HK1176934B

HK1176934B - Heteroaryl-cyclohexyl-tetraazabenzo[e]azulenes

Info

Publication number: HK1176934B
Application number: HK13104456.4A
Authority: HK
Inventors: 科西莫．多伦特; 帕特里克．施耐德
Original assignee: 霍夫曼-拉罗奇有限公司
Priority date: 2010-05-10
Filing date: 2011-05-09
Publication date: 2016-07-15

Description

Heteroaryl-cyclohexyl-tetraazabenzo [ e ] azulenes

Background

Vasopressin is a 9 amino acid peptide that is produced mainly by the paraventricular nucleus of the hypothalamus. In the periphery, vasopressin acts as a neurohormone and stimulates vasoconstriction, glycogenolysis and antidiuresis.

Three vasopressin receptors are known, all of which belong to the class I G-protein coupled receptors. The V1a receptor is expressed in brain, liver, vascular smooth muscle, lung, uterus and testis, the V1b or V3 receptor is expressed in brain and pituitary, the V2 receptor is expressed in kidney, where it regulates water reabsorption and mediates the antidiuresis of vasopressin (Robben et al (2006). AmJPhysiol renals physiol.291, F257-70, "Cellbiogica vasopressin-2 reflex daquaponin 2 Watermannelinone purpurogenicbenzodiisethionesipidus"). Thus, compounds active at the V2 receptor may cause side effects on blood homeostasis.

Oxytocin receptors are involved in the vasopressin receptor family and mediate the role of the neurohormone oxytocin in the brain and periphery. Oxytocin is believed to have a central anxiolytic effect (Neumann (2008). JNeuroendokrinol.20, 858-65, "Brainoxyocin: aneregatole and haemostasis. beta. haemolytica proteins"). Central oxytocin receptor antagonism may therefore lead to anxiogenic effects, which are considered to be undesirable side effects.

In the brain, vasopressin acts as a neuromodulator and is elevated in the tonsils during stress (Ebner et al (2002). eurjneuroci.15, 384-8., "forcedswimmingtriggersverspressuredeleasewith intracephalting stritegriensis"). It is known that stressful life events can cause major depression and anxiety (Kendler et al (2003). ArchGenpsychiatry.60, 789-96, "Life EventDimensionSoss, Humiliation, Entrap, and Dangerin the predictionof Onsetsof Majorddeprencom and GeneralizeddAnximets") and that both have very high complex lesions, with anxiety often preceding major depression (Regier et al (1998). BrJPsychiatry Suppl.24-8, "prevalence of anoxydisodermand the bipolar with morative diversity"). The V1a receptor is widely expressed in the brain and especially in the limbic regions such as the tonsils, lateral septum and hippocampus, where it plays an important role in the regulation of anxiety. In fact, V1 a-disrupted mice showed reduced anxiety behavior in the plus maze, open field and light and dark box (Bielsky et al (2004)., neuropsychopharmacology.29, 483-93, "Profundamentationanaerobacterium and reduction efficacy-likebehavionvapressing V1 arecoreknockou tm"). Down-regulation of the V1a receptor using antisense oligonucleotide injection in the septum also causes a reduction in anxiety behavior (Landgraf et al (1995). RegulPept.59, 229-39., "V1 vasopressin receptor oligodeoxygenistein reuptabin, societidinationabilities, and anddadanxiety-related anxiety"). Vasopressin or the V1a receptor are also involved in other neuropsychological diseases: genetic studies have recently linked sequence polymorphisms in the promoter of the human V1a receptor to autism spectrum disorders (Yirmiya et al (2006). 11, 488-94, "Association between vascular diseases and disorders 1 accumulator (AVPR1a), intranasal administration of vasopressin has been shown to affect the aggressiveness of human males (Thompson et al (2004). Psychoeurocorrinography.29, 35-48," Thereffects vasopressin responsive dietary disorders and physiological regulation), and elevated vasopressin levels were found in schizophrenic patients (Raindinfo et al (1987) Psychia et al, "22. Anotherapy 62. Anscholar et al.," Admixture of vascular diseases and disorders ". 20. compulsive patients" (Alirnonia promoter).

The V1a receptor also mediates the cardiovascular effects of vasopressin in the brain by centrally modulating blood pressure and heart rate in the solitary nucleus (Michelini and Morris (1999); AnnNYAcadSci.897, 198-211, "endogenesis vasopression modulated cardiac vasopression vascular hypertension exercise"). In the periphery, it induces contraction of vascular smooth muscle and chronic inhibition of the V1A receptor improves the hemodynamic parameters of myocardial infarcted rats (van kerckhoven et al (2002)., eurjpharmacol.449, 135-41, "chronovasopressin V (1A) butnotV (2) rectoninopsiperndepressor sheartheronicalcinefatdrates"). Thus, V1a antagonists with improved penetration across the blood-brain barrier are expected to be advantageous.

Vasopressin V1a receptor antagonists have been shown to be effective in clinically reducing dysmenorrhea (Brouard et al (2000). bjog.107, 614-9, "EffectofSR 49059," anoralloyctive V1 avasorpressoresistorellantonist, "invasive of dysmenorrha"). V1a receptor antagonism has also been implicated in the treatment of female sexual dysfunction (Aughton et al (2008). BrJPharmacol. doi: 10.1038/bjp.2008.253, "Pharmacological profiling of neuropeptide sorbit vascular wall and vascular tissue musculoskeletal vitro"). In a recent study, V1A receptor antagonists have been shown to have therapeutic effects in erectile dysfunction and premature ejaculation (Gupta et al (2008); brjpharmacol.155, 118-26, "oxotoxin-induced association between sexual dysfunction and sexual dysfunction in individuals V (1A)).

Technical Field

The present invention relates to heteroaryl-cyclohexyl-tetraazabenzo [ e ] azulenes as V1a receptor modulators, and in particular as V1a receptor antagonists; to their preparation, to pharmaceutical compositions containing them and to their use as medicaments.

Summary of The Invention

The present invention provides compounds of formula I for acting both peripherally and centrally in the following conditions: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior.

In particular, the invention relates to compounds of formula I

Wherein R is¹，R²And R³As described herein.

Detailed Description

The present invention provides compounds which are V1a receptor modulators, and in particular as V1a receptor antagonists. It is a further object of the present invention to provide selective inhibitors of the V1a receptor, as this selectivity is expected to provide a low likelihood of causing undesirable off-target related side effects as discussed above.

Such V1a antagonists are useful as therapeutic agents that act both peripherally and centrally in the following symptoms: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior. Specific indications for the present invention are the treatment of anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior.

V1a activity can be detected as described in the experimental section.

The following definitions of general terms used in the present description apply regardless of whether the terms in question appear alone or in combination.

As used herein, the term "C_1-6Alkyl ", alone or in combination with other groups, represents a linear hydrocarbon radical or a branched hydrocarbon radical having a single or multiple branching, in which the alkyl radical contains from 1 to 6 carbon atoms, such as methyl (Me), ethyl (Et)) Propyl, isopropyl (i-propyl), n-butyl, isobutyl (iso-butyl), 2-butyl (sec-butyl), tert-butyl (tert-butyl), and the like. Particular alkyl groups are groups having 1 to 4 carbon atoms. More particular are methyl, ethyl and isopropyl.

The term "C_1-6Alkoxy ", alone or in combination with other groups, represents the group-O-R ', wherein R' is alkyl as defined above, e.g. methoxy, ethoxy, propoxy, tert-butoxy and the like. Particular alkoxy groups are groups having 1 to 4 carbon atoms. More particularly methoxy.

The term "aryl", alone or in combination with other groups, refers to an aromatic carbocyclic group containing from 6 to 14, especially from 6 to 10, carbon atoms and having at least one aromatic ring or multiple fused rings wherein at least one ring is aromatic. Examples include phenyl (Ph), benzyl, naphthyl, biphenyl, anthracenyl, 1H-1-azoindenyl (azalenyl) or indanyl. In particular phenyl.

The term "heteroaryl", alone or in combination with other groups, refers to a cyclic aryl group having a 5 to 6 membered ring and containing 1, 2 or 3 heteroatoms, in which group at least one heterocyclic ring is aromatic. The term "5-membered heteroaryl" refers to an aryl group having a single 5-membered ring and comprising 1, 2 or 3 heteroatoms independently selected from O, S and N. A particular single 5-membered ring has 2N and 1O, 2N and 1S, 2N, 1S and 1N, or 1O and 1N. Examples of "5-membered heteroaryl" include thiazolyl, iso-thiazolylAn azole group, an isothiazolyl group,oxadiazolyl, thiadiazolyl, 1H-pyrazol-1-yl, and the like. In particular thiazol-4-yl, [1, 2, 4 ]]Oxadiazol-5-yl, [1, 2, 4 ]]Thiadiazol-5-yl, isoAn azole-3-yl group, which is,oxazol-2-yl, thiazol-2-yl, [1, 2, 4 ]]Oxadiazol-3-yl, [1, 2, 4 ]]Thiadiazol-3-yl and [1, 3, 4 ]]Oxadiazol-2-yl. A specific "5-membered heteroaryl" is attached to the cyclohexyl moiety via a carbon atom.

"5-membered heteroaryl", alone or in combination with other groups, is taken together to form two adjacent R's of "a ring comprising 4, 5, 6 or 7C^*Substituted, meaning an aryl group having a 5-membered aromatic ring and containing 1, 2 or 3 heteroatoms independently selected from O, S and N, in particular selected from O and N, and a fused non-aromatic ring having 4, 5, 6 or 7C atoms, in particular 6C atoms. Examples include 4, 5, 6, 7-tetrahydro-benzo [ d ]Different from each otherAzolyl, 4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzolyl, 5, 6-dihydro-4H-cyclopenta [ d]Different from each otherOxazoles, and the like. In particular 4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherOxazol-3-yl and 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherOxazol-3-yl.

The term "cycloalkyl" refers to a 3 to 8 membered carbocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. In particular cycloalkyl having a 3, 4, 5 or 6 membered carbocyclic ring. Examples include cyclobutyl and cyclopentyl.

The term "cyano", alone or in combination with other groups, denotes the group-CN.

The term "hydroxy", alone or in combination with other groups, denotes the group-OH.

The term "Boc" ("Boc" ), alone or in combination with other groups, denotes the group-C (═ O) O (CH)₃)₃。

The term "halogen", alone or in combination with other groups, denotes chlorine (Cl), iodine (I), fluorine (F) and bromine (Br). Specific halogens are F and Cl. In particular Cl.

The term "halogen-C_1-6Alkyl ", alone or in combination with other groups, means C substituted by one or more halogens_1-6Alkyl, especially "fluoro-C_1-6Alkyl ", for example the following groups: CF (compact flash)₃，CHF₂，CH₂F，CH₂CF₃，CH₂CH₂CF₃，CF₂CHF₂And the like.

The term "hydroxy-C_1-6Alkyl ", alone or in combination with other groups, means C substituted by one or more hydroxy groups _1-6Alkyl groups, such as the following groups: hydroxymethyl-, 2-hydroxyethyl-, 2-hydroxy-1-methyl-ethyl-or 2-hydroxypropyl-and the like.

The term "cyano-C_1-6Alkyl ", alone or in combination with other groups, means C substituted by one or more cyano groups_1-6Alkyl groups, such as the following groups: cyanomethyl-, 2-cyanoethyl-, 2-cyano-1-methyl-ethyl-or 2-cyanopropyl-, and the like.

The term "halogen-C_1-6Alkoxy ", alone or in combination with other groups, means C substituted with one or more halogens_1-6Alkoxy, especially fluoro-C_1-6Alkoxy radicalRadicals such as the following: F-CH₂-O-。

When referring to the number of substituents, the term "one or more" refers to substitution from one substituent up to the highest possible number, i.e., one hydrogen is substituted until all hydrogens are substituted with substituents. Thus, one, two or three substituents are particular. Even more in particular one or two substituents or one substituent.

The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

The term "pharmaceutical composition" encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Preferably it encompasses products comprising one or more active ingredients and optionally a carrier (including inert ingredients), as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

The term "inhibitor" refers to a compound that competes with, reduces or prevents the binding of a particular ligand to a particular receptor, or that reduces or prevents the inhibition of the function of a particular protein.

The term "half maximal inhibitory concentration" (IC)₅₀) Represents the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. IC (integrated circuit)₅₀The values can be logarithmically converted to pIC₅₀Value (-logIC)₅₀) Where higher values indicate greater efficacy of the exponential law. IC (integrated circuit)₅₀The value is not an absolute value but depends on the experimental conditions used, such as concentration. IC (integrated circuit)₅₀Values can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (biochem. Pharmacol. (1973) 22: 3099). The term "inhibition constant" (Ki) denotes the absolute binding affinity of a particular inhibitor to a receptor. It is measured using a competition binding assay and is equal to where there is no competition if there is oneThe concentration at which a particular inhibitor occupies 50% of the receptors in the presence of a sexual ligand (e.g., a radioligand). Ki values can be converted logarithmically to pKi values (-logKi), with higher values indicating greater potency of the exponential law.

By "therapeutically effective amount" is meant the amount of a compound that, when administered to a subject for the treatment of a disease state, is sufficient to effect such treatment for that disease state. The "therapeutically effective amount" will vary according to: the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the practitioner involved in the medical or veterinary medicine, and other factors.

When referring to a variable, the terms "as defined herein" and "as described herein" are incorporated by reference into the broad definition of the variable as well as the preferred, more preferred and most preferred definitions, if any.

The terms "treating", "contacting", and "reacting" when referring to a chemical reaction refer to the addition or mixing of two or more reagents under appropriate conditions to produce the specified and/or desired product. It will be appreciated that the reaction which produces the specified and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. there may be one or more intermediates produced in the mixture which ultimately results in the formation of the specified and/or desired product.

The term "aromatic" denotes the general concept of aromaticity as defined in the literature, in particular in IUPAC-Compenditum of chemical technology, 2nd, A.D.McNaught & A.Wilkinson (Eds.) Blackwell scientific publications, Oxford (1997).

The term "pharmaceutically acceptable excipient" refers to any ingredient used in formulating pharmaceutical products that is not therapeutically active and is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, bulking agents, stabilizers, antioxidants, surfactants, or lubricants.

The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like. Examples of salts with inorganic and organic acids are, but not limited to, hydrochloride, nitrate, sulfate, phosphate, sulfate, citrate, formate, fumarate, maleate, lactate, malate, acetate, succinate, tartrate, methanesulfonate, p-toluenesulfonate, trifluoroacetate and the like. In particular the hydrochloride and formate salts. In particular the hydrochloride salt.

The term "leaving group" denotes a group of meanings conventionally associated therewith in synthetic organic chemistry, i.e. an atom or group which is replaceable under the substitution reaction conditions. Examples of leaving groups include halogen, alkyl-or arylsulfonyloxy (arylenesulfonyloxy), such as methanesulfonyloxy, ethanesulfonyloxy, methylthio, phenylsulfonyloxy, toluenesulfonyloxy and thienyloxy, dihalophosphonooxy, optionally substituted benzyloxy, isopropyloxy, and acyloxy.

The following table lists the abbreviations used in this document.

(BOC)₂Di-tert-butyl O dicarbonate

(COCl)₂Oxalyl (di) chloride

AcOH acetic acid

CH₂Cl₂Methylene dichloride

((CH₃)₃CCO)₂O-trimethylacetic anhydride

CuCl cuprous chloride (I)

David-Martin high iodine 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy-3 (1H) -ketone

Alkane (I) and its preparation method

DMF dimethyl formamide

DMAP4- (dimethylamino) -pyridine

DMSO dimethyl sulfoxide

(dppf)/PdCl₂[1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

EDTA ethylene diamine tetraacetic acid

EtN₃Triethylamine

EtOAc ethyl acetate

EtOH ethanol

2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethylureaHexafluorophosphor

HATU

Acid salts

HEPES2- (4- (2-hydroxyethyl) -1-piperazinyl) -ethanesulfonic acid

HF-pyridine hydrofluoride

H₂O water

H₂SO₄Sulfuric acid

HPLC high performance liquid chromatography

KHF₂Potassium bifluoride

K₃PO₄Potassium phosphate

2, 4-bis- (4-methoxyphenyl) -1, 3, 2, 4-dithiadiphosphobutane-2, 4-bis

Lavirson reagent sulfide

MeOH methanol

MS Mass Spectrometry

Na₂CO₃Sodium carbonate

NaNO₂Sodium nitrite

NaOEt sodium ethoxide

NaOH sodium hydroxide

n-BuOH n-butanol

NCSN chlorosuccinimide

NMR nuclear magnetic resonance

PdCl₂Palladium dichloride

Pd(OAc)₂Palladium acetate

Pd(PPh)₃Tetrakis (triphenylphosphine) palladium (0)

POCl₃Phosphorus oxychloride

PtO₂Platinum oxide

p-TsOH p-toluenesulfonic acid

(PPh)₃Triphenylphosphine

RNA ribonucleic acid

RP-HPLC reversed-phase high performance liquid chromatography

RT Room temperature

RT-PCR reverse transcription-polymerase chain reaction

1-chloromethyl-4-fluoro-1, 4-dinitrogenBicyclo [2.2.2]Octane bis (tetrafluoroboric acid)

Selectfluor salt)

SOCl₂Thionyl chloride

t-BuOK Potassium tert-butoxide

THF tetrahydrofuran

Tris Tris (hydroxymethyl) -aminomethane

ZnBr₂Zinc bromide

Table 1: abbreviations

The invention also provides pharmaceutical compositions, methods of using the foregoing compounds, and methods of making the foregoing compounds.

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims. All individual embodiments may be combined.

The compounds of formula I may contain asymmetric carbon atoms. Accordingly, the present invention includes all stereoisomeric forms of the compounds of formula I, including each of the individual stereoisomers and mixtures thereof, i.e. their individual optical isomers and mixtures thereof. Additional asymmetric centers may exist depending on the nature of the different substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and it is intended that all possible optical isomers and diastereomers, both in mixtures and as pure or partially purified compounds, are encompassed by the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. The independent synthesis of these diastereomers or their chromatographic separation may be achieved as known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates derivatized, if desired, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated so as to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

This applies in particular to the aryl-Head Group (HG) of the compounds of the formula I, i.e.

Wherein at least carbon atoms 1 and 4 are asymmetric carbon atoms and R³May further comprise asymmetric carbon atoms. It is to be understood that the present invention includes all individual stereoisomers of the head group and mixtures thereof.

In particular, these head bases HG are

More particularly HG is trans.

It is also to be understood that all embodiments of the invention as described herein may be combined with each other.

In particular, the invention relates to compounds of formula I

Wherein

R¹Selected from the group consisting of:

i)H，

ii)-C_1-6-an alkyl group, unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: OH, halogen, cyano and C_1-6-an alkoxy group,

iii)-S(O)₂-C_1-6-alkyl, wherein C_1-6-alkyl is unsubstituted or substituted with 1 to 5 substituents, said substituents being independentlyThe locus is selected from the group consisting of: OH, halogen, cyano and C_1-6-an alkoxy group,

iv)-C(O)-C_1-6-alkyl, wherein C_1-6-alkyl is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: OH, halogen, cyano and C_1-6-an alkoxy group,

v)-C(O)O-C_1-6-alkyl, wherein C_1-6-alkyl is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: OH, halogen, cyano and C _1-6-an alkoxy group;

vi) cycloalkyl, unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of: OH, halogen, cyano, C_1-6-alkyl and C_1-6-an alkoxy group,

vii)-S(O)₂-(CH₂)_q-NRⁱRⁱⁱwherein

q is a number of 0 or 1,

Rⁱand RⁱⁱEach independently selected from the group consisting of H and C_1-6-alkyl, or RⁱAnd RⁱⁱTogether with the nitrogen to which they are attached form a 3-to 7-membered heterocyclic group containing one or two heteroatoms each selected from N, O and S, and which heterocyclic group is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: oxo, halogen, C_1-6-alkyl and C_1-6-an alkoxy group,

viii)-(CH₂)_r-NRⁱⁱⁱR^ivwherein

r is a number of 1, 2 or 3,

Rⁱⁱⁱand R^ivEach independently selected from the group consisting of H and C_1-6-alkyl, or RⁱⁱⁱAnd R^ivTogether with the nitrogen to which they are attached form a composition comprisingOne or two 3-to 7-membered heterocyclic groups each selected from N, O and S, and which is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: oxo, halogen, C_1-6-alkyl and C_1-6-alkoxy, and

ix)-C(O)(CH₂)_s-NR^vR^viwherein

s is a number of atoms of 1, 2 or 3,

R^vand R^viEach independently selected from the group consisting of H and C_1-6-alkyl, or R ^vAnd R^viTogether with the nitrogen to which they are attached form a 3-to 7-membered heterocyclic group containing one or two heteroatoms each selected from N, O and S, and which heterocyclic group is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: oxo, halogen, C_1-6-alkyl and C_1-6-an alkoxy group;

R²is halogen;

R³is a 5-membered heteroaryl group which is unsubstituted or substituted by (R)^*)_nSubstituted, each R^*Independently selected from the group consisting of: halogen, C_1-6Alkyl, halogen-C_1-6-alkyl and hydroxy-C_1-6-alkyl, wherein

n is 1, 2 or 3;

and two R's adjacent to each other^*A ring comprising 4, 5, 6 or 7C may be formed;

or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is methyl and R²Is chlorine.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is H and R²Is chlorine.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is Boc and R²Is chlorine.

One embodiment of the present invention are compounds of formula I,

wherein

R¹Selected from the group consisting of:

i)H，

ii)-C_1-6-an alkyl group, unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: OH, halogen, cyano and C _1-6-an alkoxy group,

iii)-S(O)₂-C_1-6-alkyl, wherein C_1-6-alkyl is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: OH, halogen, cyano and C_1-6-an alkoxy group,

v)-C(O)O-C_1-6-alkyl, wherein C_1-6-alkyl is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: OH, halogen, cyano and C_1-6-an alkoxy group;

vii)-S(O)₂-(CH₂)_q-NRⁱRⁱⁱwherein

q is a number of 0 or 1,

Rⁱand RⁱⁱEach independently selected from the group consisting of H and C_1-6-alkyl, or RⁱAnd RⁱⁱTogether with the nitrogen to which they are attached form a 3-to 7-membered heterocyclic group containing one or two heteroatoms each selected from N, O and S, and which heterocyclic group is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: oxo, halogen, C _1-6-alkyl and C_1-6-an alkoxy group,

viii)-(CH₂)_r-NRⁱⁱⁱR^ivwherein

r is a number of 1, 2 or 3,

Rⁱⁱⁱand R^ivEach independently selected from the group consisting of H and C_1-6-alkyl, or RⁱⁱⁱAnd R^ivTogether with the nitrogen to which they are attached form a 3-to 7-membered heterocyclic group containing one or two heteroatoms each selected from N, O and S, and which heterocyclic group is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: oxo, halogen, C_1-6-alkyl and C_1-6-alkoxy, and

ix)-C(O)(CH₂)_s-NR^vR^viwherein

s is a number of atoms of 1, 2 or 3,

R^vand R^viEach independently selected from the group consisting of H and C_1-6-alkyl, or R^vAnd R^viTogether with the nitrogen to which they are attached form a 3-to 7-membered heterocyclic group containing one or two heteroatoms each selected from N, O and S, and which heterocyclic group is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: an oxygen radical, a halogen radical,C_1-6-alkyl and C_1-6-an alkoxy group;

R²is halogen;

R³is a 5-membered heteroaryl group which is unsubstituted or substituted by (R)^*)_nSubstituted, each R^*Independently selected from the group consisting of: halogen, C_1-6Alkyl and halogen-C_1-6-alkyl, wherein

n＝1-2；

Or a pharmaceutically acceptable salt thereof.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Selected from the group consisting of:

i)H，

ii)-C_1-6-an alkyl group which is unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of: halogen and C_1-6-an alkoxy group,

iii)-S(O)₂-C_1-6-alkyl, wherein C_1-6-the alkyl group is unsubstituted,

iv)-C(O)-C_1-6-alkyl, wherein C_1-6Alkyl is unsubstituted or substituted by 1 to 2 OH,

v)-C(O)O-C_1-6-alkyl, wherein C_1-6-the alkyl group is unsubstituted;

vi) an unsubstituted cycloalkyl group,

vii)-S(O)₂-(CH₂)_q-NRⁱRⁱⁱwherein q is 0, and

Rⁱand RⁱⁱEach independently selected from the group consisting of H and C_1-6-a group of alkyl groups,

viii)-(CH₂)_r-NRⁱⁱⁱR^ivwherein r is 2, and

Rⁱⁱⁱand R^ivEach independently selected from the group consisting of H and C_1-6-alkyl, and

ix)-C(O)(CH₂)_s-NR^vR^viwherein s is 1, and

R^vand R^viEach independently selected from the group consisting of H and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Selected from the group consisting of: h, methyl, ethyl, isopropyl, 2, 2-difluoro-ethyl, 2-methoxy-ethyl, 2-methylamino-ethyl, acetyl, 2-dimethylamino-acetyl, 2-hydroxy-acetyl, Boc, cyclobutyl, cyclopentyl, dimethylsulfamoyl, and methanesulfonyl.

i)H，

ii)-C_1-6-alkyl, unsubstituted or substituted by 1 to 2 halogens,

iii)-S(O)₂-C_1-6-an alkyl group,

iv)-C(O)-C_1-6-alkyl, wherein C_1-6-alkyl is unsubstituted or substituted by 1 to 2 OH, and

v) unsubstituted cycloalkyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Selected from the group consisting of: h, methyl, 2, 2-difluoro-ethyl, cyclobutyl, acetyl and methanesulfonyl.

One aspect of the present inventionEmbodiments are compounds of formula I as described herein, wherein R is¹Is H.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-C_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is methyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is ethyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is isopropyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-C substituted by 1 to 2 halogens_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is 2, 2-difluoro-ethyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is 1 to 2C_1-6-alkoxy-substituted C_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is 2-methoxy-ethyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-S (O)₂-C_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is methanesulfonyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-C (O) -C_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is an acetyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-C (O) -C substituted by 1 to 2 OH_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is 2-hydroxy-acetyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-C (O) O-C_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is ¹Is Boc.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is an unsubstituted cycloalkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is a cyclobutyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is cyclopentyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-S (O)₂-(CH₂)_q-NRⁱRⁱⁱWherein q is 0 and RⁱAnd RⁱⁱEach independently selected from the group consisting of H and C_1-6-a group of alkyl groups,

a certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is a dimethylsulfamoyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is- (CH)₂)_r-NRⁱⁱⁱR^ivWherein R is 2, and RⁱⁱⁱAnd R^ivEach independently selected from the group consisting of H and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹Is 2-methylamino-ethyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is¹is-C (O) (CH)₂)_s-NR^vR^viWherein s is 1, and R^vAnd R^viEach independently selected from the group consisting of H and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is ¹Is 2-dimethylamino-acetyl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is²Is chlorine or fluorine.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is²Is chlorine.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is²Is fluorine.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Selected from the group consisting of:

i)[1，2，4](ii) a diazolyl group,

ii)[1，3，4](ii) a diazolyl group,

iii)the group of azolyl groups,

iv) a thiazolyl group,

v) [1, 2, 4] thiadiazolyl,

vi) isoAzolyl, and

vii) 1H-pyrazolyl;

each of the above being unsubstituted or substituted by (R)^*)_nSubstituted, each R^*Independently selected from halogen and C_1-6-alkyl, wherein n ═ 1, 2 or 3, or two R's adjacent to each other^*Together with the atoms to which they are attached form a ring containing 6C.

i)[1，2，4](ii) a diazolyl group,

ii)[1，3，4](ii) a diazolyl group,

iii)the group of azolyl groups,

iv) a thiazolyl group,

v) [1, 2, 4] thiadiazolyl, and

vi) isoThe group of azolyl groups,

each of the above being unsubstituted or substituted by (R)^*)_nSubstituted, each R^*Independently selected from halogen Elements and C_1-6-alkyl, wherein n is 1-2 and two R adjacent to each other^*Together with the atoms to which they are attached form a ring containing 6C.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Selected from the group consisting of:oxazol-2-yl, 1H-pyrazol-1-yl, 2-methyl-thiazol-4-yl, 3, 4, 5-trimethyl-1H-pyrazol-1-yl, 3, 5-dimethyl-1H-pyrazol-1-yl, 3-methyl- [1, 2, 4]Thiadiazol-5-yl, 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherAzol-3-yl, 4, 5, 6, 7-tetrahydro-benzo [ d]Different from each otherAzol-3-yl, 4, 5-bis (hydroxymethyl) isoAzol-3-yl, 4, 5-dimethyl-isoOxazol-3-yl, 4, 5-dimethyl-Oxazol-2-yl, 4, 5-dimethylthiazol-2-yl, 4-chloro-5-methyl-iso-methylAzol-3-yl, 4-fluoro-5-methyl-iso-methylOxazol-3-yl, 4-methyl-Oxazol-2-yl, 4-methyl-thiazol-2-yl, 5, 6-dihydro-4H-cyclopenta [ d]Different from each otherAzole, 5-chloro-4-methylthiazol-2-yl, 5-ethyl- [1, 2, 4 [ ]]Oxadiazol-3-yl, 5-ethyl-iso-Azol-3-yl, 5-isopropyl- [1, 2, 4]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Thiadiazol-3-yl, 5-methyl- [1, 3, 4 [ ]]Oxadiazol-2-yl, 5-methyl-iso-methyl Oxazol-3-yl, 5-methyl-An azole-2-yl group, which is,oxazol-2-yl and thiazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Selected from the group consisting of: 2-methyl-thiazol-4-yl, 3-methyl- [1, 2, 4 ]]Oxadiazol-5-yl, 3-methyl- [1, 2, 4 ]]Thiadiazol-5-yl, 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherOxazol-3-yl, 4, 5, 6, 7-Tetrahydro-benzo [ d]Different from each otherAzol-3-yl, 4, 5-dimethyl-isoOxazol-3-yl, 4, 5-dimethyl-Azol-2-yl, 4-chloro-5-methyl-isoAzol-3-yl, 4-fluoro-5-methyl-iso-methylOxazol-3-yl, 4-methyl-Oxazol-2-yl, 4-methyl-thiazol-2-yl,oxazol-2-yl, thiazol-2-yl, 5-ethyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-ethyl-iso-Azol-3-yl, 5-isopropyl- [1, 2, 4]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Thiadiazol-3-yl, 5-methyl- [1, 3, 4 [ ]]Oxadiazol-2-yl, 5-methyl-iso-methylOxazol-3-yl and 5-methyl-Oxazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R3 is selected from the group consisting of: [1,2,4]Oxadiazolyl, isoxazolylAzolyl group, [1, 2, 4 ]]A thiadiazolyl group,azolyl and thiazolyl, each of which is unsubstituted or substituted by (R) ^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is [1, 2, 4 ]]Oxadiazolyl, [1, 3, 4 ] methyl]Oxadiazolyl, [1, 2, 4 ]]A thiadiazolyl group,azolyl or thiazolyl, each of which is unsubstituted or substituted by 1-2C_1-6-alkyl substitution.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is a differenceAzolyl radical which is unsubstitutedOr by (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Selected from the group consisting of: 5-ethyl-isoAzol-3-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-methyl-iso-Azol-3-yl, 5-methyl- [1, 2, 4 ]]Thiadiazol-3-yl, 5-methyl- [1, 2, 4 [ ]]Oxadiazol-3-yl, 5-methyl-Oxazol-2-yl, 4-methyl-thiazol-2-yl, 4-chloro-5-methyl-iso-butylAzol-3-yl, 4, 5-dimethyl-isoOxazol-3-yl, 4, 5-dimethyl-Azol-2-yl and 4-fluoro-5-methyl-isoOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is ³Is [1, 2, 4 ]]Oxadiazolyl, which is unsubstituted or substituted by (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is [1, 2, 4 ]]Oxadiazolyl, which is unsubstituted or substituted by C_1-6-alkyl substitution.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 3-methyl- [1, 2, 4]Oxadiazol-5-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-isopropyl- [1, 2, 4]Oxadiazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-ethyl- [1, 2, 4]Oxadiazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is [1, 3, 4 ]]Oxadiazolyl, which is unsubstituted or substituted by (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is ³Is [1, 3, 4 ]]Oxadiazolyl, which is unsubstituted or substituted by C_1-6-alkyl substitution.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-methyl- [1, 3, 4]Oxadiazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is thatAzolyl radical which is unsubstituted or substituted by (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is thatAzolyl radical which is unsubstituted or substituted by (R)^*)_nWherein n is 1-2, and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-chloro-4-methylOxazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is thatAzolyl radical which is unsubstituted or substituted by (R)^*)_nWherein n is 1-2, and each R^*Independently is C_1-6-an alkyl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4, 5-dimethyl-Oxazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is ³Is 4-methyl-Oxazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is thatOxazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-methyl-Oxazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is thiazolyl, which is unsubstituted or substituted by (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-chloro-4-methylthiazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is a thiazolyl radical, which is unsubstituted or substituted by C_1-6-alkyl substitution.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4-methyl-thiazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 2-methyl-thiazol-4-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4, 5-dimethylthiazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is ³Is thiazol-2-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is [1, 2, 4 ]]Thiadiazolyl radical, unsubstituted or substituted by (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is [1, 2, 4 ]]Thiadiazolyl radicals, unsubstituted or substituted by C_1-6-alkyl substitution.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 3-methyl- [1, 2, 4]Thiadiazol-5-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-methyl- [1, 2, 4 ]]Thiadiazol-3-yl.

One embodiment of the invention is of the formulaI compound, wherein R³Is a differenceAzolyl radical which is unsubstituted or substituted by (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6Two R's adjacent to each other and of the group consisting of alkyl^*A ring containing 6C's may be formed.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is a differenceAzolyl radical of (R)^*)_nSubstituted, wherein n is 2 and each R^*Independently is C _1-6-alkyl, and two R adjacent to each other^*A ring containing 6C's may be formed.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4, 5, 6, 7-tetrahydro-benzo [ d]Different from each otherOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is a differenceAzolyl radical, each R^*Independently is C_1-6-alkyl, two R adjacent to each other^*A ring containing 5C's may be formed.

One embodiment of the invention is a process of the formula I as described hereinCompound (I) wherein R³Is 5, 6-dihydro-4H-cyclopenta [ d]Different from each otherAnd (3) azole.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4, 5-dimethyl-isoOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is a differenceAzolyl radical of (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and hydroxy-C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4, 5-bis (hydroxymethyl) iso Oxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is a differenceAzolyl radical of (R)^*)_nSubstituted, wherein n is 1-2 and each R^*Independently selected from halogen and C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4-chloro-5-methyl-isoOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 4-fluoro-5-methyl-isoOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-ethyl-isoOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 5-methyl-isoOxazol-3-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is a 1H-pyrazol-1-yl group.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 1H-pyrazol-1-yl, which is substituted by (R)^*)_nSubstituted, wherein n is 1, 2 or 3 and each R^*Independently selected from C_1-6-alkyl groups.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 3, 5-dimethyl-1H-pyrazol-1-yl.

A certain embodiment of the invention are compounds of formula I as described herein, wherein R is³Is 3, 4, 5-trimethyl-1H-pyrazol-1-yl.

Examples of compounds according to the invention are shown in the experimental part and in the table below.

Table 2: structure of selected embodiments

Specific compounds of the invention are shown in the examples. More particularly, it relates to

Trans-8-chloro-1- (4-)Azol-2-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

Cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (5-methyl- [1, 2, 4) ]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-5-methyl-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

cis-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans- (2- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethyl) -methyl-amine,

trans-1- [4- (4, 5-bis-hydroxymethyl) -isoAzol-3-yl) -cyclohexyl]-8-chloro-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-1- { 8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethanone,

trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl ]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethanone,

trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -2-hydroxy-ethanone,

trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -2-dimethylamino-ethanone,

trans-8-chloro-1- (4-)Azol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- (4-thiazol-2-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- (4-thiazol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

Trans-8-chloro-1- [4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

Trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [e](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5,6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl) Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each otherAzol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] ](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-ethyl-iso-methyl) Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2,3, 5, 10 b-tetraaza-benzo [ e ]]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl ]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]The compound of azulene-5-sulfonic acid dimethylamide,

trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5- (2, 2-difluoro-ethyl) -1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5- (2, 2-difluoro-ethyl) -1- [4- (5-methyl-iso-propyl ] -ethylAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5- (2-methoxy-ethyl) -1- [4- (5-methyl-iso-propyl ] -methyl esterAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl-iso-butyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-cyclopentyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-ethyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-ethyl-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-isopropyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-isopropyl-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methanesulfonyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methanesulfonyl-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- (4-Azol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-5-methyl-1- (4-thiazol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-5-methyl-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-5-methyl-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ] ]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene, trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Thiadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl ]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-fluoro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-fluoro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-fluoro-5-methyl-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene, and

trans-chloro-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene, or a pharmaceutically acceptable salt thereof.

Specific compounds of the invention are shown in the examples. More particularly trans-8-chloro-1- (4-)Azol-2-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-5-methyl-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-chloro-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethanone,

trans-8-chloro-5- (2, 2-difluoro-ethyl) -1- [4- (5-methyl-iso-propyl ] -ethylAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-ethyl-1- [4- (5-methyl-iso-methyl) Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-1-{ 8-chloro-1- [4- (5-methyl-iso-methyl-)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -2-dimethylamino-ethanone,

trans-8-chloro-5-isopropyl-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-fluoro-5-methyl-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H，6H-2，3，5，10 b-tetraaza-benzo [ e ] ](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (5-ethyl-iso-methyl) Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl ]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Diazoles-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5- (2, 2-difluoro-ethyl) -1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene, and

trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4] thiadiazol-3-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene,

or a pharmaceutically acceptable salt thereof.

More specific compounds are selected from the group consisting of:

trans-8-chloro-1- [4- (5-methyl- Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] ]Azulen-5-yl } -ethanone,

trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] ]Azulen-5-yl } -2-dimethylamino-ethanone fumaric acid (hydroxyfumate),

trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-ethyl-iso-methyl) Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ] ]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetranitrogenHetero-benzo [ e)]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives ^*HCl，

trans-8-chloro-5-methanesulfonyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

Cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4) ]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H，6H-23, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

or a pharmaceutically acceptable salt thereof.

The most particular compound is selected from the group consisting of:

trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives^*HCl，

trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-ne-benzo [ e ]]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl ]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl- Azol-2-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl-iso-butyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene, and

trans-8-chloro-5- (2, 2-difluoro-ethyl) -1- [4- (5-methyl-iso-propyl ] -ethylAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]And (2) azulene.

A certain embodiment of the invention is a compound as described in any of these embodiments obtainable by a process as described herein.

A certain embodiment of the invention is a compound as described in any one of these embodiments, which is obtained by a method as described herein.

A certain embodiment of the invention is a compound as described in any one of these embodiments for use as therapeutically active substance.

A certain embodiment of the invention is a compound as described in any one of these embodiments for use in the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.

A certain embodiment of the invention is a pharmaceutical composition comprising a compound as described in any of these embodiments.

A certain embodiment of the invention is a pharmaceutical composition comprising a compound as described in any of these embodiments, wherein it is used for the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.

A certain embodiment of the invention is the use of a compound as described in any one of these embodiments for the preparation of a medicament.

A certain embodiment of the invention is the use of a compound described in any one of these embodiments for the preparation of a medicament for the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.

A certain embodiment of the invention is the use of a compound described in any one of these embodiments for the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.

One embodiment of the present invention is a method for the therapeutic and/or prophylactic treatment of the following diseases: dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depression, obsessive compulsive disorder, autism spectrum disorders, schizophrenia, and aggressive behavior, comprising administering a compound as defined in any of these embodiments to a human being or animal.

In one embodiment, the compounds of formula I of the present invention may be prepared according to a process comprising the steps of: reacting a compound of formula II

With a compound of the formula III,

to obtain a compound of formula I, wherein R¹，R²And R³As defined above for formula I.

The methods are described in more detail using the following general schemes and procedures a through R.

Scheme 1: general scheme A

The compounds of formula I can be prepared by thermal condensation of a hydrazide of formula II and a thiolactam of formula III. The synthesis of the compounds of formula II is outlined in the general schemes D-R below. The compounds of formula III may be prepared according to the procedures as described in general scheme C described below. General procedure a is further illustrated below using general procedure XV.

Scheme 2: general scheme B

Wherein R is¹Compounds of formula I other than H can be prepared from compounds of formula I-2 (compounds of formula I, wherein R is R, according to methods known in the art¹Is H), for example by using inorganic bases such as carbonates or organic bases such as tertiary amines and an electrophilic reagent R¹LG (wherein LG is a leaving group such as halogen or sulfonyl) to treat a compound of formula I-2, which electrophiles are commercially available or are readily prepared according to methods and starting materials well known in the art. Alternatively, the compounds of formula I may be obtained via reductive alkylation by sequentially treating the compounds of formula I-2 with a ketone or aldehyde and a suitable reducing agent such as a borohydride derivative, e.g. sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydrideAnd (5) obtaining the product. Alternatively, wherein R¹Compounds of formula I which are acyl groups may be prepared by coupling an amine of formula I-2 with a carboxylic acid. Conventional reagents and protocols known in the art may be used to effect the amide coupling. Compounds of formula I-2 can be cleaved off substituents R of compounds of formula I by using methods known in the art ¹And then obtaining the compound. Compounds of formula I-2 the compounds of formula I-1 (compounds of formula I wherein R is R) are treated with an acid such as methanesulfonic acid or trifluoroacetic acid in dichloromethane or tetrahydrofuran or hydrochloric acid in methanol in a suitable solvent¹Is tert-butoxycarbonyl) and is conveniently obtained as a salt or free base after treatment with aqueous base. General scheme B is further illustrated below using general procedures XVI and XVII.

Scheme 3: general scheme C

Thiolactams of the formula III-1 (compounds of the formula III, where R¹Is tert-butoxycarbonyl) can be obtained as follows: the conversion of 2-nitrobenzyl alcohol of formula a to benzyl chloride of formula b can be accomplished by a chlorinating agent such as thionyl chloride in the presence of an organic tertiary amine base. Alkylation of the compound of formula b with glycine ethyl ester hydrochloride in the presence of an organic tertiary amine base and N-protection of the resulting compound of formula c with di-tert-butyl dicarbonate and a catalytic amount of 4-N, N-dimethylaminopyridine gives the compound of formula d. The nitro group can be selectively reduced by hydrogenation on palladium or platinum on carbon which has been pretreated with a zinc halide such as zinc bromide to give the aniline intermediate of formula e. The cyclization to the lactam of formula f is achieved by treating the compound of formula e with a suitable base such as potassium tert-butoxide in tetrahydrofuran. The thiolactam of formula III-1 is obtained by treating a compound of formula f with Lavirustard reagent or phosphorus pentasulfide at elevated temperature.

R＝Me，Et

X is halogen

dppf ═ 1, 1' -bis (diphenylphosphino) ferrocene

Scheme 4: general scheme D

The 4-heteroaryl-cyclohex-3-enecarboxylate intermediates of formula V can be prepared from 4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylate of formula IV and a heteroaryl boronic acid, heteroaryl boronic ester or heteroaryl trifluoroborate in a suitable organic solvent such as 1, 4-bis (R) under the conditions of a Suzuki reactionIn an alkane, tetrahydrofuran or toluene in the presence of catalytic amounts of a 1: 2 mixture of palladium (II) acetate and triphenylphosphine or a 1: 1 mixture of palladium (II) acetate and a bisphosphine ligand or tetrakis (triphenylphosphine) palladium (0) and in the presence of a base such as potassium phosphate or potassium carbonate, which are used in pure or aqueous form, at reaction temperatures ranging from room temperature to reflux. Alternatively, 4-heteroaryl-cyclohex-3-enecarboxylate intermediates of formula V can be prepared from 4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylate of formula IV and a zinc heteroaryl halide under the conditions of a Negishi reaction in a suitable organic solvent such as tetrahydrofuran and Pd (PPh)₃At reaction temperatures ranging from room temperature to reflux. Alternatively, the compound of formula V may be prepared by coupling the potassium trifluoroborate salt of formula VII with the heteroaryl halide R in the presence of a base such as potassium carbonate and a suitable palladium catalyst such as (1, 3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride in a suitable solvent such as an alcohol under reflux ³-X. The potassium trifluoroborate salt of formula VII may be prepared by treating (RS) -4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] of formula VI with potassium hydrogen difluoride in a mixture of acetone and water at room temperature]Dioxaborolan-2-yl) -cyclohex-3-enecarboxylate. The compound of formula VI can be prepared by reacting the compound of formula VI with a suitable base such as potassium acetate and a suitable palladium catalyst such as 1, 1 '-bis (diphenylphosphino) ferrocene and dichloro (1, 1' -bis (diphenyl-phenyl)Phenylphosphine) ferrocene) Palladium (II) Dichloromethane adduct in the Presence of a 1: 1 mixture in a suitable solvent such as 1, 4-bisIn an alkane, at 90 ℃ with bis (pinacolato) diboron. General scheme D is further illustrated below using general procedures I through III.

R＝Me，Et

Scheme 5: general scheme E

The 4-heteroaryl-cyclohexanecarboxylate intermediate of formula VIII is typically obtained as a mixture of cis and trans isomers by reduction of the 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula V in a suitable solvent such as ethyl acetate or an alcohol in the presence of a catalytic amount of palladium or platinum on carbon or in the presence of platinum (IV) oxide under a hydrogen (1 bar) atmosphere at room temperature. The residue R thereof³Compounds of formulae V and VIII substituted with one or more halogenated substituents other than fluorine may undergo partial or complete dehalogenation under these reaction conditions. The acid formed as a result of the dehalogenation reaction can be neutralized by adding a base such as a trialkylamine to the reaction mixture. In some cases pretreatment of palladium or platinum catalysts with zinc halides can prevent or reduce the residue R thereof ³Dehalogenation of compounds of formulae V and VIII substituted with one or more halogenated substituents other than fluorine. General scheme E is further illustrated below using general procedures VIII through IX.

Scheme 6: general scheme F

4 of formula VIII-The cis/trans mixture of heteroaryl-cyclohexanecarboxylate intermediates can in some cases be separated into the pure cis-4-heteroaryl-cyclohexanecarboxylate intermediate of formula VIII-a and trans-4-heteroaryl-cyclohexanecarboxylate intermediate of formula VIII-b by conventional methods such as silica gel column or high performance chromatography or crystallization, which can be carried out under standard conditions such as at room temperature in aqueous sodium hydroxide and an ether solvent such as 1, 4-bisA mixture of an alkane, tetrahydrofuran or diethyl ether is saponified with stirring to pure cis-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-a and trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b. Alternatively, a trans-4-heteroaryl cyclohexanecarboxylic acid intermediate of formula IX-b may be obtained as follows: epimerization of the cis-isomer in the cis/trans mixture of the 4-heteroaryl-cyclohexanecarboxylate intermediate of formula VIII in a suitable solvent such as methanol, ethanol or toluene at reflux by using a suitable base such as an alkali metal alkoxide such as methanol or sodium or potassium ethoxide, followed by subjecting the crude reaction mixture to standard conditions such as in aqueous sodium hydroxide and an ethereal solvent such as 1, 4-bis Saponification is carried out at room temperature in a mixture of alkanes, tetrahydrofuran or diethyl ether with stirring, and the crude reaction mixture may consist of a mixture of trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b and trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b. In case the epimerisation reaction is carried out in an alcohol as solvent, the crude reaction mixture may alternatively be acidified by adding concentrated sulfuric acid and heating to reflux to obtain the trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b. The cis/trans mixture of the 4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX can in some cases be isolated by conventional methods such as silica gel column or high performance chromatography or crystallization into the pure cis-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-a and trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b. General scheme F is illustrated below using general procedures X through XII is further illustrated.

Scheme 7: general scheme G

The 4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII can be converted to the hydrazide of formula II by heating with hydrazine hydrate. Alternatively, the ester of formula VIII may be prepared using aqueous sodium or potassium hydroxide and an ethereal solvent such as bis A biphasic mixture of an alkane, tetrahydrofuran or diethyl ether to the carboxylic acid of formula IX. The hydrazides of formula II can be obtained by activation of the acid intermediate of formula IX, for example with ethyl chloroformate, thionyl chloride, oxalyl chloride or a peptide coupling agent, followed by coupling with hydrazine. General scheme G is further illustrated below by general procedures XIII through XIV.

R＝Me，Et

R^A＝H，C_1-6Alkyl radical

R″′，R″″＝C_1-6Alkyl radical

Or R' "and R" "together form a ring

Scheme 8: general scheme H

The cyclohexane-1, 4-dicarboxylic acid monoester of formula X can be converted to the chlorocarbonyl-cyclohexanecarboxylic acid ester of formula XI using conventional methods for converting carboxylic acids to carboxylic acid chlorides such as sulfuryl chloride or oxalyl chloride in the presence of catalytic amounts of DMF in a suitable solvent such as dichloromethane. Acyl of formula XI in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane or tetrahydrofuranThe chlorine can be converted into the amide of the formula XII by coupling with an amine of the formula g or into the amide of the formula XIII by coupling with the formula h. The carbonyl derivative of formula XIV can be obtained by treating the acetal derivative of formula XII with an acid such as trifluoromethanesulfonic acid or by oxidizing the alcohol group using conventional methods known in the art, for example treatment with oxalyl chloride, DMSO and a base such as triethylamine or with david-martin periodinane. Cyclisation of a compound of formula XIV to a compound of formula VIII-1A Azole derivatives can be obtained by treatment with a mixture of a suitable dehydrating agent such as phosphoryl chloride or hexachloroethane, triphenylphosphine and a base such as triethylamine in a suitable solvent such as acetonitrile. General scheme H is further illustrated below by general procedures III, IV and VII.

Rⁱ＝H，Me，Et

X is halogen

Y＝S，O

LG ═ leaving group

R^A＝H，C_1-6-alkyl radical

R^B＝C_1-6-alkyl radical

Scheme 9: general scheme I

The compounds of formula VIII-1B can be halogenated to give compounds of formula VIII-1C by direct treatment with an electrophilic halogenating agent X-LG, where X is a halogen and LG is a suitable leaving group, or by continuous deprotonation with a strong base such as an alkyllithium reagent at low temperature and treatment with an electrophilic agent X-LG. Examples of halogenating agents X-LG areN-fluoro diphenyl sulphonylImines (NFSI), 1-fluoropyridinesSalts, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin or tetraalkylammonium trihalide salts. Likewise, compounds of formula VIII-1D can be halogenated by treatment with an electrophilic halogenating agent X-LG to give compounds of formula VIII-1E.

The halogenated compound of formula VIII-1C can be converted to a compound of formula VIII-1F and the halogenated compound of formula VIII-1E can be converted to a compound of formula VIII-1G under one of the following conditions: the halogenated compounds of formula VIII-1C or VIII-1E are treated sequentially with an alkyl-lithium reagent such as n-butyllithium, sec-butyllithium or tert-butyllithium in a suitable solvent, typically an ether solvent such as tetrahydrofuran or diethyl ether, usually with cooling at-78 ℃ to 0 ℃, followed by addition of the alkylating agent R ^BLG, wherein LG is a suitable leaving group, to give an alkylated compound of formula VIII-1F or VIII-1G, respectively. Alternatively, the alkylated compound of formula VIII-1F or VIII-1G may be prepared by reacting a halogenated compound of formula VIII-1C or VIII-1E with a halogenated compound of formula R, respectively^B ₄The tetraalkyltin reagent of Sn is reacted in a suitable solvent, such as N, N-dimethylacetamide, in the presence of a suitable palladium catalyst or pre-catalyst (pre-catalyst) and optionally in the presence of a co-catalyst such as copper (I) iodide, or with a compound of formula R^BThe zinc alkylhalide of ZnX is reacted in the presence of a suitable transition metal catalyst or precatalyst, e.g. a nickel or palladium complex such as bis (triphenylphosphine) nickel (II) dichloride or (1, 3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride, in a suitable solvent or mixture of solvents, e.g. N, N-dimethylacetamide or tetrahydrofuran or a mixture of tetrahydrofuran and 1, 3-dimethyl-2-imidazolidinone, or with an alkylboronic acid R^BB(OH)₂Or with alkylboronic acid esters or trialkylbutyltium derivatives R^B ₃Bi in the presence of a suitable palladium catalyst or precatalyst, e.g. tetrakis (triphenylphosphine) palladium or a mixture of palladium (II) acetate and a mono-or diphosphine derivative in the presence of a suitable base, e.g. potassium carbonate or sodium carbonate, in a suitable solvent, e.g. N, N -dimethylformamide, toluene or tetrahydrofuran or mixtures of such solvents with water.

Scheme 10: general scheme J

The 4-hydroxymethyl-cyclohexanecarboxylic acid ester of formula XVI can be prepared by: the cyclohexane-1, 4-dicarboxylic acid monoester of formula X is reduced by esterification of 4-hydroxymethyl-cyclohexanecarboxylic acid XV in an alcohol in the presence of a catalytic amount of an acid, such as concentrated sulfuric acid, at elevated temperature, usually under reflux, or by using conventional methods known in the art, e.g. borane derivatives such as borane-dimethyl sulfide complex. The alcohol intermediate of formula XVI can be oxidized to the aldehyde intermediate of formula XVII using conventional methods known in the art for oxidizing primary alcohol groups, e.g., treatment with oxalyl chloride, DMSO, and a base such as triethylamine. Hydroxamoyl chloride (hydroxamylchloride) intermediates of formula XIX can be prepared by chlorination of aldoxime intermediates of formula XVIII, which can be obtained by treating aldehyde intermediates of formula XVII with hydroxylamine hydrochloride in the presence of sodium acetate.

R＝Me，Et

R^A＝H，C_1-6-an alkyl group,

R^B＝C_1-6-an alkyl group,

or R^AAnd R^BTogether form a ring

Scheme 11: general scheme K

A modification of the formula IX-2The azole intermediate can be obtained by: 3+2 cyclization of the nitrile oxide with the enamine intermediate of formula i, the nitrile oxide being formed in situ by elimination of hydrochloric acid from the hydroxamic acid chloride of formula XIX in the presence of a base such as triethylamine, followed by elimination of morpholine by treatment with 6M hydrochloric acid at reflux. The enamine intermediate of formula i may be obtained by reacting a ketone with morpholine under conventional conditions known in the art, for example in the presence of a titanium reagent such as titanium tetrachloride or titanium tetraisopropoxide.

R＝Me，Et

R^A＝H，C_1-6-an alkyl group,

R^B＝C_1-6-an alkyl group,

or R^AAnd R^BTogether form a ring

R' "is optionally substituted C_1-6-alkyl or aryl

Scheme 12: general scheme L

An isomer of the formula IX-2AThe azole intermediate can be obtained by: 3+2 cyclization of a nitrile oxide with the enol ester intermediate of formula j, which can be formed in situ by elimination of hydrochloric acid from the hydroxamic acid chloride of formula XIX in the presence of a base such as triethylamine, followed by spontaneous elimination of the carboxylic acid R' "COOH under the reaction conditions.

R＝Me，Et

X is halogen

X′＝Br，I

R^B，R^B′＝C_1-6-alkyl radical

Scheme 13: general scheme M

The compound of formula VIII-2B may be halogenated to give a compound of formula VIII-2C by treatment with an electrophile X-LG, wherein X is a halogen and LG is a suitable leaving group. Examples of halogenating agents X-LG areN-Fluorodiphenyl sulphonamides (NFSI), 1-fluoropyridinesSalts, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin or tetraalkylammonium trihalide salts. Compounds of formula VIII-2D, wherein X' is bromine or iodine, can be converted into compounds of formula VIII-2E by reaction with an alkylzinc halide R^B' -ZnX is coupled in the presence of a suitable catalyst such as ((1, 3-diisopropylimidazol-2-ylidene) (3-chloropyridyl)) palladium dichloride in a suitable solvent or solvent mixture such as a 4: 1 mixture of tetrahydrofuran and 1, 3-dimethyl-2-imidazolidinone.

Scheme 14: general scheme N

A hetero group of the formula VIII-3The oxazole intermediate can be obtained from an intermediate of formula XX by sequential treatment with hydroxylamine hydrochloride and sodium acetate and heating at reflux in toluene in the presence of catalytic amounts of p-toluenesulfonic acid. Compounds of formula XX may be prepared by reaction of formula mIs deprotonated with a strong base such as lithium N, N-diisopropylamide at low temperature, followed by cyclization with a compound of formula XI. The compounds of formula m can be obtained from the ketones of formula i by conventional methods, for example by treatment with the hydrazine derivative NH2-NR "" R' "in the presence of catalytic amounts of an acid such as p-toluenesulfonic acid in a suitable solvent such as ethanol.

R＝Me，Et

R^B＝C_1-6-alkyl radical

Scheme 15: general scheme O

Of formula VIII-4The oxadiazole intermediate can be obtained by cyclization of a diacylhydrazine intermediate of formula XXI in the presence of triflic acid and dimethyldichlorosilane in acetonitrile at reflux. Diacylhydrazines of formula XXI can be prepared by: the cyclohexane-1, 4-dicarboxylic acid monoester of formula X is converted continuously into the anhydride by conventional methods, for example by treatment with ethyl chloroformate in the presence of a base such as triethylamine, or into another active form such as the acid chloride of formula XI, followed by treatment with a hydrazide intermediate of formula n.

R＝Me，Et

R^B＝C_1-6-alkyl radical

Scheme 16: general scheme P

Of the formula VIII-5The oxadiazole intermediate may be obtained by: an acid chloride intermediate of formula XI is treated with an N-hydroxyaminooxime (N-hydroxamine) derivative of formula o in the presence of a base such as triethylamine, followed by treatment in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid in a suitable solvent such as di (toluene di) sulfonic acidHeating in the alkane under reflux.

R＝Me，Et

R^B＝C_1-6-alkyl radical

Scheme 17: general scheme Q

Of formula VIII-6The oxadiazole intermediate may be obtained by: the N-hydroxyaminooxime intermediate of formula XXIII is treated with a carboxylic anhydride of formula p in a suitable solvent such as toluene at reflux, or the hydroxamato chloride intermediate of formula XIX is treated with a imidamide salt of formula q (imidatesalt) in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane. The N-hydroxyaminooxime intermediate of XXIII may be prepared as follows: by dehydration of an aldoxime intermediate of formula XVIII with acetic anhydride under reflux and treatment of the resulting nitrile intermediate of formula XXII with hydroxylamine hydrochloride in the presence of a base such as sodium carbonate in a suitable solvent such as an alcohol at elevated temperature, typically under reflux. General scheme Q is further illustrated below using the same procedures V, VI and XI.

Scheme 18: general scheme R

The 4-carbamoyl-cyclohexanecarboxylate of formula XXIV can be converted to a 4-thiocarbamoyl-cyclohexanecarboxylate of formula XXV by treatment with a lavonoid reagent, which cyclizes to a thiadiazole intermediate of formula VIII-7 by treatment with a thioamide derivative of formula s in the presence of iodine in a suitable solvent such as an alcohol. Alternatively, 4-thiocarbamoyl-cyclohexanecarboxylate of formula XXV may be condensed with an N, N-dimethyl carboxylic acetal of formula r to convert to an N- [ 1-dimethylamino-ethylene ] -thioacetamide intermediate of formula XXVI. Thiadiazole intermediates of formula VIII-8 can be obtained by cyclizing an intermediate of formula XXVI with hydroxylamine-O-sulfonic acid in the presence of pyridine in a suitable solvent such as an alcohol.

R＝Me，Et

RC，RC′＝H，R^*，CO₂R″′，SiR″′₃

R ″' is optionally substituted C_1-6-alkyl or aryl

Scheme 19: general scheme S

A hetero group of the formula VIII-2FThe azole intermediate can be obtained as follows: by 3+2 cyclisation of the alkyne derivative of formula t with a nitrile oxide formed in situ by elimination of hydrochloric acid from the hydroxamic acid chloride intermediate of formula XIX in the presence of a suitable base such as an amine base, for example triethylamine or ethyldiisopropylamine, or a carbonate base, for example potassium carbonate or sodium carbonate, in a suitable organic solvent, for example diethyl ether, tetrahydrofuran, dichloromethane, chloroform, toluene, benzene, hexane or ethyl acetate, or a mixture of such an organic solvent and water.

R＝Me，Et

R^A，R^A′，R^A″＝H，C_1-6-an alkyl group,

or R^AAnd R^A' or R^A' and R^AForm a ring

R″′，R″″＝C_1-6-an alkyl group,

or R' "and R" "form a ring

Scheme 10: general scheme T

4- (N' -tert-butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid esters of formula XXVIII may be prepared from 4-oxo-cyclohexanecarboxylic acid esters of formula XXVII by reductive amination with a mixture of tert-butyl hydrazinoformate and a suitable reducing agent, e.g. sodium triacetoxyborohydride and acetic acid, in a suitable solvent, e.g. dichloromethane. By using hydrochloric acid in a suitable organic solvent such as diTreatment of the N' -tert-butoxycarbonyl decomposition of an intermediate of formula XXVIII in an alkane, diethyl ether or methanol yields 4-hydrazino-cyclohexanecarboxylic acid ester hydrochloride of formula XXIX. 4-pyrazol-1-yl-cyclohexanecarboxylic acid esters of the formula VIII-9 can be obtained as follows: by condensation of 4-hydrazino-cyclohexanecarboxylic acid ester hydrochloride of formula XXIX with a 1, 3-dicarbonyl derivative of formula u, a mono-protected 1, 3-dicarbonyl derivative of formula v or a di-protected 1, 3-dicarbonyl derivative of formula w in a suitable solvent such as an alcohol, e.g. ethanol, typically at reflux temperature.

The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to those skilled in the art, for example by dissolving a compound of formula I in a suitable solvent such as diAlkane or THF and the appropriate amount of the corresponding acid. The product may generally beSeparating by filtration or by chromatography. The conversion of a compound of formula I to a pharmaceutically acceptable salt with a base can be achieved by treating the compound with such a base. One possible method for forming such salts is, for example, by reacting 1/n equivalent of a basic salt such as M (OH)_nTo a solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) and removing the solvent by evaporation or lyophilization, wherein M is the number of metal or ammonium cations and n is the number of hydroxide anions.

The compounds of formula I as well as all intermediates may be prepared according to analogous methods or according to the methods set forth herein, as long as their preparation is not described in the examples. The starting materials are commercially available, known in the art, or can be prepared by methods known in the art or similar methods.

It will be appreciated that the compounds of formula I in the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

Pharmacological testing

The compounds of the present invention exhibit V1a activity. They are selective inhibitors of the V1a receptor and therefore have the potential to have a low probability of causing undesirable off-target related side effects. The V1a activity can be measured as follows.

The human V1a receptor was cloned from total human liver RNA by RT-PCR. The coding sequence was subcloned into an expression vector after sequencing to confirm the identity of the amplified sequences. To confirm the affinity of the compounds from the present invention for the human V1a receptor, binding studies were performed. Cell membranes were prepared from HEK293 cells transiently transfected with the expression vector and grown in 20 liter fermentors using the following protocol.

50g cells were resuspended in 30ml of freshly prepared ice-cold lysis buffer (50mM HEPES, 1mM EDTA, 10mM magnesium dichloride, adjusted to pH 7.4+ complete cocktail of protease inhibitors (Roche diagnostics)). Homogenized with Polytron for 1min and on ice80% intensity sonicate 2x2 minutes (Vibracell sonication). The preparation was centrifuged at 500g for 20min at 4 ℃, the pellet discarded and the supernatant centrifuged at 43 '000 g (19' 000rpm) for 1 hour at 4 ℃. The pellet was resuspended in 12.5ml lysis buffer +12.5ml sucrose 20% and homogenized using Polytron for 1-2 min. Protein concentration was determined by Bradford method and aliquots were stored at-80 ℃ until use. For binding studies, 60mg of yttrium silicate SPA beads were used An aliquot of the membrane was mixed with binding buffer (50mM tris, 120mM sodium chloride, 5mM potassium chloride, 2mM calcium dichloride, 10mM magnesium dichloride) and mixed for 15 minutes. Then 50. mu.l of the bead/membrane mixture was added to each well of a 96-well plate followed by 50. mu.l of 4nM 3H-vasopressin (American RadiolabeledCchemicals). For the total binding measurements, 100 μ l of binding buffer was added to each well, 100 μ l of 8.4mM cryovasopressin was added for non-specific binding and 100 μ l of serial dilutions of each compound in 2% dimethylsulfoxide was added for compound testing. The plate was incubated at room temperature for 1h, centrifuged at 1000g for 1min and counted on a Packardtop-Count. Non-specific binding counts were subtracted from each well and the data were normalized to set at 100% of the maximum specific binding. To calculate the IC₅₀The curve was fitted using a non-linear regression model (XLFit) and Ki calculated using the Cheng-Prussoff equation.

The following representative data show the antagonistic activity of the compounds according to the invention for the human V1a receptor.

Table 3: human V1apKi of selected examples.

Pharmaceutical composition

The compounds of formula I as well as their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such excipients, for example for tablets, sugar-coated tablets and hard gelatine capsules. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will of course be adapted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dose of from about 10 to 1000mg per person of a compound of the formula I will be appropriate, but the above upper limits may also be exceeded if desired.

Examples of compositions according to the invention are, but not limited to:

example A

Tablets of the following composition were manufactured in a conventional manner:

table 4: possible tablet compositions

Manufacturing process

1. Ingredients 1, 2, 3 and 4 were mixed and granulated with purified water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

4. Add ingredient 5 and mix for 3 minutes; pressing on a suitable press.

Example B-1

Capsules of the following composition were made:

table 5: possible capsule ingredient composition

Manufacturing process

1. Ingredients 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.

2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Encapsulating into suitable capsule.

The compound of formula I, lactose and corn starch are first mixed in a mixer and then mixed in a mill. The mixture was returned to the mixer, to which talc (and magnesium stearate) were added and mixed thoroughly. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

Example B-2

Soft gelatin capsules of the following composition were made:

composition (I)	mg/capsule
		A compound of formula I	5
Yellow wax	8
		Hydrogenated soybean oil	8
Partially hydrogenated vegetable oils	34
		Soybean oil	110
Total of	165

Table 6: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		karion 83	8 (Dry matter)
Titanium dioxide	0.4
		Iron oxide yellow	1.1
Total of	116.5

Table 7: possible soft gelatin capsule compositions

Manufacturing process

The compound of formula I is dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are processed according to conventional procedures.

Example C

Suppositories of the following composition were made:

composition (I)	mg/suppository
		A compound of formula I	15
Suppository bolus	1285
		Total of	1300

Table 8: possible suppository composition

Manufacturing process

The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45 ℃. Thereafter, the finely powdered compound of formula I is added thereto and stirred until it is completely dispersed. Pouring the mixture into a suppository mold with a proper size, and keeping the mixture stand for cooling; the suppositories are then removed from the moulds and individually packaged in waxed paper or metal foil.

Example D

An injection of the following composition was made:

composition (I)	mg/injection
		A compound of formula I	3
Polyethylene glycol 400	150
		Acetic acid	Adding enough to pH 5.0
Water for injection	Adding to 1.0ml

Table 9: possible injection compositions

Manufacturing process

The compound of formula I is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 with acetic acid. The volume was adjusted to 1.0ml by adding the remaining amount of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Example E

Sachets of the following composition were made:

composition (I)	mg/sachet
		A compound of formula I	50
Lactose, fine powder	1015
		Microcrystalline cellulose (AVICEL PH 102)	1400
Sodium carboxymethylcellulose	14
		Polyvinylpyrrolidone K30	10
Magnesium stearate	10
		Flavoring additive	1
Total of	2500

Table 10: possible sachet composition

Manufacturing process

The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.

Examples

The following examples are provided to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

Intermediates of formula IV

(RS) -4-Trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylic acid ethyl ester

To a solution of 4-Cyclohexanone ethyl formate (25.0g, 147mmol) in tetrahydrofuran (580mL) at-78 deg.C was added a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (154mL, 154 mmol). After stirring for 1h, a solution of N-phenyl-bis (trifluoromethanesulphonimide) (55.1g, 154mmol) in tetrahydrofuran (80ml) was added. The cooling bath was removed 30 minutes after the addition was complete and the reaction mixture was stirred at room temperature for 12 h. The mixture was quenched with 1M aqueous sodium hydrogen sulfate (154ml, 154 mmol). The solvent was removed by rotary evaporation (40 ℃ water bath). The residue was partitioned between tert-butyl methyl ether (500ml) and 0.5M aqueous sodium hydroxide (400 ml). The organic layer was washed with two 400-ml portions of 0.5M aqueous sodium hydroxide solution, one portion of 200-ml saturated ammonium chloride solution and one portion of 100-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (41.8g, 94.2%) as a yellow oil which was used in the next step without further purification. MSm/e: 273([ M-C) ₂H₅]^-)。

An intermediate of formula (VI)

(RS) -4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -cyclohex-3-enecarboxylic acid ethyl ester

Reacting (RS) -4-trifluoromethylsulfonyloxy-cyclohexane-3-Enecarboxylic acid ethyl ester (3.0g, 9.92mmol), potassium acetate (2.92g, 29.8mmol) and bis (pinacolato) diboron (3.78g, 14.9mmol) in 1, 4-bisThe mixture in alkane (30ml) was purged with argon. 1, 1 '-bis (diphenylphosphino) ferrocene (0.17g, 0.30mmol) and dichloro (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloromethane adduct (0.22g, 0.30mmol) were added, followed by stirring at 90 ℃ for 18 h. The reaction mixture was partitioned between ethyl acetate (200ml) and water (150 ml). The layers were separated. The organic layer was washed with a portion of brine, dried over anhydrous sodium sulfate and concentrated to dryness. Flash chromatography with n-heptane/ethyl acetate as eluent afforded the title compound (1.95g, 70%) as a pale yellow oil. MSm/e: 281([ M + H)]⁺)

An intermediate of formula (VII)

(RS) - (4- (ethoxycarbonyl) cyclohex-1-enyl) potassium trifluoroborate

To a solution of (RS) -ethyl 4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -cyclohex-3-enecarboxylate (0.37g, 1.32mmol) in acetone (9ml) and water (3ml) was added potassium bifluoride (0.41g, 5.28 mmol). After stirring at room temperature for 4h the solvent mixture was evaporated. The residue was triturated in warm acetonitrile (20 ml). The solids were removed by filtration. The filtrate was concentrated to dryness to give the title compound (0.35g, quantitative) as a white solid, which was used in the next step without further purification.

4-heteroaryl-cyclohex-3-enecarboxylic acid ester intermediates of formula (V)

General procedure (I):

a mixture of ethyl (RS) -4-trifluoromethanesulfonyloxy-cyclohex-3-enecarboxylate (1eq), zinc heteroaryl halide (1-1.2eq) and tetrakis (triphenylphosphine) palladium (0.05eq) in dry tetrahydrofuran (0.3M) was stirred at reflux for 14-20 h. After cooling to room temperature, the reaction mixture is partitioned between an organic solvent such as tert-butyl methyl ether or ethyl acetate and water. The layers were separated. The aqueous layer is extracted with two or three portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography gives the 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula V.

General procedure (II):

to a mixture (0.2M) of potassium (RS) - (4- (ethoxycarbonyl) cyclohex-1-enyl) trifluoroborate (1eq), heteroaryl halide (1.2eq) and potassium carbonate (3eq) in an alcohol such as ethanol or methanol was added (1, 3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride (0.02 eq). The mixture was stirred at reflux for 1-20 h. After cooling to room temperature, the solvent was evaporated. The residue is triturated in an organic solvent such as tert-butyl methyl ether or ethyl acetate. The precipitate was removed by filtration. The filtrate was concentrated to dryness. Purification by flash chromatography gives the 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula V.

4-heteroaryl-cyclohex-3-enecarboxylic acid esters 1

(RS) -4-Thiazol-2-yl-cyclohex-3-enecarboxylic acid ethyl ester

The title compound was obtained as yellow oil in 33% yield from 2-bromothiazole according to general procedure (II). MSm/e: 238([ M + H)]⁺)

4-heteroaryl-cyclohex-3-enecarboxylic acid esters 2

(RS) -4- (4-methyl-thiazol-2-yl) -cyclohex-3-enecarboxylic acid ethyl ester

The title compound was obtained as yellow oil in 41% yield from 2-chloro-4-methylthiazole according to general procedure (II). MSm/e: 252([ M + H ]]⁺)

4-heteroaryl-cyclohex-3-enecarboxylic acid esters 3

(RS) -4- (2-methyl-thiazol-4-yl) -cyclohex-3-enecarboxylic acid ethyl ester

The title compound was obtained as light yellow oil in 66% yield from 4-bromo-2-methylthiazole according to general procedure (II). MSm/e: 252([ M + H ]]⁺)

An intermediate of formula (XI)

trans-4-Chlorocarbonyl-Cyclohexanecarboxylic acid methyl ester

To a solution of monomethyl trans-1, 4-cyclohexanedicarboxylate (2.0g, 11mmol) in dichloroethane (30ml) were added oxalyl chloride (1.1ml, 13mmol) and a catalytic amount of N, N-dimethylformamide at 0-5 ℃. The cooling bath was removed and the reaction mixture was stirred at room temperature for 24 h. After evaporation of the solvent, the residue was triturated in n-hexane (100 ml). The precipitate was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (2.2g, quantitative) as a colorless oil, which was used in the next step without further purification.

Amide intermediates of formula (XII), (XIII) and (XIV)

General procedure (III): amide coupling

To a solution (0.2M) of the amine of formula g or h (1.1-1.5eq) and triethylamine (1.1eq) in dichloroethane, a solution (0.2-1.0M) of the acid chloride of formula XI (1eq) in dichloroethane is added at 0-5 ℃. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 2h, the reaction mixture was partitioned between an organic solvent such as ethyl acetate or tert-butyl methyl ether and water. The layers were separated. The aqueous layer was extracted with two portions of organic solvent. The combined organic layers were washed with a portion of saturated ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the amide intermediate of formula XII or XIII, respectively.

General procedure (IV): swern oxidation

To a solution of dimethyl sulfoxide (2.4eq) in dry dichloromethane (0.1-0.2M) at-78 deg.C was added oxalyl chloride (1.2 eq). The cooling bath was removed and the reaction mixture was stirred at-50 ℃ for 5 min. A solution (0.2-0.5M) of the amide intermediate of formula XIII (1eq) in dichloromethane was added at-65 ℃. Stirring was carried out for 30 minutes, followed by addition of triethylamine (5.0 eq). The cooling bath was removed 30 minutes after the addition was complete and the reaction mixture was quenched with 1M aqueous hydrochloric acid (3eq) at-30 ℃ to-10 ℃. The mixture is partitioned between an organic solvent such as ethyl acetate and water. The layers were separated. The aqueous layer is extracted with one or two portions of an organic solvent. The combined organic layers were washed with a portion of brine or saturated ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the intermediate of formula XIV.

Amides 1

Trans-4- (2, 2-diethoxy-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in quantitative yield from aminoacetaldehyde diethyl acetal and trans-4-chlorocarbonyl-cyclohexane according to general procedure (III)Methyl alkanoate. MSm/e: 302([ M + H)]⁺)

Amides 2

Trans-4- (2-oxo-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

A solution of trans-4- (2, 2-diethoxy-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester (900mg, 2.99mmol) and trifluoromethanesulfonic acid (996mg, 4.48mmol) in 1, 2-dimethoxyethane (30ml) was heated at 40 ℃ for 4 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (100ml) and saturated aqueous sodium bicarbonate solution (50 ml). The layers were separated. The aqueous layer was extracted with two 100ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (740mg, quantitative) as a light brown viscous oil, which was used in the next step without further purification. MSm/e: 228([ M + H)]⁺)

Amides 3

Trans-4- ((S) -2-hydroxy-1-methyl-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in 56% yield from S- (+) -2-amino-1-propanol and trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester according to general procedure (III). MSm/e: 244([ M + H) ]⁺)

Amide 4

Trans-4- ((S) -1-methyl-2-oxo-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in quantitative yield from trans-4- ((S) -2-hydroxy-1-methyl-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (IV). MSm/e: 240([ M-H)]^-)

Amides 5

Trans-4- ((S) -2-hydroxy-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in 57% yield from (S) -1-aminopropan-2-ol and trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester according to general procedure (III). MSm/e: 244([ M + H)]⁺)

Amides of 6

Trans-4- (2-oxo-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in quantitative yield from trans-4- ((S) -2-hydroxy-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (IV). MSm/e: 242([ M + H)]⁺)

Amides 7

Trans-4- (2-hydroxy-1-methyl-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in 72% yield from 3-aminobutan-2-ol and trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester according to general procedure (III). MSm/e: 258([ M + H) ]⁺)

Amides 8

Trans-4- (1-methyl-2-oxo-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in quantitative yield from trans-4- (2-hydroxy-1-methyl-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (IV). MSm/e: 256([ M + H ]]⁺)

An intermediate of formula (XVI)

4-hydroxymethyl-cyclohexanecarboxylic acid ester 1

Cis/trans-4-hydroxymethyl-cyclohexanecarboxylic acid ethyl ester (3: 1)

To a solution of cis/trans-4- (hydroxymethyl) cyclohexanecarboxylic acid (10.0g, 63.2mmol) in ethanol (316ml) was added a catalytic amount of sulfuric acid. The reaction mixture was heated at reflux for 20 h. The solvent was evaporated. The residue was partitioned between ethyl acetate (150ml) and 2M aqueous sodium carbonate solution (100 ml). The aqueous layer was separated. The organic layer was washed with one part of 100-ml water and one part of 50-ml brine. The combined aqueous layers were extracted with a 100-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a colorless oil (11.5g, 98.1％)。MSm/e：187([M+H]⁺)

4-hydroxymethyl-cyclohexanecarboxylic acid ester 2

Trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester

To a solution of trans-4- (methoxycarbonyl) cyclohexanecarboxylic acid (10.0g, 53.7mmol) in tetrahydrofuran (540ml) at 0-5 ℃ was added borane-dimethylsulfide complex (6.80g, 80.6 mmol). After 15 minutes the cooling bath was removed and the mixture was stirred for 4 h. The reaction mixture was quenched with methanol (17.2g, 537mmol), stirred for 20 min and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (300ml) and filtered over a pad of Decalite. The filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (300ml) and 1M aqueous sodium hydroxide solution (100 ml). The layers were separated. The organic layer was washed with one 100ml portion of water. The combined aqueous layers were extracted with one portion of 150-ml ethyl acetate. The combined organic layers were washed with one 50ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (8.75g, 94.6%) as a colorless oil which was used without further purification. MSm/e: 172 (M) ⁺)

Intermediates of formula (XVII)

4-formyl-cyclohexanecarboxylic acid ester 1

Cis/trans-4-formyl-cyclohexanecarboxylic acid ethyl ester

To a solution of oxalyl chloride (2.8ml, 32mmol) in dichloroethane (150ml) was added dimethyl sulfoxide (5.0ml, 64mmol) at-78 ℃. The mixture was stirred at-50 ℃ for 5 minutes. In thatA solution of cis/trans-4-hydroxymethyl-cyclohexanecarboxylic acid ethyl ester (3: 1) (5.0g, 27mmol) in dichloroethane (30ml) was added at-65 ℃. Stirring was carried out for 30 min, followed by addition of triethylamine (18.7ml, 134 mmol). The cooling bath was removed 15 minutes after the addition was complete and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated to about 20-30ml by rotary evaporation. The residue was partitioned between ethyl acetate (200ml) and 0.5M aqueous hydrochloric acid (100 ml). The layers were separated. The aqueous layer was extracted with a 100 portion of ethyl acetate. The combined organic layers were washed with one portion of 100-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (4.9g, 98%) as a pale yellow oil, which was used in the next step without further purification. MSm/e: 185([ M + H)]⁺)

4-formyl-cyclohexanecarboxylic acid ester 2

Trans-4-formyl-cyclohexanecarboxylic acid methyl ester

To a solution of dimethyl sulfoxide (9.53g, 122mmol) in dry dichloromethane (400ml) at-78 deg.C was slowly added oxalyl chloride (7.74g, 61.0 mmol). The cooling bath was removed and the reaction mixture was stirred at-50 ℃ for 5 min. A solution of trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (8.75g, 50.8mmol) in dichloroethane (108ml) was added at-65 ℃. Stirring was carried out for 30 min, followed by addition of triethylamine (25.7g, 254 mmol). The cooling bath was removed 15 minutes after the addition was complete. The reaction mixture was quenched with 1M aqueous hydrochloric acid (152ml, 152mmol) at-10 ℃. And (5) separating the layers. The organic layer was washed with two 250ml portions of water and one portion of 100-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (9.3g, quantitative) which was used in the next step without further purification.

Intermediate of formula (XVIII)

4- (Oxime-methyl) -cyclohexanecarboxylic acid ester 1

Cis/trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid ethyl ester

To a solution of cis/trans-4-formyl-cyclohexanecarboxylic acid ethyl ester (4.56g, 24.8mmol) in ethanol (248ml) were added sodium acetate (2.44g, 29.7mmol) and hydroxylamine hydrochloride (2.06g, 29.7 mmol). Stirring was carried out at room temperature for 16h, followed by evaporation of the solvent. The residue was partitioned between ethyl acetate (200ml) and 1M aqueous sodium carbonate solution (100 ml). The layers were separated. The aqueous layer was extracted with one portion of 200-ml ethyl acetate. The combined organic layers were washed with one portion of 100-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (5.15g, quantitative) as a pale yellow oil, which was used in the next step without further purification. MSm/e: 200([ M + H ]]⁺)

4- (Oxime-methyl) -cyclohexanecarboxylic acid ester 2

Trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid methyl ester

To a solution of trans-4-formyl-cyclohexanecarboxylic acid methyl ester (8.65g, 50.8mmol) in methanol (250ml) at 0-5 ℃ was added sodium acetate (12.5g, 152mmol) and then hydroxylamine hydrochloride (10.6g, 152 mmol). The cooling bath was removed 10 minutes after the addition was complete and the mixture was stirred for 20 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (300ml) and 0.5M aqueous sodium hydroxide solution. The layers were separated. The organic layer was washed with one portion of 150-ml 0.5M aqueous sodium hydroxide solution. The combined aqueous layers were extracted with a portion of 150ml ethyl acetate. The combined organic layers were washed with one part of 150ml of 0.5M aqueous hydrochloric acid and one part of 100-ml brine, over anhydrous sodium sulfate Dried and concentrated in vacuo to give the title compound (8.5g, 90%) as a colorless oil, which was used in the next step without further purification. MSm/e: 185 (M)⁺)

An intermediate of formula (XIX)

4- (chloro (hydroxyimino) methyl) -cyclohexanecarboxylic acid ester 1

Cis/trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylic acid ethyl ester

To a solution of cis/trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid ethyl ester (0.50g, 2.5mmol) in N, N-dimethylformamide (12.5ml) was added N-chlorosuccinimide (0.37g, 2.8mmol) at 0 ℃. The cooling bath was removed 10 minutes after the addition was complete and the mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between diethyl ether (150ml) and water (50 ml). The layers were separated. The organic layer was washed with one part of 50-ml water and one part of 30-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (0.58g, 99%) as a colorless oil, which was used in the next step without further purification. MSm/e: 198([ M-Cl)]⁺)

4- (chloro (hydroxyimino) methyl) -cyclohexanecarboxylic acid ester 2

Trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylic acid methyl ester

To a solution of trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid methyl ester (5.0g, 27mmol) in N, N-dimethylformamide (135ml) was added N-chlorosuccinimide (3.78g, 28.3mmol) at 0-5 ℃. The cooling bath was removed and the mixture was stirred for 1 h. The reaction mixture was partitioned between diethyl ether (250ml) and an ice-water mixture (200 ml). The organic layer was washed with two 200ml portions of water and one 100ml portion of brine. The combined aqueous layers were extracted with one portion of 150-ml diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.1g, quantitative) as a colorless viscous oil, which was used in the next step without further purification.

An intermediate of formula (XX)

Trans-4- [2- (dimethyl-hydrazono) -cyclohexanecarbonyl ] -cyclohexanecarboxylic acid methyl ester

a) N' -cyclohexylidene-N, N-dimethyl-hydrazine

To a solution of cyclohexanone (2.00g, 20.4mmol) and N, N-dimethylhydrazine (1.50ml, 20.4mmol) in ethanol (20ml) was added a catalytic amount of toluene-4-sulfonic acid monohydrate. The reaction mixture was stirred at 70 ℃ for 72 h. The solvent was evaporated and the residue was purified by Kugelrohr distillation (60-80 ℃, 5 mbar) to give the title compound (2.50g, 87%) as a colorless oil. MSm/e: 141([ M + H)]⁺)

a) Trans- (RS) -4- [2- (dimethyl-hydrazono) -cyclohexanecarbonyl]-Cyclohexanecarboxylic acid methyl ester

To a solution of N, N-diisopropylamine (1.59ml, 11.2mmol) in dry tetrahydrofuran (10ml) at 0-5 deg.C was added 1.6M N-butyllithium in N-hexane (7.00ml, 11.2 mmol). After 15 minutes N' -cyclohexylidene-N, N-dimethyl-hydrazine (1.50g, 10.7mmol) was added followed by stirring for 90 minutes. The resulting solution was added dropwise to a solution of trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (2.19g, 10.7mmol) in dry tetrahydrofuran (50ml) at-65 ℃ with a catheter. The reaction mixture was stirred at-78 ℃ for 20 h. The cooling bath was removed and the reaction mixture was quenched by the addition of acetic acid (0.65ml, 11mmol) at-5 ℃. The mixture was partitioned between ethyl acetate (150ml) and saturated ammonium chloride solution (100 ml). The layers were separated. The aqueous layer was extracted with one 100-ml portion of ethyl acetate. The combined organic layers were washed with one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/ethyl acetate as eluent gave the title compound (0.98g, 30%) as a pale yellow oil, 60% pure. MSm/e: 309([ M + H ] ]⁺)

An intermediate of formula (XXI)

Trans-4- (N' -acetyl-hydrazinocarbonyl) -cyclohexanecarboxylic acid methyl ester

To a solution of monomethyl trans-1, 4-cyclohexanedicarboxylate (1.0g, 5.4mmol) and triethylamine (1.6ml, 11mmol) in dry tetrahydrofuran was added ethyl chloroformate (0.54ml, 5.6mmol) at 0-5 ℃. After 1h, the precipitated ammonium salt was removed by filtration. A solution of acetohydrazide (0.46g, 5.6mmol) in tetrahydrofuran (5ml) was added to the filtrate at room temperature and the mixture was stirred for 48 h. The reaction mixture was partitioned between ethyl acetate (250ml) and water (250 ml). The layers were separated. The aqueous layer was extracted with two 250-ml portions and an additional six 150-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (0.83g, 64%) as a white solid. MSm/e: 241([ M-H)]^-)

An intermediate of formula (XXII)

General procedure (V)

A solution of the aldoxime intermediate of formula XVIII (1eq) in acetic anhydride (21eq) is heated at reflux for 16-24 h. After cooling to room temperature, the reaction mixture was partitioned between 2M aqueous sodium hydroxide and ethyl acetate. The layers were separated. The aqueous layer is extracted with an organic solvent such as ethyl acetate or t-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography affords intermediates of formula XXII.

4-cyano-cyclohexanecarboxylic acid ester 1

Cis-4-cyano-cyclohexanecarboxylic acid ethyl ester

And

4-cyano-cyclohexanecarboxylic acid ester 2

Trans-4-cyano-cyclohexanecarboxylic acid ethyl ester

Cis-4-cyano-cyclohexanecarboxylic acid ethyl ester and trans-4-cyano-cyclohexanecarboxylic acid ethyl ester were obtained from cis/trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid ethyl ester after chromatographic separation according to general procedure (V).

Cis-4-cyano-cyclohexanecarboxylic acid ethyl ester was obtained as a colorless liquid in 70% yield. MSm/e: 181 (M)⁺)

Trans-4-cyano-cyclohexanecarboxylic acid ethyl ester was obtained as a colorless liquid in 15% yield. MSm/e: 181 (M)⁺)

4-cyano-cyclohexanecarboxylic acid ester 3

Cis/trans-4-cyano-cyclohexanecarboxylic acid ethyl ester (4: 1)

The title compound was obtained as light yellow liquid in 88% yield from cis/trans- (E/Z) -4- (hydroxyimino-methyl) -cyclohexanecarboxylic acid ethyl ester according to general procedure (V). MSm/e: 181 (M)⁺)

An intermediate of formula (XXIII)

General procedure (VI)

A mixture of the nitrile intermediate of formula XXII (1.0eq), sodium carbonate (1.0-1.2eq) and hydroxylamine hydrochloride (1.0-1.2eq) in ethanol (0.2M) was heated at reflux for 24-72 h. The solvent was evaporated. The residue was pulverized in ethyl acetate. The solid was removed by filtration and washed with ethyl acetate. The filtrate was extracted with three portions of 0.1M aqueous hydrochloric acid solution. The combined aqueous layers were adjusted to pH8 by the addition of a base such as sodium carbonate or sodium hydroxide and extracted with two portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the hydroxyaminooxime intermediate of formula XXIII.

4- (N-Hydroxycarbamimidoyl) -cyclohexanecarboxylic acid ester 1

Cis-4- (N-hydroxamimidyl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as off-white solid in 32% yield from cis-4-cyano-cyclohexanecarboxylic acid ethyl ester according to general procedure (VI). MSm/e: 215([ M + H)]⁺)

4- (N-hydroxamimidyl) -cyclohexanecarboxylic acid ester 2

Cis/trans-4- (N-hydroxamimidyl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as white solid in 28% yield from cis/trans-4-cyano-cyclohexanecarboxylic acid ethyl ester according to general procedure (VI). MSm/e: 215([ M + H)]⁺)

An intermediate of formula (XXV)

Trans-4-thiocarbamoyl-cyclohexanecarboxylic acid methyl ester

A solution of trans-4-carbamoyl-cyclohexanecarboxylic acid methyl ester (2.00g, 10.8mmol) and Lavirsone reagent (2.2g, 5.4mmol) in tetrahydrofuran (55ml) was heated at reflux for 3.5 h. The heating bath was removed and the solvent was evaporated. The residue was purified by flash chromatography with n-heptane/ethyl acetate as eluent to give a pink solid, which was triturated in toluene (10 ml). The precipitate was collected by filtration and dried under vacuum to give the title compound (1.04g, 48%) as an off-white solid. MSm/e: 202([ M + H ] ]⁺)

An intermediate of formula (XXVI)

Trans-4- [ 1-dimethylamino-ethylenethiocarbamoyl ] -cyclohexanecarboxylic acid methyl ester

A mixture of trans-4-thiocarbamoyl-cyclohexanecarboxylic acid methyl ester (0.72g, 3.6mmol) and N, N-dimethylacetamide dimethyl acetal (0.95g, 7.2mmol) was stirred at room temperatureOvernight. The solvent was evaporated. Flash chromatography with n-heptane/ethyl acetate as eluent afforded the title compound (0.90g, 93%) as a yellow oil. MSm/e: 271([ M + H)]⁺)

An intermediate of formula (XXVIII)

4- (N' -tert-Butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ester 1

Cis-4- (N' -tert-Butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ethyl ester

And

4- (N' -tert-Butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ester 2

Trans-4- (N' -tert-Butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ethyl ester

A solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (1.00g, 5.88mmol), tert-butyl hydrazinoformate (1.16g, 8.81mmol) and acetic acid (0.34ml, 5.9mmol) in dichloromethane (29ml) was stirred at room temperature for 1h and subsequently cooled to 0 ℃ on an ice-water bath. Sodium triacetoxyborohydride (2.49g, 11.8mmol) was added at 0-5 ℃. The cooling bath was removed after the addition was complete. The mixture was stirred at room temperature for 20h, followed by quenching with ethanol (5 ml). The reaction mixture was washed with one 50-ml portion of water. The aqueous layer (pH4) was extracted with two 50-ml portions of dichloromethane. The combined organic layers were washed with one 50ml portion of 2M aqueous sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography using N-heptane/ethyl acetate as eluent gave cis-4- (N '-tert-butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ethyl ester (1.05g, 62%) and trans-4- (N' -tert-butoxycarbonyl-hydrazine Yl) -cyclohexanecarboxylic acid ethyl ester (0.63g, 37%). Cis-4- (N' -tert-butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ethyl ester was obtained as a viscous colorless oil. MSm/e: 287([ M + H)]⁺)。

Trans-4- (N' -tert-butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ethyl ester was obtained as a white solid. MSm/e: 287([ M + H)]⁺)。

An intermediate of formula (XXIX)

4-hydrazino-cyclohexanecarboxylic acid ester hydrochloride 1

Trans-4-hydrazino-cyclohexanecarboxylic acid ethyl ester hydrochloride

Trans-4- (N' -tert-Butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ethyl ester (0.625g, 2.18mmol) was added to 1, 4-bisA solution of 4M hydrogen chloride in an alkane (5.5ml, 22mmol) was stirred at room temperature for 3 days. The precipitate was collected by filtration, washed with tert-butyl methyl ether and dried under vacuum to give the title compound in quantitative yield as a white solid. MSm/e: 187([ M + H ]]⁺)。

4-hydrazino-cyclohexanecarboxylic acid ester hydrochloride 2

Cis-4-hydrazino-cyclohexanecarboxylic acid ethyl ester hydrochloride

Cis-4- (N' -tert-butoxycarbonyl-hydrazino) -cyclohexanecarboxylic acid ethyl ester (1.03g, 3.60mmol) was added to 1, 4-bisA solution of 4M hydrogen chloride in an alkane (9.0ml, 36mmol) was stirred at room temperature for 3 days. The precipitate was collected by filtration, washed with tert-butyl methyl ether and dried under vacuum to give the title compound in quantitative yield as a white solid. MSm/e: 187([ M + H ] ]⁺)。

4-heteroaryl-cyclohexanecarboxylic acid ester intermediates of formula (VIII)

General procedure (VII):oxazole formation

To a solution of the keto-amide intermediate of formula XIV (1eq), hexachloroethane (3eq) and triethylamine (6eq) in acetonitrile (0.1M) was added triphenylphosphine (3eq) in small portions at 0-5 ℃. The cooling bath was removed 10 minutes after the addition was complete and stirring was continued for 2 h. The reaction mixture is partitioned between an organic solvent such as ethyl acetate and saturated aqueous ammonium chloride. The layers were separated. The aqueous layer was extracted with two portions of organic solvent. The combined organic layers were washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography to give compounds of formula VIII-1AAn azole intermediate.

General procedure (VIII): platinum (IV) oxide catalyzed hydrogenation

A solution of the 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula V in ethyl acetate (0.1M) was purged with argon. Platinum (IV) oxide (0.3eq) was added and the flask was then filled with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (1 bar) for 1-16 h. By usingThe catalyst was removed by filtration. The filtrate was concentrated to dryness to give a cis/trans mixture of the crude 4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII, which can usually be used without further purification And (4) carrying out the next step.

General procedure (IX): carbon supported palladium catalytic hydrogenation

A solution (0.1M) of the 4-heteroaryl-cyclohex-3-enecarboxylate intermediate of formula V and optionally a base such as triethylamine (1eq) in an organic solvent such as ethyl acetate or toluene is purged with argon. 10% palladium on activated carbon (0.05eq) was added, followed by filling the flask with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (1 bar) for 20-72 h. By usingThe catalyst was removed by filtration. The filtrate was washed with one portion of water. The aqueous layer was extracted with one or two portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness to give a cis/trans mixture of the crude 4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII, which can usually be used in the next step without further purification.

General procedure (X): epimerization followed by re-esterification

A mixture of the cis/trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII and sodium ethoxide (3-6eq) in ethanol was heated at reflux for 20-72 h. Under these reaction conditions, partial saponification of the resulting trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b to the trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b may occur. Such trans-4-heteroaryl-cyclohexanecarboxylic acid intermediates of formula IX-b can be converted to trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediates of formula VIII-b by: the mixture was continuously cooled to 0-5 ℃, concentrated sulfuric acid (7-9eq) was added and the mixture was heated under reflux for 1-2 h. After cooling to room temperature, the reaction mixture was partitioned between an organic solvent such as ethyl acetate or tert-butyl methyl ether and 2M aqueous sodium carbonate solution. The layers were separated. The aqueous layer is extracted with two or three portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Purification by flash chromatography gives the trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b.

General procedure (XI))：1，2，4-Oxadiazole formation

A solution (0.1M) of the hydroxyaminooxime intermediate of formula XXIII (1eq) and the carboxylic anhydride of formula p (3eq) in toluene was heated at reflux for 16-24 h. After cooling to room temperature, the reaction mixture was neutralized by adding solid sodium carbonate. The solvent was evaporated. The residue is triturated in an organic solvent such as tert-butyl methyl ether or ethyl acetate. The solids were removed by filtration. The residue was concentrated in vacuo. Purification by flash chromatography to give 1, 2, 4-An oxadiazole intermediate.

General procedure (XIX): pyrazole formation

A mixture (0.1M) of 4-hydrazino-cyclohexanecarboxylic acid ester hydrochloride of formula XXIX (1eq) and a dicarbonyl derivative of formula u, v or w (1-1.1eq) in ethanol was heated at reflux for 1-2 h. After cooling to room temperature, the reaction mixture is partitioned between an organic solvent such as ethyl acetate or dichloromethane and saturated aqueous bicarbonate. The layers were separated and the aqueous layer was extracted with two organic solvents. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the pyrazole intermediate of formula (VIII-9), which was typically used in the next step without further purification.

4-heteroaryl-cyclohexanecarboxylic acid esters 1

Trans-4-Azol-2-yl-cyclohexanecarboxylic acid methyl ester

Trans-4- (2-oxo-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester (830mg,3.65mmol) and phosphorus oxychloride (2.80g, 18.3mmol) were heated at 100 ℃ for 20 h. After cooling to room temperature, the reaction mixture was poured onto crushed ice and basified to pH7-8 by addition of 1M aqueous sodium hydroxide solution. The mixture is extracted with three 100ml portions of ethyl acetate. The combined organic layers were washed with one 50ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/ethyl acetate as eluent gave the title compound (175mg, 23%) as a white solid, 90% pure according to GC. MSm/e: 210([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid esters 2

Trans-4- (4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as white solid in 38% yield from trans-4- ((S) -1-methyl-2-oxo-ethylcarbamoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (VII). MSm/e: 224([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid esters 3

Trans-4- (5-methyl-Azol-2-yl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as off-white solid in 76% yield from trans-4- (2-oxo-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (VII) 。MSm/e：224([M+H]⁺)

4-heteroaryl-cyclohexanecarboxylic acid esters 4

Trans-4- (4, 5-dimethyl-Azol-2-yl) -cyclohexanecarboxylic acid methyl ester

The title compound was obtained as light brown solid in 62% yield from trans-4- (1-methyl-2-oxo-propylcarbamoyl) -cyclohexanecarboxylic acid methyl ester according to general procedure (VII). MSm/e: 238([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid esters 5

Cis/trans-4-thiazol-2-yl-cyclohexanecarboxylic acid ethyl ester (3: 1)

The title compound was obtained as colorless oil in 62% yield from (RS) -4-thiazol-2-yl-cyclohex-3-enecarboxylic acid ethyl ester according to general procedure (VIII). MSm/e: 240([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 6

Cis/trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (4: 1)

The title compound was obtained as a colorless oil according to general procedure (VIII)Obtained in 54% yield from (RS) -4- (4-methyl-thiazol-2-yl) -cyclohex-3-enecarboxylic acid ethyl ester. MSm/e: 254([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 7

Cis/trans-4- (2-methyl-thiazol-4-yl) -cyclohexanecarboxylic acid ethyl ester (3: 1)

The title compound was obtained as colorless oil in 52% yield from (RS) -4- (2-methyl-thiazol-4-yl) -cyclohex-3-enecarboxylic acid ethyl ester according to general procedure (VIII). MSm/e: 254([ M + H) ]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 8

Trans-4- (5-methyl-iso)Azol-3-yl) -cyclohexanecarboxylic acid methyl ester

To a solution of methyl trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylate (5.90g, 26.9mmol) and isopropenyl acetate (53.8g, 537mmol) in dichloromethane (134ml) was added triethylamine (5.44g, 53.7mmol) at 0-5 ℃. The cooling bath was removed 15 minutes after the addition was complete and the mixture was stirred for 20 h. The reaction mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (250ml) and 0.1M aqueous hydrochloric acid (200 ml). The organic layer was washed with a 100ml portion of 0.1M aqueous hydrochloric acid. The combined aqueous layers were extracted with a portion of 150ml ethyl acetate. The combined organic layers were washed with one part of 200ml of 2M sodium carbonate and one part of 100-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluentThe title compound (3.00g, 50%) was obtained as an off-white solid. MSm/e: 224([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 9

Trans-4- (4-bromo-5-methyl-iso-methyl)Azol-3-yl) -cyclohexanecarboxylic acid methyl ester

Reacting trans-4- (5-methyl-iso)A solution of oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester (295mg, 1.32mmol) and N-bromosuccinimide (235mg, 1.32mmol) in N, N-dimethylformamide (2.6ml) was stirred at room temperature for 16 h. The reaction mixture was partitioned between ethyl acetate (50ml) and 0.1M aqueous sodium hydroxide (50 ml). The layers were separated. The aqueous layer was extracted with a 50ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (399mg, 100%) as a pale yellow oil, which was used in the next step without further purification. MSm/e: 302([ M + H) ]⁺)

4-heteroaryl-cyclohexanecarboxylic acid esters 10

Trans-4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexanecarboxylic acid methyl ester

At room temperature, to trans-4- (4-bromo-5-methyl-iso-isomerAzol-3-yl) -cyclohexanecarboxylic acid methyl ester (660mg, 2.18mmol) and 2M solution of methyl zinc chloride in tetrahydrofuran (1.64ml, 3.28mmol) to a solution of tetrahydrofuran in a 4: 1 mixture of tetrahydrofuran and 1, 3-dimethyl-2-imidazolidinone (12ml) was added (1, 3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride (29.7mg, 43.7. mu. mol). The reaction mixture was heated at 50 ℃ for 2 h. The reaction mixture was partitioned between tert-butyl methyl ether (100ml) and 0.1M aqueous hydrochloric acid (100 ml). The layers were separated. The aqueous layer was extracted with a 100ml portion of tert-butyl methyl ether. The combined organic layers were washed with two 50ml portions of water and one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/ethyl acetate as eluent gave the title compound (460mg, 84%) as a pale yellow oil, 90% pure according to GC. MSm/e: 238([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid esters 11

Trans-4- (4-chloro-5-methyl-isoAzol-3-yl) -cyclohexanecarboxylic acid methyl ester

Reacting trans-4- (5-methyl-iso)A mixture of oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester (250mg, 1.12mmol) and N-chlorosuccinimide (164mg, 1.23mmol) in N, N-dimethylformamide (2.2ml) was stirred at room temperature for 24 h. The reaction mixture was partitioned between tert-butyl methyl ether (50ml) and water (50 ml). The layers were separated. The aqueous layer was extracted with a 50ml portion of t-butyl methyl ether. The combined organic layers were washed with one 50ml portion of 0.1M aqueous sodium hydroxide solution, one 50ml portion of water and one 30ml portion of brine, Dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (275mg, 95%) as a pale yellow oil, which was used in the next step without further purification. MSm/e: 257 (M)⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 12

Trans-4- (4-fluoro-5-methyl-isoAzol-3-yl) -cyclohexanecarboxylic acid methyl ester

Reacting trans-4- (5-methyl-iso)Oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester (250mg, 1.12mmol) anda mixture of (476mg, 1.34mmol) in acetonitrile (5.6ml) was heated at 90 ℃ for 20 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 50ml portions of ethyl acetate. The combined organic layers were washed with a 25ml portion of water/brine (1: 1), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/tert-butyl methyl ether as eluent gave the title compound (35mg, 13%) as a pale yellow oil. MSm/e: 241([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 13

Trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid methyl ester

Reacting trans-4- [2- (dimethyl-hydrazono) -cyclohexanecarbonyl]A mixture of methyl cyclohexanecarboxylate (0.95g, 3.1mmol), sodium acetate (0.28g, 3.4mmol) and hydroxylamine hydrochloride (0.24g, 3.4mmol) in methanol (15ml) was stirred at room temperature for 16 h. The reaction mixture was partitioned between ethyl acetate (100ml) and water (50 ml). The layers were separated. The aqueous layer was extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue (0.88g) was dissolved in toluene (15 ml). After addition of a catalytic amount of toluene-4-sulfonic acid monohydrate, the mixture was heated at reflux for 3 h. The solvent was evaporated. Purification using n-heptane/ethyl acetate as eluent gave the title compound (0.58g, 72%) according to ¹³The regioisomeric purity by C-NMR was about 90%. MSm/e: 264([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 14

Trans-4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexanecarboxylic acid methyl ester

To a solution of trans-4- (N' -acetyl-hydrazinocarbonyl) -cyclohexanecarboxylic acid methyl ester (0.55g, 2.3mmol) in acetonitrile (23ml) at room temperature were added trifluoromethanesulfonic acid (0.51ml, 5.9mmol) and dimethyldichlorosilane (0.30ml, 2.5mmol) successively. The mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was poured onto ice. The pH was adjusted to 3 by addition of 1M aqueous sodium hydroxide (2.3ml, 2.3 mmol). The aqueous layer was extracted with three portions of 150-ml ethyl acetate. The combined organic layers were washed with one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the firstCrude product of batch (0.23 g). A second batch (0.37g) was similarly obtained from 0.33g of trans-4- (N' -acetyl-hydrazinocarbonyl) -cyclohexanecarboxylic acid methyl ester. The two batches were combined and purified by flash chromatography with n-heptane/ethyl acetate as eluent to give the title compound (0.23mg, 46%) as a white solid. MSm/e: 225([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 15

Trans-4- (3-methyl- [1, 2, 4 ] ]Oxadiazol-5-yl) -cyclohexanecarboxylic acid methyl ester

To a solution of acetamidoxime (0.19g, 2.6mmol) and triethylamine (0.36ml, 2.6mmol) in tetrahydrofuran (24ml) was added trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (0.50g, 2.4mmol) at 0-5 ℃. The cooling bath was removed after the addition was complete and the mixture was stirred for 30 minutes. The precipitated ammonium salt was removed by filtration and washed with tetrahydrofuran. The filtrate was concentrated to dryness. The residue is redissolved in 1, 4-bisAlkane (24 ml). The mixture was treated with a catalytic amount of toluene-4-sulfonic acid monohydrate and heated at reflux overnight (16 h). The solvent was evaporated. Flash chromatography with n-heptane/ethyl acetate as eluent afforded the title compound (0.48g, 88%) as a light brown oil. MSm/e: 225([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 16

Trans-4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexanecarboxylic acid methyl ester

At room temperature, to trans-4- [ 1-dimethylamino-ethylenethiocarbamoyl]To a solution of methyl cyclohexanecarboxylate (0.87g, 3.2mmol) and pyridine (0.52ml, 6.5mmol) in ethanol (6ml) was added a solution of hydroxylamine-O-sulfonic acid (0.45 g; 3.6mmol) in methanol (3 ml). After stirring overnight, the reaction mixture was partitioned between 1M aqueous hydrochloric acid (100ml) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with one 100-ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography with n-heptane/ethyl acetate as eluent afforded the title compound (0.68g, 88%) as a yellow oil. MSm/e: 241([ M + H) ]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 17

Cis/trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid ethyl ester

To a suspension of cis/trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylic acid ethyl ester (1.85g, 7.92mmol) and iminoctaacetic acid ethyl ester hydrochloride (1.96g, 15.8mmol) in dichloromethane (40ml) at 0-5 ℃ was added triethylamine (2.2ml, 16 mmol). The cooling bath was removed 15 minutes after the addition was complete and stirred at room temperature for 18h, followed by heating at reflux for 4 h. The reaction mixture was washed with one 50-ml portion of 1M aqueous hydrochloric acid. The aqueous layer was extracted with two 50-ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography using n-heptane/tert-butyl methyl ether as eluent gave the title compound (1.05g, 56%) as a colorless oil. MSm/e: 239([ M + H ]]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 18

Cis-4- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as light yellow oil in 75% yield from cis-4- (N-hydroxamimidyl) -cyclohexanecarboxylic acid ethyl ester and acetic anhydride according to general procedure (XI). MSm/e: 239([ M + H ]]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 19

Cis/trans-4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as yellow liquid in 92% yield from cis/trans-4- (N-hydroxamimidyl) -cyclohexanecarboxylic acid ethyl ester and propionic anhydride according to general procedure (XI). MSm/e: 253([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 20

Cis/trans-4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as a yellow liquid in 92% yield from cis/trans-4- (N-hydroxamimidyl) -cyclohexanecarboxylic acid ethyl ester and isobutyric anhydride according to general procedure (XI). MSm/e: 267([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 21

Trans-4- (5-methyl- [1, 2, 4] thiadiazol-3-yl) -cyclohexanecarboxylic acid methyl ester

To a solution of trans-4-thiocarbamoyl-cyclohexanecarboxylic acid methyl ester (0.30g, 1.5mmol) and thioacetamide (0.67g, 8.9mmol) in methanol (7ml) was added a solution of iodine (2.65g, 10.4mmol) in methanol (15ml) at room temperature. After stirring for 48h, the reaction mixture was partitioned between 0.1M sodium thiosulfate solution (100ml) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by Kugelrohr distillation. The distillate was purified by flash chromatography using n-heptane/tert-butyl methyl ether as eluent to give the title compound (0.021g, 5%) as a pale yellow oil, which was purified 20% trans-4- (3-methyl- [1, 2, 4) ]Thiadiazol-5-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 241([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 22

Trans-4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid methyl ester

Reacting trans-4- (4-methyl-A solution of oxazol-2-yl) -cyclohexanecarboxylic acid methyl ester (277mg, 1.24mmol) and N-chlorosuccinimide (182mg, 1.36mmol) in N, N-dimethylformamide (2.5ml) was stirred at room temperature for 6 h. The reaction mixture was partitioned between tert-butyl methyl ether (25ml) and 0.1M aqueous sodium hydroxide (25 ml). The layers were separated. The aqueous layer was extracted with a 25-ml portion of tert-butyl methyl ether. The combined organic layers were washed with three 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (285mg, 89%) as a pale yellow solid, which was used in the next step without further purification. MSm/e: 258([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 23

Cis/trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 5)

The title compound was obtained as yellow oil in 97% yield from cis/trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (4: 1) according to general procedure (X). MSm/e: 254([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 24

Cis/trans-4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 5)

A solution of cis/trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 5) (200mg, 0.789mmol) and N-chlorosuccinimide (116mg, 0.868mmol) in N, N-dimethylformamide (1.6ml) was stirred at 50 ℃ for 1 h. The reaction mixture was partitioned between tert-butyl methyl ether (25ml) and 0.1M aqueous sodium hydroxide (25 ml). The layers were separated. The aqueous layer was extracted with a 25-ml portion of tert-butyl methyl ether. The combined organic layers were washed with three 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (209mg, 92%) as a pale yellow solid which was used in the next step without further purification. MSm/e: 288([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 25

Cis/trans-4- (5-bromo-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 5)

A solution of cis/trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 5) (319mg, 1.26mmol) and N-bromosuccinimide (247mg, 1.38mmol) in N, N-dimethylformamide (1.6ml) was stirred at room temperature for 1 h. The reaction mixture was partitioned between tert-butyl methyl ether (25ml) and 0.1M aqueous sodium hydroxide (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of tert-butyl methyl ether. The combined organic layers were washed with two 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (371mg, 89%) as a pale yellow solid, which was used in the next step without further purification. MSm/e: 334([ M + H) ]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 26

Cis/trans-4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 7)

To a solution of cis/trans-4- (5-bromo-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 5) (371mg, 1.12mmol) and 2M zinc methyl chloride in tetrahydrofuran (0.837ml, 1.67mmol) in a 5: 1 mixture of tetrahydrofuran and 1, 3-dimethyl-2-imidazolidinone (6ml) was added (1, 3-diisopropylimidazol-2-ylidene) (3-chloropyridyl) palladium (II) chloride (15.2mg, 22.3. mu. mol) at room temperature. The reaction mixture was heated at 50 ℃ for 2 h. After cooling to room temperature, the reaction mixture was partitioned between tert-butyl methyl ether (25ml) and 0.1M aqueous sodium hydroxide (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of tert-butyl methyl ether. The combined organic layers were washed with two 25-ml portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/ethyl acetate as eluent gave the title compound (170mg, 57%) as a colourless oil, 80% pure according to GC. MSm/e: 268([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid ester 27

Trans-4- (4, 5-bis-hydroxymethyl-isoAzol-3-yl) -cyclohexanecarboxylic acid methyl ester

To a mixture of methyl trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylate (0.900g, 4.10mmol) and but-2-yne-1, 4-diol (0.370g, 4.30mmol) in 1, 2-dichloroethane (41.0ml) was added chloro (1, 5-cyclooctadiene) (pentamethylcyclopentadienyl) ruthenium (II) (0.0778g, 205. mu. mol) and triethylamine (0.713ml, 5.12mmol) at room temperature. The reaction mixture was stirred for 20 h. The solvent was evaporated. The residue was triturated in ethyl acetate (50 ml). The solid was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography with n-heptane/ethyl acetate as eluent afforded the title compound (0.758g, 69%) as a light brown oil.

4-heteroaryl-Cyclohexanecarboxylic acid ester 28

Trans-4-pyrazol-1-yl-cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as light brown oil in quantitative yield from trans-4-hydrazino-cyclohexanecarboxylic acid ethyl ester hydrochloride and 1, 1, 3, 3-tetraethoxypropane according to general procedure (XIX). MSm/e: 223([ M + H)]⁺)。

4-heteroaryl-cyclohexanecarboxylic acid ester 29

Cis-4-pyrazol-1-yl-cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as light brown oil in quantitative yield from cis-4-hydrazino-cyclohexanecarboxylic acid ethyl ester hydrochloride and 1, 1, 3, 3-tetraethoxypropane according to general procedure (XIX). MSm/e: 223([ M + H) ]⁺)。

4-heteroaryl-cyclohexanecarboxylic acid ester 30

Trans-4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid ethyl ester

The title compound, rootObtained as off-white solid in 96% yield from trans-4-hydrazino-cyclohexanecarboxylic acid ethyl ester hydrochloride and pentane-2, 4-dione according to general procedure (XIX). MSm/e: 251([ M + H)]⁺)。

4-heteroaryl-cyclohexanecarboxylic acid ester 31

Trans-4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid ethyl ester

The title compound was obtained as light brown solid in quantitative yield from trans-4-hydrazino-cyclohexanecarboxylic acid ethyl ester hydrochloride and 3-methylpentane-2, 4-dione according to general procedure (XIX). MSm/e: 265([ M + H)]⁺)。

4-heteroaryl-cyclohexanecarboxylic acid intermediates of formula (IX)

General procedure (XII): epimerization followed by saponification

A mixture of the cis/trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII and sodium ethoxide (3-6eq) in ethanol was heated at reflux for 20-72 h. Under these reaction conditions, partial saponification of the resulting trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b to a trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b may occur. The reaction mixture is partitioned between 0.5M hydrochloric acid solution and an organic solvent such as ethyl acetate or tert-butyl methyl ether. The pH of the aqueous layer was adjusted to 1-3. The layers were separated. The aqueous layer is extracted with one or two portions of an organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to provide a mixture of trans-4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula VIII-b and trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b. Redissolving the mixture in 1, 4-bis Alkane (0.1-0.2M) and 2M oxyhydrogenAqueous sodium chloride (10-20eq) and stirred at room temperature for 16-24 h. The reaction mixture is partitioned between 0.5M hydrochloric acid solution and an organic solvent such as ethyl acetate or tert-butyl methyl ether. The pH is adjusted to 1-3. The layers were separated. The aqueous layer is extracted with one or two portions of an organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness to give the trans-4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula IX-b.

4-heteroaryl-cyclohexanecarboxylic acid intermediate 1

Trans-4-thiazol-2-yl-cyclohexanecarboxylic acid

The title compound was obtained as light brown solid in 60% yield from cis/trans-4-thiazol-2-yl-cyclohexanecarboxylic acid ethyl ester (3: 1) according to general procedure (XII). MSm/e: 210([ M-H ]]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 2

Trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid

The title compound was obtained as colorless oil in 90% yield from cis/trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (4: 1) according to general procedure (XII). MSm/e: 226([ M + H)]⁺)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 3

Trans-4- (2-methyl-thiazol-4-yl) -cyclohexanecarboxylic acid

The title compound was obtained as light brown solid in 71% yield from cis/trans-4- (2-methyl-thiazol-4-yl) -cyclohexanecarboxylic acid ethyl ester (3: 1) according to general procedure (XII). MSm/e: 224([ M-H) ]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 4

Cis/trans-4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexanecarboxylic acid (3: 7)

a)4- (1-methylene-propyl) -morpholine

To a solution of 2-butanone (6.2ml, 69mmol) and morpholine (18.1ml, 208mmol) in n-pentane (400ml) at 0-5 deg.C was added dropwise a 1M solution of titanium tetrachloride in dichloromethane (38.1ml, 38.1 mmol). The cooling bath was removed and the mixture was stirred for 20 h. The precipitate was removed by filtration and washed with two 100-ml portions of diethyl ether. The filtrate was concentrated in vacuo. The residue was distilled on a Vigrella column in a Kugelrohr furnace (1 mbar, 40-70 ℃) to give the title compound (5.1g, 52%) as a colorless oil.

b) Cis/trans-4- (5-ethyl-iso-methyl) Azol-3-yl) -cyclohexanecarboxylic acid (3: 7)

To a solution of cis/trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylic acid ethyl ester (2.35g, 10.1mmol) and 4- (1-methylene-propyl) -morpholine (4.26g, 30.2mmol) in dichloromethane (100ml) was added triethylamine (1.40ml, 10.1mmol) at 0-5 ℃. The cooling bath was removed 30 minutes after the addition was complete. After stirring for 20h the solvent was evaporated. The residue was redissolved in 6M aqueous hydrochloric acid (100ml) and the mixture was heated at reflux for 3 h. After cooling to room temperature, the reaction mixture was partitioned between crushed ice (300g) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/tert-butyl methyl ether as eluent gave the title compound (0.42g, 19%) as a white solid. MSm/e: 222([ M-H) ]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 5

Cis-4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid

And

4-heteroaryl-cyclohexanecarboxylic acid intermediate 6

Trans-4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid

At 0-5 deg.CTo a solution of cis/trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylic acid ethyl ester (1.20g, 5.13mmol) and 1-morpholinocyclohexene (1.72g, 10.3mmol) in dichloromethane (50ml) was added triethylamine (0.72ml, 5.1 mmol). The cooling bath was removed 30 minutes after the addition was complete. After stirring for 4h the solvent was evaporated. The residue was redissolved in 6M aqueous hydrochloric acid (50ml) and the mixture was heated at reflux for 1 h. After cooling to room temperature, the reaction mixture was partitioned between crushed ice (100g) and ethyl acetate (50 ml). The layers were separated. The aqueous layer was extracted with two 50-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification using n-heptane/ethyl acetate as eluent to give cis-4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherOxazol-3-yl) -cyclohexanecarboxylic acid (0.40g, 31%) as a white solid (MSm/e: 248([ M-H)]^-) And trans-4- (4, 5, 6, 7-tetrahydro-benzo [ d ] ]Different from each otherOxazol-3-yl) -cyclohexanecarboxylic acid (0.09g, 7%) as a white solid (MSm/e: 248([ M-H)]^-))。

4-heteroaryl-cyclohexanecarboxylic acid intermediate 7

Trans-4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid

Reacting trans-4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid methyl ester (285mg, 1.11mmol) in 1, 4-bisA mixture of an alkane (5.5ml) and 2M aqueous sodium hydroxide (5.5ml, 11mmol) was stirred at room temperature for 4 h. The reaction mixture was partitioned between ethyl acetate (25ml) and water (25 ml). The aqueous layer was acidified to pH 2. The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were washed with one portion of 10-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound, (245mg, 91%) as a white solid. MSm/e: 242([ M-H)]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 8

Cis/trans-4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid (1: 5)

Cis/trans-4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 5) (209mg, 0.726mmol) in 1, 4-bisA mixture of an alkane (7.3ml) and 2M aqueous sodium hydroxide (3.6ml, 7.3mmol) was stirred at room temperature for 12 h. The reaction mixture was partitioned between ethyl acetate (25ml) and 0.1M aqueous hydrogen chloride (25 ml). The layers were separated. The aqueous layer (pH2) was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were washed with one portion of 10-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (170mg, 90%) as a white solid. MSm/e: 258([ M-H) ]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 9

Cis/trans-4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexanecarboxylic acid

Cis/trans-4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexanecarboxylic acid ethyl ester (1: 7) (170mg, 0.636mmol) in 1, 4-bisA mixture of an alkane (6.4ml) and 2M aqueous sodium hydroxide (3.2ml, 6.4mmol) was stirred at room temperature for 24 h. The reaction mixture was partitioned between ethyl acetate (25ml) and water (25 ml). The aqueous layer was acidified to pH4-5 by the addition of 2M aqueous hydrogen chloride (3.2 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were washed with one portion of 20-ml brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (136mg, 89%) as a white solid. MSm/e: 240([ M-H)]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 10

Trans-4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid

To a solution of methyl trans-4- (chloro (hydroxyimino) methyl) cyclohexanecarboxylate (0.900g, 4.10mmol) and 4-cyclopentenylmorpholine (1.23ml, 8.19mmol) in dichloromethane (21ml) was added triethylamine (0.714ml, 5.12mmol) at 0-5 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The solvent was evaporated. The residue was redissolved in 6M aqueous hydrogen chloride (20.5ml) and stirred under reflux for 4 h. After cooling to room temperature, the reaction mixture was poured onto ice, basified with 2M aqueous sodium hydroxide (80ml) and washed with two 50-ml portions of ethyl acetate. The combined organic layers were extracted with two 50-ml portions of 1M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH2-3 by addition of concentrated HCl and extracted with three 100-ml portions of ethyl acetate And (6) taking. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (50 ml). The precipitate was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography with n-heptane/ethyl acetate as eluent to give the title compound (0.060g, 6%) as an off-white solid. MSm/e: 234([ M-H)]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 11

Trans-4-pyrazol-1-yl-cyclohexanecarboxylic acid

Trans-4-pyrazol-1-yl-cyclohexanecarboxylic acid ethyl ester (95mg, 0.43mmol) was added to 1, 4-bisA mixture of an alkane (4.3ml) and 2M aqueous sodium hydroxide (2.2ml, 4.4mmol) was stirred at room temperature for 20 h. The pH was adjusted to 2 by addition of 2M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (80mg, 96%) as a pale brown solid. MSm/e: 193([ M-H)]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 12

Cis-4-pyrazol-1-yl-cyclohexanecarboxylic acid

Cis-4-pyrazol-1-yl-cyclohexanecarboxylic acid ethyl ester (95mg, 0.427mmol) was added to 1, 4-bis A mixture of an alkane (4.3ml) and 2M aqueous sodium hydroxide (2.2ml, 4.4mmol) was stirred at room temperature for 20 h. The pH was adjusted to 2 by addition of 2M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (79mg, 95%) as a pale brown solid. MSm/e: 193([ M-H)]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 13

Trans-4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid

Trans-4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid ethyl ester (162mg, 0.647mmol) was added to 1, 4-bisA solution of an alkane (6.5ml) and 2M aqueous sodium hydroxide (3.2ml, 6.4mmol) was stirred at room temperature for 15 h. The pH was adjusted to 3 by addition of 2M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (116mg, 81%) as a pale brown solid. MSm/e: 221([ M-H)]^-)

4-heteroaryl-cyclohexanecarboxylic acid intermediate 14

Trans-4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid

Trans-4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid ethyl ester (180mg, 0.681mmol) was added to 1, 4-bisAlkane (6.8ml) and 2M aqueous sodium hydroxide (3.4ml, 6.8mmol) were stirred at room temperature for 3 days. The pH was adjusted to 3 by addition of 2M aqueous hydrochloric acid. The mixture was partitioned between ethyl acetate (25ml) and water (25 ml). The layers were separated. The aqueous layer was extracted with two 25-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (141mg, 88%) as a pale brown solid. MSm/e: 235([ M-H)]^-)

Hydrazide intermediates of formula (II)

General procedure (XIII): formation of hydrazides from acids

To a solution of the 4-heteroaryl-cyclohexanecarboxylic acid intermediate of formula (IX) (1eq) and triethylamine (1.05eq) in tetrahydrofuran (0.2M) at 0 ℃, ethyl chloroformate (1.05eq) was added. The reaction mixture was stirred at 0 ℃ for 1 h. The ammonium salts were removed by filtration. The filtrate was added to a cold solution (0.2M) of hydrazine hydrate (2eq) in methanol. The reaction mixture was stirred at room temperature for 2-16 h. The solvent is evaporated under reduced pressure and the residue is partitioned between an organic solvent such as ethyl acetate or dichloromethane and water. The organic layer was separated. The aqueous layer is extracted with two or three portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the hydrazide intermediate of formula (II), which was typically used in the next step without further purification.

General procedure (XIV): formation of hydrazides from esters

A mixture (0.2-1M) of the 4-heteroaryl-cyclohexanecarboxylic acid ester intermediate of formula (VIII) (1eq) and hydrazine hydrate (2-6eq) in n-butanol is heated at reflux for 16-72 h. After cooling to room temperature, the reaction mixture is partitioned between an organic solvent such as ethyl acetate or dichloromethane and water. The layers were separated and the aqueous layer was extracted with two portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford the hydrazide intermediate of formula (II), which was typically used in the next step without further purification.

Hydrazide 1

Trans-4-Azol-2-yl-cyclohexanecarboxylic acid hydrazide

The title compound was obtained as a white solid in 61% yield from trans-4-Oxazol-2-yl-cyclohexanecarboxylic acid methyl ester. MSm/e: 210([ M + H)]⁺)

Hydrazide 2

Trans-4- (4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as a white solid in 92% yield from trans-4- (4-methyl-Oxazol-2-yl) -cyclohexanecarboxylic acid. MSm/e: 224([ M + H)]⁺)

Hydrazide 3

Trans-4- (5-methyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as an off-white solid in 93% yield from trans-4- (5-methyl- Oxazol-2-yl) -cyclohexanecarboxylic acid. MSm/e: 224([ M + H)]⁺)

Hydrazide 4

Trans-4- (4, 5-dimethyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as a white solid in 73% yield from trans-4- (4, 5-dimethyl-Oxazol-2-yl) -cyclohexanecarboxylic acid. MSm/e: 238([ M + H)]⁺)

Hydrazide 5

Trans-4-thiazol-2-yl-cyclohexanecarboxylic acid hydrazide

The title CompoundObtained as light brown solid in 79% yield from trans-4-thiazol-2-yl-cyclohexanecarboxylic acid according to general procedure (XIII). MSm/e: 226([ M + H)]⁺)

Hydrazide 6

Trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 59% yield from trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid according to general procedure (XIII). MSm/e: 240([ M + H)]⁺)

Hydrazide 7

Trans-4- (2-methyl-thiazol-4-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as off-white solid in 94% yield from 4- (2-methyl-thiazol-4-yl) -cyclohexanecarboxylic acid according to general procedure (XIII). MSm/e: 240([ M + H)]⁺)

Hydrazide 8

Trans-4- (5-methyl-iso)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as a white solid at 91% according to general procedure (XIV) The ratio is from trans-4- (5-methyl-iso)Oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 224([ M + H)]⁺)

Hydrazide 9

Trans-4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as a white solid in quantitative yield from trans-4- (4, 5-dimethyl-iso-methyl) according to general procedure (XIV)Oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 238([ M + H)]⁺)

Hydrazide 10

Trans-4- (4-chloro-5-methyl-isoAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 95% yield from trans-4- (4-chloro-5-methyl-iso-methyl) -iso-butyl according to general procedure (XIV)Oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 258([ M + H)]⁺)

Hydrazide 11

Trans-4- (4-fluoro-5-methyl-isoAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as off-white solid in 89% yield from trans-4- (4-fluoro-5-methyl-iso-propyl) -according to general procedure (XIV)Oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 242([ M + H)]⁺)

Hydrazide 12

Cis/trans-4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as a white solid in quantitative yield from cis/trans-4- (5-ethyl-iso-tert-butyl) according to general procedure (XIII)Oxazol-3-yl) -cyclohexanecarboxylic acid. MSm/e: 238([ M + H) ]⁺)

Hydrazide 13

Trans-4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 91% yield from trans-4- (4, 5, 6, 7-tetrahydro-benzo [ d ] according to general procedure (XIII)]Different from each otherOxazol-3-yl) -cyclohexanecarboxylic acid. MSm/e: 264([ M + H)]⁺)

Hydrazide 14

Cis-4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as amorphous off-white solid in quantitative yield from cis-4- (4, 5, 6, 7-tetrahydro-benzo [ d ] according to general procedure (XIII)]Different from each otherOxazol-3-yl) -cyclohexanecarboxylic acid. MSm/e: 264([ M + H)]⁺)

Hydrazide 15

Trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 78% yield from trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c) according to general procedure (XIV)]Different from each otherOxazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 264([ M + H)]⁺)

Hydrazide 16

Trans-4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexanecarboxylic acid hydrazide

The crude title compound was obtained as a pink liquid in 60% yield from trans-4- (5-methyl- [1, 3, 4) according to general procedure (XIV)]Oxadiazol-2-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 225([ M + H) ]⁺)

Hydrazide 17

Trans-4- (3-methyl- [1, 2, 4]]Oxadiazol-5-yl) -cyclohexanecarboxylic acid hydrazide

The title compound, according to general procedure (XIV),from trans-4- (3-methyl- [1, 2, 4] as a white solid in 65% yield]Oxadiazol-5-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 225([ M + H)]⁺)

Hydrazide 18

Trans-4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 80% yield from trans-4- (3-methyl- [1, 2, 4] according to general procedure (XIV)]Thiadiazol-5-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 241([ M + H)]⁺)

Hydrazide 19

Trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 60% yield from trans-4- (5-methyl- [1, 2, 4) according to general procedure (XIV)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 225([ M + H)]⁺)

Hydrazide 20

Cis-4- (5-methyl- [1, 2, 4]]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as off-white solid in 61% yield from cis-4- (5-methyl- [1, 2, 4) according to general procedure (XIV)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid ethyl ester. MSm/e: 225([ M + H)]⁺)

Hydrazide 21

Cis/trans-4- (5-ethyl- [1, 2, 4) ]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as yellow solid in 96% yield from cis/trans-4- (5-ethyl- [1, 2, 4) according to general procedure (XIV)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid ethyl ester. MSm/e: 239([ M + H ]]⁺)

Hydrazide 22

Cis/trans-4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as light yellow oil in 68% yield from cis/trans-4- (5-isopropyl- [1, 2, 4) according to general procedure (XIV)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid ethyl ester. MSm/e: 253([ M + H)]⁺)

Hydrazide 23

Trans-4- (5-methyl- [1, 2, 4] thiadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound, according to general procedure (XIV), as an off-white solid (which was substituted with approximately 20% trans-4- (3-methyl- [1, 2, 4)]Thiadiazol-5-yl) -cyclohexanecarboxylic acid hydrazide contamination) in 95% yield from trans-4- (5-methyl- [1, 2, 4)]Thiadiazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 241([ M + H)]⁺)

Hydrazide 24

Trans 4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as a white solid in 72% yield from trans-4- (5-chloro-4-methyl-Oxazol-2-yl) -cyclohexanecarboxylic acid. MSm/e: 258([ M + H) ]⁺)

Hydrazide 25

Trans-4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 30% yield from cis/trans-4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid (1: 5) according to general procedure (XIII). MSm/e: 274([ M + H)]⁺)

Hydrazide 26

Cis/trans-4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexanecarboxylic acid hydrazide (1: 7.5)

The title compound was obtained as white solid in 75% yield from cis/trans-4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexanecarboxylic acid (1: 5) according to general procedure (XIII). MSm/e: 254([ M + H)]⁺)

Hydrazide 27

Trans-4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as off-white solid in 71% yield from trans-4- (5, 6-dihydro-4H-cyclopenta [ d ] according to general procedure (XIII)]Different from each otherOxazol-3-yl) -cyclohexanecarboxylic acid. MSm/e: 250([ M + H ]]⁺)

Hydrazide 28

Trans-4- (4, 5-bis-hydroxymethyl-isoAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as light yellow solid in quantitative yield from trans-4- (4, 5-di-hydroxymethyl-iso-p-butyl) according to general procedure (XIV)Oxazol-3-yl) -cyclohexanecarboxylic acid methyl ester. MSm/e: 270([ M + H) ]⁺)

Hydrazide 29

Trans-4-pyrazol-1-yl-cyclohexanecarboxylic acid hydrazide

The title compound was obtained as off-white solid in 69% yield from trans-4-pyrazol-1-yl-cyclohexanecarboxylic acid according to general procedure (XIII). MSm/e: 209([ M + H)]⁺)

Hydrazide 30

Cis-4-pyrazol-1-yl-cyclohexanecarboxylic acid hydrazide

The title compound was obtained as off-white solid in 72% yield from cis-4-pyrazol-1-yl-cyclohexanecarboxylic acid according to general procedure (XIII). MSm/e: 209([ M + H)]⁺)

Hydrazide 31

Trans-4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as white solid in 88% yield from trans-formula-4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid according to general procedure (XIII). MSm/e: 237([ M + H)]⁺)

Hydrazide 32

Trans-4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid hydrazide

The title compound was obtained as off-white solid in 78% yield from trans-4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid according to general procedure (XIII). MSm/e: 251([ M + H)]⁺)

Thiolactam intermediates of formula III

7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-Carboxylic acid tert-butyl ester

a) 4-chloro-2-chloromethyl-1-nitro-benzene

To a solution of 5-chloro-2-nitrobenzyl alcohol (80g, 0.42mol) and triethylamine (64ml, 0.46mol) in dichloromethane (840ml) was added thionyl chloride (34ml, 0.46mol) dropwise over 30 minutes while maintaining the internal temperature below 32 ℃ by cooling with a water bath. The reaction mixture was stirred for 3 h. The solvent was evaporated and the residue triturated in warm tert-butyl methyl ether (970 ml). The ammonium salt was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (85g, 99%) as a brown oil, which was used in the next step without purification. MSm/e: 205 (M)⁺)。

b) (5-chloro-2-nitro-benzylamino) -acetic acid ethyl ester

A mixture of 4-chloro-2-chloromethyl-1-nitro-benzene (85g, 0.41mol), glycine ethyl ester hydrochloride (70g, 0.50mol) and triethylamine (121.4ml, 0.8665mol) in ethanol (1000ml) was heated at reflux for 8 h. The solvent was evaporated and the residue triturated in warm tert-butyl methyl ether. The ammonium salt was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (111g, 99%) as an amorphous brown solid, which was used in the next step without purification. MSm/e: 273(M + H)⁺)。

c) [ tert-Butoxycarbonyl- (5-chloro-2-nitro-benzyl) -amino ]-Ethyl acetate

A solution of ethyl (5-chloro-2-nitro-benzylamino) -acetate (110g, 0.403mol), di-tert-butyl dicarbonate (180g, 0.807mol) and 4-N, N-dimethylaminopyridine (2.51g, 0.0202mol) in dichloromethane (1200ml) was stirred at 0 ℃ for 2h and at room temperature for a further 16 h. The solvent was evaporated and the crude product was purified by flash chromatography with cyclohexane/ethyl acetate mixture as eluent to give the title compound (76.4g, 51%) as a light yellow viscous oil. MSm/e: 373(M + H)⁺)。

d) [ (2-amino-5-chloro-benzyl) -tert-butoxycarbonyl-amino]-Ethyl acetate

To [ tert-butoxycarbonyl- (5-chloro-2-nitro-benzyl) -amino]To a solution of ethyl acetate (69.0g, 0.186mol) in ethyl acetate (1200ml) was added zinc bromide (8.5g, 0.037 mol). After 15 minutes the reaction mixture was purged with argon. After addition of the palladium catalyst (10% on activated carbon, 7.9g, 0.0074mol), the mixture is hydrogenated at ambient pressure over a period of about 48h until about 13l of hydrogen are consumed. The catalyst was removed by filtration and the filtrate was washed with two portions each of saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (60.6g, 95.5%) as a pale yellow waxy solid. MSm/e: 343(M + H) ⁺)。

e) 7-chloro-2-oxo-1, 2, 3, 5-tetrahydro-benzo [1, 4 ]]Diaza derivatives -4-Carboxylic acid tert-butyl ester

To [ (2-amino-5-chloro-benzyl) -tert-butoxycarbonyl-amino group at 5 ℃ with cooling on an ice-water bath]To a solution of ethyl acetate (60g, 0.18mol) in tetrahydrofuran (600ml) was added potassium tert-butoxide (22g, 0.19mol) in small portions. After the addition was completed, the cooling bath was removed and the reaction mixture was stirred at room temperature for 3h, followed by addition of water (400ml), saturated aqueous ammonium chloride solution (280ml) and ethyl acetate (800 ml). After 10 minutes, the precipitate was collected by filtration. The layers were separated from the filtrate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was combined with the precipitate collected by filtration before and crystallized from hot ethyl acetate to obtain the title compound (46g, 88%) as a white solid. MSm/e: 295 (M-H)⁺)。

f) 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives -4-Carboxylic acid tert-butyl ester

Reacting 7-chloro-2-oxo-1, 2, 3, 5-tetrahydro-benzo [1, 4 ]]Diaza derivativesA mixture of tert-butyl 4-carboxylate (41.1g, 0.139mol) and 2, 4-bis- (4-methoxyphenyl) -1, 3, 2, 4-dithiadiphosphetane-2, 4-disulfide (31.5g, 0.0763mol) in tetrahydrofuran (1100ml) was heated at reflux for 3 h. The solvent was evaporated and the residue triturated in tert-butyl methyl ether. The precipitate was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized from hot ethanol to give the title compound (37.5g, 86.4%) as a pale yellow solid. MSm/e: 311 (M-H) ⁺)。

7-fluoro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1, 4[ diazepine ]-4-Carboxylic acid tert-butyl ester

According to the above for the synthesis of 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester using 5-fluoro-2-nitrobenzyl alcohol instead of 5-chloro-2-nitrobenzyl alcohol in step a) to obtain the title compound in comparable yield as a pale yellow solid. MSm/e: 297 (M-H)⁺)。

General procedure (XV): condensation of hydrazides and thiolactams to triazoles

A mixture (0.1-0.2M) of the hydrazide of formula II (1-1.5eq) and the thiolactam of formula III (1eq) in n-butanol is heated at reflux for 16-72 h. After cooling to room temperature, the solvent was evaporated and the residue was purified by flash chromatography to give the compound of formula I. When a thiolactam of the formula III-1 (a compound of the formula III, wherein R is¹Is tert-butoxycarbonyl group)The N-tert-butoxycarbonyl group of the resulting triazole product of formula I-1 may be partially or completely thermally cleaved and, in addition or as a separate product, a secondary amine of formula I-2 obtained.

General procedure (XVI-a): cleavage of N-tert-butoxycarbonyl (N-BOC) groups

A solution of the N-BOC derivative of formula I-1 (1eq) in 1.25M methanol or 1.5M ethanolic hydrogen chloride solution (10-20eq HCl) was heated at 50 ℃ for 15-60 minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give the secondary amine of formula I-2 as the hydrochloride salt. Optionally, the free base may be obtained by partitioning the hydrochloride salt between a 1M aqueous solution of sodium hydroxide and an organic solvent such as ethyl acetate or dichloromethane. The layers were separated and the aqueous layer was extracted with two portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the free base of the compound of formula I-2.

General procedure (XVI-b): cleavage of N-tert-butoxycarbonyl (N-BOC) groups

A solution of the N-BOC derivative of the general formula I-1 (1eq) and trifluoroacetic acid (10-20eq) in dichloromethane was stirred at room temperature for 6-24 h. The reaction mixture is partitioned between 1M aqueous sodium hydroxide and an organic solvent such as ethyl acetate or dichloromethane. The layers were separated and the aqueous layer was extracted with two portions of organic solvent. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the free base of the compound of formula I-2.

General procedure (XVII-a): reductive N-alkylation

A mixture of the compound of formula I-2 (1eq, 0.1-0.2M), as the free base or as the hydrochloride salt, triethylamine (1eq when the hydrochloride salt of the compound of formula I-2 is used) and an aldehyde or ketone (8eq) in methanol is heated at reflux for 2-6 h. After cooling to 0 ℃, sodium cyanoborohydride (2-3eq) was added. The reaction mixture was stirred at room temperature for 3-16h and quenched with 1M aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography gives the N-alkyl compounds of formula I.

General procedure (XVII-b): reductive N-alkylation

A mixture of the compound of formula I-2 (1eq, 0.1-0.2M), aldehyde or ketone (2eq) and acetic acid (2eq) in 1, 2-dichloroethane as free base was stirred at room temperature for 5 h. After addition of sodium triacetoxyborohydride (2.2eq), the reaction mixture was stirred for 20 h. Quench with methanol and N-ethyldiisopropylamine (2eq) and concentrate the mixture under vacuum. RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the N-alkyl derivatives of formula I.

General procedure (XVIII): reductive N-methylation

A mixture of the compound of formula I-2 (1eq, 0.1-0.2M), sodium acetate (1.1eq), acetic acid (1.1eq) and aqueous formaldehyde (36%, 1.4eq) as the free base in dichloromethane was stirred at room temperature for 0.5-2 h. After cooling to 0 ℃, sodium triacetoxyborohydride (1.6eq) was added. The cooling bath was removed and the mixture was stirred at room temperature for 2-16 h. The reaction was quenched by addition of 1M aqueous sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography to give the compound of formula I-3, i.e., wherein R¹A compound of formula I which is methyl.

Example 1

Trans-8-chloro-1- (4-)Azol-2-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as light yellow solid in 28% yield according to general procedure (XV).

Hydrazide: trans-4-Azol-2-yl-cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 470([ M + H)]⁺)

Example 2

Trans-8-chloro-1- (4-)Azol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]Azulene derivatives

The title compound was obtained as a yellow solid in quantitative yield from trans-8-chloro-1- (4-Azol-2-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 370([ M + H ]]⁺)。

Example 3

Trans-8-chloro-5-methyl-1- (4-Azol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 63% yield from trans-8-chloro-1- (4-Azol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 384([ M + H)]⁺)。

Example 4

Trans-8-chloro-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 71% yield according to general procedure (XV).

Hydrazide: trans-4- (4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 484([ M + H)]⁺)

Example 5

Trans-8-chloro-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]Azulene derivatives

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 384([ M + H)]⁺)。

Example 6

Trans-8-chloro-5-methyl-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as an off-white solid in 67% yield from trans-8-chloro-1- [4- (4-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 398([ M + H)]⁺)。

Example 7

Trans-8-chloro-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 57% yield according to general procedure (XV).

Hydrazide: trans-4- (5-methyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

Example 8

Trans-8-chloro-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl ]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as an off-white solid in quantitative yield from trans-8-chloro-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 384([ M + H)]⁺)。

Example 9

Trans-8-chloro-5-methyl-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 75% yield from trans-8-chloro-1- [4- (5-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 398([ M + H)]⁺)。

Example 10

Trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-4H，6H-2，3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 59% yield according to general procedure (XV).

Hydrazide: trans-4- (4, 5-dimethyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 498([ M + H) ]⁺)

Example 11

Trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 84% yield according to general procedure (XVI-b)

Trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 398([ M + H)]⁺)。

Example 12

Trans-8-chloro-5-methyl-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 59% yield from trans-8-chloro-1- [4- (4, 5-dimethyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 412([ M + H)]⁺)。

Example 13

Trans-8-chloro-1- (4-thiazol-2-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 57% yield according to general procedure (XV).

Hydrazide: trans-4-thiazol-2-yl-cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e ][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 486([ M + H)]⁺)

Example 14

Trans-8-chloro-1- (4-thiazol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- (4-thiazol-2-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] according to general procedure (XVI-b)]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 386([ M + H)]⁺)。

Example 15

Trans-8-chloro-5-methyl-1- (4-thiazol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 50% yield from trans-8-chloro-1- (4-thiazol-2-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] according to general procedure (XVII-a)]Azulene and paraformaldehyde. MSm/e: 400([ M + H ]]⁺)。

Example 16

Trans-8-chloro-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 52% yield according to general procedure (XV).

Hydrazide: trans-4- (4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e ][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 500([ M + H ]]⁺)

Example 17

Trans-8-chloro-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 91% yield from trans-8-chloro-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl according to general procedure (XVI-b)]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 400([ M + H ]]⁺)。

Example 18

Trans-8-chloro-5-methyl-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 55% yield from trans-8-chloro-1- [4- (4-methyl-thiazol-2-yl) -cyclohexyl according to general procedure (XVII-a)]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 414([ M + H ]]⁺)。

Example 19

Trans-8-chloro-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 72% yield according to general procedure (XV).

Hydrazide: trans-4- (2-methyl-thiazol-4-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 500([ M + H ]]⁺)

Example 20

Trans-8-chloro-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 93% yield from trans-8-chloro-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl according to general procedure (XVI-b)]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butylAnd (3) obtaining an ester. MSm/e: 400([ M + H ]]⁺)。

Example 21

Trans-8-chloro-5-methyl-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 67% yield from trans-8-chloro-1- [4- (2-methyl-thiazol-4-yl) -cyclohexyl according to general procedure (XVII-a)]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 414([ M + H ]]⁺)。

Example 22

Trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 39% yield according to general procedure (XV).

Hydrazide: trans-4- (5-methyl-iso)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

Example 23

Trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- [4- (5-methyl-iso-propyl) -according to general procedure (XVI-a)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 384([ M + H)]⁺)。

Example 24

Trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 54% yield from trans-8-chloro-1- [4- (5-methyl-iso-propyl) -according to general procedure (XVII-a)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 398([ M + H)]⁺)。

Example 25

Trans-8-chloro-5-ethyl-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]Azulene derivatives

The title compound according to the general formulaUsing procedure (XVII-b), as a light brown solid, trans-8-chloro-1- [4- (5-methyl-iso-5) in 11% yieldAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and acetaldehyde. MSm/e: 412([ M + H)]⁺)。

Example 26

Trans-8-chloro-5-isopropyl-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 69% yield from trans-8-chloro-1- [4- (5-methyl-iso-propyl) -according to general procedure (XVII-b)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and acetone. MSm/e: 426([ M + H)]⁺)。

Example 27

Trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl-iso-butyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 40% yield from trans-8-chloro-1- [4- (5-methyl-iso-propyl) -according to general procedure (XVII-b)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene andcyclobutanone. MSm/e: 437([ M + H)]⁺)。

Example 28

Trans-8-chloro-5- (2, 2-difluoro-ethyl) -1- [4- (5-methyl-iso-propyl ] -ethyl Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

Trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]A mixture of azulene (50.0mg, 0.130mmol), cesium carbonate (84.9mg, 0.261mmol) and 2, 2-difluoroethyl triflate (41.8mg, 0.195mmol) in acetonitrile (1.3ml) was heated at 70 ℃ for 20 h. After cooling to room temperature, the reaction mixture was partitioned between 1M aqueous sodium hydroxide (2ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three portions of 5-ml ethyl acetate. The combined organic layers were concentrated under vacuum. Preparative RP-HPLC using water (0.05% formic acid)/methanol as eluent gave the title compound (13mg, 21%) as an off-white solid. MSm/e: 448([ M + H ]]⁺)。

Example 29

Trans-8-chloro-5- (2-methoxy-ethyl) -1- [4- (5-methyl-iso-propyl ] -methyl esterAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

Trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3,5, 10 b-tetraaza-benzo [ e ]]A mixture of azulene (50mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and 2-bromoethyl methyl ether (0.025ml, 0.26mmol) in acetonitrile (1.3ml) was heated at 70 ℃ for 20 h. After cooling to room temperature, the reaction mixture was partitioned between 1M aqueous sodium hydroxide (2ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three portions of 5-ml ethyl acetate. The combined organic layers were concentrated under vacuum. Preparative RP-HPLC using water (0.05% formic acid)/methanol as eluent gave the title compound (17mg, 29%) as an off-white solid. MSm/e: 442([ M + H) ]⁺)。

Example 30

Trans- (2- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethyl) -methyl-amines

Trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]A mixture of azulene (50.0mg, 0.130mmol), cesium carbonate (170mg, 0.521mmol) and 2-methylaminoethylchloride hydrochloride (67.7mg, 0.521mmol) in acetonitrile (1.3ml) was heated at 70 ℃ for 20 h. After cooling to room temperature, the reaction mixture was partitioned between 1M aqueous sodium hydroxide (2ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three portions of 5-ml ethyl acetate. The combined organic layers were concentrated under vacuum. Preparative RP-HPLC using water (0.05% formic acid)/methanol as eluent gave the title compound as the hydroreformates salt (hydroformylat) which was released by filtration on aminopropyl modified silica gel (10g) using methanol (20ml) as eluent. The filtrate was concentrated to dryness. The residue was redissolved in ethyl acetate, filtered through absorbent cotton and concentrated to dryness to give the title compound (38mg, 66%) as an off-white solid. MSm/e: 441([ M + H)]⁺)。

Example 31

Trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl) Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethanone

Trans-8-chloro-1- [4- (5-methyl-iso-methyl) at room temperatureAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]To a solution of azulene (50mg, 0.13mmol) and triethylamine (0.036ml, 0.26mmol) in dichloromethane (1.3ml) was added acetyl chloride (0.019ml, 0.26 mmol). Stirred for 45 min, then quenched with methanol (0.5 ml). The mixture was concentrated under vacuum. Preparative RP-HPLC using water (0.05% formic acid)/methanol as eluent gave the title compound (24mg, 43%) as a white solid. MSm/e: 426([ M + H)]⁺)。

Example 32

Trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -2-hydroxy-ethanones

A solution of glycolic acid (11.9mg, 0.156mmol) and HATU (59.4mg, 0.156mmol) in N, N-dimethylformamide (1.0ml) was stirred at room temperature for 5 minutes. Continuous addition of trans-8-chloro-1- [4- (5-methyl-iso-methyl-)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene (50.0mg, 0.130mmol) and N-ethyldiisopropylamine(0.055ml, 0.31 mmol). The reaction mixture was stirred for 1 h. Preparative RP-HPLC using water (0.05% formic acid)/methanol as eluent gave the title compound (43mg, 75%) as a pale yellow solid. MSm/e: 442([ M + H) ]⁺)。

Example 33

Trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -2-dimethylamino-ethanone hydro-reforming product

A solution of N, N-dimethylglycine (16.1mg, 0.156mmol) and HATU (59.4mg, 0.156mmol) in N, N-dimethylformamide (1.0ml) was stirred at room temperature for 5 minutes. Adding trans-8-chloro-1- [4- (5-methyl-iso-methyl) in turnAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene (50.0mg, 0.130mmol) and N-ethyldiisopropylamine (0.055ml, 0.31 mmol). The reaction mixture was stirred for 1 h. Preparative RP-HPLC using water (0.05% formic acid)/methanol as eluent gave the title compound (51mg, 76%) as an off-white solid. MSm/e: 469([ M + H)]⁺)。

Example 34

Trans-8-chloro-5-methanesulfonyl-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

Trans-8-chloro-1- [4- (5-methyl-iso-methyl) at room temperatureAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]To a solution of azulene (50mg, 0.13mmol) and triethylamine (0.036ml, 0.26mmol) in dichloromethane (1.3ml) was added methanesulfonyl chloride (0.020ml, 0.26 mmol). Stirred for 45 min, then quenched with methanol (0.5 ml). The mixture was concentrated under vacuum. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (37mg, 62%) as a white solid. MSm/e: 462([ M + H) ]⁺)。

Example 35

Trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-sulfonic acid dimethylamide

Trans-8-chloro-1- [4- (5-methyl-iso-methyl) at room temperatureAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]To a solution of azulene (50mg, 0.13mmol) and triethylamine (0.036ml, 0.26mmol) in dichloromethane (1.3ml) was added sulfamoyl chloride (0.028ml, 0.26 mmol). Stirred for 20h, then quenched with methanol (0.5 ml). The mixture was concentrated under vacuum. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (42mg, 66%) as a white solid. MSm/e: 491([ M + H ]]⁺)。

Example 36

Trans-8-fluoro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 73% yield according to general procedure (XV).

Thiolactam: 7-fluoro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 468([ M + H)]⁺)

Example 37

Trans-8-fluoro-1- [4- (5-methyl-iso) Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as an off-white solid in 72% yield from trans-8-fluoro-1- [4- (5-methyl-iso-propyl) -according to general procedure (XVI-b)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 368([ M + H)]⁺)。

Example 38

Trans-8-fluoro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound, rootFollowing general procedure (XVII-a), as a white solid, trans-8-fluoro-1- [4- (5-methyl-iso-propyl) in 78% yieldAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 382([ M + H)]⁺)。

Example 39

Trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 58% yield according to general procedure (XV).

Hydrazide: trans-4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e ][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 498([ M + H)]⁺)

Example 40

Trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound according toGeneral procedure (XVI-b) as an off-white solid in 87% yield from trans-8-chloro-1- [4- (4, 5-dimethyl-iso-propyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 398([ M + H)]⁺)。

EXAMPLE 41

Trans-8-chloro-1- [4- (4, 5-dimethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 88% yield from trans-8-chloro-1- [4- (4, 5-dimethyl-iso-propyl) -according to general procedure (XVII-a)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 412([ M + H)]⁺)。

Example 42

Trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 75% yield according to general procedure (XV).

Hydrazide: trans-4- (4-chloro-5-methyl-iso Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 518([ M + H)]⁺)

Example 43

Trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as an off-white solid in quantitative yield from trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-propyl) -according to general procedure (XVI-b)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 418([ M + H)]⁺)。

Example 44

Trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 81% yield from trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-propyl) -according to general procedure (XVII-a)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5,10 b-tetraaza-benzo [ e ]]Azulene and paraformaldehyde. MSm/e: 432([ M + H)]⁺)。

Example 45

Trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

Hydrazide: trans-4- (4-fluoro-5-methyl-isoAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 502([ M + H)]⁺)

Example 46

Trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as an off-white solid in quantitative yield from trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-propyl) -according to general procedure (XVI-b)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetranitrogenHetero-benzo [ e)]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 402([ M + H)]⁺)。

Example 47

Trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as off-white solid in 60% yield from trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-propyl) -according to general procedure (XVII-a)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 416([ M + H ]]⁺)。

Example 48

Cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] ]Azulene-5-carboxylic acid tert-butyl ester

And

example 49

Trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

Cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester and trans-8-chloro-1- [4- (5-ethyl-iso-butyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester was obtained after chromatographic separation according to general procedure (XV).

Hydrazide: cis/trans-4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-Carboxylic acid tert-butyl ester cis-8-chloro-1- [4- (5-ethyl-iso-butyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester was obtained as a white solid in 39% yield. MSm/e: 498([ M + H)]⁺)

Trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester was obtained as a white solid in 39% yield. MSm/e: 498([ M + H)]⁺)

Example 50

Cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl ]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as a white solid in quantitative yield from cis-8-chloro-1- [4- (5-ethyl-iso-propyl) -according to general procedure (XVI-a)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 398([ M + H)]⁺)。

Example 51

Cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 34% yield from cis-8-chloro-1- [4- (5-ethyl-iso-propyl) -according to general procedure (XVII-a)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 412([ M + H)]⁺)。

Example 52

Trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- [4- (5-ethyl-iso-propyl) -according to general procedure (XVI-a)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 398([ M + H) ]⁺)。

Example 53

Trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 68% yield from trans-8-chloro-1- [4- (5-ethyl-iso-propyl) -according to general procedure (XVII-a)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 412([ M + H)]⁺)。

Example 54

Trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as light yellow solid in 77% yield according to general procedure (XV).

Hydrazide: trans-4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 524([ M + H)]⁺)

Example 55

Trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as light yellow solid in 84% yield from trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ] according to general procedure (XVI-a) ]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 424([ M + H)]⁺)。

Example 56

Trans-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 41% yield from trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ] according to general procedure (XVII-a)]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and multimersFormaldehyde is obtained. MSm/e: 438([ M + H)]⁺)。

Example 57

Cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexanes

Tert-butyl 4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylate the title compound was obtained as light yellow solid in 75% yield according to general procedure (XV).

Hydrazide: cis-4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

Example 58

Cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each other Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as off-white solid in quantitative yield from cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ] according to general procedure (XVI-a)]Different from each otherAzol-3-yl) -cyclohexyl]-4H，6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 424([ M + H)]⁺)。

Example 59

Cis-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 57% yield from cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ] according to general procedure (XVII-a)]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 438([ M + H)]⁺)。

Example 60

Trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexanes

Tert-butyl 4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylate the title compound was obtained as white solid in 86% yield according to general procedure (XV).

Hydrazide: trans-4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

Example 61

Trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 92% yield from trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ] according to general procedure (XVI-a)]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 424([ M + H)]⁺)。

Example 62

Trans-8-chloro-5-methyl-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 81% yield from trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c ] according to general procedure (XVII-a)]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 438([ M + H)]⁺)。

Example 63

Trans-8-chloro-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 23% yield according to general procedure (XV).

Hydrazide: trans-4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 485([ M + H)]⁺)

Example 64

Trans-8-chloro-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- [4- (5-methyl- [1, 3, 4 ] according to general procedure (XVI-b)]Oxadiazol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 385([ M + H ]]⁺)。

Example 65

Trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 52% yield from trans-8-chloro-1- [4- (5-methyl- [1, 3, 4 ] according to general procedure (XVII-a)]Oxadiazol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 399([ M + H) ]⁺)。

Example 66

Trans-8-chloro-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 79% yield according to general procedure (XV).

Hydrazide: trans-4- (3-methyl- [1, 2, 4 ]]Oxadiazol-5-yl) -cyclohexanecarboxylic acid hydrazide

Example 67

Trans-8-chloro-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as a white solid in 93% yield from trans-8-chloro-1- [4- (3-methyl- [1, 2, 4 ] according to general procedure (XVI-a)]Oxadiazol-5-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 385([ M + H ]]⁺)。

Example 68

Trans-8-chloro-5-methyl-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 76% yield from trans-8-chloro-1- [4- (3-methyl- [1, 2, 4 ] according to general procedure (XVII-a) ]Oxadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 399([ M + H)]⁺)。

Example 69

Trans-8-chloro-1- [4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as light yellow solid in 63% yield according to general procedure (XV).

Hydrazide: trans-4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 501([ M + H ]]⁺)

Example 70

Trans-8-chloro-1- [4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- [4- (3-methyl- [1, 2, 4] according to general procedure (XVI-a)]Thiadiazol-5-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 401([ M + H)]⁺)。

Example 71

Trans-8-chloro-5-methyl-1- [4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- [4- (3-methyl- [1, 2, 4 ] according to general procedure (XVII-a)]Thiadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 415([ M + H ]]⁺)。

Example 72

Trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 87% yield according to general procedure (XV).

Hydrazide: trans-4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

Example 73

Trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as an off-white solid in quantitative yield from trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] according to general procedure (XVI-a)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 385([ M + H ] ]⁺)。

Example 74

Trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 76% yield from trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 399([ M + H)]⁺)。

Example 75

Trans-8-chloro-5-ethyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 28% yield from trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and acetaldehyde. MSm/e: 413([ M + H)]⁺)。

Example 76

Trans-8-chloro-5-isopropyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 13% yield from trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] according to general procedure (XVII-a) ]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and acetone. MSm/e: 427([ M + H)]⁺)。

Example 77

Trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 27% yield from trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and cyclobutanone. MSm/e: 439([ M + H)]⁺)

Example 78

Trans-8-chloro-5-cyclopentyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was prepared according to general procedure (XVII-a)As a white solid, from trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] in 46% yield]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and cyclopentanone. MSm/e: 453([ M + H)]⁺)。

Example 79

Trans-8-chloro-5- (2, 2-difluoro-ethyl) -1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]Azulene derivatives

Trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]To a mixture of azulene hydrochloride (0.100g, 0.237mmol) and N-ethyldiisopropylamine (0.122ml, 0.712mmol) in dichloromethane (2.4ml) was added 2, 2-difluoroethyl trifluoromethanesulfonate (0.061g, 0.29 mmol). After stirring for 16h, the reaction mixture was partitioned between ethyl acetate (50ml) and 0.5M aqueous sodium hydroxide (50 ml). The layers were separated. The aqueous layer was extracted with a 50ml portion of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography with n-heptane/2-propanol as eluent afforded the title compound (0.031g, 33%) as a colorless solid. MSm/e: 449([ M + H)]⁺)。

Example 80

Trans-1- { 8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethanone

Trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] methyl ester at room temperature]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]To a solution of azulene hydrochloride (0.10g, 0.24mmol) and triethylamine (0.70ml, 0.50mmol) in dichloromethane (4.8ml) was added acetyl chloride (0.019ml, 0.26 mmol). After stirring for 16h, the reaction mixture was concentrated under vacuum. Flash chromatography using n-heptane/2-propanol as eluent afforded the title compound (0.003g, 3%) as a white solid. MSm/e: 427([ M + H) ]⁺)。

Example 81

Trans-8-chloro-5-methanesulfonyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

Trans-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] methyl ester at room temperature]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]To a solution of azulene hydrochloride (0.100g, 0.24mmol) and triethylamine (0.70ml, 0.50mmol) in dichloromethane (4.8ml) was added methanesulfonyl chloride (0.020ml, 0.26 mmol). After stirring for 16h, the reaction mixture was concentrated under vacuum. Flash chromatography with n-heptane/2-propanol as eluent afforded the title compound (0.053g, 48%) as a white solid. MSm/e: 463([ M + H)]⁺)。

Example 82

Cis-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 61% yield according to general procedure (XV).

Hydrazide: cis-4- (5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

Example 83

Cis-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as a white solid in 88% yield from cis-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] according to general procedure (XVI-a)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 385([ M + H ]]⁺)。

Example 84

Cis-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 75% yield from cis-8-chloro-1- [4- (5-methyl- [1, 2, 4 ] according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde.

MSm/e：399([M+H]⁺)。

Example 85

Cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

And

example 86

Trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

Cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetAza-benzo [ e)]Azulene-5-carboxylic acid tert-butyl ester and trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester was obtained after chromatographic separation according to general procedure (XV).

Hydrazide: cis/trans-4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-Carboxylic acid tert-butyl ester cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Tert-butyl azulene-5-carboxylate, obtained as yellow solid in 21% yield. MSm/e: 499([ M + H ]]⁺)

Trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Tert-butyl azulene-5-carboxylate as yellow solid, obtained in 28% yield MSm/e: 499([ M + H ]]⁺)

Example 87

Trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo[e]Azulene hydrochloride

The title compound was obtained as an off-white solid in quantitative yield from trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4 ] according to general procedure (XVI-a) ]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 399([ M + H)]⁺)。

Example 88

The title compound was obtained as a white solid in 84% yield from trans-8-chloro-1- [4- (5-ethyl- [1, 2, 4 ] according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 413([ M + H)]⁺)

Example 89

Cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as an off-white solid in quantitative yield from cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4 ] according to general procedure (XVI-a)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 399([ M + H)]⁺)。

Example 90

Cis-8-chloro-5-ethyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]Azulene derivatives

The title compound was obtained as a white solid in 82% yield from cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4 ] according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 413([ M + H)]⁺)。

Example 91

Cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

And

example 92

Trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H，6H-2，3，5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

Cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester and trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester was obtained after chromatographic separation according to general procedure (XV).

Hydrazide: cis/trans-4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-Carboxylic acid tert-butyl ester cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4) ]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Tert-butyl azulene-5-carboxylate, obtained as a white solid in 16% yield. MSm/e: 499([ M + H ]]⁺)

Trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Tert-butyl azulene-5-carboxylate, obtained as a white solid in 19% yield. MSm/e: 499([ M + H ]]⁺)

Example 93

Trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as a white solid in quantitative yield from trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4) according to general procedure (XVI-a)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 413([ M + H)]⁺)。

Example 94

The title compound was obtained as a white solid in 94% yield from trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4) according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]Azulene hydrochloride and paraformaldehyde. MSm/e: 427([ M + H)]⁺)。

Example 95

Cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride

The title compound was obtained as a white solid in quantitative yield from cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4) according to general procedure (XVI-a)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 413([ M + H)]⁺)

Example 96

Cis-8-chloro-5-isopropyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 74% yield from cis-8-chloro-1- [4- (5-isopropyl- [1, 2, 4) according to general procedure (XVII-a)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene hydrochloride and paraformaldehyde. MSm/e: 427([ M + H)]⁺)。

Example 97

Trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4] thiadiazol-3-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

a) Trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Thiadiazol-3-yl) -cyclohexyl ]-5, 6-dihydro -4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene derivatives

The title compound was obtained as off-white solid contaminated with approximately 25% trans-8-chloro-1- [4- (3-methyl- [1, 2, 4] thiadiazol-5-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene by the sequential use of general procedures (XV) and (XVI-a) in 33% yield.

Hydrazide: trans-4- (5-methyl- [1, 2, 4] thiadiazol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 401([ M + H)]⁺)

b) Trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Thiadiazol-3-yl) -cyclohexyl]-5, 6-dihydro -4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene derivatives

The title compound was synthesized according to general procedure (XVII-a) in 30% yield as white solid (which was substituted with 25% trans-8-chloro-5-methyl-1- [4- (3-methyl- [1, 2, 4)]Thiadiazol-5-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene contamination) from trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Thiadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 415([ M + H ] ]⁺)

Example 98

Trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 27% yield according to general procedure (XV).

Hydrazide: trans-4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexanecarboxylic acid hydrazide

Example 99

Trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 84% yield from trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 410([ M + H)]⁺)。

Example 100

Trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a white solid in 57% yield from trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl ]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 432([ M + H)]⁺)。

Example 101

Trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

Hydrazide: trans-4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 534([ M + H)]⁺)

Example 102

Trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 86% yield from trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl according to general procedure (XVI-b)]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 434([ M + H)]⁺)。

Example 103

Trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 46% yield from trans-8-chloro-1- [4- (5-chloro-4-methyl-thiazol-2-yl) -cyclohexyl according to general procedure (XVII-b) ]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene and paraformaldehyde. MSm/e: 448([ M + H ]]⁺)。

Example 104

Trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 49% yield according to general procedure (XV).

Hydrazide: cis/trans-4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexanecarboxylic acid hydrazide (1: 7.5)

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 514.5([ M + H)]⁺)

Example 105

Trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as off-white solid in 93% yield from trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl according to general procedure (XVI-b)]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 414([ M + H ]]⁺)。

Example 106

Trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as a white solid in 45% yield from trans-8-chloro-1- [4- (4, 5-dimethyl-thiazol-2-yl) -cyclohexyl according to general procedure (XVIII)]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]And (4) obtaining the azulene. MSm/e: 428([ M + H)]⁺)。

Example 107

Trans-8-chloro-1- [4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each otherAzol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

a) Trans-8-chloro-1- [4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each other Azol-3-yl) -cyclohexanes Base of]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as a brown solid with a purity of 85% in 13% yield according to general procedure (XV).

Hydrazide: trans-4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each otherAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 510([ M + H ]]⁺)

b) Trans-8-chloro-1- [4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each other Azol-3-yl) -cyclohexyl]-5，6- dihydro-4H-23, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a brown solid with a purity of 85% in 98% yield according to general procedure (XVI-b). MSm/e: 415([ M + H ] ]⁺)

c) Trans-8-chloro-1- [4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each other Azol-3-yl) -cyclohexyl]-5-A Radical-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene derivatives

The title compound was obtained as a pale yellow solid with a purity of 90% in 76% yield from trans-8-chloro-1- [4- (5, 6-dihydro-4H-cyclopenta [ d ] according to general procedure (XVIII)]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]And (4) obtaining the azulene. MSm/e: 424([ M + H)]⁺)

Example 108

Trans-1- [4- (4, 5-bis-hydroxymethyl) -isoAzol-3-yl) -cyclohexyl]-8-chloro-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e]Azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 11% yield according to general procedure (XV).

Hydrazide: trans-4- (4, 5-bis-hydroxymethyl-isoAzol-3-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 530([ M + H)]⁺)

Example 109

Trans-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 47% yield according to general procedure (XV).

Hydrazide: trans-4-pyrazol-1-yl-cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 469([ M + H)]⁺)

Example 110

Trans-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as light yellow solid in 81% yield from trans-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -4H according to general procedure (XVI-b),6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 369([ M + H)]⁺)

Example 111

Trans-8-chloro-5-methyl-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as white solid in 86% yield from trans-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] according to general procedure (XVIII)]And (4) obtaining the azulene. MSm/e: 383([ M + H)]⁺)

Example 112

Cis-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 67% yield according to general procedure (XV).

Hydrazide: cis-4-pyrazol-1-yl-cyclohexanecarboxylic acid hydrazide

Example 113

Cis-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as light yellow solid in 89% yield from cis-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -4H, 6H-2, 3, 5,10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 369([ M + H)]⁺)

Example 114

Cis-8-chloro-5-methyl-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as white solid in 87% yield from cis-8-chloro-1- (4-pyrazol-1-yl-cyclohexyl) -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] according to general procedure (XVIII)]And (4) obtaining the azulene. MSm/e: 383([ M + H)]⁺)

Example 115

Trans-8-chloro-1- [4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as off-white solid in 52% yield according to general procedure (XV).

Hydrazide: trans-4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 497([ M + H)]⁺)

Example 116

Trans-8-chloro-1- [4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as an off-white solid in quantitative yield from trans-8-chloro-1- [4- (3) according to general procedure (XVI-b)5-dimethyl-pyrazol-1-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 397([ M + H)]⁺)

Example 117

Trans-8-chloro-1- [4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as white solid in 90% yield from trans-8-chloro-1- [4- (3, 5-dimethyl-pyrazol-1-yl) -cyclohexyl according to general procedure (XVIII)]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]And (4) obtaining the azulene. MSm/e: 411([ M + H ]]⁺)

Example 118

Trans-8-chloro-1- [4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexyl ] -4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene-5-carboxylic acid tert-butyl ester

The title compound was obtained as white solid in 45% yield according to general procedure (XV).

Hydrazide: trans-4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexanecarboxylic acid hydrazide

Thiolactam: 7-chloro-2-thioxo-1, 2, 3, 5-tetrahydro-benzo [ e][1，4]Diaza derivatives-4-carboxylic acid tert-butyl ester MSm/e: 511([ M + H)]⁺)

Example 119

Trans-8-chloro-1- [4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexyl ] -5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as off-white solid in quantitative yield from trans-8-chloro-1- [4- (3, 4, 5-dimethyl-pyrazol-1-yl) -cyclohexyl according to general procedure (XVI-b)]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acid tert-butyl ester. MSm/e: 411([ M + H ]]⁺)

Example 120

Trans-8-chloro-1- [4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexyl ] -5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ] azulene

The title compound was obtained as white solid in 84% yield from trans-8-chloro-1- [4- (3, 4, 5-trimethyl-pyrazol-1-yl) -cyclohexyl according to general procedure (XVIII)]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]And (4) obtaining the azulene. MSm/e: 425([ M + H)]⁺)

Claims

1. A compound of formula I

Wherein

R¹Selected from the group consisting of:

i)H，

ii)-C_1-6-an alkyl group which is unsubstituted or substituted with 1 to 2 substituents independently selected fromA group consisting of: halogen and C_1-6-an alkoxy group,

iii)-S(O)₂-C_1-6-alkyl, wherein C_1-6-the alkyl group is unsubstituted,

v)-C(O)O-C_1-6-alkyl, wherein C_1-6-the alkyl group is unsubstituted;

vi) unsubstituted C_3-8-a cycloalkyl group,

vii)-S(O)₂-(CH₂)_q-NRⁱRⁱⁱwherein q is 0 and

viii)-(CH₂)_r-NRⁱⁱⁱR^ivwherein r is 2, and

ix)-C(O)(CH₂)_s-NR^vR^viwherein s is 1, and

R²Is halogen;

R³is a 5-membered heteroaryl group, said 5-membered heteroaryl group being selected from oxazolyl, thiazolyl, isoheteroarylAn azole group, an isothiazolyl group,oxadiazolyl, thiadiazolyl or 1H-pyrazol-1-yl, which is unsubstituted or substituted by_n(iii) substituted, each R is independently selected from the group consisting of: halogen, C_1-6Alkyl, halogen-C_1-6-alkyl and hydroxy-C_1-6-alkyl, wherein

n is 1, 2 or 3;

and when R is³In the case of isoxazolyl, two R's adjacent to each other may form a ring comprising 5 or 6C;

Or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R¹Selected from the group consisting of: h, methyl, ethyl, isopropyl, 2, 2-difluoro-ethyl, 2-methoxy-ethyl, 2-methylamino-ethyl, acetyl, 2-dimethylamino-acetyl, 2-hydroxy-acetyl, Boc, cyclobutyl, cyclopentyl, dimethylsulfamoyl, and methanesulfonyl.

3. A compound according to claim 1, wherein R¹Selected from the group consisting of:

i)H，

ii)-C_1-6-alkyl, unsubstituted or substituted by 1 to 2 halogens,

iii)-S(O)₂-C_1-6-an alkyl group,

v) unsubstituted C_3-8-a cycloalkyl group.

4. A compound according to any one of claims 1-2, wherein R¹Selected from the group consisting of: h, methyl, 2, 2-difluoro-ethyl, cyclobutyl, acetyl and methanesulfonyl.

5. A compound according to any one of claims 1-2, wherein R²Is chlorine.

6. A compound according to any one of claims 1-2, wherein R³Selected from the group consisting of:

i)[1，2，4](ii) a diazolyl group,

ii)[1，3，4](ii) a diazolyl group,

iii)the group of azolyl groups,

iv) a thiazolyl group,

v) [1, 2, 4] thiadiazolyl,

vi) isoAzolyl, and

vii) 1H-pyrazolyl;

Each of the above is unsubstituted or substituted by (R)_nSubstituted, each R is independently selected from the group consisting of halogen and C_1-6-alkyl, wherein n is 1, 2 or 3, or when R is³In the case of isoxazolyl, two R's adjacent to each other form a ring containing 6C together with the atoms to which they are attached.

7. A compound according to any one of claims 1-2, wherein R³Selected from the group consisting of:

i)[1，2，4](ii) a diazolyl group,

ii)[1，3，4](ii) a diazolyl group,

iii)the group of azolyl groups,

iv) a thiazolyl group,

v) [1, 2, 4] thiadiazolyl, and

vi) isoThe group of azolyl groups,

each of the above is unsubstituted or substituted by (R)_nSubstituted, each R is independently selected from the group consisting of halogen and C_1-6-alkyl, wherein n is 1-2 and when R³In the case of isoxazolyl, two R's adjacent to each other may form a ring containing 6C together with the atom to which they are attached.

8. A compound according to any one of claims 1-2, wherein R³Selected from the group consisting of:oxazol-2-yl, 1H-pyrazol-1-yl, 2-methyl-thiazol-4-yl, 3, 4, 5-trimethyl-1H-pyrazol-1-yl, 3, 5-dimethyl-1H-pyrazol-1-yl, 3-methyl- [1, 2, 4]Thiadiazol-5-yl, 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherAzol-3-yl, 4, 5, 6, 7-tetrahydro-benzo [ d ]Different from each otherAzol-3-yl, 4, 5-bis (hydroxymethyl) isoAzol-3-yl, 4, 5-dimethyl-isoOxazol-3-yl, 4, 5-dimethyl-Oxazol-2-yl, 4, 5-dimethylthiazol-2-yl, 4-chloro-5-methyl-iso-methylAzol-3-yl, 4-fluoro-5-methyl-iso-methylOxazol-3-yl, 4-methyl-Oxazol-2-yl, 4-methyl-thiazol-2-yl, 5, 6-dihydro-4H-cyclopenta [ d]Different from each otherAzole, 5-chloro-4-methylthiazol-2-yl, 5-ethyl- [1, 2, 4 [ ]]Oxadiazol-3-yl, 5-ethyl-iso-Azol-3-yl, 5-isopropyl- [1, 2, 4]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Thiadiazol-3-yl, 5-methyl- [1, 3, 4 [ ]]Oxadiazol-2-yl, 5-methyl-iso-methylOxazol-3-yl, 5-methyl-An azole-2-yl group, which is,oxazol-2-yl and thiazol-2-yl.

9. A compound according to any one of claims 1-2, wherein R³Selected from the group consisting of: 2-methyl-thiazol-4-yl, 3-methyl- [1, 2, 4 ]]Oxadiazol-5-yl, 3-methyl- [1, 2, 4 ]]Thiadiazol-5-yl, 4, 5, 6, 7-tetrahydro-benzo [ c]Different from each otherAzol-3-yl, 4, 5, 6, 7-tetrahydro-benzo [ d]Different from each otherAzol-3-yl, 4, 5-dimethyl-isoOxazol-3-yl, 4, 5-dimethyl-Azol-2-yl, 4-chloro-5-methyl-isoAzol-3-yl, 4-fluoro-5-methyl-iso-methylOxazol-3-yl, 4-methyl-Oxazol-2-yl, 4-methyl-thiazol-2-yl, Oxazol-2-yl, thiazol-2-yl, 5-ethyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-ethyl-iso-Azol-3-yl, 5-isopropyl- [1, 2, 4]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-methyl- [1, 2, 4 ]]Thiadiazol-3-yl, 5-methyl- [1, 3, 4 [ ]]Oxadiazol-2-yl, 5-methyl-iso-methylOxazol-3-yl and 5-methyl-Oxazol-2-yl.

10. A compound according to any one of claims 1-2, wherein R³Selected from the group consisting of: [1,2,4]Oxadiazolyl, isoxazolylAzolyl group, [1, 2, 4 ]]A thiadiazolyl group,azolyl and thiazolyl, each of which is unsubstituted or substituted (R)_nSubstituted, n-1, 2 or 3, each R is independently selected from the group consisting of halogen and C_1-6-alkyl groups.

11. A compound according to any one of claims 1-2, wherein R³Selected from the group consisting of: 5-ethyl-isoAzol-3-yl, 5-methyl- [1, 2, 4 ]]Oxadiazol-3-yl, 5-methyl-iso-Azol-3-yl, 5-methyl- [1, 2, 4 ]]Thiadiazol-3-yl, 5-methyl- [1, 2, 4 [ ]]Oxadiazol-3-yl, 5-methyl-Oxazol-2-yl, 4-methyl-thiazol-2-yl, 4-chloro-5-methyl-iso-butylAzol-3-yl, 4, 5-dimethyl-isoOxazol-3-yl, 4, 5-dimethyl-Azol-2-yl and 4-fluoro-5-methyl-isoOxazol-3-yl.

12. A compound according to any one of claims 1-2 selected from the group consisting of:

cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ e ]]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl ]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-1- { 8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H，6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulen-5-yl } -ethanone,

trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo[e](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ c)]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo[e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl) Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5, 6-dihydro-4H-cyclopenta [ d)]Different from each otherAzol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-chloro-4-methyl-Azol-2-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1-[4- (5-Ethyl- [1, 2, 4 ]]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-ethyl-iso-methyl) Azol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-isopropyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo[e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl ]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5，6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methanesulfonyl-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-methyl-1- [4- (4-methyl- Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-fluoro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetranitrogenHetero-benzo [ e)](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-fluoro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1-2 selected from the group consisting of:

trans-1- { 8-chloro-1- [4- (5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] ]Azulen-5-yl } -2-dimethylamino-ethanone,

trans-8-fluoro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-4H，6H-2，3，5，10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl) Azol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-1- [4- (4-chloro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl radical]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl 1-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (4, 5, 6, 7-tetrahydro-benzo [ d ]]Different from each otherAzol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (5-methyl- [1, 3, 4)]Oxadiazol-2-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]Azulene-5-carboxylic acidA tertiary butyl ester,

trans-8-chloro-1- [4- (3-methyl- [1, 2, 4)]Oxadiazol-5-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] ](ii) azulene-5-carboxylic acid tert-butyl ester,

trans-8-chloro-5-methyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-5-cyclopentyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexanesBase of]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

cis-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ] ](ii) azulene-5-carboxylic acid tert-butyl ester,

cis-8-chloro-1- [4- (5-ethyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5-methyl-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4-, (5-isopropyl- [1, 2, 4]Oxadiazol-3-yl) -cyclohexyl]-4H, 6H-2, 3, 5, 10 b-tetraaza-benzo [ e ]](ii) azulene-5-carboxylic acid tert-butyl ester,

or a pharmaceutically acceptable salt thereof.

14. A compound according to any one of claims 1-2 selected from the group consisting of:

Trans-8-chloro-1- [4- (5-ethyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The content of HCl in the azulene is shown in the specification,

trans-8-chloro-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The content of HCl in the azulene is shown in the specification,

trans-8-chloro-1- [4- (5-methyl-iso)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The content of HCl in the azulene is shown in the specification,

trans-8-chloro-5-cyclobutyl-1- [4- (5-methyl- [1, 2, 4)]Oxadiazol-3-yl) -cyclohexyl]-56-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4, 5-dimethyl)-Azol-2-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e]The feed additive comprises (A) azulene and (B),

trans-8-chloro-1- [4- (4-fluoro-5-methyl-iso-methyl)Azol-3-yl) -cyclohexyl]-5, 6-dihydro-4H-2, 3, 5, 10 b-tetraaza-benzo [ e ]The feed additive comprises (A) azulene and (B),

15. A process for the preparation of a compound of formula I according to any one of claims 1 to 14, comprising the steps of: reacting a compound of formula II

Reacting with a compound of formula III in n-butanol under reflux conditions,

to give a compound of the formula I, wherein R¹，R²And R³As defined in claim 1.

16. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 14.

17. The use of a compound of formula I according to any one of claims 1-14 for the preparation of a medicament for the prevention or treatment of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.