

[1.2.4]triazolo[4,3-al[1]benzazepine, 109. 8-fluoro-1-(cis-4-methoxy-4-methylcyclohexyl)-5,5-dimethyl-5 ,6-dihydro-4H-

[1 2,4]triazo!o[4,3-a][1]benzazepine,

110. 8'-chloro-T-(trans-4-methoxy-4-methylcyGlohexyl)-2,3,5,6-tet rahydro-4'l-l,6'l-l- spiro[pyran-4,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

111. 8'-chloro-T-(cis-4-methoxy-4-methy!cydohexy!)-2,3,5 6-tetrahydro-4'H,6'H- spiro[pyran-4,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine], or

112. methyl S~chloro-1-[frans-4~(pyridin-2-ylamino)cyclohexyl]~5,6~dihyd ro-4H~

[1 ,2,4]friazo!o[4,3-a][1]benzazepine~5~carboxyiate.

The present invention also relates to the synthesis of compounds of formula (I). Accordingly, the compounds of formula (!) of the present Invention can be prepared by one of the following methods:

In so far as, in the compound of general formula (I), R 2 is a hydrogen, R 3 is a C(0)R 5 group, R 5 is a C,.. 4 alkoxy group and ring A is a cydoaikyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y, the compounds of general formula (I) of the present invention are prepared by reacting the compounds of general formula (II)

- wherein ring B and Y are as defined above for genera! formula (1) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - and the compounds of genera! formu!a (!!!)

- wherein R 1 is as defined above for general formula (I), 3 is a C(0)R 5 group and R 5 is Ci- 4 aikoxy group.

The procedure is shown in detail in Scheme 1:

In step a) of Scheme 1 the acid hydrazide of general formula (II) is reacted with the benzazepine-fhione of general formula (111). The reaction is preferably carried out in a suitable solvent, at the boiling point of the solvent, with a reaction time required from 4 to 120 hours. Suitable solvents include e.g. xylene, n-butanol, 1 ,4-dioxane.

Preferred embodiments are, for example, the following:

i) reaction of (II) and (HI) in xylene at 140°C for 20 to 120 hours, or

ii) reaction of (II) and (ill) in n-butanol at 110°C for 20 to 50 hours.

Synthesis of the acid hydrazides of general formula (II) can be carried out in various ways ( Scheme 2):

In step a) of Scheme 2, the carboxylic acid esters of general formula (IV) are reacted with hydrazine hydrate in a suitable alcohol at the boiling point of the solvent to obtain the acid hydrazides of general formula (II) or, in step c), the carboxylic acids of general formula (V) is reacted with fe/f-butyl-carbazate and the protecting group of the protected carboxylic acid hydrazide derivative of general formula (VI) is removed with a suitable acid (step d)).

Preferred embodiments are, for example, the following:

step a) methanol or ethanol, hydrazine hydrate, reflux temperature, 4 to 50 hours; step b) methanol, thionyl chloride, 0 to 25°C, 4 to 24 hours; step c) ferf-butyl-carbazate, /V, V~dimefbylformam!de, A/,/V-di!sopropy!etby!am!ne, A/~(3~ dimethy!aminopropyl)-/V-ethylcarbodiimide hydrochloride, 1- hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours;

step d) hydrogen chloride in ethyl acetate, room temperature, 4 to 20 hours.

The carboxylic acid esters of general formula (IV) and the carboxylic acids of general formula (V) are either commercially available or can be prepared according to the methods described in the Examples.

The key intermediate benzazepine-thione derivative of genera! formula (i !!-a) - wherein R 1 is as defined above for general formula (I) - can be prepared according to the procedure shown in Scheme 3:

(lll-a) (X)

Scheme 3

The acid derivative of general formula (VII) - wherein R 1 is as defined above for genera! formula (I) - is esterified (step a)) to give the ester derivative of genera! formula (VI! I) from which oxime derivative of genera! formula (IX) is prepared (step b)). The oxime of genera! formula (IX) is converted by Beckmann rearrangement to the benzazepine compound of genera! formula (X) (step c)) from which the benzazepine-thione derivative of general formula (lll-a) Is prepared (step d)).

Preferred embodiments are, for example, the following:

step a) methanol, concentrated sulfuric acid, reflux temperature, 4 to 20 hours;

step b) methanol, sodium acetate, hydroxy!amine hydrochloride, reflux temperature, 2 to 6 hours;

step c) polyphosphoric acid, 100 to 120°C, 15 to 60 minutes;

step d) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 6 to 20 hours; Further intermediates shown in Scheme 4 to 6 can be prepared from the benzazepine derivative of general formula (X) - wherein R 1 is as defined above for genera! formula (I).

Scheme 4

In step a) of Scheme 4, the acetyl derivative of genera! formula (XI) can be obtained either in one step or in three consecutive steps. The compound of genera! formula (X!) is a key intermediate, from which the dioxo!ane compound of genera! formula (XII) (step b)), the dif!uoro derivative of general formula (XI! !) (step c)), the protected compound of general formula (XIV) (step d)) - wherein PG 1 is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), preferably 4-methoxybenzyl group - and the hydroxy compound of general formula (XV-a) (step e-1)) can be prepared. The hydroxy derivative of genera! formula (XV) is prepared by reduction of the compound of genera! formula (XIV) (step e-2)), from which the monof!uoro compound of general formula (XVI) can be prepared (step f)). Following removal of the protecting group from the latter, the compound of general formula (XVII) is obtained (step g)). The unprotected hydroxy derivative of general formula (XV-a) can be converted to the compound of general formula (X!X) (step h)) by protecting the free hydroxy group - wherein PG 2 is a protecting group different from PG 1 (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 2 Protection for the Hydroxyl Group, Including 1 ,2- and 1 ,3-Dio!s, pages 17-471), preferably a siiyi protecting group. Preferred embodiments are, for example, the following:

step a) methyl lithium solution, tetrahydrofuran, diethyl ether, (~1Q°C) to 5°C, 2 to 3 hours or

step i) aqueous sodium hydroxide solution, methanol, room temperature 0.5-3 hours, then

step ii) N-methoxymethanamine hydrochloride, /V-(3-dimethylaminopropyl)-A/'- ethylcarbodiimide hydrochloride, L/,/V-dimeihyiformamide, N,N- diisopropylethylamine or thethylamine, 1-hydroxybenzotriazole hydrate, room temperature, 2 to 20 hours, then

step iii) methylmagnesium bromide solution in diethyl ether, tetrahydrofuran, (~10°C) to 0°C, 2 to 12 hours;

step b) ethylene glycol, p-toiuenesuifonic acid, toluene, reflux temperature, 6 to 12 hours;

step c) and f) diethylaminosulfur trifiuoride, dichloro ethane; (-78) to 10°C, 4 to 12 hours;

step d) 4-methoxybenzylchloride, sodium hydride, A ,A/-dimethylformamide, 0 to 25°C, 3 to 6 hours;

step e-1) and e-2) sodium borohydride, ethanol or methanol, room temperature, 0.5 to 2 hours;

step g) i) ammonium cerium nitrate, water, acetonitrile, 0 to 25°C, 6 to 18 hours, or ii) trif!uoroacetic acid, dichloromethane, room temperature, 12 to 24 hours, or iii) trifluoromethanesulfonic acid, dichloromethane, room temperature, 2 to 12 hours;

step h) fe/f-butyldimethylsilyl trifluoromethanesulfonate, 2,6-lutidine, dichloromethane, A/,A/-dimethylformamide, 0 to 25°C, 6 to 18 hours.

The alcohol derivative of general formula (XV) is provided with a protecting group (step a) of Scheme 5) - wherein PG 1 is a protecting group, preferably 4-methoxybenzyl, PG 2 is a protecting group other than PG 1 (Peter G. M Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 2 Protection for the Hydroxyl Group, Including 1 ,2- and 1 ,3-Diols, pages 17-471), preferably a silyl protecting group - to obtain the compound of general formula (XVIII). The protecting group PG 1 is removed from the latter (step b)) to obtain the compound of general formula (XIX). The compound of general formula (XX) - wherein alkyl represents a C h alky! group - can be prepared by the alkylation of the hydroxy compound of general formula (XV) (step c)) and then the compound of general formula (XXI) can be prepared by removing the PG 1 protecting group from the latter.

Preferred embodiments are, for example, the following:

step a) trimethyichlorosiiane, imidazole, N, AZ-dimethylformamide, room temperature, 4 to 12 hours;

step b) and d) i) ammonium cerium nitrate, water, acetonitrile, 0 to 25°C, 6 to 18 hours, or

ii) trlfluoroacetic acid, dichloromethane, room temperature, 12 to 24 hours, or

Hi) trifluoromethanesulfonic acid, dichloromethane, room temperature, 2 to 12 hours;

step c) i) sodium hydride, alkyl halide, A/,A/-dimethylformamide, 0 to 100°C, 12 to 48 hours, or

ii) sodium hydride, diaikyi sulfonate, A/,/V-dimethylformamide, 0 to 100°C, 12 to 48 hours, or

Hi) silver oxide, alkyl halide, A/,/V-dimethylformamide, room temperature, 48 to 120 hours.

As shown in Scheme 6, the nitrogen atom of the benzazepine derivative of general formula (X) is protected by a protecting group (step a)) to obtain the protected benzazepine derivative of general formula (XXII) - wherein PG 1 is a protecting group ((Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), preferably 4-methoxybenzyl - followed by reduction of the ester group (step b)) to obtain the hydroxy compound of general formula (XXIII) The compound of general formula (XXV) - wherein alkyl represents a C h alky! group - is prepared from the latter by alkylation (step c)) - following removal of protecting group PG 1 (step d)) to obtain the compound of general formula (XXIV) The benzazepine-thlone derivative of general formula (I! l-b) is prepared in step e).

Preferred embodiments are, for example, the following:

step a) 4-methoxybenzyl chloride, sodium hydride, A/,A/-dimethylformamide, 0 to 25°C, 3 to 6 hours;

step b) lithium aluminum hydride, tetrahydrofuran, (-20) to 0°C, 0 1 to 1 hour;

step c) i) sodium hydride, alkyl halide, L/,/V-dimethyiformamide, 0 to 100°C, 12 to 48 hours, or

Si) sodium hydride, dialkyl sulfonate, A ,A/~dimethylformamide, 0 to 100°C, 12 to 48 hours, or

Sis) silver oxide, alkyl halide, A/,A/-dimethylformamide, room temperature, 48 to 120 hours;

step d) i) ammonium cerium nitrate, water, acetonitrile, 0 to 25°C, 8 to 18 hours, or ii) trifiuoroacetic acid, dich!oromethane, room temperature, 12 to 24 hours, or US) trifluoromethanesulfonic acid, dichioromethane, room temperature, 2 to 12 hours;

step e) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 8 to 20 hours.

The compounds of genera! formula (l-b) can be prepared by reacting the compounds of general formula (II) with the compounds of genera! formula (ll!-a) ( Scheme 7)

Scheme 7

- wherein ring B, Y, R ! are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

Preferred embodiments are, for example, the following:

i) reaction of (II) and (I I i-a) in xylene at 140°C for 20 to 120 hours, or

ii) reaction of (II) and (I I l-a) in n-butanol at 110°C for 20 to 50 hours, or

Hi) reaction of (II) and (I I l-a) in 1 ,4-dioxane at 110°C for 20 to 50 hours. The thus obtained compounds of general formula (i-b) if desired can also be converted to another compound of the general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the preparation of the enantiomers from the racemic mixtures. This is illustrated in detail in Scheme 8 and 9:

The compounds of general formula (l-c) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloaikyi or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - can be prepared by hydrolysis (step a)) of the compounds of general formula (l-b) then the acid amides of formula (l-d) (step b)) or of formula (l-g) (step e)) - wherein ring B, Y, R 1 is as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocyde containing 1 N, wherein ring A is attached via the ring nitrogen to Y, R’ represents a hydrogen, R” represents a Ci-4aikly or Gy 2 group, or R’ and R” taken together with the N to which they are attached form a heterocyde - can be obtained from the compound of general formula (I- c). The nitriles of general formula ( e) can be prepared from the acid amides of general formula (l-d) (step c)) from which the tetrazoles of general formula (i-f) are obtained (step d)). The oxadiazole derivatives of general formula (l-h) can also be prepared from the acids of general formula (i-c) (step f)).

Preferred embodiments are, for example, the following:

step a) methanol, sodium hydroxide, room temperature, 1 to 20 hours;

step b) ammonium chloride, A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride, A/,A/~dimethy!formam!de, A/,A/-diisopropylethylamine or triethylamine, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours; step c) pyridine, phosphorous oxychloride, room temperature, 2 to 20 hours;

step d) sodium azide, ammonium chloride, A/,A/-dimethylformamide, 100 to 130°C, 2 to 8 hours;

step e) /) the appropriate amine derivative, /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide hydrochloride, V,/V-dimethyiformamide, N,N- diisopropyiethylam!ne or triethylamine, 1-hydroxybenzotriazoie hydrate, room temperature, 4 to 20 hours or

//) oxalyl chloride, dichloromethane, room temperature 0 5 to 2 hours, then pyridine and the appropriate amine derivative, room temperature 1 to 5 hours; step f) A/-(3~dimethy!aminopropyl)-A -ethyicarbodiimide hydrochloride, N,N- dimethylformamide, 1-hydroxybenzotriazole hydrate, A/~hydroxyacetamide, 80 to 120°C, 4 to 20 hours.

In addition, hydroxymethyl derivatives of general formula (i-i) can be prepared by reduction of compounds of general formula (l-b) (step a) of Scheme 9}

Scheme 9

- wherein ring B, Y, R 1 are as defined above for genera! formula (i), ring A is a cycioa!ky! or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

The compounds of genera! formula (l-i) if desired can a!so be converted to another compound of the genera! formu!a (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the preparation of the enantiomers from the racemic mixtures. For example, by catalytic hydrogenation, compounds may be prepared wherein R 1 is a hydrogen atom (not shown in Scheme). Further derivatives can be prepared by alkylation or acylation to obtain the compounds of genera! formula (l-j) (step b)) - wherein ring B, Y, R 1 is as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycie containing 1 N, wherein ring A is attached via the ring nitrogen to Y and R is a!ky! or acyl group.

From the compounds of general formula (!-k) obtained by the methanesu!fony!ation of the compounds of general formula (l-i) (step c)) the nitrile derivatives of general formula (!-i) (step d)), the fluoro compounds of general formula (!-m) (step e)) and the amine derivatives of genera! formula (l-n) (step f)) ~ wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocyde containing 1 N, wherein ring A is attached via the ring nitrogen to Y, R 10 and R 11 is an optionally substituted C^alkyl as defined above for general formula (I); or R 10 and R 11 taken together with the N to which they are attached form an optionally substituted heterocycle - can also be prepared. When OR represents a carbamate in genera! formula (l-j), the compounds can be prepared from the compounds of general formula (l-k) according to step g)·

Preferred embodiments are, for example, the following:

step a) dichloromethane, diethyl ether, lithium aluminium hydride, (-30) to (-10)°C, 15 to 60 minutes;

step b) i) sodium hydride, alkyl halide, /\/,/V-dimethylformamide or tetrahydrofuran, (-5) to 40°C, 2 to 10 hours, or

Si) sodium hydride, acetonitrile, isocyanate derivative, room temperature, 4 to 20 hours, or

Hi) acyl chloride, pyridine, room temperature, 4 to 20 hours, or

iv) acyl chloride, dichloromethane, triethylamine or A/,A/-diisopropylethylamine, room temperature, 4 to 20 hours, or

v) acid anhydride, pyridine, room temperature, 4 to 20 hours, or

vi) acid, A/,A/,/V',/V'-tetramethyl-0-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, A/,A/-dimethylformamide, A/,A-diisopropylethylamine, room temperature, 4 to 20 hours, or

vii) acid, A/-(3-dimethylaminopropyl)-/V'-ethylcarbodiimide hydrochloride, N,N- diisopropylethylamine, /V,A/-dimethylformamide, 1-hydroxybenzotriazo!e hydrate, room temperature, 4 to 20 hours;

step c) methanesuifonyi chloride, dichloromethane, triethylamine 4~ dimethy!aminopyridine, room temperature, 2 to 20 hours;

step d) sodium cyanide, A/,A/-dimethyiformamide, 70 to 100°C, 3 to 20 hours;

step e) tetrabutylammonium fluoride, tetrahydrofuran, 50 to 70°C, 4 to 20 hours;

step f) amine, A/,A/-dimethylformamide, A/,A/-diisopropylethyiamine, 80 to 120°C, 3 to 20 hours;

step g) secondary amine, A/,A/-dimethy!formamide, triethylamine, cesium carbonate, 100°C, 12 to 48 hours.

Further derivatives shown in Scheme 10 can be prepared from the compounds of general formula (!-k).

Step a) yields the azide compound of general formula (l-o) - wherein ring B, Y, R 1 are as defined above for general formula (l), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - from which the amine derivatives of general formula (l-p) can be prepared by reduction (step b)). The amine derivatives of general formula (l-p) are the starting materials of the alkyl compounds of general formula (l-q) (step c)) and the acyl compounds of general formula (I- r) (step d)) - wherein ring B, Y, R 1 are as defined above for formula (l), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y, R”’ represents an optionally substituted Ci -4 alkyl or Cy 3 as defined above for R 10 and R 11 in general formula (I), and acyl is C(G)R 13 as defined above for R 10 and R 11 in general formula (I). Compounds of general formula (l-n) wherein R 10 and R 11 are optionally substituted C h alky! can also be prepared from compounds of general formula (I- p) according to step e).

Preferred embodiments are, for example, the following:

step a) sodium azide, A/,A/-dimethylformamide, 60 to 100°C, 2 to 8 hours;

step b) triphenyiphosphine, tetrahydrofuran, water, room temperature, 4 to 20 hours; step c) i) sodium hydride, alkyl halide, /V, V~dimethylformamide or tetrahydrofuran, (-5) to 40°C, 2 to 10 hours, or

Si) ketone, 1 ,2-dichioroethane, acetic acid, sodium triacetoxyborohydride, room temperature, 4 to 20 hours;

step d) S) acyl chloride, pyridine, room temperature, 4 to 20 hours, or

ii) acyl chloride, dlchloromethane, triethyiamine or /V,A -diisopropylethylamine, room temperature, 4 to 20 hours, or

Hi) acid anhydride, pyridine, room temperature, 4 to 20 hours, or iv) acid, A/,A/,A/',A/-tetramethyl-0-(1H-benzctriazcl-1-yl)uroniunn bexaf!uoropbosphate, /V,/V~dimethylformamide, A/ ^ /V-diisopropylethylamine, room temperature, 4 to 20 hours, or

v) acid, A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride, N,N- diisopropyiethyiamine, A/./V-dirnethylformamide, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours;

step e) aldehyde, 1 ,2-dichloroethane, acetic acid, sodium triacetoxyborobydride, room temperature, 4 to 20 hours.

According to Scheme 11 the methoxybenzazepine derivative of general formula (XXV!) - wherein R 1 is as defined above for general formula (I) - is prepared with methylation (step a)) of the compound of general formula (X!l), and the latter is further reacted without isolation with an acid hydrazide of general formula (II) (step b)) to give the compound of general formula (l-s) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloaikyi or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via a ring nitrogen to Y After removing the ketal protecting group (step c)), the oxo compound of general formula (l-t) is obtained - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalky! or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via a ring nitrogen to Y. Reduction of the compound of general formula (l-t) yields the hydroxy compounds of general formula (l-u) (step d)). Compounds of genera! formula (l-u) can be oxidized with an appropriate oxidizing agent (step e)) to yield compounds of general formula (l-t), while compounds of general formula (l-t) can be further reacted to obtain amine derivatives of genera! formula (!~aa) - wherein the meaning of R is C h alky! group optionally substituted with an aikoxy group.

Preferred embodiments are, for example, the following:

step a) dichioromethane, trifluoroacetic acid or potassium carbonate, trimethyloxonium tetrafluoroborate, room temperature, 20 to 25 hours;

step b) acid hydrazide of general formula (II), dichioromethane or acetonitrile, 50°C, 6 to 20 hours;

step c) methanol, concentrated hydrochloric acid, 70°C, 2 to 8 hours;

step d) sodium borohydride, ethanol or methanol, room temperature, 1 to 2 hours step e) Dess-Martin periodinane, dichioromethane, 0°C to room temperature, 1 to 5 hours;

step f) appropriate amine, 1 ,2-dichloroethane, sodium triacetoxyborohydride, acetic acid, room temperature, 4 to 20 hours.

The compounds of general formula (l-j) wherein alkyl represents a Ci^alkyl group and ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y can be prepared by reacting a compound of formula (II) with a compound of general formula (I !l-b) ( Scheme 12)

Preferred embodiments are, for example, the following:

i) reaction of (II) and (lli-b) in xylene at 140°C for 20 to 120 hours, or

Si) reaction of (II) and (lll-b) in n-butanol at 110°C for 20 to 50 hours, or

Hi) reaction of (II) and (lll-b) in 1 ,4-dioxane at 110°C for 20 to 50 hours.

The benzazepine-thione derivative of general formula (l!!-c) is prepared from the difluoro derivative of general formula (XIII) (step a) of Scheme 13) - wherein R 1 is as defined above for general formula (I) - and the latter is reacted with an acid hydrazide of general formula (II) (step b)) to obtain the compound of general formula (i-v) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

Preferred embodiments are, for example, the following:

step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 8 to 20 hours;

step b) i) reaction of (II) and (lli-c) in xylene at 140°C for 20 to 120 hours, or

ii) reaction of (II) and (ll!~c) in n-butanol at 110°C for 20 to 50 hours, or Hi) reaction of (II) and (!i!-c) in 1 ,4-dioxane at 110°C for 20 to 50 hours.

The benzazepine-thione derivative of general formula (! I i-d) - wherein R is as defined above for general formula (I) - is prepared from the monofiuoro derivative of general formula (XVI I) (step a) of Scheme 14) and the latter is reacted with an acid hydrazide of general formula (II) (step b) to obtain the compound of general formula (!~w) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalky! or a 4- to 7-membered saturated heferocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

Preferred embodiments are, for example, the following:

step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 8 to 20 hours;

step b) i) reaction of (II) and (i!l-d) in xylene at 140°C for 20 to 120 hours, or

ii) reaction of (II) and (lii-d) in n-butanol at 110°C for 20 to 50 hours, or Hi) reaction of (II) and (!!l-d) in 1 ,4-dioxane at 110°C for 20 to 50 hours.

The benzazepine-thione derivative of genera! formula (!i!-e) - wherein R 1 is as defined above for general formula (i), PG 1 is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 2 Protection for the Hydroxyl Group, Including 1 ,2- and 1 ,3-Dio!s, pages 17-471), preferably a silyl protecting group - is prepared from the protected hydroxy compound of general formula (XIX) (step a) of Scheme 15) and the latter is reacted with an acid hydrazide of general formula (II) (step b) to obtain the compound of general formula (l-x) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalkyl or a 4~ to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

The protecting group of the compound of general formula (l-x) is removed thus the hydroxy derivatives of general formula (l-u) can also be prepared by this synthesis route.

Preferred embodiments are, for example, the following:

step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 6 to 20 hours;

step b) i) reaction of (II) and (lll-e) in xylene at 140°C for 20 to 120 hours, or

ii) reaction of (II) and (lll-e) in n-butanol at 110°C for 20 to 50 hours, or Hi) reaction of (II) and (lll-e) in 1 ,4-dioxane at 1 10°C for 20 to 50 hours; step c) tetrabutyiammonium fluoride, tetrahydrofuran, room temperature, 3 to 10 hours.

The benzazepine-thione derivative of general formula (ll!-f) - wherein R 1 is as defined above for general formula (I) and alkyl represents a C h alky! group - is prepared from the alkyl derivative of general formula (XXI) (step a) of Scheme 16) and the latter is reacted with an acid hydrazide of general formula (II) (step b) to obtain the compound of general formula (l-y) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a eycioa!ky! or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.

Preferred embodiments are, for example, the following:

step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 8 to 20 hours;

step b) i) reaction of (II) and (ill-f) in xylene at 140°C for 20 to 120 hours, or

Si) reaction of (II) and (lll-f) in n-bufanol at 1 10°C for 20 to 50 hours, or

Hi) reaction of (II) and (!l!-f) in 1 ,4-dioxane at 1 10°C for 20 to 50 hours.

In so far as, in the compound of general formula (I), R 2 is a C h alky! group, R 3 is a C(0)R s group, R 5 is Ci-4alkoxy group and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y, the compounds of general formula (I) of the present invention are prepared by reacting the compounds of general formula (II)

- wherein ring B and Y are as defined above for general formula (I), ring A is a eyc!oalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - and the compounds of general formula (XXVil)

- wherein R 1 is as defined above for general formula (I), R 2 is a Ci-4alkyl group, R 3 is a C(0)R 5 group and R 5 is Ci-4alkoxy group.

The procedure is described in detail in Scheme 17:

Preferred embodiments of step a) of Scheme 17 are, for example, the following:

i) xylene, 140°C, 20 to 120 hours, or ii) n-butano!, 110°C, 20 to 50 hours, or

Hi) 1 ,4 dioxane, 110°C, 20 to 50 hours.

The key intermediate for the synthesis of the benzazepine-thione derivative of genera! formuia (XXVII) may be prepared by one of the following syntheses:

Method A (Scheme 18):

The ketone group of the compound of general formula (VIII) is protected by a dioxolane ring (step a)), and the resulting compound of general formula (XXVIII) is alkylated (step b)) to obtain the compound of general formula (XXIX) - wherein R 1 is as defined above for general formula (!) and R 2 is a C h alky! group. The latter is deprotected (step c)) and from the resulting derivative of general formula (XXX) the oxime compound of general formula (XXXI) is prepared (step d)). The oxime of general formula (XXXI) is converted by Beckmann rearrangement to the benzazepine compound of genera! formula (XXXII) (step e)).

Scheme 18

Preferred embodiments are, for example, the following:

step a) ethylene glycol, toluene, p-toluenesulfonic add, reflux temperature, 2 to 12 hours;

step b) lithium diisopropylamide, alkyl iodide, tetrahydrofuran, (~78)°C, 0.5 to 2 hours; step c) i) methanol, concentrated hydrochloric acid, 70°C, 2 to 6 hours, or

ii) aqueous acetic acid, 110°C, 5 to 20 hours;

step d) methanol, sodium acetate, hydroxylamine hydrochloride, reflux temperature, 3 to 6 hours;

step e) poiyphosphoric acid, 100 to 120°C, 15 to 60 minutes. Method B (Scheme 19):

The protected benzazepine derivative (XXil) - wherein R 1 is as defined above for formula (I) and PG 1 is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895- 1193), preferably 4-metboxybenzyl group - is alkylated (step a)) and then the compound of formula (XXXIII) is deprotected (step b)) to obtain the compound of formula (XXXII).

Scheme 19

Preferred embodiments are, for example, the following:

step a) i) sodium hydride, A/,A/-dimethylformamide, alkyl iodide, O to 100°C, 1 to 12 hours, or

ii) lithium diisopropylamide, alkyl iodide, tetrahydrofuran, (-78)°C, 0.5 to 2 hours; step b) i) ammonium cerium nitrate, water, acetonitrile, 0 to 25°C, 8 to 18 hours, or ii) trifluoroacetic acid, dichioromethane, room temperature, 12 to 24 hours, or iii) trifluoromethanesulfonic acid, dichioromethane, room temperature, 2 to 12 hours.

Method C (Scheme 20):

The compound of general formula (XXXV) ~ wherein R 1 is as defined above for general formula (!) and R 2 is a C h alky! group - is prepared from the compound of general formula (XXXIV) (step a)) and the resulting compound of general formula (XXXV) is hydrolyzed (step b)) to obtain the compound of general formula (XXXVI). The latter is ring- closed (step c)) and the resulting compound of genera! formula (XXXVI I) is esterified (step d)). The resulting compound of general formula (XXX) is converted to the compounds of general formula (XXXII) by the steps of Scheme 18.

Preferred embodiments are, for example, the following:

step a) lithium diisopropyiamide, tetrahydrofuran, bromoacetic add tert-butyl ester, 0 to 20°C, 3 to 6 hours;

step b) methanol, sodium hydroxide, room temperature, 3 to 6 hours;

step c) sulphuric add, room temperature, 0 5 to 1 5 hours;

step d) thionyl chloride, methanol, 80°C, 8 to 8 hours.

The amine derivatives of general formula (XXXIV) are either commercially available or can be prepared according to the methods described in the Examples

The benzazepine-thione derivative of general formula (XXVI I -a) is prepared from the key intermediate of general formula (XXXII) (step a) of Scheme 21) and the latter is reacted with the add hydrazide of formula (II) to obtain the compounds of general formula (l-z) (step b)) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloaikyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y and R 2 is a C h alky! group. The compounds of general formula (l-z) can also be synthesized from the compound of general formula (XL-a) (step d)) and the latter can be obtained from the compound of general formula (XXVI l-a) by methylation (step c)).

Preferred embodiments are, for example, the following:

step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 6 to 20 hours;

step b) i) reaction of (II) and (XXVI l-a) In xylene at 140°C for 20 to 120 hours, or

ii) reaction of (II) and (XXVI l-a) in n-butanol at 110°C for 20 to 50 hours, or Hi) reaction of (II) and (XXVil-a) in 1,4-dioxane at 110°C for 20 to 50 hours; step c) iodometbane, potassium carbonate, acetone, room temperature, 4 to 24 hours; step d) i) reaction of (II) and (XXVI l)-a) in xylene in the presence of catalytic hydrogen chloride at 140°C for 4 to 20 hours, or

ii) reaction of (II) and (XXVII-a) in 1 ,4-dioxane in the presence of catalytic hydrogen chloride at 110°C for 4 to 20 hours.

The compounds of general formula (l-z) - in a manner similar to the compounds of general formulae (l-b) or (l-i) ~ if desired can also be converted to another compound of the general formula (!) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the preparation of the enantiomers from the racemic mixtures, for example with any of the methods shown in Scheme 8 to 10.

In so far as, in the compound of general formula (I), R 2 is a hydrogen, R 3 is a

C(0)NH 2 group, and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H- [1 ,2,4]triazo!o[4,3-a][1]benzazepine core, the compounds of general formula (I) of the present invention are prepared by reacting the compounds of general formula (XXXVIII)

(XXXV I !!)

- wherein ring B and Y are as defined above for genera! formula (!), ring A is a 4- to 7- membered saturated heterocycie containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core - and the compounds of genera! formula (XXX!X)

- wherein R 1 is as defined above for general formula (!), R 2 is a hydrogen and R 3 is C(0)NH 2 group.

The procedure is illustrated in detail in Scheme 22:

Preferred embodiments of step a) of Scheme 22 are, for example, the following:

i) melt (without solvent), 120 to 150°C, 3 to 72 hours, or

ii) sulfolane, 140 to 180°C, 3 to 72 hours.

The amine derivatives of general formula (XXXVIII) are either commercially available or can be prepared according to the methods described in the Examples. The triazolo-benzazepine derivatives of general formula (XXXIX) - wherein R 1 is as defined above for general formula (I) - can be prepared by the procedure of Scheme 23:

The compounds of general formula (lll-a) are methylated (step a)) and the resulting compound of general formula (XL-b) is reacted with formyl hydrazine (step b)) to obtain the compounds of general formula (XLI) - wherein R 1 is as defined above for general formula (I) The latter is brominated (step c)) to obtain the bromo derivative of general formula (XLI!) - wherein R 1 is as defined above for general formula (I). From the resulting bromo derivative of general formula (XLI I) the compounds of general formula (XLI! I) is prepared by hydrolysis (step d)) and then the acid amide of general formula (XXXIX) is formed in step e). From the acid amide of general formula (XXXIX) the nitril derivative of general formula (LI I) can also be synthesized (step f)) and the latter can be reacted with the compounds of general formula (XXXVI 11)

(XXXVII!)

- wherein ring B and Y are as defined above for general formula (I), ring A is a 4- to 7~ membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core - to yield the compounds of general formula (l-ac).

Preferred embodiments are, for example, the following:

step a) iodomethane, potassium carbonate, acetone, room temperature, 4 to 24 hours; step b) formyihydrazine, 1 ,4-dioxane, 90°C, 3 to 10 hours;

step c) A/-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 60 minutes;

step d) methanol, sodium hydroxide, room temperature, 1 to 20 hours; step e) ammonium chloride, A/~(3~dimethylaminopropyi)-A '-ethyicarbodiimide hydrochloride, A/,A/-dimethylformamide, A/,A/-diisopropylethyla ine or triethylamine, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours step f) trifiuoroacetic anhydride, dichloromethane, triethylamine, 0°C to room temperature, 1 to 5 hours;

step g) i) melt (without solvent), 120 to 150°C, 3 to 72 hours, or

si) sulfolane, 140 to 180°C, 3 to 72 hours.

The compounds of general formula (l-aa) prepared according to Scheme 22 if desired can also be converted to another compound of the general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the preparation of the enantiomers from the racemic mixtures, for example using steps c) and d) shown in Scheme 8.

The compounds of general formula (I), wherein R 1 is as defined above for general formula (I), R 2 is a hydrogen or Ci^alkyl, R 3 is a Ci. 4 alkyl group, or R 2 and R 3 jointly represent -(CH 2 )p-0-(CH 2 )q- or-(CH 2 )r group (p is 1 , 2 or 3; q is 1 , 2 or 3; r Is 4, 5 or 6) can be prepared by the procedures described in detail in Scheme 24:

(!-ad)

Scheme 24 Diethyl malonate derivative of general formula (XLIV) - wherein R 2 is a hydrogen or Ci_4aikyi, R 3 is a Chalky! group, or R 2 and R 3 jointly represent -(CH2) P -0-(CH2)q- or -CCHzjr group (p is 1 , 2 or 3; q is 1 , 2 or 3; r is 4, 5 or 6) - is converted by Grignard reaction (step a)) to the benzyl derivative of general formula (XLV), wherein R 1 represents either a hydrogen or fluorine. The free acid of general formula (XLVi) is prepared by hydrolysis of compound of genera! formula (XLV) under basic conditions (step b)). Decarboxylation (step c)) of compound of genera! formula (XLVi) yields compound of general formula (XLVi I), from which compound of general formula (XLVI 11) is prepared by treatment with concentrated sulfuric acid (step d)). Oxime derivative of general formula (XLIX) is then prepared (step e)) from compound of general formula (XLVI 11), which is converted by Beckmann rearrangement (step fj) to the benzazepine compound of general formula (L). In case R 3 is a hydrogen, compound of general formula (L) is chlorinated or brominated (step g)) to obtain the compound of genera! formula (LI) Compound of general formulae (LI) or (L) are converted to compound of general formula (l-ad) (step h)), wherein R 1 as defined above for genera! formula (I), R 2 is a hydrogen or Ci- 4 alkyl, R 3 is a Ci -4 alkyl group, or R 2 and R 3 jointly represent -(CHsj p -O- (CH2) q - or -(Ch )r group (p is 1 , 2 or 3; q is 1 , 2 or 3; r is 4, 5 or 6), ring B and Y are as defined above for general formula (!) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y

Preferred embodiments of the synthesis of Scheme 24 are, for example, the following: step a) benzylmagnesium chloride or 3-fluorobenzy!magnesium chloride, diethyl ether, room temperature, 2 to 12 hours;

step b) 2 M aqueous sodium hydroxide, ethanol, reflux temperature, 2 hours;

step c) heating at 180-200°C, 3-5 minutes;

step d) sulfuric acid, 35 to 40°C, 80 minutes

step e) methanol, sodium acetate, hydroxy!amine hydrochloride, reflux temperature, 2 to 6 hours;

step f) poiyphosphoric acid, 100 to 120°C, 15 to 60 minutes;

step g) bromine, acetic acid/water, room temperature, 30 to 90 minutes or N- chlorosuccimide, D F, room temperature, 30 to 90 minutes

step h) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours,

//) iodomethane, potassium carbonate, acetone, 40°C 1 to 3 hours,

Hi) acid hydrazide of formula (II), few drops of concentrated hydrochloric acid, 1 ,4-dioxane, reflux, 1 to 3 hours

or i) trimethyloxonium tetrafiuoroborate, trifluoroacetic acid or potassium carbonate, dieh!oromethane, room temperature, 2 to 4 hours;

//) acid hydrazide of formula (II), few drops of trifluoroacetic acid, 1 ,4-dioxane or acetonitrile, reflux, 1 to 8 hours.

The acid hydrazides of general formula (II), wherein ring B and Y are as defined above for general formula (I) and ring A is a cycloalkyl or a 4- to 7-membered saturated heferocycie containing 1 N, wherein ring A is attached via the ring nitrogen to Y, can be synthesized in various ways as described in Scheme 2.

The compound of general formula (l-m) can also be synthesized according to the methods described in Scheme 25.

Scheme 25

A compound of general formula (X) - wherein R 1 is as defined above for general formula (!) - is reduced (step a)) and the obtained hydroxy compound of general formula (Llll) is converted to a fluorine derivative of general formula (LIV) (step b)). The compound of general formula (l- ) can be synthesized either directly from the benzazepine-thione of general formula (LV) (step e)), which is obtained from a compound of general formula (LIV) in step c), or from the methylsulfanyi derivative of general formula (LVI I) in step h). The latter can be prepared from the benzazepine-thione of general formula (LV) by methy!ation (step f)). An alternative synthetic pathway is to methylate the compound of general formula (LIV) (step d)) and reacting the obtained methoxy derivative of general formula (LVI) in situ with a compound of general formula (II) (step g) to yield compound of general formula (l-m).

Preferred embodiments of the synthesis of Scheme 25 are, for example, the following: step a) lithium aluminum hydride, diethyl ether, tetrahydrofuran, (-40) to 0°C, 0.1 to 2 hours;

step b) diethylamino sulphur trifluoride, dichloromethane; (-78) to 10°C, 4 to 12 hours; step c) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

Si) Lawesson reagent, tetrahydrofuran, room temperature, 6 to 20 hours;

step d) trimethyloxonium tetrafluoroborate, trifluoroacetic acid or potassium carbonate, dichloromethane, room temperature, 2 to 4 hours;

step e) i) reaction of acid hydrazide of formula (II) and (LV) in xylene at 140°C for 20 to 120 hours, or

Si) reaction of acid hydrazide of formula (II) and (LV) in n-butanol at 110°C for 20 to 50 hours, or

Hi) reaction of acid hydrazide of formula (II) and (LV) in 1 ,4-dioxane at 110°C for 20 to 50 hours

step f) iodomethane, potassium carbonate, acetone, room temperature, 4 to 24 hours; step g) acid hydrazide of formula (II), dichloromethane or acetonitrile, 50°C, 6 to 20 hours;

step h) reaction of acid hydrazide of formula (II) and (LVII) in 1 ,4~dioxane at 110°C for 2 to 20 hours.

The compounds of general formula (l-ad) of the present invention, wherein R 1 as defined above for general formula (I), R 2 is a hydrogen or Ci-4alkyl, R 3 is a Ci^aikyi group, or R 2 and R 3 jointly represent -(CH 2 ) P -0-(GH 2 )q- or -(CH2) r - group (p is 1 , 2 or 3; q is 1 , 2 or 3; r is 4, 5 or 6), and ring A is a 4~ to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,8-dihydro-4H- [1 ,2,4]triazo!o[4,3-a][1]benzazepine core, can be prepared according to the methods described in Scheme 26.

Scheme 26 The compound of the general formula (LI) - wherein R 1 as defined above for general formula (I), R 2 is a hydrogen or Ci^alkyl, R 3 is a C h alky! group, or R 2 and R 3 jointly represent -(CH 2 )p-0-(CH 2 )q- or -(CH2)r group (p is 1 , 2 or 3; q is 1 , 2 or 3; r is 4, 5 or 6) - is reacted with Lawesson reagent (step a}} to yield the benzazepine-thlone derivative of general formula (LVHI), which is methylated (step b)) and the obtained compound of the general formula (LIX) is reacted with formyl hydrazine (step c)) to yield the compound of the general formula (LX). The latter is brominated (step d)) to obtain the bromo derivative of general formula (LXI), which is reacted (step e)) with the compounds of general formula (XXXVIII)

(XXXVIII)

- wherein ring B and Y are as defined above for general formula (I), ring A is a 4- to 7~ membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core - to yield the compounds of general formula (l-ae).

Preferred embodiments of the synthesis of Scheme 26 are, for example, the following: step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or

ii) Lawesson reagent, tetrahydrofuran, room temperature, 8 to 20 hours;

step b) iodomethane, potassium carbonate, acetone, room temperature, 4 to 24 hours; step c) formylhydrazine, 1 ,4-dioxane, 90°C, 3 to 10 hours;

step d) A/-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 80 minutes;

step e) i) melt (without solvent), 120 to 150°C, 3 to 72 hours, or

ii) sulfolane, 140 to 180°C, 3 to 72 hours.

The reagents and detailed process steps required for the above reactions are set forth in the Examples.

An aspect of the present invention is novel intermediates represented by the general formulae (lli-a), (X), (XL! I), (LI) and (LIV) synthesised in the process for preparing the compound of formula (I) wherein R 1 is as defined above for general formula (I), especially methyl 7-chloro-2-oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine-4-carboxylate (Intermediate 3), methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1 H-1-benzazepine-4-carboxylate (Intermediate 4), methyl 1-bromo-8-chloro-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5- carboxyiate (Intermediate 24), 7~chioro-4-(fiuoromethyl)-1 ,3,4,5~tetrahydro-2H~1~ benzazepin-2-one (Intermediate 36) or wherein R 2 and R 3 jointly represent -(CHaj p -O- (CHajq- or -(CHsjr- group (p is 1 , 2 or 3; q is 1 , 2 or 3; r is 4, 5 or 8). The activity data of each of the compounds of genera! formula (I) of the present invention are determined in vitro and in vivo by the methods described below.

Human vasopressin Via receptor binding assay

Ceils and radioligand

The immortalized 1321 N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutive!y and stably expressing human vasopressin Via receptor and vasopressin (8-L-Arginine), [Phenyialanyl-3,4,5- 3 H(N)] labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.

Membrane-preparation: Membrane preparation of immortalized 1321 N1 cells expressing the propagated human Vasopressin Via receptor was made according to Jarvis's method (Jarvis ei al., J Pharmacol Exp Ther 2004, 310:407-16). Cells were suspended in preparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized with glass homogenizing potter. To separate the raw membrane fraction two consecutive centrifugation procedures (40,000 g for 20 minutes at 4°C) were executed, then the membrane was taken into the preparatory buffer during a final washing step, it was divided into aliquots which were stored at -80°C until the time of measurement.

The protein content of the prepared membrane was determined according to Lowry’s method using standard dilution line of bovine serum albumin (BSA) (Lowry et al., JBioi Chem 1951 , 193:265-75).

Receptor binding test: In the receptor binding assay, the substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each concentration. To determine the final affinity value, the results of at least two independent experiments were taken info account. The assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane preparation of 1321 N1 cells expressing the human Vasopressin Via receptor (167 pg/m!) and Vasopressin (8-L-Arginine), [Phenyialanyl-3,4,5- 3 H(N)j as radioligand (1 nM).

Non-specific binding values were determined in the presence of unlabelled 1.2x1 O 6 M (Arg 8 )-vasopressin Samples were incubated in a total volume of 0.33 ml for 60 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% polyethyleneimine-impregnated UniFi!tert® GF/B™. After drying the filter plates, 40 mI Microscint~20 (Packard) scintillation cocktail was added to the samples. Finally, radioactivity was measured using MicroBeta 2 Microplate Counter (Perkin Elmer).

The ICso data (i.e. the concentration of the unknown substance which displaces 50% of specific bound radioligand) is calculated from the concentration-displacement cun/e using the sigmoid fitting mathematical method y = (A1-A2)/(1+(x/x 0 )p)+A2 with Origin 7.5. software (OriginLab Corporation, Northampton, USA). During fitting, the asymptotes are not fixed. The Ki values (inhibition constant) are given with Cheng-Prusoff equation K, = 1C SO /[1 +(L/K D )] wherein [L] is the radioligand concentration used in the experiment and [K D ] is the affinity of the radioactiveiy labelled ligand for the given receptor. The K D is determined beforehand using the Scatchard curve.

Functional assay to test compounds on human vasopressin Via receptor expressing cell line

Cells

The immortalized 1321 N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutiveiy and stably expressing human vasopressin Via receptor were used to measure the prepared compounds. The ordinary secondary messenger pathway of the measured GPCR receptor was used, the endogenous G q~ associated system.

Method

Using 30,000 ceils/plate, compounds were measured on 96~wel! plates. The buffer composition of the measurements was the following (expressed in mM): 140 NaCI, 5 KCi, 2 CaCh, 2 MgCh, 10 glucose, 10 HEPES (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid), 2 probenecid, pH = 7.4. FLIPR Calcium 5 kit (Molecular Devices) was used as fluorescent dye, the medium was not removed prior to filling with the dye and the cells were not washed out either before or after. The incubation was performed at room temperature, the final concentration of DMSO was 1 %. The materials to be measured were administered in 15 to 20 minutes pretreatment, at least two parallels of each compound in each concentration was measured.

Fluorescence signal was used to determine the intracellular Ca 2+ level, the reader was FlexStation II96. Cytoplasmic Ca 2+ concentrations were measured by fluorometry using the FlexStation M98 plate reader (excitation: 485 nm, emission: 525 nm). The fluorescence signal was logged in every 1.4 seconds for 1 minute. The reference compounds used were the following: (Arg 8 )-vasopressin as agonist at concentration of ECeo, determined for each plate, and relcovaptan as antagonist at 1 mM. The % of inhibition at each concentration and the ICso value of the compounds were determined where a concentration line was also measured.

The total AVP concentration-response curve was recorded on each plate. The effect of compounds measured was expressed by percentage of relative inhibition compared to control response. For the graphic representation of the data, nonlinear four parameter alignments were applied using SoftMaxPro software according to the following formula: y = A-D/(1+(x/C) A B)+D, wherein: A = 0 and D = 100 - lower / upper fixed asymptotes, y = percentage of inhibition, x = logarithm of concentrations of the tested compound, B = steepness of curve and C - IC 50 (the concentration belonging to the 50% inhibition of the control response). The average ICso values were calculated from at least three independent measurements in all cases.

Table 1 : The effectiveness of the compounds of the present invention measured in human vasopressin Via receptor binding assay and functional assay

Mouse vasopressin Via receptor binding assay

Cells and radioligand

The immortalized 1321 N1 cell line (B9/1321 N1 clone) constitutively and stably expressing mouse vasopressin Via receptor vasopressin (8-L-Arginine), [Phenylaianyi- 3,4,5- 3 H(N)j labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.

Method

Membrane-preparation: Membrane preparation of immortalized 1321 N1 cells expressing the propagated mouse Vasopressin Via receptor was made according to Jarvis's method (Jarvis ef ai., J Pharmacol Exp Ther 2004, 310:407-16). Cells were suspended in preparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized with glass homogenizing potter. To separate the raw membrane fraction two consecutive centrifugation procedures (40,000 g for 25 minutes at 4°C) were executed, then the membrane was taken into the preparatory buffer during a final washing step, it was divided into aliquots which were stored at -80°C until the time of measurement.

The protein content of the prepared membrane was determined according to Lowry’s method using standard dilution line of bovine serum albumin (BSA) (Lowry et a!., J Biol Chem 1951 , 193:265-75). Receptor binding test: In the receptor binding assay, the substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each concentration. To determine the final affinity value, the results of at least two independent experiments were taken into account. The assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane preparation of 1321 N1 cells expressing the mouse vasopressin Via receptor (152 pg/ml) and vasopressin (8-L-Arginine), [Phenyla!any!- 3,4,5- 3 H(N)] as radioligand (~ 35-50% concentration of K D ).

Non-specific binding values were determined in the presence of an unlabelied 1.2x10 6 M (Arg 8 )-vasopressin. Samples were incubated in a total volume of 0.33 ml for 80 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% poiyethyleneimine-impregnated UniFi!ter® GF/B™ After drying the filter plates, 40 m! Microscint-20 (Packard) scintillation cocktail was added to the samples. Finally, radioactivity was measured using MicroBeta 2 Microplate Counter (Perkin Elmer).

The radioligand damping ability of a substance is determined in at least two independent experiments. Specific radioligand binding can be defined as the difference between total and non-specific binding in the presence of a saturation amount of the unlabelied ligand or different concentrations of the substance to be tested. The results are given as a percentage of inhibition of the specific binding achieved in the presence of the substance to be tested.

The ICso data (i.e. the concentration of the unknown substance which displaces 50% of specific bound radioligand) is calculated from the concentration-displacement curve using the sigmoid fitting mathematical method y = (A1-A2)/(1+(x/x 0 )p)+A2 with Origin 7.5. software (OriginLab Corporation, Northampton, USA). During fitting, the asymptotes are not fixed. The Kj values (inhibition constant) are given with Cheng-Prusoff equation K, = IC SO /[1 +(L/K D )] wherein [L] is the radioligand concentration used in the experiment and [K D ] is the affinity of the radioactively labelled ligand for the given receptor. The K D is determined beforehand using the Scatchard curve.

Table 2: The binding affinity of certain compounds of the present invention measured in mouse vasopressin Via receptor binding assay

Human vasopressin V2 receptor binding assay

Ceils and radioligand

The immortalized 1321 N1 cell line (Perkin Elmer, ES-383-M400UA)(LotNo: 1765208) stably and constitutively expressing human vasopressin V2 receptor, CHO-K1 cell membrane expressing human Vasopressin V2 receptor (Perkin Elmer, 6110541400UA) and vasopressin (8-L-Arginine), [Phenylalany!~3,4,5- 3 H(N)] labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.

Method

Receptor binding test: In the receptor binding assay, the substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each concentration. To determine the final affinity value, the results of at least two independent experiments were taken into account. The assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane preparation of 1321 N1 cells expressing the human vasopressin V2 receptor (1 ,82 pg/ml) and Vasopressin (8-L-Arginine), [Pheny!aiany!- 3,4,5- 3 H(N)j as radioligand (-'concentration of KD).

Non-specific binding values were determined in the presence of an un!abel!ed 1.2x10 6 M (Arg 8 )~vasopressin. Samples were incubated in a total volume of 0.55 ml for 90 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% polyethyleneimine-impregnated UniFiiter® GF/B™. After drying the filter plates, 40 pi Microscint-20 (Packard) scintillation cocktail was added to the samples. Finally, radioactivity was measured using MicroBeta 2 Microplate Counter (Perkin Elmer).

The radioligand displacement ability of a substance is determined in at least two independent experiments. Specific radioligand binding can be defined as the difference between total and non-specific binding in the presence of a saturation amount of the uniabel!ed ligand or different concentrations of the substance to be tested. The results are given as a percentage of inhibition of the specific binding achieved in the presence of the substance to be tested.

The !Cso data (i.e. the concentration of the unknown substance which displaces 50% of specific bound radioligand) is calculated from the concentration-displacement curve using the sigmoid fitting mathematical method y = (A1-A2)/(1+(x/x 0 )p)+A2 with Origin 7.5. software (OhginLab Corporation, Northampton, USA). During fitting, the asymptotes are not fixed. The K· values (inhibition constant) are given with Cheng-Prusoff equation K· = IC SO /[1 +(L/K D )] wherein [L] is the radioligand concentration used in the experiment and [K D ] is the affinity of the radioactiveiy labelled ligand for the given receptor. The K D is determined beforehand using the Scatchard curve.

Table 3: The binding affinity of certain compounds of the present invention measured in human vasopressin V2 receptor binding assay on 1321 N1 cell line

Method

Receptor binding assays were performed in at least 8 concentrations, with two or rather three parallel samples in each concentration, in at least two independent experiments using an incubation buffer (50 mM Tris-HCi, 5 mM MgGh, pH 7.4 + 0.1% BSA), membrane preparation of CHO-K1 cells (Perkin Elmer, 6110541400UA) expressing the human vasopressin V2 receptor (7 pg/mI) and Vasopressin (8-L-Arginine), [Phenylalanyl- 3,4,5- 3 H(N)] as radioligand (-concentration of KD).

Non-specific binding values can be determined in the presence of an unlabelled 1.2 x 10- 6 M (Arg 8 )-vasopressin. Samples incubated in a total volume of 0.55 mL for 90 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a polyethyleneimine-impregnated UniFiiter® GF/B™. The filterplates were washed three times with 0.5 mL of ice-cold washing buffer (50 mM Tris-HCI, pH 7.4). After drying the filter plates, 40 m! of Microscint20 (Packard) scintillation cocktail was added to each well. Finally, radioactivity was measured using Tri-Carb 29QQTR liquid scintillation analyzer (Perkin Elmer).

The radioligand displacement ability of a substance is determined in at least two independent experiments. Specific radioligand binding can be defined as the difference between total and non-specific binding in the presence of a saturation amount of the unlabelled ligand or different concentrations of the substance to be tested. The results are given as a percentage of inhibition of the specific binding achieved in the presence of the substance to be tested.

The !Gso data (i.e the concentration of the unknown substance which displaces 50% of specific bound radioligand) is calculated from the concentration-displacement curve using the sigmoid fitting mathematical method y = (A1-A2)/(1 +(x/xo)p)+A2 with Origin 7.5. software (GhginLab Corporation, Northampton, USA). During fitting, the asymptotes are not fixed. The Kj values (inhibition constant) are given with Cheng-Prusoff equation K; = IC SO /[1 + (L/KD)] wherein [L] is the radioligand concentration used in the experiment and [KD] is the affinity of the radioactively labelled ligand for the given receptor. The KD is determined beforehand using the Scafchard curve.

Affinity data (K,) measured on the 1321 N1 cell line expressing human vasopressin V2 receptor are in very close correlation with K, results generated with CHO-K1 ceil line expressing human vasopressin V2 receptor.

Animals

Male mice (NMRI, ToxiCoop) weighing 18-40 g were used. Animals were kept at least 5 days after delivery, during housing and measurements they could feed and drink ad libitum. The experiments were permitted by the Local Animal Protection Committee and carried out in accordance with the European Animal Protection Directives (EU Directive 2010/63/Elf}.

Method

Animal behaviour as measured by an automated behavioural analysis system (LABORAS™). The sensors located below platforms detect the mechanical vibration generated by the movement of the animal, and transform into an electrical signal (Quinn et al , J Neurosci Methods 2003, 130:83-92). After analysing signals, the system analyses the time spent with the following behavioural parameters: locomotion, immobility, climbing, grooming. The grooming algorithm by definition is able to measure the scratching behavioural response. During the experiment, mice were pretreated with the test substance or vehicle, and after the pretreatment period scratching-inducing compound (s.c. 0.3 mg/kg oxytocin) was administered, and then the animals were individually placed into measuring cages. Their behaviour was observed for 1 hour. To reduce the exploratory activity, the animals were measured after a 1-hour habituation to the cage. The behavioural parameters were compared to the parallel measured parameters of the control animals.

The behavioural Inhibitory effect of the substances was calculated with average values of parallel measured vehicle treated groups and presented as the percentage of inhibition: 0% was expressed as average value of scratching behaviour of vehicle pretreated animals (and phys. saline s.c. pretreated with vehicle), while 100% was expressed as average value of scratching of vehicle pretreated animals that received oxytocin subcutaneously. For statistical analysis one-way analysis of variance (A NOVA) with Tukey post hoc test were used.

Surprisingly, it has been found that certain compounds of the present invention produced significant effect on the mouse Via receptor in vivo functional test.

Table 4: The efficacy of certain compounds of the present invention in the mouse in vivo Via functional test: the inhibition of oxytocin- induced scratching behavior response after 10 mg/kg p.o pretreatment in mice.

The present invention will be further illustrated by the following embodiments without limiting the scope of the present invention to them. From the above description part and from the examples, the person skilled in the art may ascertain the essential features of the invention and without departing from its essence and scope, may make certain changes and modifications in order to adapt the invention to various applications and conditions. As a result, the invention is not limited to the following illustrative examples, but rather to the scope determined by the appended claims.

In general, the compounds of general formula (I) can be prepared according to the common general knowledge of the person skilled in the art and/or the methods described for the working examples and/or intermediates. Solvents, temperatures, pressures and other reaction conditions can be easily selected by the person skilled in the art. Starting materials are commercially available and/or can be easily prepared by the person skilled in the art. During the preparation of compounds combinatorial techniques can be used, for example, where the present intermediate groups are suitable for the use of these methods.

In describing the synthesises, the following terms and abbreviations have been used:

dry = anhydrous

Boc = tert- butoxycarbonyi Dess-Martin periodinane = 1 , 1 , 1-tris(acetyioxy)-1 , 1-dihydro-1 ,2-benziodoxo!-3-(1 H)-one

DIPEA = /V,A/-diisopropyl-ethylamine

DMAP = 4-dimethylamino-pyridine DMF = A/,A/~dimethylformamide

EDC = A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride HOBt = 1~hydroxybenzotriazole hydrate

HBTU = A/,A/,A/',A/-tetramethyl-0-(1H-benzotriazol-1-yl)uronium hexafluorophosphate K 2 CO 3 = potassium carbonate

Lawesson reagent = 2,4-bis(4-methoxyphenyl)-1 ,3,2,4-dithiadiphosphethane-2 4-disulfide

Meidrum’s acid = 2,2-dimethyl-1 ,3-dioxane-4,6-dione

MgS0 4 = magnesium sulfate

NaBhU = sodium borohydride

NaBH(GAc) 3 = sodium triacetoxyborohydride

NaCI = sodium chloride

Na 2 C0 3 = sodium carbonate

NaHCOs = sodium bicarbonate

NaOAc = sodium acetate

NaOH = sodium hydroxide

Na 2 S0 4 = sodium sulfate

Pd/C = palladium on carbon

Pt/C = platinum on carbon

THF = tetrahydrofuran

methyl 7 Chloro-4-oxo-1 ,

6.0 g (26.7 mmoi) of 7-chioro-4-oxo-1 ,2,3,4-tetrabydronaphthaiine-2-carboxyiic acid (R. D. Haworth et al., J Chem Soc 1943, 10) was dissolved in 100 mL of methanol and 0.5 mL of concentrated sulphuric acid was added and the mixture was stirred overnight at reflux temperature, then concentrated. The residue was dissolved in a mixture of diethyl ether and ethyl acetate (1 : 1) and washed with 10% NasCOs solution and water. The aqueous phases were extracted with ethyl acetate. The combined organic phases were washed with saturated NaCi solution, dried over anhydrous Na 2 SG4, filtered and concentrated. Thus, 6.27 g (98.4%) of the title product was obtained as beige crystals. MS (ESI) m/z 239.1 (M+H) + .

6.27 g (26.3 mmol) of methyl 7-chloro-4-oxo-1 ,2,3,4-tetrahydronaphthaline-2- carboxy!ate (Intermediate 1) was dissolved in 220 mL of methanol, then 6.57 g (80 mmol) of anhydrous NaOAc and 5.55 g (80 mmol) of hydroxylamine hydrochloride were added. The mixture was refluxed for 3 hours and then stirred overnight at room temperature. The reaction mixture was concentrated, water was added, extracted with ethyl acetate, the combined organic phases were washed with saturated NaC! solution, dried over anhydrous Na 2 SG4, filtered and concentrated. Thus, 6.63 g (99.4%) of title product was obtained as yellowish crystals. MS (ESI) m/z 254.1 (M+H) + .

methyl 7-chjoro-2-oxo-2,3,4 ' 5-tetrahvdro-1H-1-benzazepjne-4-carboxylate

6.57 g (25.9 mmol) of methyl 7-chloro-4-(hydroxiimino)-1 , 2,3,4- tetrahydronaphthaline-2-carboxyiate (Intermediate 2) was added to 60.0 g of polyphosphoric acid and stirred at 110°C for 20 minutes. Ice was added to the reaction mixture and stirred for 10 minutes it was then extracted with ethyl acetate, the combined organic phases were washed with saturated NaC! solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated. The residue was purified by column chromatography using cyclohexane:ethyl acetate=2: 1 as eluent. Thus, 3.03 g (46.2%) of the title product was obtained as white crystals. MS (ESI) m/z 254.1 (M+H) + .

methyl 7-chjoro-2-thjoxo-2.3.4.5-tetrahydro-1H-1-benzazepsne-4-carb oxylate

1.50 g (5.9 mmol) of methyl 7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4- carboxyiate (Intermediate 3) was dissolved in 80 mL of pyridine, 3.11 g (7.7 mmol) of Lawesson reagent was added and the reaction mixture was stirred at reflux temperature for 2 hours, then concentrated. 15 mL of water and 60 mL of saturated NaHCC solution were added to the residue and the highly precipitated suspension was stirred for 30 minutes. The precipitated yellow product was filtered off and dried in vacuo over phosphorus pentoxide at 50°C. Thus, 1.58 g (99.9%) of the title product was obtained as yellow crystals. MS (ESI) m/z 270.1 (M+H) + . fert-butyl 2-(rfraf?s-4-(trif!uoro ethvj¾cvcjohexyncarbonvj>hvdrazine carboxylate

2.13 g (10.9 mmol) of fra/?s-4-(trifluoromethyi)cyclohexanecarboxyiic acid (Manchester Organics Ltd) was dissolved in 50 mL of DMF. 1.44 g (10.9 mmol) of tert- buty!hydrazine carboxylate, 4.75 mL (27.3 mmol) of DIPEA, 2.00 g (13.10 mmol) of HOBt and 2.51 g (13.1 mmol) of EDC was added to the solution. The reaction mixture was stirred at room temperature for 36 hours, and then concentrated. 40 mL of saturated NaHC0 3 solution was added to the residue and after a short stirring the precipitate was filtered, washed with water and dried in a vacuum oven over phosphorus pentoxide. Thus, 3.35 g (99%) of the title product was obtained as white powder. GC-MS (El) m/z 310.1.

4-itnfjuoroiTtethyncy ohexane carboxylic acid hydrazide

3.35 g (10.79 mmol) of /erf-butyl 2~{[frans-4-(tnfiuoromethyl)cyciohexyi]carbonyi}- hydrazine carboxylate (intermediate 5) was dissolved in a mixture of 50 mL of ethyl acetate and 20 mL of ethanol, and then 30 mL of 2.5 M hydrogen chloride solution in ethyl acetate was added to the solution. The reaction mixture was stirred at room temperature for 16 hours, then 150 mL of diethyl ether was added and it was cooled in an ice-water bath. The precipitated product was filtered and washed with diethyl ether. The filtered material was stirred with 100 mL of saturated NaHCOs solution (pH ~ 8), filtered, washed with water, and dried in a vacuum oven over phosphorous pentoxide. Thus, 1 77 g (78%) of the title product was obtained as white powder. GC-MS (E!) m/z 210.1.

methyl 4-fpiperidjn-1 -yjmethy0cyclohexane carboxylate

0.30 g (1.8 mmol) of methyl frans-4-formylcyclohexane carboxylate (Synthonix) was dissolved in 10 mL of 1 ,2-dichioroethane, and 0.52 mL (5.3 mmol) of piperidine and 0.19 mL (3.4 mmol) of acetic acid were added to the solution. The resulting mixture was cooled to 0°C and 1.16 g (5.5 mmol) of NaBH(OAc)3 was added, and the reaction mixture was stirred at room temperature for 16 hours. Then, 30 mL of water was added to the reaction mixture and the pH of the mixture was adjusted to about 9 with N3 2 00 3 solution. The mixture was extracted twice with 20 mL of dichloromethane, the combined organic phases were dried over anhydrous IVIgSO*, filtered and concentrated. Thus, 0.40 g (95%) of the title product was obtained which was used without further purification.

£rang-4-fpipendin-1-ylmethvncy ohexane carboxylic acid hydrazide

0.40 g (1.68 mmol) of methyl frans-4-(pipendin-1-ylmethyl)cydohexane carboxylate (Intermediate 7) was dissolved in 5 mL of methanol, and the solution was poured info a pressure-resistant glass reactor. 5 mL (100 mmol) of hydrazine hydrate was added and the reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was concentrated and cyclohexane and anhydrous toluene were evaporated off the residue. Thus, 0.39 g (97%) of the title product was obtained as white powder. GC-MS (El) m/z 239.2.

frans-4-ipyrrolidin-l-yjcarbonvncycjohexane carboxylic acid hydrazide

a) methyl fra/7s-4-(pynrolidin-1-ylcarbonyl)cyclohexane carboxylate

A mixture of 186 mg (1 mmol) of irans- 4-(methoxycarbonyi)cydohexane carboxylic acid (Combi-Blocks Inc.), 83.5 m!_ (1 mmol) of pyrrolidine, 5 mL of dry DMF, 348 mΐ_ (2 mmol) of D!PEA, 230 mg (1.2 mmol) of EDC and 162 mg (1.2 mmol) of HOBt was stirred at room temperature for 24 hours. Ethyl acetate and aqueous NaHCC solution were added to the reaction mixture and the phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed with 1 A/ hydrochloric acid and wafer, dried over anhydrous Na 2 S0 4 , filtered and concentrated. Thus, 180 mg (75%) of the title product was obtained. GC-MS (El) m/z 239.

b) fra/?s-4-fpyrrolidin-1-ylcarbonyr)CYciohexane carboxylic acid hydrazide

180 mg (0,75 mmol) of methyl frans-4-(pyrroiidin-1-yicarbonyl)cyciohexane carboxylate, 1.1 mL of methanol and 1.1 mL of hydrazine-hydrate were stirred in a pressure- resistant glass reactor at 75°C for 24 hours. The reaction mixture was concentrated and cyclohexane was added, then evaporated off. Thus, 183 mg (76%) of the title product was obtained. GC-MS (El) m/z 239.

carboxylsc acid hydrazide

a) methyl 4-(morpholin-4-ylcarbonyl)cvclohexane carboxylate

The title product was prepared from trans 4-(methoxycarbonyl)cyciohexane carboxylic acid (Combi-Blocks Inc.) and morpholine according to the method described in step a) of Intermediate 9. GC-MS (El) m/z 255.

b) frans-4-(morpholin-1-vicarbonyl)cyclohexane carboxylic acid hydrazide

The title product was prepared from methyl frans-4-(morpholin-4- yicarbonyljcyclohexane carboxylate according to the method described in step b) of Intermediate 9. GC-MS (El) m/z 255.

Intermediate 11 rboxylic acid hydrazide

The title product was prepared from methyl frar?s-4-(dimethylamino)cyclohexane carboxylate (EP 1 582 521 A1 (05.10.2005) TANABE SEIYAKU CO.) according to the method described for intermediate 8. MS (ESI) m/z 186.3 (M+H) +

^rans-4-fmorphojsn-4-vncycSohexane carboxylic acid hydrazide

The title product was prepared from methyl fra/7s-4-(morpholin-4-yl)cyclohexane carboxylate (EP 1 582 521 A1 (05.10.2005) TANABE SEIYAKU CO.) according to the method described for intermediate 8. GC-MS (El) m/z 227.

1-(pyrimidin-2-vnazetidine-3-carboxylic acid hvdrazide

The title product was prepared from methyl 1-(pyrimidin-2-yl)azetidine-3-carboxylate

(WO 2006/124748 A2 (23.1 1.2006) LEXICON GENETICS INCORP.) according to the method described for intermediate 8. MS (ESI) m/z 194.2 (M+H) + .

1 - 2-ynazetidine-3-carboxyiic acid hydrazide

The title product was prepared from methyl 1-(pyridin-2-yl)azetidine-3-carboxyiate (WO 2017/007756 A1 (12.01.2017) RODIN THERAPEUTICS INC.) according to the method described for intermediate 8. GC-MS (El) m/z 192.

ethyl -3-methyl-2-oxo-1-oxa-3-azasDsror4.5ldecane-8-carboxylate

ethyl -3-iriethyl-2-oxo-1-oxa-3-azaspirQf4.5]decane-8-carbQxylate

1.8 g (45.0 mmol) of 60% sodium-hydride dispersion in oil was suspended in 60 mL of dry DMF, cooled to 0-5°C, then 6.00 g (26.4 mmol) of a ~1 : 1 mixture of ethyl (c/s)-2-oxo- 1-oxa-3-azaspiro[4.5]decane-8-carboxylate and ethyl (frans)-2-oxo-1-oxa-3- azaspiro[4 5]decane~8-carboxylate (WO 2008/092887 A1 , (07.08.2008) GLAXO GROUP LTD.) dissolved in 60 mL of DMF was added dropwise in such a way that the temperature of the mixture remained between 0 and 5°C. The reaction mixture was stirred for 20 minutes at this temperature, then 2.46 mL (39.5 mmol) of iodomethane was added dropwise over 20 minutes. The mixture was stirred for a further hour at 0-5°C, allowed to warm to room temperature and stirred for 3 hours at this temperature. Then, 1 8 mL (31 mmol) of acetic acid was added dropwise over 10 minutes, after stirring for 15 minutes, the reaction mixture was concentrated and 90 mL of n-heptane was evaporated off the residue twice. 180 mi of ethyl acetate, 90 mL of saturated NaHCOs solution and 90 mL of water were added to the residue, the phases were separated, the organic phase was washed with 90 mL of NaCi, dried over NaaSG^ filtered and concentrated. The residue was purified by column chromatography using toiuenelsopropanol^gS:/ as eluent. The appropriate fractions were concentrated and the residues were crystallized with diisopropyl ether. Thus, 1.38 g (22%) of ethyl (frans)~3-methyl~2~oxo-1-oxa-3-azaspiro[4.5]decane~8~carboxy late (Intermediate 15) and 2.45 g (39%) of ethyl (c/s)-3-methyl-2-oxo-1-oxa-3-azasplro[4.5]decane-8-carboxyia te (Intermediate 16) were obtained as white powder. GC-MS (El) m/z 241.

(^hb¾-3-hΐ6ίHn1-2-oco-1-oc3-3-3Z35rΐGqG4·5M6q3P6-8-q3^o cnIϊo acid hvdrazide

The title product was prepared from ethyl (fra/?s)-3-methy!-2-oxo-1-oxa-3- azaspiro[4.5]decane-8-carboxylate (Intermediate 15) according to the method described for Intermediate 8. GC-MS (El) m/z 227.

Intermediate 18

(c/s¾-3-methyl-2-oxo-1-oxa-3-az ne-8-carbox¥ljc acid hydrazide

The title product was prepared from ethyl (c/s^S-methyl-C-oxo-l-oxa-S- azaspiro[4.5]decane-8~carboxylate (Intermediate 18) according to the method described for Intermediate 8. GC-MS (El) m/z 227.

a) methyl frans-4-(azetidin-1-ylcarbonyl)cyclohexane carboxylate

The title product was prepared from fra/is-4-(methoxycarbony!)cydohexane carboxylic acid (Combi-Blocks Inc.) and azetidine according to the method described in step a) of Intermediate 9. GC-MS (El) m/z 225.

b) fr ~ ans-4~fazetidin-1-¥icarbon¥l)cydohexane carboxylic acid hydrazide

The title product was prepared from methyl fra/?s-4-(azetidin-1- yicarbonyi)cyclohexane carboxylate according to the method described in step b) of Intermediate 9. GC-MS (El) m/z 225.

a) methyl fra/7s-4-(piperidin-1-ylcarbonyl)cyclohexane carboxylate

The title product was prepared from frans~4~(methoxycarbonyl)cyclohexane carboxylic acid (Combi-Blocks Inc.) and piperidine according to the method described in step a) of Intermediate 9. GC-MS (El) m/z 253.

b) fra/7s-4-(piperidin-1-ylcarbonyl)cyclohexane carboxylic acid hydrazide

The title product was prepared from methyl frar?s~4~(piperidin-1- yicarbonyl)cyclohexane carboxylate according to the method described in step b) of Intermediate 9. GC-MS (El) m/z 253. butyi 4-friTans-4-(hvdrazinylcarbonyl)cvclohexyllcarbonyl>piper azine-1-

a) ferf-butyl 4- 4-(methoxycarbonyl)cvdohexyncarbonyl)piperazine-1-carboxylai e

The title product was prepared from fra/7s-4-(methoxycarbonyl)cyclohexane carboxylic acid (Combi-Blocks Inc.) and ferf-butyl piperazine~1 -carboxylate according to the method described in step a) of Intermediate 9, which was used without further purification b) fra/?s-4-(Morpholin-1-ylcarbonyl)cvclohexane carboxylic acid hvdrazide

The title product was prepared from ferf-butyl 4-{[frans-4-(methoxycarbonyi)- cyclohexyl]carbonyl}piperazine-1 -carboxylate according to the method described in step b) of intermediate 9, which was used without further purification. methyl 7-chjoro-2- drO 3H-1-benzazepine-4-carboxylate

A solution of 250 mg (0.93 mmol) of methyl 7-cbloro-2-thioxo-2,3,4,5-tetrahydro-1 H- 1-benzazepine-4-carboxylate (Intermediate 4), 18.5 mL of acetone, 259 mg (1.87 mmol) of K 2 CO 3 and 0.18 mL (2.89 mmol) of iodomethane was stirred at room temperature for 20 hours. The reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate, the organic phase was dried over anhydrous NaaSCu, filtered, and concentrated. Thus, 261 mg (99%) of the title product was obtained. MS (ESI) m/z 284.1 (M+H) + . methyl 8-chloro-5,6-dihvdro-4H-i -a1f1]benzazepine-5-carboxylate

261 mg (0.92 mmol) of methyl 7-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-1- benzazepine-4-carboxylate (intermediate 22) was dissolved in 6 mL of 1 ,4-dioxane, and the solution was warmed to 90°C. 277 mg (4.61 mmol) of formyl hydrazide was added under argon over 4 hours. The reaction mixture was then stirred at 90°C for another 8 hours and after cooling to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography using d!chioromethane:methanol=95:5 as eluent. Thus, 188 mg (74%) of the title product was obtained. MS (ESI) m/z 278.1 (M÷H) + .

methyl 1 bro8Tto-8-chjoro-5,6 dihvdrO 4H-n,2 ' 4]tnazojoi4.3-a1f1]benzazepine 5

187 mg (0.67 mmol) of methyl 8-chloro-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine-5-carboxy!ate (Intermediate 23) was dissolved in 15 mL of THF. 120 mg (0.68 mmol) of A/~bromosuecinimide was added and the resulting pale yellow solution was stirred at reflux temperature for 60 minutes with illumination by an RH-50Q type halogen lamp (Tracon Electric). At this time, the colour of the solution initially darkened and then gradually became discoloured. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography using cydohexane:ethyi acetate=1 : 1 to 1 :4 as eluent. Thus 226 mg (94%) of the title compound were obtained. MS (ESI) m/z 358.0 (M+H) + .

methyl T- 1 -benzazepine-4-carboxylate

100 mg (0.43 mmol) of methyl 7-methyl-2-oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine-

4-carboxylate (which was prepared according to the method described for intermediate 3) was dissolved in 10 mL of THF, then 105 mg (0.26 mmol) of Lawesson reagent was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was first concentrated, then saturated NaHGC solution was added to the residue and it was stirred for 60 minutes. The precipitated product was filtered off, washed with water, and dried. Thus, 80 mg (75%) of the title product was obtained. MS (ESI) m/z 250.2 (M+H) + .

The title product was prepared from methyl 7-methoxy-2-oxo-2,3,4,5-tetrahydro-1 H- 1-benzazepine-4-carboxylate (which was prepared according to the method described for Intermediate 3) according to the method described for Intermediate 25. MS (ESI) m/z 266.1 (M+H) + .

The title product was prepared from methyl 7~bromo-2-oxo-2,3,4,5~tetrahydro-1 H~1~ benzazepine-4-carboxyiate (which was prepared according to the method described for Intermediate 3) according to the method described for Intermediate 25. MS (ESI) m/z 316.0 (M+H) + .

The title product was prepared from methyl 7-bromo~2~thioxo-2,3,4,5-tetrahydro-1H- l-benzazepine-4-carboxy!ate (intermediate 27) according to the method described for Intermediate 22. MS (ESI) m/z 330.1 (M+H) + .

a) 1-bromo-8-chloro-5,6-dihvdro-4H- a1f1lbenzazepine-5-carboxyljc acid

A mixture of 631 mg (1.77 mmol) of methyl 1-bromo-3-ch!oro-5,6-dlhydro-4H- [1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxyiate (Intermediate 24), 13 mL of THF, 6.5 mL of methanol, 6 5 mL of water and 379 mg (9.03 mmol) of lithium hydroxide hydrate was stirred at room temperature for 2.5 h, then the solvents were evaporated and the remaining water solution was diluted with 10 mL of water. The pH of the solution was adjusted to 5 with 1M hydrochloric acid, the precipitated product was filtered and washed with water. The mother liquor was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The so obtained residue and the filtered product was combined to yield 433 mg (71%) of the title compound. MS (ESI) m/z 343 9 (M+H) + .

To an ice-cold mixture of 620 mg (1 8 mmol) of 1-bromo~8~chloro-5,6-dihydro~4H- [1 ,2,4]triazo!o[4 3-a][1]benzazepine-5-carboxylic add (Step a) of intermediate 29), 8 mL of DMF, 498 mg (3.25 mmol) of HOBt, 0.88 mL (5.06 mmol) of DIPEA and 623 mg (3.25 mmol) of EDC 290 mg (5.48 mmol) of ammonium chloride was added and the reaction mixture was stirred at 5°C for 0.5 h, then at room temperature for 20 h. After completion of the reaction the mixture was diluted with water and brine and extracted with ethyl acetate. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated. The residue was crystallized from ethyl acetate to yield 428 mg (69%) of the title compound. MS (ESI) m/z 343.0 (M+H) + .

Intermediate 30

methyl (5s,8sl-1-oxo-2-iDropan-2-vn-2-azaspiror4.5]decane-8-carbox jate

A stirred mixture of 0.9 g (4.0 mmol) of dimethyl frans-1-(2-oxoefby!)cyclohexane-1 ,4- dicarboxylate (WO 2011/143150 At (05.10.2011) SANQF!), 40 mL of 1 ,2-dichloroethane, 316 pL (3.71 mmol) of isopropylamine and 637 pL (11.1 m ol) of acetic acid was cooled to 5°C and 2.36 g (11.1 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to keep the internal temperature below 5°C. After completion of the addition the reaction mixture was stirred at room temperature for 2 h, then diluted with water. The pH of the mixture was adjusted to 8 by addition of 10% K 2 CO 3 solution, the phases were separated and the water phase was extracted with dichioromethane. The combined organic phases were successively washed with 10% K 2 CO 3 solution, water and brine, dried over Na 2 S0 4 filtered and concentrated. The residue was dissolved in 40 mL of dry THF and 330 mg (2.94 mmol) of potassium tert-butoxide was added. The reaction mixture was stirred at room temperature for 3 h, then neutralized by addition of solid CO 2 . After addition of water the THF was evaporated and the water phase was extracted with ethyl acetate. The organic phase was dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash column chromatography using cyclohexane : ethyl acetate = 45:55 mixture as eluent to yield 56 mg (6%) of methyl (5s,8s)-1-oxo-2-(propan-2-yl)-2-azaspiro[4 5]decane-8-carboxyiate (Intermediate 30) as the first fraction and 172 mg (19%) of methyl (5r,8r)-1-oxo-2-(propan-2- yi)-2-azaspiro[4.5]decane-8-carboxylate (Intermediate 31) as the second fraction. GO S (El) m/z 253.

Intermediate 32

{5r,8r¾-1-exo-2-(proDan-2-¥n-2-azaspiroi4.5]decane-8-carbe hvdrazlde

The title compound was prepared from methyl (5r,8r)-1-oxo-2-(propan-2-y!)-2- azaspiro[4.5]decane-8-carboxylate (Intermediate 31 ) according to the method described in Step b) of Intermediate 9. GC-MS (El) m/z 253. Intermediate 33

4-(1-lifeft-butyl(dimethvnsil¥noxyiethvn-7-chloro-1 ,3,4,5-tetrahvdro-2 -1 - benzazepin-2-one

a) 7-chloro-2-oxo-2.3.4.5-tetrahvdro-1H-1-benzazepine-4-carboxy lic acid

A mixture of 12.38 g (48.8 mmol) of methyl 7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-1- benzazepine~4-carboxylate (Intermediate 3), 55 mL of methanol and 12 mL of 50% NaOH solution was stirred at room temperature for 0.5 h, then cooled to 0°C and 105 mL of 5% hydrochloric acid solution was added. After stirring at 0°C for 10 min, the precipitated product was filtered off, washed with water and dried to yield 11.1 g (95%) of the title compound. MS (ESI) m/z 240.2 (M÷H) + .

b) 7~chioro-A/-metboxy-/V-methvi~2~oxo-2,3,4.5-tetrahydro-1H-1- benzazepine~4- carboxamide

The title compound was prepared from 7-cb!oro-2-oxo-2,3,4,5~tetrahydro-1H~1~ benzazepine-4-carboxylic acid (Step a) of Intermediate 33) and N-methoxymethanamine hydrochloride according to the method described in Step a) of intermediate 9, and it was used without further purification in the next step.

c) 4-acet¥l-7-chloro-1 ,3,4.5-tetrah¥dro-2H-1-benzazepin-2-one

Under argon a mixture of 2.5 g (8.84 mmol) of 7-cbloro-A/-methoxy-/V-methyl-2-oxo- 2,3,4,5-tetrabydro-1H-1-benzazepine-4-carboxamide (Step b) of Intermediate 33) in 100 mL of dry THF was cooled to -15°C, and 14.7 mL (44.1 mmol) of 3M methylmagnesium bromide solution in diethyl ether was added. The reaction mixture was stirred between -10°C and 0°C for 3 h, then quenched by addition of saturated NH 4 CI solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaaSOi, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol = 96:4 as eluent to yield 1.6 g (76%) of the title compound. MS (ESI) m/z 238.2 (M+H) + .

d) 7-chloro-4-(t-hydroxyethyj)-t ,3,4,5-tetrahydro-2H-1-benzazepin-2-one

A mixture of 300 mg (1 26 mmol) of 4-acetyl-7-chloro-1 ,3,4,5-tetrahydro-2H-1- benzazepin-2-one (Step c) of Intermediate 33), 50 mL of ethanol and 96 mg (2.5 mmol) of NaBhU was stirred at room temperature for 0.5 h, then quenched by addition of 1 M hydrochloric acid solution and the ethanol was evaporated. The water phase was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over NaaSC , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol = 95:5 as eluent to yield 235 mg (78%) of the title compound as a 63:37 mixture of diastereomers. MS (ESI) m/z 240.2 (M+H) + .

e) 4-(1-frfe/f-butyl(dimethyl)silylloxy)ethyl)-7-chloro-1.3.4.5 -tetrahvdro-2H-1-benzazepin-2- one

A stirred mixture of 665 mg (2.77 mmol) of 7-chloro-4-(1-hydroxyethyl)-1 , 3,4,5- tetrabydro~2H~1-benzazepin-2-one (Step d) of Intermediate 33), 5 mL of DMF, 50 mL of dichloromethane and 0.8 mL (6.94 mmol) of 2,6-lutidine was cooled to 0°C and under argon 792 mg (3.0 mmol) of fe/f-butyldimethylsi!yl trifluoromethanesulfonate was added. The reaction mixture was allowed to warm to room temperature and if was stirred at this temperature for 16 h. The dichloromethane was evaporated, 10 mL of water and 10 mL of saturated NaHCOs solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaaSCU, filtered and concentrated. The residue was purified by flash column chromatography using cyc!obexane:ethy! acetate = 75:25 as eluent. The first fraction was 200 mg (20%) of one of the diastereomers, the second fraction was 191 mg (19%) of a mixture of diastereomers and the third fraction was 326 mg (33%) of the other diastereomer. MS (ESI) m/z 354.2 (M÷H) + .

The title compound was prepared from 4-(1-{[fe/f-butyl(dimethyi)sily!]oxy}etbyi)-7- chloro-1 ,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step e) of Intermediate 33) according to the method described for Intermediate 4, and if was used without further purification in the next step. The same method was used either in case of a mixture of diastereomers (second fraction of Step e) of Intermediate 33) or in case of the separated diastereomers (first and third fractions of Step e) of Intermediate 33).

a) ethyl 4-hydroxy-4-methylcyclohexanecarboxylate

Under argon to a stirred solution of 100 mL (220 mmol) of 2M trimethyialuminum in toluene a solution of 3.7 mL (55 mmol) of ethyl 4-oxocyclohexanecarboxyiate in 50 mL of toluene was added over 2.5 h at -60°C. After completion of the addition the mixture was stirred at -60°C for 0.5 h, then allowed to warm to -20°C over 2 h. The reaction mixture was transferred over 25-30 min via a cannula to an ice-cold mixture of 180 mL of ethyl acetate, 425 mL of water, 75 mL of concentrated hydrochloric acid and 100 g of crushed ice while keeping the internal temperature below 10°C. The phases were separated, the organic phase was successively washed with 400 mL of water and 400 mL of brine, dried over Na 2 SG 4 , filtered and concentrated to yield 5.44 g (53%) of title compound. According to 1 HNMR spectroscopy it was a 28:72 mixture of cis- and trans- isomers. This mixture was used in the next step without further purification.

b) ethyl 4-methoxy-4-methylcvclohexanecarboxylate

Under argon to a stirred mixture of 2.16 g (54 mmol) of 60% sodium hydride in mineral oil, 34 mL of dry THF, 200 mg (0.54 mmol) of tetrabutylammonium iodide, 49 mg (0.72 mmol) of imidazole and 3.36 mL (54 mmol) of iodomethane a solution of 3.36 g (18 mmol) of ethyl 4-hydroxy-4-methyleyc!obexaneearboxylate (Step a) of Intermediate 35) in 21 mL of dry THF was added over 30-40 min at 20-25X. The reaction mixture was stirred at room temperature for 3 h, then cooled to 0-5°C and 2.28 mL (40 mmol) of acetic acid was added over 10 min. The mixture was stirred for 15 min, then poured into a mixture of 280 mL of diethyl ether and 120 mL of saturated NaHCC solution. The phases were separated, the organic phase was washed with brine, dried over NazSG^ filtered and concentrated. The residue was purified by column chromatography using n-hexane : ethyl acetate=85: 15 as eluent to yield 2.3 g (64%) of the title compound. According to 1 HNMR spectroscopy it was a 21 :79 mixture of cis- and trans- isomers.

c) 4-methoxy-4-methylcyclohexanecarbohydrazide

The title compound was prepared from ethyl 4-methoxy-4- methylcyciohexanecarboxylate (Step b) of intermediate 35) according to the method described in Step b) of Intermediate 9. According to ^ HNMR spectroscopy it was a 21 :79 mixture of c/s- and trans- isomers.

a) 7-chloro-4-(hvdroxymethyl)-1.3.4.5-tetrahvdro-2H-1-benzazepi n-2-one

Under argon a stirred mixture of 500 mg (1.97 mmol) of methyl 7-ch!oro-2-oxo- 2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxyiate (Intermediate 3), 15 mL of dry diethyl ether and 20 mL of dry THF was cooled to -40°C and 4.33 mL (4.33 mmol) of 1 M lithium aluminum hydride solution in diethyl ether was added. The reaction mixture was stirred at -20°C for 1 h, then allowed to warm to 0°C and water was cautiously added. The THF was evaporated and the water phase was extracted with ethyl acetate, the combined organic phases were washed with brine, dried over Na 2 S0 4 , filtered and concentrated to yield 422 mg (95%) of the title compound MS (ESI) m/z 228.1 (M+H) +

b) 7-chloro-4-(fluoromethyl)-1 ,3.4.5-tetrahvdro-2H-1-benzazepin-2-one

Under argon a stirred mixture of 532 mg (2.36 mmol) of 7-chloro-4-(hydroxymethyl)~ 1 ,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step a) of Intermediate 36) and 50 mL of dry dichloromethane was cooled to ~78°C and a solution of 950 mg (5.89 mmol) of (diethyiamino)sulpbur trifluoride in 1 mL of dichloromethane was added dropwise. The reaction mixture was allowed to warm to 0°C over 4 h, stirred at this temperature for 45 min, then saturated NaHC0 3 solution was added. The phases were separated, the water phase was extracted with dichloromethane, the combined organic phases were washed with brine, dried over NazSC , filtered and concentrated. The residue was purified by reversed phase flash column chromatography using water (containing 0.1 % trifiuoroacetic acid) and acetonitrile=60:40 as eluent to yield 222 mg (41 %) of the title compound. MS (ESI) m/z 228.1 (M+H) + . intermediate 37

7-Ghforo-4-(fluQromethyn~1,3,4.5-tetrahydro-2H~1~benzazepine ~2~thione

The title compound was prepared from 7-chloro-4-(fluoromethyl)-1 ,3,4,5-tetrahydro- 2H-1-benzazepin-2-one (Step b) of intermediate 38) according to the method described for Intermediate 4, and it was used without further purification in the next step.

Intermediate 38

methyl 7 fiuorO 2-oxo-2,3.4,5-tetrahvdro-1H 1-benzazepine-4-carboxylate

a) methyl 7-fluoro-4-(hvdroxyimjno)-- The title compound was prepared from methyl 7-f!uoro-4-oxo-1 , 2,3,4- tetrahydronaphthalene-2-carboxyiate (US5595872 (03 09 1993) Bristol-Myers Squibb Company) according to the method described in intermediate 2, and it was used without further purification in the next step.

b) methyl 7-fiuoro-2-oxo-2,3.4,5-tetrahydro-1H-1-benzazep!ne-4-carboxy late

The title compound was prepared from methyl 7-fluoro-4-(hydroxyimino)-1 , 2,3,4- tetrahydronaphthalene-2-carboxyiate (Step a) of Intermediate 38) according to the method described for intermediate 3. MS (ESI) m/z 238.2 (M+H) + .

methyl

The title compound was prepared from methyl 7-fiuoro-2-oxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (Step b) of Intermediate 38) according to the method described for Intermediate 4, and it was used without further purification in the next step.

7-fjuoro-4-(fjuoromethv0~ ro-2H-1-benzazepjn-2-one

a) 7-fluoro-4-(hydroxymethyl)-1 ,3,4,5-tetrahydro-2H-1-benzazepin-2-one

The title compound was prepared from methyl 7-fluoro-2-oxo-2,3,4,5-fetrahydro-1H- 1-benzazepine-4-carboxylate (Step b) of Intermediate 38) according to the method described in Step a) of Intermediate 36, and if was used without further purification in the next step b) 7-fluoro-4-(fluoromethyl)-1 ,3,4,5-tetrahydro-2H-1-benzazepin-2-one

The title compound was prepared from 7-f!uoro-4-(hydroxymethy!)-1 , 3,4,5- tetrahydro-2H-1-benzazepin-2-one (Step a) of intermediate 40) according to the method described in Step b) of Intermediate 36, and it was used without further purification in the next step.

Intermediate 41 7-fjuoro-4-(fiuorometh¥n-1.3,4,5-tetrahvdro-2H-1-benzazepin e-2-thione

The title compound was prepared from 7-f!uoro-4-(fiuorometby!)-1 ,3,4,5-tetrabydro- 2H-1-benzazepin-2-one (Step b) of Intermediate 40) according to the method described for Intermediate 4, and it was used without further purification in the next step.

4- ro-2H-1-benzazepin-2-one

a) 4-ih¥droxymethyl)-7-methyM ,3,4,5-tetrahydro-2H-1-benzazepin-2-one

The title compound was prepared from methyl 7-methyl-2-oxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (obtained according to the method described for Intermediate 3) according to the method described in Step a) of Intermediate 38, and it was used without further purification in the next step.

b) 4-(fluoromethyl)-7-methyl-1 ,3,4,5-tetrahYdro-2H-1-benzazepin-2-one

The title compound was prepared from 4-(hydroxymethyl)-7-methyl-1 , 3,4,5- tetrahydro-2H-1-benzazepin-2-one (Step a) of intermediate 42) according to the method described in Step b) of Intermediate 36. MS (ESI) m/z 208.2 (M+H) + .

The title compound was prepared from 4-(fluoromethyl)-7-methyl-1 ,3,4 5-tetrahydro- 2H-1-benzazepin-2-one (Step b) of Intermediate 42) according to the method described for Intermediate 4, and it was used without further purification in the next step.

methyl 7-fluoro-2-(meth¥lsulfan¥n-4,5-dihvdro-3H-1-benzazepine-4- carboxyjate

The title compound was prepared from methyl 7-fluoro-2-thioxo-2,3,4,5-tetrahydro- 1H-1-benzazepine-4-carboxylate (intermediate 39) according to the method described for Intermediate 22. MS (ESI) m/z 268.1 (M+H) + . ntermediate 45

methyl 7-chioro-4-methyl-2-oxo-2,3,4,5-tetrahvdro-1H-1-benzazepjne- 4-carboxylate

A stirred mixture of 1.0 g (3.94 mmol) of methyl 7-chloro-2-oxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (Intermediate 3) in 10 mL of dry DMF was cooled to 0°C and under argon 205 mg (5.12 mmol) of 60% sodium hydride in mineral oil was added. The mixture was stirred at this temperature for 1 h, then 0.8 mL (5.9 mmol) of 4-methoxybenzyi chloride was added and the reaction mixture was stirred at room temperature for 20 h. After completion of the reaction the mixture was diluted with water and brine, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over NazSC , filtered and concentrated. The residue was purified by flash column chromatography using cyclohexane : ethyl acetate^ 4:1 as eluent to yield 820 mg (56%) of the title compound. MS (ESI) m/z 374.1 (M+H)*.

b] _ methyl _ 7-chloro-1-(4-methoxybenzyl)-4-methyl-2-oxo-2,3,4,5-tetrahyd ro-1H-1- benzazepine-4-carboxylate

A stirred solution of 600 mg (1.61 mmol) of methyl 7-chloro-1-(4-methoxybenzyl)-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxyiate (Step a) of Intermediate 45) in 30 mL of dry THF was cooled to -7G°C and under argon 1.2 mL (2.4 mmol) of 2.0 M lithium diisopropylamide solution in THF/heptane/ethyibenzene was added. The mixture was stirred at this temperature for 2 h, then 0.2 mL (3.2 mmol) of iodomethane was added and the reaction mixture was allowed to warm to 0°C over 2 h. After completion of the reaction was quenched by addition of saturated ammonium chloride, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography using cyclohexane and ethyl acetate= 4: 1 as eluent to yield 460 mg (74%) of the title compound. MS (ESI) m/z

388.1 (M+H) + .

c) methyl 7-chloro-4-methyl-2-oxo-2,3,4,5-tetrabydro-1H-1-benzazepine- 4-carboxyiafe

A mixture of 460 mg (1.2 mmol) of methyl 7-ehloro-1-(4-methoxybenzyl)-4-methyl-2- oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate (Step b) of Intermediate 45), 20 mL of acetonitrile, 5 mL of water and 1.95 g (3.56 mmol) of ammonium cerium(IV) nitrate was stirred at room temperature for 2 h, then diluted with water. The pH of the mixture was adjusted to 8 by addition of saturated NaHCO solution, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaaSG^ filtered and concentrated. The residue was purified by flash column chromatography using cyclohexane and ethyl acetate= 4: 1 as eluent to yield 190 mg (60%) of the title compound. MS (ESI) m/z

268.1 (M÷H) + . intermediate 46

methyl 7-chforo-4-methyll~2-thioxo-2,3 AS-tetrahydro- j H- 1 -benzazepine-4-carboxylate

The title compound was prepared from methyl 7-chloro-4-mefbyl-2-oxo-2, 3,4,5- tetrahydro-1 H-1-benzazepine-4-carboxylate (Step c) of Intermediate 45) according to the method described for Intermediate 25, and it was used without further purification in the next step. ntermedsate 47

methyl 7-chlQro~4~eth¥li-2~oxo-2.3.4.5~tetrahydro--1 HA -benzazepine~4-carboxylate

a] _ methyl _ 7-chloro-1-(4-methoxybenzyl)-4-ethyl-2-oxo-2,3,4,5-tetrahvdr o-1H-1- benzazeplne-4-carboxYlate

The title compound was prepared from methyl 7-ch!oro-1-(4-methoxybenzy!)-2-oxo- 2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxyiafe (Step a) of intermediate 45) and iodoethane according to the method described in Step b) of Intermediate 45, and it was used without further purification in the next step

b) methyl 7-chloro-4-ethyl-2-oxo-2.3,4,5-tetrahvdro-1H-1-benzazepine-4 -carboxylate

The title compound was prepared from methyl 7-chloro-1-(4-methoxybenzyl)-4-ethyl- 2-oxo-2,3,4,5-tetrahydro-1/- 1-benzazepine-4-carboxylate (Step a) of Intermediate 47) according to the method described in Step c) of Intermediate 45 MS (ESI) m/z 282.1 (M÷H) + .

The title compound was prepared from methyl 7-chloro-4-ethyl-2-oxo-2, 3,4,5- tetrahydro-1H-1-benzazepine-4-carboxy!ate (Step b) of Intermediate 47) according to the method described for Intermediate 25, and it was used without further purification in the next step. methyl 7-chloro-4-ethyl·2- 3H-1-bepzazepsne-4-

The title compound was prepared from methyl 7-chloro~4-ethyl~2-thioxo-2, 3,4,5- tetrahydro-1H-1-benzazepine-4-carboxy!ate (intermediate 48) according to the method described for intermediate 22, and it was used without further purification in the next step.

tert- butyl 2-ii3 ' 3-dif!uorocvc onvnhvdrazjne carboxytate

The title compound was prepared from 3,3-dif!uoro-cyclobutane carboxylic acid (Combi-Blocks Inc.) according to the method described for Intermediate 5. GC-MS (Ei) m/z 250 1

3.3-difluorocvcjobutane carboxylic acid hvdrazsde

The title compound was prepared from fe/t-butyl 2-[(3,3- difluorocyclobuty!)carbonyl]bydrazine carboxylate (Intermediate 50) according to the method described for Intermediate 8 GC-MS (El) m/z 150 1.

-bromo-8-chloro-5,6-dihvdro-4H- ,3-ainibenzazepine-5-carbonjtriSe

A stirred solution of 155 mg (0.45 mmol) of 1-bromo-8-chloro-5,8~dihydro-4H~ [1 ,2, 4]triazo!o[4,3-a][1]benzazepine- 5-carboxamide (Step b) of intermediate 29), 77 mL of dry dichioromethane and 400 pL (2.86 mmol) of triethylamine was cooled to 0°C and 105 pL (0.73 mmol) of trifiuoroacetic anhydride was added. The temperature of the mixture was allowed to warm to room temperature and the reaction mixture was stirred at this temperature for 1 h, then cooled to 0°C and 400 pL (2 86 mmol) of triethylamine and 105 pL (0.73 mmol) of trifiuoroacetic anhydride were added. The mixture was stirred at room temperature for 2.5 h, then diluted with saturated NaHCC solution. The phases were separated and the water phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over 143 2 30 4 , filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanoi:ammonium hydroxide^ 180: 10: 1 as eluent to yield 125 mg (85%) of the title compound. MS (ESI) m/z 323.0 (M+H) + .

a) diethyl ri-(3-fluorophenyl)-2-methylpropan-2-yllpropanedioate

Under argon 33 ml (16.5 mmol) of 0.5M 3-fluorobenzylmagnesium chloride (Alfa Aesar) solution in 2-Me-THF was slowly added via a dropping funnel to a solution of 3.0 g (15.0 mmol) of diethyl (propan-2-ylidene)propanedioate (Aldrich) and 150 mL of diethyl ether in 4 hours. Then the stirring was continued at room temperature for 18 hours. After that, the reaction was quenched with 1 M hydrochloric acid solution, extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na 2 S0 4, filtered and concentrated. Thus, 4.30 g (92.5%) of the title product was obtained as a yellow oil. MS (ESI) m/z 31 1.1 (M+H) + .

b) n-(3-fluorophenyl)-2-methylpropan-2-vnpropanedioic acid

A solution of 4.30 g (13.9 mmol) of diethyl [1-(3-fluorophenyl)-2-methylpropan-2- yiljpropanedioate, 60 mL of 2 M aqueous NaOH (120 mmol) and 60 mL of ethanol was stirred at 50°C overnight. The organic solvent was removed in vacuo, the residue was acidified with 3 M hydrochloric acid and extracted with dich!oromethane, dried over anhydrous Na 2 SG4, filtered and concentrated. Thus, 3.43 g (97 %) of the title product was obtained as a brownish oil. MS (ESI) m/z 255.1 (M+H) \

3.43 g (13.5 mmol) of [1-(3-fiuorophenyl)-2-methyipropan-2-yi]prapanedioic acid was heated at 21 OX until gas evolution ceased, then cooled to room temperature. Thus, 2.35 g (83 %) of the title product was obtained as an oil. MS (ESI) m/z 21 1.1 (M+H) + .

d) 8-fluoro-3,3-dimethvi-3,4-dihvdronaphthalei>1 (2H)-one

Concentrated sulfuric acid (8 ml) was added to 2.35 g (1 1.2 mmol) of 4-(3- fluorophenyi)-3,3-dimethyibutanoic acid, and the resulting mixture was stirred at 40°C for 1 hour. After that, it was poured on ice, extracted with ethyl acetate, washed with saturated NaCI solution, dried over anhydrous NaaSC , filtered and concentrated. Thus, 1.51 g (70 %) of the title product was obtained as a brownish oil. MS (ESI) m/z 193.4 (M÷H) + .

e) N-(8-fluoro-3.3-dimethvi-3.4-dihvdronaphthalen-1 (2H)-ylidene)hvdroxylamine

A solution of 1.51 g (7.86 mmol) of 6-fluoro-3,3-dimethyl-3,4-dihydronaphthalen- 1 (2H)~one, 3.01 g (43.3 mmol) of hydroxylamine hydrochloride (Aldrich), 3.61 g (44.0 mmol) of anhydrous sodium acetate (Aldrich) and 55 mL of methanol was refluxed overnight. Then the solvent was removed in vacuo, water and ethyl acetate were added, phases were separated, the water phase was extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na2SG4, filtered and concentrated. Thus, 1.45 g (89 %) of the title product was obtained as a beige solid. MS (ESI) m/z 208.1 (M+H) \

f) 7-fiuoro-4,4-dimeth¥M ,3,4,5-tetrabydro-2l-l-1-benzazepin-2-one

1.45 g (7.00 mmol) of N~(6~fluoro~3,3~dimefhyi-3,4~dibydronaphthalen~1 (2H)- ylidene)hydroxyiamine was added to 15.0 g of poiyphosphoric acid and stirred at 130X for 20 minutes ice was added to the reaction mixture and stirred for 10 minutes. It was then extracted with chloroform, dried over anhydrous NasSC^, filtered and concentrated. The residue was triturated with diethyl ether and the precipitates were collected by suction. Thus, 1.10 g (76 %) of the title product was obtained as white crystals. MS (ESI) m/z 208.2 (M+H'f.

7-fluoro-4-{propan-2-vn-1.3.4,5-tetrahvdro-2H-1-benzazepin-2 -one

The title product was prepared from diethyl 2-(2-methylpropylidene)malonate (Combi blocks), according to the method described for Intermediate 53. MS (ESI) m/z 222.1 (M+H) ÷ .

a) diethyl (l-benzylcvclopentyl)propanedioate

Under argon 12 mL (24 mmol) of 2 M benzylmagnesium chloride solution in THF (Aldrich), was slowly added via a dropping funnel to a solution of 5.0 g (22.1 mmol) of 2- cyc!opentyiidenemalonic acid diethyl ester (Lehnert, W., Tetrahedron 1973, 29: 635-638) and 100 mL of diethyl ether in 4 hours. Then the stirring was continued at room temperature for 18 hours. After that, the reaction was quenched with 1 hydrochloric acid solution, extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous NaaSG^ filtered and concentrated. Thus, 5.82 g (80 %) of the title product was obtained as an oil. MS (ESI) m/z 319.4 (M+H) + .

A solution of 5.62 g (17.7 mmol) of diethyl (l-benzylcyclopentyl)propanedioate (Step a) of Intermediate 55), 80 mL of 2 M aqueous NaOH (120 mmol) and 30 mL of ethanol was refluxed for 2 hours. The organic solvent was removed in vacuo, the residue was acidified with 3M hydrochloric acid and extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na2SG4, filtered and concentrated. Thus, 3.52 g (76 %) of the title product was obtained as an oil. MS (ESI) m/z 263.3 (M+H) + .

3.52 g (13.4 mmol) of (l-benzylcyciopentyi)propanedioic acid (Step b) of intermediate 55) was heated at 180°C until gas evolution ceased, then cooled to room temperature. Thus, 2.90 g (99 %) of the title product was obtained as an oil. MS (ESI) m/z 219.1 (M+H) + .

d) TH-spiroicyclopentane-1 ,2'-naphfhaienl-4'(3'H)-one

20 mL of concentrated sulfuric acid (Aldrich) was added to 2.90 g (13.3 mmol) of (1- benzylcyclopenty!)acetic acid (Step c) of Intermediate 55), and the resulting mixture was stirred at 35°C for 1 hour. After that, it was poured on ice, extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated. The residue was taken up in dichloro ethane and filtered on silica pad to remove coloring impurities. Thus, 1.41 g (53 %) of the title product was obtained as an oil. MS (ESI) m/z 201.2 (M+H) + .

e) N-TH-spiro[cvclopentane-1 ,2'-naphthalenl-4'(3'H)-ylidenehvdroxylamine

A solution of 1.41 g (7.05 mmol) of H-spiro[cyclopentane-1 ,2'-napbthalen]-4'(3'H)- one (Step d) of Intermediate 55), 1.95 g (28 mmol) of hydroxylamine hydrochloride (Aldrich), 2.30 g (28 mmol) of anhydrous sodium acetate (Aldrich) and 40 mL of methanol was refluxed for 2 hours. Then the solvent was removed in vacuo, water and ethyl acetate were added, phases were separated, the water phase was extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na2SG4, filtered and concentrated. Thus, 1.33 g (88 %) of the title product was obtained as a beige solid. MS (ESI) m/z 216.1 (M+H) + .

f) 1 ,5-dihvdrospirori-benzazepine-4, T-cvclopentanl-2(3H)-one 1.33 g (6.19 mmol) of N-TH~spiro[cyciopentane-1 ,2'-napbthalen]-4'(3'H)~ ylidenehydroxylamine (Step e) of Intermediate 55) was added to 20 0 g of polyphosphoric acid and stirred at 1 10°C for 20 minutes. Ice was added to the reaction mixture and stirred for 10 minutes. It was then extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na 2 SG4, filtered and concentrated. The residue was purified by column chromatography using cyclohexane:ethyl acetate=2: 1 as eluent. Thus, 0.51 g (38 %) of the title product was obtained as white crystals. MS (ESI) m/z 216.1 (M+H) + .

Intermediate 56

4-(propan-2-yl¾~1 ,3A -1 ~benzazepin~2--one

The title product was prepared from diethyl 2-(2-methyipropy!idene)ma!onate (Combi Blocks) according to the method described for Intermediate 53. MS (ESI) m/z 204.1 (M+H) \

Intermediate 57

one

The title product was prepared from diethyl tetrabydro-4H-pyran-4- yiidenepropanedioate (Griffiths et al., Heiv Chim Acta 1991 , 74( 2):309-314) according to the method described for intermediate 53. MS (ESI) m/z 232.2 (M+H)T

Intermediate 58

I .^.S.S’-tetrahvdrospiroil -benzazepineAS'-furanl^Offl-one

The title product was prepared from diethyl dihydrofuran-3(2H)-ylidenepropanedioate (Griffiths et ai , He!v Chim Acta 1991 , 74(2): 309-314) according to the method described for Intermediate 53. MS (ESI) m/z 218.2 (M÷H) + .

Intermediate 59 1 ,5,5’. e , -tetrahvdro-4 , H-spiron-benzazepjne-4.3 , -pyran]- one

The title product was prepared from diethyl dihydro-2H-pyran-3(4H)- ylidenepropanedioate (Griffiths et al., Helv Chim Acta 1991 , 74{ 2):309-314) according to the method described for Intermediate 53. MS (ESI) m/z 232 1 (M+H) + .

Intermediate 60

7-bromo-1.5-dih¥drospiroi C¥clopentan1-2(3ffl-one

To a solution of 0.51 g (2.37 mmol) of 1 ,5-dihydrospiro[1-benzazepine-4,T- cyclopentan]~2(3/-/)~one (Intermediate 55), 10 mL of acetic acid and 2 mL of water a solution of 0 121 mL (2.37 mmol) of bromine (Aldrich) and 3 mL of acetic acid was slowly added. After stirring the reaction mixture for 1 hour at room temperature, it was poured on ice, the precipitation was filtered by suction and dried. Thus, 0 50 g (72 %) of the title product was obtained as beige crystals MS (ESI) m/z 294.2 & 296 1 (M+H) + .

Intermediate 61

7-bromo-4-(propan-2~¥B -2H-1-benzazepin-2-one

The title product was prepared from 4-(propan-2-yl)-1 ,3,4,5-tetrahydro-2H-1- benzazepin-2-one (Intermediate 56) according to the method described for Intermediate 60 MS (ESI) m/z 282.1 & 284 1 (M÷H) + .

Intermediate 62

7-bromo-1,5-di benzazepine-4 ' 4’--oxanl-2i3H)-Qne The title product was prepared from 1 ,5-dihydrospiro[1-benzazepine-4,4'-oxanj- 2(3H)-one (intermediate 57) according to the method described for Intermediate 60. MS (ESI) m/z 310.1 & 312.1 (M+H) + .

7-bromo-1 ,S-dihydrospiron-benzazepjne-4,3 , -oxolan1-2i3H¾ One

The title product was prepared from 1 ,4',5,5'-tetrahydrospiro[1-benzazepine-4,3'- furan]-2(3H)-one (Intermediate 58) according to the method described for Intermediate 60. MS (ESI) m/z 296.2 & 298.2 (M÷H) + .

7-chjoro-1.5-dshvdrospiroi1-benzazepine-4.4 ! -oxanl-2i3H¾-one

To a solution of 0.73 g (3.16 mmol) of 1 ,5-dihydrospiro[1-benzazepine-4,4'-oxan]- 2(3H)-one (Intermediate 57) and 20 mL of DMF 0.59 g (4.42 mmol) of N-chlorosuccinimide was added. After stirring the reaction mixture for 1 hour at room temperature, it was poured on ice, the precipitation was filtered by suction and dried. Thus, 0.58 g (69 %) of the title product was obtained as yellow crystals. MS (ESI) m/z 266.1 (M÷H) + .

7 Chloro-1 ,S-dshvdrospiroi1-benzazepjne-4,3 i -oxan]-2i3 ¾-one

The title product was prepared from 1 ,5,5',6'-tetrahydro-4'H-spiro[1-benzazepine- 4,3'-pyran]-2(3H)-one (intermediate 59) according to the method described for intermediate 64. MS (ESI) m/z 266.2 (M+H) + .

7-chjoro-1 ,5-dshvdrospiroi1-benzazepine-4.3 , -oxoianl- one

The title product was prepared from 1 ,4',5,5'-teirahydrospiro[1-benzazepine-4,3'- furan]-2(3H)-one (Intermediate 58) according to the method described for Intermediate 64. MS (ESI) m/z 252.2 (M+H) + .

Intermediate 67

frans-4- ecarbohydrazide

a) methyl frans-4-(pyridin-2-ylamino)cydohexanecarboxylate

A mixture of 1.5 g (7.745 mmol) of methyl frans-4-aminocyclabexanecarboxyiate hydrochloride, 4 mL (46.5 mmol) of 2-fiuoropyridine and 1.35 mL (7.75 mmol) of DIPEA was stirred at 125 °C in a pressure-resistant glass reactor for 20 hours, then cooled to room temperature. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with 2x30 mL of water and saturated NaCI solution, the organic phase was dried over anhydrous Na 2 S0 4 , filtered and concentrated to yield 325 mg (18%) of the title compound. MS (ESI) m/z 235.1 (M+H) + .

b) frans-4-(pynd!n-2-ylamino)cydohexanecarbohydrazide

The title compound was prepared from methyl fra/?s-4-(pyridin-2- yiamino)cyclohexanecarboxyiate (Step a) of Intermediate 67) according to the method described in Step b) of intermediate 9 and if was used without further purification in the next step.

Example 1

methyl 8-chloro-1 - 4-ipyndin-2-yloxy¾C¥Clohexyn-5,6-dihydro-4H- A solution of 92 mg (0.34 mmol) of methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1- benzazepine-4-carboxyiate (Intermediate 4), 96.5 mg (0.41 mmol) of frans~4~(pyridin~2~ yioxy)cyclohexane carboxylic acid hydrazide (WO2010/060836 A1 (03.06.2010) F. HOFFMANN-LA ROCHE AG.) and 10 mL of xylene was stirred at reflux temperature for 3 days. The reaction mixture was concentrated and the residue was purified by column chromatography using diehloromethane:methanol=2G: 1 as eluent. Thus, 68 mg (44.0%) of the title product was obtained. MS (ESI) m/z 454.2 (M÷H) + .

Example 2

8 Chloro-1- 4-ipyridin-2-yloxy¾cvclohexyn-S,8 djhvdro-4H-i1 ,2.4]tnazeloi4,3-

0.85 g (1.88 mmol) of methyl 8-chloro-1-[/rans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4/-/-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate (Example 1 ) was dissolved in 60 mL of methanol, then 20 mL of 2 M NaOH solution was added and the mixture was stirred overnight. Methanol was then evaporated from the reaction mixture, the pH of the aqueous phase was adjusted to 3 with 1 hydrochloric acid solution, then extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated. Thus, 0.83 g (99.9%) of the title product was obtained. MS (ESI) m/z 439.1 (IVRH) +

Example 3

-chloro-1 -l

0.4 g (0.91 mmol) of 8~chloro-1-[frans~4~(pyridin-2-yioxy)cyclohexyl]-5,6-dihydro ~4H- [1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxyiic acid (Example 2), 0.25 g (1.64 mmol) of HOBt and 0.314 g (1.64 mmol) of EDC was dissolved in 3 mL of dry DMF. The reaction mixture was cooled in ice-water bath and 0.146 g (2.73 mmol) of ammonium chloride and 0.443 mL (2.55 mmol) of D!PEA were added under argon. The reaction mixture was stirred at 0°C for 2 hours and then at room temperature overnight. Water was added to the reaction mixture, extracted with ethyl acetate, the combined organic phases were washed with saturated NaCI solution, dried over anhydrous NaaSCU, filtered and concentrated in vacuo. Thus, 0.34 g (85.4%) of the title product was obtained. MS (ESI) m/z 438.2 (M-s-H)*.

Example 4

8-ch loro-1 -Itrans- 4-

0 26 g (0.60 mmol) of 8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro- 4H-[1 ,2,4]iriazo!a[4,3-a][1]benzazepine-5-carboxamide (Example 3) was dissolved in 4 4 mL of pyridine. Then, it was cooled to 5°C and 56 mI_ (0.60 mmol) of phosphorus oxychloride was added to the reaction mixture. This mixture was stirred at room temperature overnight. The reaction mixture was then concentrated, water was added to the residue and the pH of the aqueous phase was adjusted to 9 with 1 M NaOH solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous NaaSCh, filtered and concentrated. The residue was purified by column chromatography using dichioromethane:methanoi=2Q:1 as eluent. Thus, 0.177 g (70.2%) of the title product was obtained. MS (ESI) m/z 420.2 (M÷H) + .

The title product was prepared from 8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyi]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylic acid (Example 2) and dimethylamine (2 M solution in THF) according to the method described in Example 3. MS (ESI) m/z 466.2 (M+H) + .

The title products were prepared from the racemic 8~chioro-/V,A/-dimethyl-1-[frans~4~ (pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5- carboxamide (Example 5) by chiral preparative HPLC (CHIRALPAK IA with preparative 20 pm stationary phase, 2.5x20cm; F=15ml_/min, eluent: n-hexane:EtOH=75:25 + 0.3% diethylamine; isocratic, t= : 25 0 C). Retention time of the first eluting compound is 11.3 min; [a 5 = -8.3° (c=0.1 ; methanol); retention time of the second eluting compound is 19.7 min;

[a 5 = +4.9° (c=0.1 ; methanol). The absolute configuration of the compounds was not determined.

8-chjoro-W-ipropan-2-¥n-1-ifra/?s-4-

!,2,41tnazojoi4,3-airilbenzazepine-5-carboxamide

The title product was prepared from 8-cbloro-1-[ira/?s-4-(pyridin-2-y!oxy)cyelohexyl]-

5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylic acid (Example 2) and isopropylamine according to the method described in Example 3. MS (ESI) m/z 480.2 (M+H) + .

Example 9

{8-chloro-1-ifra/?s-4-{D¥ridjn-2-vfox¥)cvdohex¥n-5.8-dihv dro-4H-i1,2,4ltnazoloi4,3-

The title product was prepared from 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]- 5 > 8-dihydro-4H-[1 ,2 4]triazolo[4,3-a][1]benzazepine-5-carboxylic acid (Example 2} and pyrrolidine according to the method described in Example 3 MS (ESI) m/z 492.2 (M+H) +

Example 10

f8-chloro-1-i rans-4-(pyridin-2-¥loxy¾C¥clohex¥n-5.6-dih¥dro-4H-n .2,4ltnazoloi4,3-

The title product was prepared from S~chloro-1-[frans-4~(pyridin-2-yloxy)cyciohexyi]- S^-dihydro^H-Cl ^^jtriazolo^.S-aji^ljbenzazepine-S-carboxylic acid (Example 2) and morpholine according to the method described in Example 3. MS (ESI) m/z 508.2 (M÷H) + .

a]nibenzazepin-5-¥lM1 ,1 -dioxidothiomorpholin-4-¥nmethanone

The title product was prepared from 8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylic acid (Example 2) and thiomorpholine-1 ,1-dioxide according to the method described in Example 3. MS (ESI) m/z 556.2 (M+H) + .

{8-chloro-1-ifra/?s-4-{D¥ridjn-2-vfox¥)cvcjohex¥n-5.8-dih vdro-4H-i1 ,2,4ltnazojoi4,3- a1lf11benzazepin-5~¥ methanoj

1.11 g (2.51 mmol) of methyl 8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate (Example 1) was dissolved in a mixture of 60 mL of dry diethyl ether and 60 mL of dry dich!oromethane and the solution was cooled to -20°C. A solution of 5.5 mL of 1 M lithium aluminium hydride in diethyl ether was added dropwise to the mixture and stirred at -20°C for 20 minutes. Water was carefully added to the reaction mixture, then the diethyl ether was evaporated in vacuo. The aqueous phase was then extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous NaaSG^ filtered and concentrated in vacuo. Thus, 0.955 g (85.4%) of the title product was obtained. MS (ESI) m/z 425.2 (M+H)\

n ^^ltriazoloj^S-ainibenzazepine-S-yliUmethanol

f(5S¾-8-chloro-1- 4-(P¥ridin-2-¥lox¥¾C¥ciohexyn-5.6-dih¥dro-4H-

ri .2,41tnazofolf4,3-a]rHbenzazepine-5-¥ll>methanQj

The title products were prepared from the racemic {8-chloro-1~[frans~4-(pyridin-2~ yloxy)eyclobexyl]~5,6~dihydro-4H-[1 ,2,4]triazo!o[4,3-a][1]benzazepin~5~yl}methanoi

(Example 12) by chiral preparative HPLC (CHIRALPAK IC with preparative 20 pm stationary phase; 2.5x20 cm; F=15 mL/min; eluent: n-hexane:EtOH=75:25; isocratic; t=25°C). The first eluting compound (retention time 7.0 min) was {(5R)-8-chloro-1-[fra/?s-4-(pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-yl}methanol (Example 13); [a]¾ 5 = +11.9° (c=0.1 ; chloroform); the second eluting compound (retention time 7.8 min) was {(5S)-3-ch!ora-1-[frans-4-(pyridin-2-yloxy)cyc!ahexyl]-5,6-d ihydro-4H- [1 ,2,4]triazo!o[4 3-a][1]benzazepine-5-yl}methanol (Example 14); [a]¾ X = -11.1° (c=0.1 ; chloroform). The absolute configuration of the compounds was determined by VCD method and by 1 H NMR spectroscopy of the diastereomeric pairs synthesised therefrom.

Example 15

8-chloro-5-(methoxymethvn-1-r^rans-4-ipyridin-2-yloxy)cvcloh exyll-5.6-djhvdro-4H- n .2,41triazolor4.3-a]i1]benzazepine

70 mg (0.16 mmol) of {8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihyd ro- 4H-[1 ,2,4]triazclo[4,3-a][1]benzazepin-5-yl}methanol (Example 12) was dissolved in 2 mL of dry THE, then the solution was cooled to -5°C. 13 mg (0.32 mmol) of 60% sodium hydride dispersion in oil was added and stirred under cooling for 90 minutes, then 12 pL (0.2 mmol) of iodomethane was added to the reaction mixture and stirred at room temperature for 2 hours. Next 12 pL (0.2 mmol) of iodomethane was again added and the mixture was heated at 40°C for 2 hours. The reaction was diluted with 30 mL of water, then extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous NasSC^, filtered, and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=50:1 as eluent. Thus, 20 mg (28%) of the title product was obtained. MS (ESI) m/z 439 2 (M+H) + .

Example 16

{8-chloro-1-ifrar?s-4-(pyridjn-2-yloxy)cvclohexyn-5,6-dihvdr o-4H-i1,2,41tnazoloi4,3- ainibenzazep -S-ylImethyl-morpheline-^-carboxylate

a) _ {8-cbloro-1-i/rans-4-Cpyridin-2-yioxy)cvclohexyll-5,6-dibydr O-4rt-n ,2,4]triazoloi4,3- alHlbenzazepin-5-yl}methyl-methanesulfonate

0.855 g (2.01 mmol) of {8-cbloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dibyd ro- 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanol (Example 12) was dissolved in 80 mL of dry dichlorcmethane, then cooled to OX. To this, 0.785 mL (5.63 mmol) of triethylamine, 0.258 mL (3.38 mmol) of ethanesulfonyl-chloride and 34 mg (0.28 mmol) of DMAP were added. The reaction mixture was stirred for 1 hour at OX and then at room temperature overnight. The reaction mixture was washed with saturated NaHCOs solution and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with saturated NaC! solution, dried over anhydrous NazSC^, filtered and concentrated. Thus, 1.0 g (99%) of the title product was obtained. MS (ESI) m/z 503 1 (M+H) + .

alHlbenzazepin-5-yl)methyl-morpholin-4-carboxylate

0.053 g (0.108 mmol) of {8-chloro-1-[fra/7S-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihyd ro-

4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yi}methy!-mefbanesulfona te (step a) of Example 16) was dissolved in 5 mL of dry DMF. To this, 0.030 mL (0.212 mmol) of triethylamine, 0.038 g (0.117 mmol) of cesium carbonate and 0.050 mL (0.573 mmol) of morpholine were added, and the mixture was stirred at 100X for two days. The reaction mixture was then allowed to cool, wafer was added and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCi solution, dried over anhydrous NasSO , filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=20:1 as eluent. Thus, 0 013 g (23.0%) of the title product was obtained. MS (ESI) m/z 538.2 (M+H) + .

{8-chloro-1- 4-(D¥ridin-2-v!ox¥¾cvc!ohexyn-5,8-djhvdro-4H-i1 ,2.4]triazojoi4,3-

40 mg (0.09 mmol) of {8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihyd ro- 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanol (Example 12) was dissolved in 3 mL of dry THF, cooled to 5°C and 24 pL (0.17 mmol) of triethylamine was added while introducing argon. 14 mg (0.10 mmol) of 4-fluorophenyl isocyanate in 1 mL of dry THF was added to this reaction mixture. The reaction did not take place even at reflux temperature, therefore it was concentrated. The resulting material was dissolved in 5 mL of acetonitrile and 4 mg (0.09 mmol) of 60% sodium hydride dispersion in oil was added. This reaction mixture was stirred overnight at room temperature then concentrated. The residue was purified by column chromatography using dichloromethane:methanol=20: 1 as eluent. Thus, 35 mg (66%) of the title product was obtained. MS (ESI) m/z 562.2 (M+H) + .

5-(azidometh¥n-8-chioro-1 -r rar?s-4-ipyridin-2-¥loxy¾cvdohexyn-5.6-dihvdro-4H-

0.418 g (0.83 mmol) of {8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydr o- 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methyl-methanesulfona te (step a) of Example 16), 10 mL of dry DMF and 0.162 g (2.49 mmol) of sodium azide were filled to a pressure- resistant glass reactor, then stirred at 80°C for 4 hours. Water was then added to the reaction mixture and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na2SG4, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=20: 1 as eluent. Thus, 0.26 g (69.5%) of the title product was obtained. MS (ESI) m/z 450.2 (M+H) + .

1 -l8-chloro-1 - 4-{pyridjn-2-¥joxy¾cvcjohex¥n-5.8-djh¥dro-4H-i1.2,4ltnaz o!oi4,3- ainibenzazepin-5-¥l}methane amine

0.242g (0.54 mmol) of 5-(azidomethyl)-8-chloro-1-[frans-4-(pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine (Example 18) was dissolved in 20 mL of THF, then 1 mL of water and 0.423 g (1.81 mmol) of triphenylphosphine were added. The reaction mixture was stirred under argon at room temperature overnight, then concentrated and the residue was purified by column chromatography using dichioromethane:methanol:ammonium hydroxide=10: 1 :Q.1 as eluent. Thus, 0.183 g (80%) of the title product was obtained. MS (ESI) m/z 424.2 (M+H)T

8-chloro-5-(mo

100 mg (0.20 mmol) of {8~ebloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6~dibydr o~ 4H-[1 ,2,4jtriazolo[4,3-a][1jbenzazepin-5-yi}methyl-methanesulfona te (step a) of Example 18), 3 mL of dry DMF, 0.42 mL (2.39 mmol) of DIPEA and 0.21 mL (2.39 mmol) of morpholine were filled to a pressure-resistant glass reactor, then stirred at 1 10°C for one day. The reaction mixture was then allowed to cool, water was added and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCi solution, dried over anhydrous NaaSCL, filtered and concentrated. The residue was purified by column chromatography using dichloromethane^ethano SOi l as eluent. Thus, 59 mg (80%) of the title product was obtained. MS (ESI) m/z 494.2 (M+H) + .

1 -f8-chloro-1 -i rans-4-(pyridin-2-¥loxy¾C¥clohex¥n-5,e-djh¥dro-4H-n .2,4ltnazoloi4,3- airi1benzazepjn-5- djmeth¥jmethane amine

The title product was prepared from {8-chloro-1-[frans-4-{pyridin-2-ylQxy)cyciohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methyl-methanesulfona te (step a) of Example 16) and dimethylamine (2 M solution in THF) according to the method described in Example 20. MS (ESI) m/z 452,2 (M+H) + . jV-i 8-ch!oro-1-ifraws-4-iD¥ridin-2-¥jox¥¾C¥Cjohex¥0-S.8-ds hvdro-4H-i1.2,4]tnazojoi4,3-

50 mg (0.12 mmol) of 1-{8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihy dro-

4H-[1 ,2,4]triazo!o[4,3-a][1]benzazepin-5-yi}methanamine (Example 19) was dissolved in 5 mL of 1 ,2-dichloroethane, then 14 pL (0.25 mmol) of acetic acid, 45 pL (0.61 mmol) of acetone, and 77 mg (0.37 mmol) of sodium triacetoxyborohydride were added. The reaction mixture was stirred for one day at room temperature, then water was added. The pH of the aqueous phase was adjusted to pH=9 with 1 M NaOH solution and the organic phase was separated. The aqueous phase was extracted with dich!oromethane and the combined organic phases were washed with saturated NaCI solution, dried over anhydrous NazSC , filtered and concentrated. The residue was purified by column chromatography using dich!oromethane:methanol:ammonium hydroxide=10:1 :0.1 as eluent. Thus, 46 mg (83.6%) of the title product was obtained MS (ESI) m/z 466.2 (M÷H) +

methyl 8-chloro-

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5~tetrahydro-1H~ 1-benzazepine-4-carboxylate (Intermediate 4) and 1-(pyri idin-2-yl)azetidine-3-carboxylic acid hydrazide (Intermediate 13) according to the method described in Example 1. MS (ESI) m/z 411. 1 (M+H) \

Example 24

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H- 1-benzazepine~4-carboxylate (Intermediate 4) and fran$~4~(dirnethy!amino)cyciohexane carboxylic acid hydrazide (intermediate 11) according to the method described in Example 1. MS (ESI) m/z 403.2 (M+H) \

methyl 8-chlorO 1 ifra/iS 4 Ctnfjuoromethvncvclohexyn-S,8-dshvdro-4H-

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-ietrahydra-1H- 1-benzazepine-4-carboxylate (Intermediate 4) and fra/?s-4-(trifiuoromethyl)cyciohexane carboxylic acid hydrazide (Intermediate 6) according to the method described in Example 1. MS (ESI) m/z 428.1 (M+H) + methyl 8-chloro-1-r rans-4-imorpholjn-4-¥nc¥clohexyn-5.8-dihvdro- ri,2,4ltriazolor4,3-ali1lbenzazepjne-5-carboxylate

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5~tetrahydro-1 H~ 1-benzazepine-4-carboxy!ate (Intermediate 4) and frans-4-(morpholin-4-yl)cydohexane carboxylic add hydrazide (Intermediate 12) according to the method described in Example 1. MS (ESI) m/z 445.2 (M÷H) + .

63 mg (0.15 mmol) of {8-chloro-1-[frans-4-(pyridin-2-yloxy)cydohexyl]-5,6-dihydro - 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yi}methanoi (Example 12) was dissolved in 15 mL of ethanol, then 65 mg of 10% Pd/C was added to the solution and hydrogenated at room temperature. After completion of the reaction , the catalyst was filtered off, washed with ethanol and the filtrate was concentrated. The residue was purified by column chromatography using dichioromethane:methanol:ammonium hydroxide^ 10: 1 :0.1 as eluent. Thus, 23 g (39%) of the title product was obtained. MS (ESI) m/z 391.2 (M÷H) + .

methyl 8-chjoro-1 - 5.6-dih¥dro-4H-

A solution of 56.8 mg (0.21 mmol) of methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (Intermediate 4), 75.6 mg (0.32 mmol) of trans- 4-(pyrrolidin-1- ylcarbonyhcyclohexane carboxylic acid hydrazide (Intermediate 9) and 2 mL of n-butano! was refluxed for 28 hours, then the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography using dichioromethane:methanol=9: 1 as eluent. Thus, 29.6 mg (31 %) of the title product was obtained. MS (ESI) m/z 457.2 (M+H) +

f8-chloro-1-ifrans-4-(P¥ndjn-2-ylox¥)cvdohexyn-5,8-djhy dro-4H-i1 ,2,4ltriazoloi4,3- a]i1]benzazepin-5-yl}acetonitrile

A mixture of 100 mg (0.20 mmol) of {8-cbloro-1-[ffa/?s-4-(pyridin-2-yloxy)cyciohexyi]- 5,6-dihydrc-4H-[1 ,2,4]triazclo[4,3-a][1]benzazepin-5-yl}methyl-methanesuifona te (step a) of Example 16), 10 mL of dry DMF and 25 mg (0.52 mmol) of sodium cyanide was stirred in pressure-resistant glass reactor at 80°C for 5 hours. Water was then added to the reaction mixture and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na2SG4, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=20:1 as eluent. Thus, 62 mg (71.8%) of the title product was obtained. MS (ESI) m/z 434.2 (M+H) + . Example 30

8-chloro-5-if4-methylplperaz j n-1-vnmethvn-1-ifrans-4-(pyrid j n-2-vSoxy¾cy ohexyn-

5,8-dihvdro-4H i1.2,4]triazoloi4 ' 3-ali1lbenzazepjne

The title product was prepared from {8-chloro-1-[#ra/7s-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methyl-methanesulfona te (step a) of Example 16) and 1 -methyl-piperazine according to the method described in Example 20. MS (ESI) m/z 507.2 (M+H) + .

8-chloro-5-(fluorometh¥n-1 - 4-fP¥ridin-2-yloxy¾cyclohexyn-5.6-dshydro-4H-

n .2.4]triazolor4.3-a]i1]benzazepine

100 mg (0.20 mmol) of {8-chlorc-1-[fra/7s-4-(pyridin-2-yloxy)cycichexyl]-5,6-dihyd ro- 4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methyl-methanesulfona te (step a) of Example 16) and 1 mL of 1 tetrabutyiammonium fluoride solution in THF were stirred under argon at reflux temperature overnight. Water was then added to the reaction mixture and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous NaaSC^, filtered and concentrated. The residue was purified by preparative HPLC (Kinetex EVO C18 with 5 pm loading; 150x21.2 mm; F = 20mL/min; eluent: A: wafer, B: acetonitrile, gradient: B% 15 70; t=40°C). Thus, 21 mg (24.7%) of the title product was obtained. MS (ESI) m/z 427.2 (M+H) +

A mixture of 50 mg (0 11 mmol) of 8-chloro-1-[#/a/7s-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylic acid (Example 2), 21 g (0.13 mmol) of HOBt, 26 mg (0.13 mmol) of EDC and 1 mL of DMF was stirred under argon at room temperature for 15 minutes, then 10 mg (0.13 mmol) of A/-hydroxyacetamidine and further 1 mL of DMF were added. The reaction mixture was stirred overnight at 100°C. The reaction mixture was then allowed to cool to room temperature, water was added and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCi solution, dried over anhydrous Na 2 S0 4 , filtered, and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=50:1 as eluent. Thus, 29 mg (53.7%) of the title product was obtained. MS (ESI) m/z 477.2 (M÷H) + .

A mixture of 90 mg (0.21 mmol) of 8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carbonitrile (Example 4), 2.5 mL of DMF, 133 mg (2.04 mmol) of sodium azide and 111 mg (2.08 mmol) ammonium chloride was stirred in a pressure-resistant glass reactor at 115°C for 4 hours. The reaction mixture was allowed to cool, water was added and extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous NaaSCU, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=3:1 as eluent. Thus, 54 mg (54 5%) of the title product was obtained. MS (ESI) m/z 463.2 (M+H) + .

AWS-chloro-l

The title product was prepared from 1-{8-chloro-1-[fra/7s-4-(pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanamine

(Example 19) and tetrahydro~4H-pyran-4-one according to the method described in Example

22. MS (ESI) m/z 508.2 (M+H) + .

The title product was prepared from 1-{8-chloro-1-[frans-4-(pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanamine

(Example 19) and 4,4-difluoro-cyclohexanone according to the method described in Example 22. MS (ESI) m/z 542.2 (M+H) + .

methyl 8-chjoro-1- 3- eth¥j-2-oxo-1-oxa-3-azaspiror4.5ldec-8-vn-5,6-djh¥dro-

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5~tetrahydro-1H~ 1-benzazepine-4-carboxylate (intermediate 4) and (frans)-3-metbyi-2-oxo-1-oxa-3- azaspiro[4 5]decane-8-carboxylic acid hydrazide (Intermediate 17) according to the method described in Example 1. MS (ESI) m/z 445.2 (IVRH) +

jV-f{8-chloro-1- fraws-4-(pyridjn-2-yloxy¾C¥cjohexyn-5,8-dshydro-4H-n ,2,41tnazoioi4,3-

45 mg (0.12 mmol) of 1-{8-cbloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6~diby dro~ 4H-[1 ,2,4]triazolo[4,3-a][1]benzazep!n-5-yl}methanamine (Example 19) was dissolved in 5 mL of pyridine, then 0.10 mL (1.06 mmol) of acetic acid anhydride was added. The reaction mixture was stirred at room temperature for 4 hours, then concentrated. The residue was dissolved in water. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated. Thus, 44 mg (89.0%) of the title product was obtained. MS (ESI) m/z 466.2 (M+H) + .

The title product was prepared from 1-{8-chloro~1~[frans-4-(pyhdin~2~ yloxy)eyc!obexyi]-5,6-dihydro-4H-[1 ,2,4]triazo!o[4,3-a][1]benzazepin-5-yl}methanamine (Example 19) and 3-oxetanone according to the method described in Example 22. MS (ESI) m/z 480.2 (M÷H) + . Example 39

methyl 8-chloro-1 - 4-(morpho n-4-ylcarbonyl)cvclohexyn-5,8-dihydro-4H-

5-carboxylate

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (intermediate 4) and frans-4-(morpholin-1- yicarbony!)cyclohexane carboxylic acid hydrazide (intermediate 10) according to the method described in Example 28. MS (ESI) m/z 473.2 (M+H) + .

methyl 8-o^qGq-1-|o/5-3-ίTί6ίΐΊ¥ΐ·-2-oco-1-oc3-3-3Z35rIί ,, oG4·5ΐ€ΐIqo·-8-nP-5,8-oIIHn€ΐIί ,, o-4 ·/- 5-carboxylate

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-ietrahydro-1H- 1-benzazepine-4-carboxylate (Intermediate 4) and (c/s)-3-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decane-8-carboxy!ic acid hydrazide (Intermediate 18) according to the method described in Example 1. MS (ESI) m/z 445 2 (M+H) + .

methyl 8~chloro-1-i1-fpyndin-2-ynazetidin-3-yn~5,8-dihydro-4H~i1 ,2.4]tr , iazojoi4,3- ainibenzazepine-5-carboxylate

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydra-1H- 1-benzazepine-4-carboxylate (Intermediate 4) and 1-(pyridin-2-yl}azetidine-3-carboxylic acid hydrazide (Intermediate 14) according to the method described in Example 28. MS (ESI) m/z 410.1 (M+H) + .

methyl 1-ifrans-4-iazetidin 1 Vjcarbonvj¾cvcjohexyn-8-chloro-S,8 djhvdro-4H

The title product was prepared from methyl 7-cb!aro-2-thioxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (Intermediate 4) and frans-4-(azetidin-1- y!carbonyl)cyclohexane carboxylic acid hydrazide (Intermediate 19) according to the method described in Example 1. MS (ESI) m/z 443.2 (M÷H) + .

8-chloro-1- -ylmeth¥n-5,8-dihydro-

The title product was prepared from {8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]- 5 > 8-dihydro-4H-[1 ,2 4]triazolo[4,3-a][1]benzazepin-5-yl}methyl-methanesulfonate (step a) of Example 16) and pyrrolidine according to the method described in Example 20. MS (ESI) m/z 478.2 (M+H) + .

Example 44

The title product was prepared from 1-{8-chloro-1-[irans-4-(pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanamine

(Example 19) and 2-methyipropana! according to the method described in Example 22. MS (ESI) m/z 536.3 (M÷H) + .

methyl 8 Chlor ,8 dihvdro-4H

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (Intermediate 4) and f/ar?s-4-(piperidin-1- yicarbonyl)cyclohexane carboxylic acid hydrazide (Intermediate 20) according to the method described in Example 28. MS (ESI) m/z 471.2 (M+H) + .

chloro-5.8-dih¥dro-4H-n zazepine-5-carboxylate

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxy!ate (Intermediate 4) and /erf-butyl 4-{[frans-4- (hydrazinylcarbonyl)cyclohexyl]carbonyl}piperazine-1-carboxy late (Intermediate 21) according to the method described in Example 28. MS (ESI) m/z 572.2 (M+H) + .

methyl 8-chjoro-1-rfraf?s-4-iDiperazin-1-vjcarbon¥ncvclohex¥n-5.8 -dih¥dro-4H- ¥jate hydrochloride

41 mg (0.07 mmol) of methyl 1-(frans-4-{[4-(/erf-butoxycarbonyl)piperazin-1- yl]carbonyl}cyclohexyl)-8-Ghloro-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5- carboxyiate (Example 48) was dissolved in 1 mL of ethyl-acetate and 1 mL of 2.5M hydrogen chloride solution in ethyl acetate was added to the solution. The reaction mixture was stirred at room temperature for 1 hour and then diethyl ether v / as added. The precipitated product was filtered and washed with diethyl ether. Thus, 30.5 mg (84%) of the title product was obtained. MS (ESI) m/z 472.2 (M+H) + . methyl 8-methoxy-1- 4-iP¥ridin-2-ylox¥¾C¥clohexyn-5,8-dih¥dro-4H-

The title compound was prepared from methyl 7-methoxy-2-thloxo-2, 3,4,5- tetrahydro-1H-1-benzazepine-4-carboxyiate (intermediate 26) according to the method described in Example 1. MS (ESI) m/z 449.3 (M+H) + . methyl S-methyli-

ri .2.4]triazolor4.3-a]rilbenzazeplne-5-carboxylate

The title compound was prepared from methyl 7-methyl-2-thioxo-2,3,4,5-tetrahydro- 1H-1-benzazepine-4-carboxylate (Intermediate 25) according to the method described in Example 1. MS (ESI) m/z 433 2 (M÷H) + . Example 50

8-chloro-^-(4-fluorophenvn-1-i rans-4-(pyridjn-2-¥joxy¾C¥ ohexyn-5.e-djhvdro-4H- carboxamjde

To an ice-cold mixture of 100 mg (0 23 mmol) of 8-chloro-1-[frans-4-(pyridin-2~ yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylic acid (Example 2), 15 mL of DMF, 84 mg (0 55 mmol) of HOBt, 151 mI_ (0.87 mmol) of DIPEA and 105 mg (0.55 mmol) of EDC 25 mg (0.23 mmol) of 4-fluoroaniline was added and the reaction mixture was stirred at 5°C for 0.5 h, then at room temperature for 20 h. After completion of the reaction the mixture was diluted with water and brine and extracted with ethyl acetate. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash column chromatography using dichioromethane:methanol = 95:5 as eluent to yield 105 mg (87%) of the title compound MS (ESI) m/z 532.1 (M+H) + methyl 8-bromo-1- 4-(pyridin-2-vjoxy¾cvclohexyn-5,8-dihvdro-4H-

ri .2,41tnazojor4.3-airi1benzazepsne-5-carboxySate

The title compound was prepared from methyl 7-bromo-2-thioxo-2,3,4,5-tetrahydro- 1H-1-benzazepine-4-carboxylate (Intermediate 27) according to the method described in Example 1. MS (ESI) m/z 499 1 (M+H) + . Example 52

1-f1,4'-bipiperidin-1 -¥n-8~chloro-5,8-dihvdro~4H-ri ,2,4ltriazojQr4,3~3inibenzazepine~

S-carboxamlde

A mixture of 34 mg (0.1 ol) of 1-bromo-8-chloro-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine- 5-carboxamide (intermediate 29), 0.3 mL of suifoiane and 218 mg (1.3 mmol) 4-piperidinopiperidine was stirred at 180°C for 3 h, then cooled to room temperature. The reaction mixture was diluted with dichloromethane, washed with brine, the organic phase was dried over MgSG 4 , filtered and concentrated. The residue was purified by flash column chromatography using dichioromethane:methanoi:ammonium hydroxide = 9: 1 :0.1 as eluent to yield 13 mg (30%) of the title compound. MS (ESI) m/z 429.2 (M+H) + .

Example 53

methyl 8-chloro-1-r(5r.8r¾-1-oxo-2-(propan-2-¥n-2-azaspsror4.5lde c-8-vn-5,8-dihvdro-

The title compound was prepared from methyl 7~chloro-2-thioxo-2,3,4,5-tetrahydro~ 1 H-1-benzazepine-4-carboxylate (intermediate 4) and (5r,8r)-1-oxo-2-(propan-2-y!)-2- azaspiro[4.5]decane-8-carbohydrazide (Intermediate 32) according to the method described in Example 28. MS (ESI) m/z 471.2 (M+H) + .

Example 54

a) . 5-(1- -8-chloro-1

The title compound was prepared from 4-(1-{[te/t-butyl(dimethyl)silyi]oxy}ethyi)-7- chloro-1 ,3,4,5-tetrahydro-2H-1-benzazepine-2-thione (Intermediate 34) according to the method described in Example 1. It was a 55:45 mixture of diastereomers. MS (ESI) m/z 553.2 (M+H) + .

b) 1-{8-chloro-1-ifrans-4-(pyndin-2-yloxy)cydohexyll-5.6-dihydr o-4H-n ,2,4ltriazoloi4,3- a][1]benzazepin-5-y!}ethano!

A stirred mixture of 222 mg (0.4 mmol) of 5- ( 1 -{[terf- b uty I (d i m ethy I) s i ly I ] oxyjethy I)- 8- chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4 i4-[1 > 2,4]triazolo[4,3- a][1]benzazepine (Step a) of Example 54) and 40 mL of dry THF was cooled to 0°C and 0.8 mL (0.8 mmol) of 1M tetrabutylammonium fluoride solution in THF was added and the reaction mixture was stirred at room temperature for 20 h, then concentrated. Water was added to the residue and it was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SG 4 , filtered and concentrated. The residue was purified by flash column chromatography using dich!oromethane:methanoi = 9:1 as eluent to yield 172 g (98%) of the title compound. It was a 54:46 mixture of diastereomers. MS (ESI) m/z 439.1 (M+H) + .

1-i8-chloro-1- 4-(pyridin-2-vtoxy¾cvctohexyn-5,8-dihvdro-4H-i1.2.4ltriazoj oi4.3-

A stirred mixture of 142 mg (0.32 mmol) of 1-{8-chloro-1-[fra/7s-4-(pyridin-2- yioxy)cyc!ohexyl]-5,6-dihydro-4H-[1 ,2,4]triazo!a[4,3-a][1]benzazepin-5-yl}ethano! (Example 54) and 10 mL of dichioromethane was cooled to 0°C and 206 mg (0.48 mmol) of Dess- Martin periodinane was added. The reaction mixture was stirred at room temperature for 3 h, then filtered. The filtrate was diluted with water, the phases were separated and the water phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over NazSC^, filtered and concentrated. The residue was purified by flash column chromatography using dich!oromethane:methanoi = 95:5 as eluent to yield 11 1 mg (79%) of the title compound. MS (ESI) m/z 437.2 (M+H) + .

8-chjoro-5-(fjuoromethvn-1 - 4-inethoxy-4-methvjcvdohexyi¾-5.6-dihvdro-4H-

The title compound was prepared from 7-chloro-4-(fluoromethyl)-1 ,3,4,5-tetrahydro- 2H-1~benzazepine-2-thione (Intermediate 37) and 4-methoxy-4-methylcyclohexane- carbohydrazide (Step c) of Intermediate 35) according to the method described in Example 1. MS (ESI) m/z 378.2 (M+H) \

1 -i8-chlorO 1-rfraf?S 4-fpyridjn 2-vjoxy¾cvcjohexyn-5 ' e-dihvdro-4H-i1 ,2,41tna2oloi4,3- ainibenzazepjn-5-¥j}-A -(2-methoxyethvnethanamine

A mixture of 30 mg (0.07 mmol) of 1-{8-chloro-1-[fra/7s-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethanone (Example 55), 5 mL of 1 ,2- dichloromethane, 24 pL (0.275 mmol) of 2-methoxyethylamine, 30 pL of acetic acid and 29 mg (0.137 mmol) of NaBH(OAc)3 was stirred at room temperature for 4 b, then concentrated. The pH of the residue was adjusted to 9 by addition of 1 M NaOH, then the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanoi = 97:3 as eluent to yield 12 mg (35%) of the title compound. It was a 58:42 mixture of diastereomers. MS (ESI) m/z 496.3 (M÷H) + .

Example 58 meth¥l 8-fluoro-1- 4-(P¥ndjn-2-¥lox¥¾C¥cjohex¥n-5.e-djh¥dro-4H-

The title compound was prepared from methyl 7-fluoro-2-thioxo-2,3,4,5-tetrahydro- 1H-1-benzazepine-4-carboxylate (Intermediate 39) according to the method described in Example 1. MS (ESI) m/z 437 4 (M+H) + .

8-chloro-5-(fluorometh¥n-1 -ifrar?s-4-(tnfluorometh¥l¾C¥clohexyn-5,6-djh¥dro-4H-

The title compound was prepared from 7-chloro-4-(fluoromethyl)-1 ,3,4,5-tetrahydro- 2H-1-benzazepine-2-thione (Intermediate 37) and frans-4-(trifiuoromethyl)cyciohexane- carbohydrazide (Intermediate 6) according to the method described in Example 1. MS (ESI) m/z 402 3 (M+H) + .

Example 60

5-(fjuoromethvn-1- yn-5,6-djhvdro-4H-

The title compound was prepared from 8-ch!oro~5~(f!uoromethyl)~1~(frans~4~methoxy- 4-methylcyclohexy!)-5,6-dihydro-4H-[1 ,2,4]triazoio[4,3-a][1]benzazepine (Example 56) according to the method described in Example 27. MS (ESI) m/z 344.3 (MH-H} + .

Example 61 4-(pyridin-2-vjoxy¾cvcjohex¥n-5,8-djh¥dro-4H-i1 ,2,4ltriazolor4,3-

The title compound was prepared from methyl 8~fluoro~1-[frans-4-(pyridln~2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate

(Example 58) according to the method described in Example 12. MS (ESI) m/z 409.3 (M+H) + .

8-fjuoro-5 hex¥n-5,6-djhvdro-4H-

The title compound was prepared from /’-fluoro-4-(fluoromethyl)-1 ,3,4,5-tetrahydro- 2H-1-benzazepine-2-thione (Intermediate 41) according to the method described in Example 1. MS (ESI) m/z 411 3 (M+H) \

c/s-(race -(8-chjoro-1-ifrans-4-ipvndsn-2·

chjoro-1-ifraas-4-ipyndsn-2-v!oxy¾cvc!ohexyn-5,8-dihvdrO 4H-

ri,2,4ltriazojor4,3-ali1lbenzazepjn-5-¥j}ethano!

5-ic/s-(racem)-1-{iteff-butvl(djmethvl)silvnoxv)ethvil-8-chi oro-1-ifra/?s-4-{pvridin-2- and

1-{ffe/i-butyl(dimethyl)silylloxy)ethyn-S~chloro-1-IYrans-4~ fpyridin-2- cvclohexyil-5.6-

The title compounds were prepared from the separated single diastereomers of 4-(1- {[ferf-butyl(dimethyl)silyl]oxy}ethyl)-7-chloro-1 ,3,4,5-tetrahydro-2H-1-benzazepine-2-thione (Intermediate 34) according to the method described in Example 1 They were single diastereomers, but their configuration was not determined MS (ESI) m/z 553.3 (M+H) + b) _ c/s-(racem)-1-f8-chloro-1 4-(pyridin-2-yloxy)cvclohexyn-5.6-dihvdro- f1 ,2,4ltriazoloi4,3-alf1lbenzazepin-5-yll-ethanoi and trans- (racem)- 1 -(8-chloro- 4-

(pyridin-2-yloxy)cyciohexyil-5,8-dihydro-4H-n ,2,41triazoio[4,3-ainibenzazepin-5-yl}ethanoi The title compounds were prepared from 5-[c/s-(racem)-1-{[ferf- butyl(dimethyl)silyl]oxy}ethyl]-8-chloro-1-[fra/7s-4-(pyridi n-2-yloxy)cyciohexyl]-5,6-dlhydro- 4H-[1 ,2,4]triazoio[4,3-a][1]benzazepine and S-ltrans-ifacemyi-ilteri- butyi(dimethyi)siiyl]oxy}ethyi]~8-chioro-1-[frans~4-(pyridin -2~yloxy)cyclohexyl]-5,8-dihydro- 4H-[1 ,2,4jtriazoio[4,3-a][1jbenzazepine (Step a) of Example 83 and 84) according to the method described in Step b) of Example 54. They were single diastereomers, but their configuration was not determined. MS (ESI) m/z 439.4 (M+H) + .

' 2,4]triazojof4,3-a]f1]benzazepin-5-yl}ethanoll

i1ffl-1 (5S¾-8-chloro-1-rfrai7s-4-(P¥ndin-2-¥jox¥¾cyclohexyn-5. 8-dih¥dro-4H- ri.2,4]tnazolor4.3-a]i1]benzazepln-5-¥llethanoj

The title compounds were obtained from the separated diastereomers: cis-( racem)- 1-{8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexylj-5,6-dihy dro-4H-[1 2,4]triazolo[4,3- a][1]benzazepin-5-yl}ethano! and frans-(racem)-1-{8-chlaro-1-[frans-4-(pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}ethanol (Example 63 and 64) by chiral preparative HPLC (CHIRALPAK IG preparative 20 pm stationary phase; 5x30cm; F=50ml_/min; e!uens: n-heptane: isopropanol=8:2; isocratic; t=25°C). Separation of one of the racemic mixture resulted in two compounds, the optical rotation of the first eluting compound (T r 13.9 min) was [a 0 = +14° (c=0.1 ; chloroform); and that of the second eluting compound (T r 16.7 min) was [ab° = -12° (c=0.1 ; chloroform). Separation of the other racemic mixture resulted in further two compounds, the optical rotation of the first eluting compound (T r 19.0 min) was [a]¾ 0 = +21° (c=0.1 ; chloroform); and that of the second eluting compound (T r 21.5 min) was [a 0 = -16° (c=0.1 ; chloroform). The absolute configuration of the compounds was not determined. Example 69

5-ffjuoromethvn-8-methyl-1-ifra??s-4-(pyndin-2-yloxy¾cvcjoh exyn-5,6-dlhvdro-4H-

The title compound was prepared from 4-(fluoromethyl)-7-methyl-1 ,3,4,5-tetrahydro- 2H-1-benzazepine-2-thione (Intermediate 43) according to the method described in Example 1. MS (ESI) m/z 407.3 (M+H) \

oro~ 5-(fluorometh¥n-1 -ifrans-4-(pvndin-2-vlex¥¾cvclohexvn-5,6-dihydro-4H-

The title compounds were obtained from the racemic 8-chloro-5-(fluoromethyl)-1- [frans-4-(pyridin-2-yloxy)cyclobexyl]-5,8-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine (Example 31) by chiral preparative HPLC (CHIRALPAK IG preparative 20 pm stationary phase; 5x30cm; F=50mL/min; eluent: fe/f-butyl methyl etherdichloro ethane^tOH^OOiS^; Isocratic; t=25°C) The first eluting compound (retention time 20.2 min) was (5S)-8-chloro-5- (fluoromeihyl)-1-[frans-4-(pyridin-2-y!oxy)cyclahexyl]-5,6-d ihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine (Example 70), [a]¾° = +6.3° (c=0.1 ; dichloromethane); and the second eluting compound (retention time 22.9 min) was (5R)-8-chloro-5-(fluoromethyl)-1-[fra/7s-4- (pyridin~2~y!oxy)cyc!ohexyi]~5,S-dibydro-4H-[1 ,2,4]friazo!o[4,3-a][1]benzazepine (Example 71), [a]o° = -8.9° (c=0.1 ; dichloromethane). The absolute configuration of the compounds was determined by VCD method. methyl 8-fl ihvdro-4H-

A mixture of 270 mg (0.1 mmol) of methyl 7-fluoro-2-(metby!suifanyi)-4,5-dihydra-3H- 1-benzazepine-4-carboxy!ate (Intermediate 44), 20 mL of 1 ,4-dioxane, 210 mg (0.1 mmol) of frans~4~(trifluoromethyi)cyciohexane-carbohydrazide (intermediate 8) and 10 pL of concentrated hydrochloric acid was refluxed for 1 h, then concentrated. The residue was purified by flash column chromatography using dichioromethane:methanol = 95:5 as eluent to yield 145 mg (35%) of the title compound. MS (ESI) m/z 412.1 (M+H) + .

8-chloro-1-i4-(2.3-dimethylphenvnpiperazin-1 -vn-5.8-dihvdro-4H-n .2.4ltriazolor4.3- a]i1]benzazepine-5-carboxamide

The title compound was prepared from 1-bromo-8-chloro-5,6-dihydro-4H- [1 ,2, 4]triazoio[4,3-a][1lbenzazepine- 5-carboxamide (intermediate 29) and 1-(2,3- dimethylphenyi)piperazine according to the method described in Example 52. MS (ESI) m/z 451.2 (M+H) + .

The title compound was prepared from methyl 8-fiuoro~1~[frans-4-

(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5- carboxyiate (Example 72) according to the method described in Example 12. MS (ESI) m/z 384.2 (M+H) + . {8-chjoro-5-methyl·1- 4H-

n ,2,41triazofoi4,3-a]i1]benzazepin-5-yl methano!

a) methyl 8-chloro-5-methyl-1-rfrans-4-(pyridin-2-yloxy)cvclohexyll-5, 6-dihydro-4/-/- i1.2.4ltriazoloi4.3-ali1lbenzazepine-5-carboxylate

The title compound was prepared from methyl 7-chloro-4-methyl-2-thioxo-2,3 4,5- tetrahydro-1H-1-benzazepine-4-carboxylate (Intermediate 46) according to the method described in Example 1. MS (ESI) m/z 467.1 (M+H) + .

b) _ (8-chloro-5-meth¥l-1-i/rans-4-(pyridin-2-ylox¥)cvclohex¥l l-5.6-dihvdro-4H- i1.2.4ltriazoloi4.3-ali1lbenzazepin-5-yl)methanol

The title compound was prepared from methyl 8-chloro-5-methyl-1-[frans-4-(pyridin- 2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate (Step a) of Example 75) according to the method described in Example 12. MS (ESI) m/z 439.1 (M+H) + .

i8-chjoro-5-ethyj-1-ifra??s-4-{p¥ndjn-2-vjox¥¾cvcjohexyn- 5,6-djhvdro-4H- n ' 2,41t!iazoio[4,3-a]f1]benzazepin-5-

a) methyl 8-chloro-5-ethyl-1-iYrans-4-(pyridin-2-vjoxy)cvclobexyll-5.8 -dihydro-4H- i1 ,2,4]triazo j of4,3-a][Hbenzazepine-5-carbox¥iate

The title compound was prepared from methyl 7-chloro-4-ethyl-2-(methylsulfanyl)- 4,5-dihydro-3H-1-benzazepine-4-carboxylate (Intermediate 49) according to the method described in Example 72. MS (ESI) m/z 481.2 (MH-H) + .

b) {8-chloro-5-ethyl-Hffans-4-(pyridin-2-yjox¥)cyclohexyjl-5,6 -dihydro-4H- i1 ,2.4ltriazoloi4.3-ali1lbenzazepin-5-yl)methanol

The title compound was prepared from methyl 8-ch!oro-5-eihyl-1-jYrans-4-{pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxylate (Step a) of Example 76) according to the method described in Example 12. MS (ESI) m/z 453.2 (M+H) + .

iSSl-8-fjuoro-5-iffuorometh¥n-1 -r^rans-4-(P¥ndsn-2-v!ox¥lc¥cSohexyn-5,8-dih¥dro-4H-

(5W-8-f!uoro-5-{fluorome 5,8-dih¥dro-4H-

The title compounds were obtained from the racemic 8-f!uoro-5-(fiuorometbyi)-1- [frans-4-(pyridin-2-y!oxy)cyclohexyl]-5,8-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine (Example 82) by chiral preparative HPLC (CHIRALPAK IA preparative 20 p stationary phase; 2 5x2Gcm; F=15mL/min; eluent: fe/t-buty! methyl ether:dichloromethane=75:25; isocratic; t=25°C). The optical rotation of the first eluting compound (T r 16 6 min) was [«I D 0 = +9° (c=0.1 ; dichloromethane); and that of the second eluting compound (T r 19.0 min) was [a ° = -10° (c=0.1 ; dichloromethane). The absolute configuration of the compounds was not determined.

8-chiorO 1-f4-f3-chiorophen¥r¾piperazin-1 ¥n-5,8-dih¥dro-4H-f1 ,2,4]triazojor4,3- ainibenzazepine-5-carboxamide

The title compound was prepared from 1~bromo~8~chloro-5,6-dihydro~4H- [1 , 2, 4]triazolo[4,3-a][1]benzazepine- 5-carboxamide (Intermediate 29) and 1-(3- chiorophenyl)piperazine according to the method described in Example 52. MS (ESI) m/z 457.2 (M+H) + .

The title compound was prepared from 1-bromo-8-chloro~5,8~dihydro-4H~

[1 ,2,4]triazoio[4,3-a][1]benzazepine- 5-carboxamide (Intermediate 29) and 1~(pyridin~2~ y!)piperazine according to the method described in Example 52. MS (ESI) m/z 424.2 (M÷H) + .

8-chloro-1 -[4-(pyndsn-2-yloxy¾psperidin-1 -vn-5.8-dihvdro-4H i1.2,4]triazolo[4 ' 3- ne-

The title compound was prepared from 1-bromo-8-chioro-5,6-dihydro-4H- [1 ,2,4]triazoio[4,3-a][1]benzazepine- 5-carboxamide (Intermediate 29) and 2-(piperidin~4~ yioxy)pyridine according to the method described in Example 52. MS (ESI) m/z 439.2 (M+H) ÷ . Example 82

5 i(benzvjoxy¾methvn-8-chjoro-1-r rar?s-4-(pyridin-2-yloxy)cvclohexyn-5.8 dihvdro-

4H-n 2 4ltriazoloi4 3-a1f11benzazepsne

A stirred mixture of 100 mg (0.24 mmol) of {8-chloro-1-[frans-4-(pyridin-2- yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanol

(Example 12) in 3 mL of dry DMF was cooled to 0°C and under argon 24 mg (0.59 mmol) of 60% sodium hydride in mineral oil was added. The mixture was stirred at this temperature for 0.5 h, then 70 mI_ (0.59 mmol) of benzyl bromide and 27 mg (0.07 mmol) of tetrabutylammonium iodide were added and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction the mixture was diluted with saturated ammonium chloride solution, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over NaaSC , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol= 95:5 as eluent to yield 44 mg (36%) of the title compound. MS (ESI) m/z 515.2 (M+H) +

methyl 8-chloro-1-(3.3-djfluorocvdobutyl¾-5,6-dihvdro- triazolor4,3-

airi1benzazepine-5-carboxylate

The title compound was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro- 1 H-1-benzazepine-4-carboxyiate (Intermediate 4) and 3,3-difiuorocyclobutane carboxylic add hydrazide (intermediate 51) according to the method described in Example 1. MS (ESI) m/z 368.1 (M÷H) + .

The title compound was prepared from methyl 7-chloro-2-fhioxo-2,3,4,5-tetrahydro~ 1 H-1-benzazepine~4~oarboxylate (Intermediate 4) and frans-4-(piperidin~1~ ylmethyl)cyclohexane carboxylic acid hydrazide (Intermediate 8) according to the method described in Example 1. MS (ESI) m/z 457.3 (M+H) + .

f8-chloro-1-ifra¥-4-(pyridin-2-vjoxy¾cvcjohexyn-5.8-dihvdr o-4H-i1.2.4ltriazoioi4.3- alfllb etate

A mixture of 100 mg (0.24 mmol) of {8-chloro-1-[frar)s-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-yl}methanol (Example 12), 5 mL of dichioromethane, 57 pL (0.7 mmol) of pyridine, 67 pL (0.7 mmol) of acetic anhydride and 3 mg (0.02 mmol) of DMAP was stirred at room temperature for 20 h, then diluted with water and extracted with dichioromethane. The combined organic layers were washed with brine, dried over ix^SC filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol= 97:3 as eluent to yield 38 mg (35%) of the title compound. MS (ESI) m/z 467.1 (M+H) + .

8-chjoro-1 spiroi2-ben2ofuran-1 ,4 ! -piperidin1-1 , -yi¾-5 6-dihydro-4H-

-5-carboxamide

The title compound was prepared from 1-bromo-8-chloro-5,6-dihydro-4H- [1 ,2,4]triazo!o[4,3~a][1]benzazepine- 5-carboxamide (Intermediate 29) and 3H~spiro[2~ benzofuran-1 ,4'-piperidine] (Combi-Blocks) according to the method described in Example 52. MS (ESI) m/z 450.2 (M+H) + .

Example 87 8-chloro-fV-(pyridin-2-vn-1- 4-(pyridin-2- 8-djhvdro-4H-

i1.2,4ltnazo!oi4,3-a]i1]benzazepine-5-carboxamide

To a stirred solution of 361 mg (0.82 mmol) of 8-chloro-1-[fra/7s-4-(pyridin-2- yloxy)cyc!ohexy!]-5,6-dihydra-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxy!ic acid (Example 2) in 25 mL of dicbloromethane 446 pL (5.3 mmol) of oxalyi chloride and 50 pL of DMF were added. The reaction mixture was stirred at room temperature for 30 min, then concentrated. The residue was dissolved in 5 mL of pyridine and 155 mg (1.64 mmol) of 2- aminopyridine was added. The so obtained reaction mixture was stirred at room temperature for 2 h, then concentrated and the residue was purified by preparative HPLC (XINETEX EVO 5 pm stationary phase; 150x21.2 mm; F=20mUmin; e!uens: (water+0.1 % trifluoroacetic acid): (methanol:acetonitrile=2:1)=52:48; isocratic; t=40°C) to yield 12.7 mg (3%) of the title compound. MS (ESI) m/z 515.2 (M+H) + .

A stirred solution of 78.6 mg (0.175 mmol) of 8-chloro-1-(1'H,3H-spiro[2-benzofuran- 1 ,4'-piperidin]-T-yl)-5,6-dibydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carboxamide (Example 86), 30 mL of dry dicbloromethane and 153 pL (1.1 mmol) of trietbylamine was cooled to 0°C and 40 pL (0.28 mmol) of trif!uoroaceiic anhydride was added. The temperature of the mixture was allowed to warm to room temperature and the reaction mixture was stirred at this temperature for 1 h, then 153 pL (1.1 mmol) of trietbylamine and 40 pL (0.28 mmol) of trifluoroacetic anhydride were added. The mixture was stirred at room temperature overnight, then 153 pL (1.1 mmol) of triethylamine and 80 pL (0.56 mmol) of trifluoroacetic anhydride were added and stirring was continued at room temperature overnight. The reaction mixture was diluted with saturated NaHCOs solution, the phases were separated and the water phase was extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over NazSC^, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol:ammonium hydroxide^ 180:10:1 as eluent to yield 11.5 mg (15%) of the title compound. MS (ESI) m/z 432.1 (M÷H) + .

8-chloro-1-i4-(2,3-dimeth¥jphenvnpiperazin-1-vn-5,8-dihvdro -4H-ri.2.4]triazolor4.3-

A mixture of 100 mg (0 31 mmol) of 1-bromo-8-chioro-5,8~dihydro-4H~ [1 ,2,4]triazolo[4,3-a][1]benzazepine-5-carbonitrile (Intermediate 52) and 412 mg (2.18 mmol) of 1-(2,3-dimethylphenyl)piperazine was stirred under argon at 180°C for 4 b, then cooled to room temperature. The residue was purified by column chromatography using diehioromethane:metbano!:ammonium hydroxide^ 180:10:1 as eluent to yield after crystallization from diethyl ether 28 mg (21 %) of the title compound. MS (ESI) m/z 433.1 (M+H) + .

The title compound was prepared from 1-bromo-8-chloro-5,8-dihydro-4H-[1 ,2,4]thazolo[4,3- a][1jbenzazepine-5-carbonitrile (Intermediate 52) and 1-(pyridin-2-y!)piperazine according to the method described in Example 89. MS (ESI) m/z 406.1 (M+H) + .

a) 7-fluoro-4.4-dimethyl-1.3,4,5-tetrahvdro-2H-1-benzazepine-2- thione

To a solution of 1.10 g (5.31 mmol) of 7-fluoro-4,4-dimethy!-1 ,3,4,5-tetrahydro-2H-1- benzazepin-2-one (Intermediate 53) and 10 mL of pyridine 2.79 g (6.90 mmol) of Lawesson reagent was added and the reaction mixture was refluxed for 2 hours. After this, the solvent was removed in vacuo, the residue was triturated with saturated NaHCCb and the precipitates were collected by filtration. Thus, 1.00 g (84 %) of the title product was obtained which was used without further purification.

b) 7-fluoro-4,4-dimethyl-2-(methylsulfanyl)-4,5-dihvdro-3rt-1-b enzazepine

To a mixture of 0.40 g (1.68 mmol) of 7-fluoro-4,4-dimethyl-1 ,3 4,5-tetrahydro-2H-1- benzazepine-2-thione (step a) of Example 91), 6.60 g (4.78 mmol) of potassium carbonate and 30 mL of acetone 0.297 mL (4.78 mmol) of iodomethane was added and the reaction mixture was stirred at 40°C for 1 hour. After evaporation of the solvent, water and ethyl acetate were added to the residue, the phases were separated and the water phase was extracted with ethyl acetate. The combined organic phases were washed with saturated NaCI solution, dried over anhydrous Na 2 S0 4 , filtered and concentrated. Thus, 0.40 g (99 %) of the title product was obtained which was used without further purification.

c) 8-fluoro-5,5-dimethyl-1-fffans-4-fpyridin-2- ,6-dihydro-4H-

f 1 ,2,41triazoioF4,3-ain Ibenzazepine

To a mixture of 0.30 g (1.26 m ol) of 7-fluoro-4,4-dimethyl-2-(methylsulfanyl)-4,5- dibydro-3H-1-benzazepine (step b) of Example 91), 0.30 g (1.26 mmol) of fra/?s-4-(pyridin-2- yioxy)cyc!ohexane carboxylic acid hydrazide (WO2010/060836 A1 (2010.06.03) F. HOFFMANN-LA ROCHE AG.) and 20 mL of 1 ,4-dioxane 0.010 mL of concentrated hydrochloric acid was added and the reaction mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was purified by column chromatography using dichloromethane:methanol=20:1 as eluent. Thus, 0.108 g (21 %) of the title product was obtained. MS (ESI) m/z 407.2 (IVRH) +

i-fjuoro-5-i

The title product was prepared from 7-fluoro-4-(propan-2-yl)-1 ,3,4,5-tetrahydro-2H-1- benzazepin-2-one (Intermediate 54) according to the method described in Example 91. MS (ESI) m/z 421.2 (M+H)\

The title product was prepared from 7-bromo-1 ,5-dihydrospiro[1-benzazepine-4,T- cyc!apentan]-2(3H)-one (Intermediate 60) according to the method described in Example 91. MS (ESI) m/z 493.1 & 495.1 (M+H) + .

The title product was prepared from 7-bromo-4-(propan-2-yl)-1 ,3,4,5-tetrahydro-2H- 1-benzazepin-2-one (Intermediate 61) according to the method described in Example 91. MS (ESI) m/z 481.1 & 483 1 (M+H) + . Examp le 95

8 , -bromo- -i rans-4-{pyridin-2-¥joxy)c¥ ohex¥n-2.3,5,6-tetrah¥dro-4'f/.e’H-

SDiroipyran-4,5' 1]benzazeDinel

a) 7-bromo-2-methoxy-3.5-dihydrospirof1-benzazepine-4,4'-oxanel

A mixture of 0.193 g (0.62 mmol) of 7-bromo-1 ,5-dibydrospiro[1-benzazepine-4,4'- oxan]-2(3H)-one (Intermediate 62), 0.183 g (1.24 mmol) of frimeihyioxonium tetrafluoroborate, 0.343 g (2.48 mmol) of potassium carbonate and 30 mL of dichloromethane was stirred at room temperature for 3 hours. Then the reaction mixture was filtered and the filtrate was concentrated. Thus, 0.190 g (98%) of the title product was obtained which was used without further purification.

b) 8'-bromo-T-lYrans-4-{pyridin-2-¥jox¥)c¥clohexyll-2,3.5,6- tetrah¥dro-4'H,6'H-spiroipyran- 4,5'-i1 ,2,41triazolo[4,3-aimbenzazepine1

To a mixture of 0.190 g (0.62 mmol) of 7-bromo-2-mefboxy~3,5~dihydrospiro[1~ benzazepine-4,4'-oxane], 0.161 g (0.68 mmol) of frans~4-(pyridin~2~yloxy)cyclohexane carboxylic acid hydrazide (W02Q10/060836 A1 (03.06.2010) F. HOFFMANN-LA ROCHE AG.) and 20 mL of 1 ,4-dioxane 0.010 mL of trifiuoroacetic acid was added and the reaction mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was purified by column chromatography using dichloromethane:methanol=20:1 as eluent. Thus, 0.144 g (45%) of the title product was obtained. MS (ESI) m/z 509.2 & 511.2 (M+H) \

Example 96

8-fjuoro-5,5-dlmeth¥l-1-rfra??s-4 tnfluorometh¥nc¥dohexyn-5,6-dihvdro-4H-

The title product was prepared from 7-fluoro-4,4-dimethyl-2-(methylsulfanyl)-4,5- dihydro-3H-1-benzazepine (step b) of Example 91) and frans-4-(trifluoromethyl)cyclohexane carboxylic add hydrazide (Intermediate 6) according to the method described in step c) of Example 91. MS (ESI) m/z 382.2 (M+H) + .

The title products were prepared from the racemic 8-bromo-5-(propan-2-yl)-1-[/rans- 4-(pyridin-2-yloxy)cyciohexy!]-5,6-dihydro-4H-[1 ,2,4]triazoio[4,3-a][1]benzazepine (Example 94) by chiral preparative HPLC (CHIRALPAK IC with preparative 20 pm stationary phase, 2.5x20cm; F=2Q mL/min, eluent: ferf-butyl methyl ether:dichloromethane:ethanol =85:13:2; isocratic, t=25°C). Retention times were determined by analytical HPLC (CHIRALPAK lA with 5 pm stationary phase, 250x4.6 mm; F=1 mL/min, eluent: ferf-butyl methyl ether:dichloromethane:ethanol=85:10:5; isocratic, t=35°C): first eluting material is 15.0 min; Mo 5 -5.0° (c=0.1 ; dichloromethane); MS (ESI) m/z 481.2 & 483.2 (M+H) + ; second eluting material is 18.5 min; [a]¾ 5 = +10.0° (c=0.1 ; dichloromethane); MS (ESI) m/z 481.2 & 483.2 (MH-H} + . Absolute configuration of the compounds was not determined.

8'- dih¥dro-4’/i8'H--spiroifuran-3.5 , ~

ri ,2,4ltriazolor4,3-ali1lbenzazepinel

The title product was prepared from 7-bromo-1 ,5-dihydrospiro[1-benzazepine-4,3'- oxolan]-2(3H)-one (intermediate 83) according to the method described in Example 95. MS (ESI) m/z 495.1 & 497.2 (M+H) + .

8’-chloro-1 , -rfrans-4-ipyridin-2-vjoxy¾cvcjohexyj]-2,3,5,8-tetrah vdro-4 , H.8 , H- spjroipyran-4,5

The title product was prepared from 7-chloro-1 ,5-dihydrospiro[1-benzazepine-4,4'- oxan]-2(3H)-one (Intermediate 84) according to the method described in Example 95. MS (ESI) m/z 485.2 (M+H)\

S'-chloro-l’-ifrans^-ipyndsn^-yloxyIcvcjohexyn-S.S-dshvdro ^H.^H.S’H-spjroipyran-

3.5’-i1.2.4]triazolor4.3-ainibenzazepinel

The title product was prepared from 7-chloro-1 ,5-dihydrospiro[1-benzazepine-4,3'- oxan]-2(3H)-one (intermediate 85) according to the method described in Example 95. MS (ESI) m/z 485.3 (M+H) ÷

8 , -chjoro- -ί^raps-4-(pypdsp-2-v!oxylcvcSohe yP-4,5-dshvdro-4Ή,6Ή-spsGoGfϋGan-3,5 ί - i1.2,4]triazoloi4 ' 3-ali1lbenzazepjnel

The title product was prepared from 7-chloro-1 ,5-dihydrospiro[1-benzazepine-4,3'- oxolan]-2(3H)-one (Intermediate 88) according to the method described in Example 95. MS (ESI) m/z 451.2 (M+H) + . Example 103

8'-chjoro- -i rans-4-(trifluoromethvncvdohexyn-2,3,5.8-tetrahvdro-

SDiroipyran-4,5 , -

The title product was prepared from 7-chloro-1 ,5-dihydrospiro[1-benzazepine-4,4'- oxan]-2(3H)-one (Intermediate 84) and fra/?s-4-(trifluoromethyl)cyclohexane carboxylic acid hydrazide (Intermediate 8) according to the method described in Example 91. MS (ESI) m/z 440.2 (M+H) + .

The title products were prepared from the racemic 8'-broma-T-jYra/?s-4-(pyridin-2- yloxy)cyciohexyl]-4,5-dihydro-4 , H,6'i4-spiro[furan-3,5'-[1 ,2,4]triazolo[4 3-a][1]benzazepine] (Example 99) by chiral preparative HPLC (CHIRALPAK IG with preparative 20 pm stationary phase, 5x30cm; F=5Q mL/min, eluent: n-heptane:ethanol=6:4; isocratic, t=25°C) Retention times were determined by analytical HPLC (CHIRALPAK IG with 5 pm stationary phase, 250x4.8 mm; F=1 mL/min, eluent: n-heptane^thanol^e^; isocratic, t=25°C): first eluting material is 18.6 min; [a]¾ 5 = +10.0° (c=0.11 ; CHCb); MS (ESI) m/z 495.2 & 497.2 (M+H) + ; second eluting material is 23.0 min; [a 5 = -3.8° (c=0.105; CHCb); MS (ESI) m/z 495.2 & 497.2 (M+H) ÷ . Absolute configuration of the compounds was not determined.

The title products were prepared from the racemic 8‘-ch!oro-1'-[frans-4-(pyndin-2- yloxy)cydohexy!]-5,6-dihydro-4H,4'H,6'H-spiro[pyran-3,5'-[1 ,2,4]triazolo[4,3- a][1]benzazepine] (Example 101) by chiral preparative HPLC (CHIRALPAK !G with preparative 20 pm stationary phase, 5x30cm; F=50 mL/min, eluent: n~hepfane:ethano!=6:4; isocratic, t=25°C). Retention times were determined by analytical HPLC (CHIRALPAK IG with 5 pm stationary phase, 250x4.6 mm; F=1 mL/min, eluent: n-heptane:ethanol=6:4; isocratic, t=25°C): first eluting material is 20.2 min; [ajjy^ +19.0° (c=0.11 ; CHC ) ; MS (ESI) m/z 465 2 (M÷H) + ; second eluting material is 26.5 min; [ ]¾ X = -7.6° (c=0.105; CHC ); MS (ESI) m/z 465.2 (M+H) \ Absolute configuration of the compounds was not determined.

ri ,2,41triazojor4,3-ainibenzazepjne

To a mixture of 0.15 g (0.63 m ol) of 7-fluoro-4,4-dimethyl-2-(methylsulfanyl)-4,5- dibydro-3H-1-benzazepine (step b) of Example 91), 0.18 g (0.95 mmol) of 4-methoxy-4- methylcyclohexane-1-carbohydrazide (Step c) of Intermediate 35) and 20 mL of 1 ,4-dioxane 0.010 mL of concentrated hydrochloric acid was added and the reaction mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was purified by preparative HPLC (Ghromoiith Prep RP18 column, 100x25mm, 25mL/min, A: water+0.1% trifluoroacetic acid; B: acetonitrile + 0.1% trifluoroacetic add; gradient: 0-12 min; B: 0-49%; 12-24 min; B: 49- 90%; T=40°C). Retention times by analytical HPLC (Chromolith Performance RP18 column; 100x4, 6mm; 1ml_/min; eluent: A: water+0.1 % trifluoroacetic acid; B: acetonitrile + 0.1% trifluoroacetic acid; gradient: 0-10 min; B: 0-90%; 10-15 min; B: 90%; T=40°C): first eluting material is 8.62 min; irans isomer; 0.088g (39%); MS (ESI) m/z 358.3 (M+H) ÷ ; second eluting material is 8.95 min; c/s isomer; 0.021g (9%); MS (ESI) m/z 358.2 (M+H) + .

a) T- methoxy-S.S-dihvdrosp oxanel

A mixture of 0.35 g (1.32 mol) 7-chloro-1 ,5-dihydrospiro[1-benzazepine-4,4'-oxan]- 2(3H)-one (intermediate 54), 0.583 g (3.95 mmol) of trimethyioxonium tetrafluoroborate, 0.73 g (5.27 mmol) of potassium carbonate and 25 mL of dich!orometbane was stirred at room temperature for 3 hours. Then the reaction mixture was filtered and the organic phase was concentrated. Thus, 0 35 g (98%) of the title product was obtained and was used in the next reaction step without further purification and characterization.

b) 8 l -chloro-1'-(4-methoxy-4-methylcydohexyl)-2.3,5,6-tetra hvdro-4'H,8'i-l-spiroipyran-4,5 l - [ 1 ,2,41triazoio[4,3-ain Ibenzazepine]

To a mixture of 0.35 g (1.31 mol) of 7-chioro-2-methoxy-3,5-dihydrospiro[1- benzazepine-4,4'-oxane], 0.74 g (3.95 mmol) of 4-methoxy-4-methylcyclohexane-1- carbohydrazide (Step c) of intermediate 35) and 20 mL of 1 ,4-dioxane there was added 0.030 mL of trifiuoroacetic acid and the reaction mixture was stirred at 75°C overnight. After evaporation of the solvent, the residue was purified by preparative HPLC (Kinetex EVO column with 5 pm loading, 150x21.2mm, 20 mL/min, eluent: 20 mrnol/L (NH 4 ) 2 C0 3 :acetonitri!e = 65:35; isocratlc; T=40°C). Retention times with were determined by analytical HPLC (Klnetex EVO column with 5 pm loading; 150x4, 6mm; 1 mL/min; eluent: 20mmol/l (Nh ^CC^acetonitrile = 65:35; isocratlc; T= Q°C): first eluting material is 5.53 min; trans isomer; 0 056g (10%); MS (ESI) m/z 416.2 (M+H) + ; second eluting material is 8.06 min; cis isomer; 0.016g (3%); MS (ESI) m/z 416.3 (M+H) ÷ .

methyl 8-chj dih¥dro-4H-

The title product was prepared from methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H- 1-benzazepine-4-carboxylate (Intermediate 4) and frans-4-(pyridin-2-ylamino)cyclohexane- carbohydrazide (Intermediate 67) according to the method described in Example 1. MS (ESI) m/z 452.1 (M+H) +

The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention however is not limited to the following pharmaceutical compositions.

A) Solid oral dosage forms

I. Tablets

Active substance(s) 0.01 - 90%

Filler 1 - 99.9%

Binder 0 - 20%

Disintegrant 0 - 20%

Lubricant 0-10%

Other specific excipient(s) 0 - 50%

II. Orodispersible films

Active substance(s) 0.01 - 90%

Film forming agent 1 - 99.9%

Plasticiser 0 - 40% Other specific excipient(s) 0 - 50%

B) Liquid ora! dosage forms

Hi. Oral suspensions

Active substances(s) 0.01 - 50% Liquid vehicle 10 - 99.9% Wetting agent 0 - 50% Thickener 0 - 50% Buffering agent q.s.

Osmotic agent 0 - 50% Preservatives q.s.

IV. Syrups

Active substance(s) 0.01 - 50% Solvent 10 - 99.9%

Sugar component 1 - 20% Flavouring agents 0 - 10%

C) Parenteral dosage forms

V. Intravenous injections

Active substance(s) 0.01 - 50% Solvent 10 - 99.9% Co-solvent 0 - 99.9% Osmotic agent 0 - 50% Buffering agent q.s.

D) Other dosage forms

VI. Suppositories

Active substance(s) 0.01 - 50% Suppository base 1 - 99.9% Surface-active agents 0 - 20% Lubricant 0 - 20% Preservatives q.s.

VII. Eye drops Active substance(s) 0 01 - 50%

Water 0 - 99 9%

Solvent 0 - 99.9%

Osmotic agent 0 - 20%

Viscosity enhancer 0 - 20%

Bufferin agent q.s

Preservatives q.s.