TW201524967A - Use of a pharmaceutical composition for emergency contraception - Google Patents

Abstract

The invention relates to a pharmaceutical composition for non-hormonal emergency contraception. It comprises 2H-indazoles as novel EP2 receptor antagonists in combination with COX inhibitors (COX means cyclooxygenases).

Description

Use of emergency contraception pharmaceutical compositions

The present invention relates to the subject matter stated in the scope of the patent application, that is, 2H-carbazole and at least one cyclooxygenase inhibitor (COX inhibition) comprising at least one novel EP2 receptor antagonist according to formula (I) A pharmaceutical composition for use in non-hormonal emergency contraception.

Various methods and pharmaceutical compositions, such as condoms, pessaries, intrauterine pessaries, and various oral monophasic or multiphagous contraceptives can be used to prevent unwanted pregnancies. However, despite various methods of contraception, there are still unprotected sexual intercourse, even when pregnancy is undesirable.

This is the case, for example, in the case of a rape victim or when a contraceptive device, such as a condom, is destroyed. If ovulation, or if ovulation has occurred, to prevent fertilization under these conditions, it is possible to avoid pregnancy. For this purpose, emergency protection measures must be taken very quickly after sexual intercourse.

In addition to intrauterine contraception by copper-containing intrauterine devices (eg, GynFix), emergency contraception pills (ECP) are especially used for emergency contraception. This is equivalent to the mechanism of action of the method for drug induced abortion (eg, mifepristone).

Copper-containing intrauterine devices have high contraceptive efficiency. However, this administration is an invasive procedure which can only be carried out under sterile conditions by an experienced person skilled in the art (Gemzell-Danielsson et al., Gynecol Endocrinol. (2013) 29 Supplement 1:1-14). therefore, Copper-containing intrauterine devices are used primarily for emergency contraception in situations where long-lasting contraception is also required over the next few months and years.

ECP approved for emergency contraception are Postinor®, Plan B® and Levonelle® (single dose of 1.5 mg levonorgestrel (LNG) in 72 hours) and ellaOne® (single dose within 120 hours after sexual intercourse) With 30 mg of ulipristal acetate (UPA)). Such formulations are described in, for example, the application EP 1 448 207 (LNG; Richter Gedeon) and the application WO 2011/069871 (UPA; HRA Pharma) and WO 2011/091892 (UPA, Ulmann et al.). Levonorgestrel is a progesterone derivative, and ulipristal acetate is a selective progesterone receptor modulator. Thus, both are hormone methods for preventing or delaying ovulation by suppressing the peak of LH (Gemzell-Danielsson and Berger; Contraception. (2013); 87(3): 300-8). The effectiveness of both methods decreases with the time elapsed between unprotected sexual intercourse and administration of LNG or UPA. In eight studies examining the effectiveness of LNG emergency contraception, the effectiveness was between 59% and 94% (Trussel; Best Pract Res Clin Obstet Gynaecol. (2009); 23(2): 199-209). As a possible side effect, both methods affect the menstrual cycle and menstruation (Cheng et al; Cochrane Database Syst Rev. August 15, 2012; 8: CD001324.doi: 10.1002/14651858.CD001324.pub4.).

Other hormonal methods for emergency contraception are the use of aromatase inhibitors (WO 2007/000056, Casper et al.) and GnRH analogues (WO 2005/019457, Siler-Khodr et al).

Since the method for emergency contraception is hormonal, a non-hormone pharmacological method for women who do not want to use or cannot use the hormonal contraceptive for medical or personal reasons is required. Another advantage of the non-hormone method is the fact that it does not affect the menstrual cycle.

No. 8,173,593 B2 describes a non-hormonal method for emergency contraception, wherein the use of an endothelin receptor antagonist that inhibits ovulation is disclosed. Administration of BQ-788 and JKC301 resulted in 65% and 45% ovulation inhibition, respectively. It can also be suppressed in the late stage of ovulation where LNG is no longer fully effective. effect.

It has long been known that prostaglandins are female reproductive biology processes, such as key molecules that regulate ovulation and fertilization. The action of prostaglandins is mediated through their G-protein coupled receptors located in the cell membrane. Of particular interest are prostaglandin E ₂ (PGE ₂ ), which affects a variety of cellular effects by binding to functionally distinct receptor subtypes, namely EP ₁ , EP ₂ , EP ₃ and EP ₄ receptors. The receptor subtype of prostaglandin E ₂ binding is particularly important for receptor-mediated effects associated with the regulation of fertility. Therefore, it may be shown that EP2 knockout mice (EP2 ^-/- ), such as mice that no longer have the functional PGE ₂ receptor subtype EP2, have weakened reproductive function, and these animals have a smaller number after each pregnancy. Generation (Matsumoto et al. Biology of Reproduction; (2001); 64: 1557-1565). Similarly, it may be shown that these EP2 knockout mice (Hizaki et al. Proc Natl Acad Sci USA; (1999); 96(18): 10501-10506) exhibit significantly reduced cumulus expansion and severe low fertility, which are It is considered to have a causal relationship with reduced reproductive processes such as ovulation and fertilization. Therefore, the EP2 receptor is an important target for the development of drugs for regulating female fertility.

The application DE 10 2009 049 662 A1 describes 2-5-disubstituted 2H-carbazoles which have a high binding affinity and selectively antagonize the EP2 receptor. In particular, it is disclosed that such EP2 receptor antagonists are used as contraceptives, rather than for emergency contraception.

In a paired study by cynomolgus macaques, it was shown that the continuously administered EP2 receptor antagonist had a low fertility effect (Peluffo et al. 2012, Annual Meeting of the American Society for Reproductive Medicine). However, continuous administration does not correspond to the use of emergency contraception.

The application of 2H-carbazole is described in the application of Summit Corporation Plc. (WO2007/091107), CM Sun et al. (WO 2008/070599) and Janssen Pharmaceutica NV (WO 2010/124102). The compound disclosed in WO2007/091107 interacts with the utropine A promoter and is claimed to be used for the treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia. quality. WO 2008/070599 describes compounds that bind to the VGEFR-3 receptor. It is advocated for the treatment of cancer. The compound described in application WO 2010/124102 inhibits monoterpene glycerol lipase (MGL) and is claimed for the treatment of inflammatory pain. None of the three mentioned applications revealed whether the compound binds to the EP2 receptor and is suitable for birth control.

Several research groups have studied the effects of COX inhibitors on female ovulation. Thus, Pall et al. examined the effect of rofecoxib on ovulation (Pall et al; Human Reproduction; (2001); 16(7): 1323-1328). In this study, 25 mg of active compound was used for 9 consecutive days. In 4 of the 6 patients, ovulation was delayed for more than 48 hours.

Edelmann et al. 2013 tested the effect of daily oral administration of 400 mg celecoxib on ovulation. Depending on the time and duration of administration, an increase in ovulation dysfunction of 25% to 30% was observed. Ovulation dysfunction is characterized by flat LH (luteinizing hormone) peaks and/or by anovulation (Edelmann et al. Contraception. (2013); 87(3): 352-357). In 2010, Edelmann et al. showed that daily administration of 400 mg celecoxib over the entire cycle increased the cycle length from 27.2 +/- 2.4 days to 28.5 +/- 2.5 days and changed the time and height of the LH peak (Edelmann et al. Contraception; (2010); 81 (6): 496-500). Both results show that celecoxib has limited benefits for emergency contraception.

In a preliminary study of 6 women treated with 3 x 50 mg indomethacin daily for at least 3 days, it was shown that in 5 cases, indomethacin was administered to delay ovulation for 2-12 days. The treatment was initiated when the dominant follicle had reached a maximum size of >16 mm or LH was detected in urine (Athanasious et al. Fertil Steril.; (1996); 65(3): 556-60). The study also confirmed the results by Killick S and Elstein M.1987, in which indomethacin was administered at a dose of 2 x 100 mg daily for 5 days to cause ovulation inhibition (Killick S and Elstein M. Fertil Steril.; (1987) ); 47(5): 773-7).

Clinical studies by Bata et al. 2006 showed that administration of meloxicam reversibly delayed ovulation for 5 days (Bata et al, J Clin Pharmacol (2006); 46: 925-932). This result was confirmed by Jesam et al. 2010 (Jesam et al. Hum Reprod.; (2010); 25(2): 368-73). in In this clinical study, 30 mg or 15 mg of meloxicam was administered daily during the 5 day period during the late follicular phase. 90.9% (30 mg meloxicam group) or 50.0% (15 mg meloxicam group) ovulation abnormalities, indicating that meloxicam is suitable for emergency contraception.

In general, COX inhibitors are known to be relatively well tolerated; however, Castellsague et al. 2012 and Varas-Lorenzo et al. 2013 indicate an increased risk of cardiovascular and gastrointestinal events for this class of substances. It is therefore recommended to use relatively low doses (Castellsague et al. Drug Saf.; (2012); 35(12): 1127-46; Varas-Lorenzo et al. Pharmacoepidemiol Drug Saf.; (2013); doi: 10.1002/pds. 3437. [Electronic publishing precedes printing]).

In a preparatory study, Massai et al. 2007 tested the use of levonorgestrel (LNG) and meloxicam for ovulation time associated with emergency contraception (Massai et al. Human Reproduction; (2007) 22(2): 434- 439). In this study, 2 lozenges of 0.75 mg LNG (especially known under the trade name Postinor-2) in each case were administered either independently or together with 15 mg of meloxicam. In the treatment group receiving the combination of meloxicam and LNG, there was a tendency to decrease the frequency of ovulation compared to the group treated only by LNG. This effect is more pronounced as the dosage of the tablet is taken later than the time of ovulation.

In WO 2010/149273 (Bayer Pharma AG), a low dose of levonorgestrel (which does not inhibit ovulation on its own) is shown to achieve almost complete inhibition of rat ovulation when combined with piroxicam.

The Massai et al. 2007 and WO 2010/149273 methods comprise a hormone component in the form of levonorgestrel, and thus do not represent a non-hormone alternative to the pure hormone method, unless the hormone acts as a COX inhibitor.

Accordingly, it is an object of the present invention to provide a method for emergency contraception based on pharmacological non-hormone methods and thus providing an alternative to the hormonal method.

According to the invention, this object is achieved by the use of a non-hormonal pharmaceutical composition comprising at least one EP2 receptor antagonist according to formula (I) and at least one COX inhibitor.

The EP2 receptor antagonists of the formula I according to the invention are described in the patent application PCT/EP2012/073556, which is hereby incorporated by reference. In this application, it is especially advocated for contraception and emergency contraception. Additionally, a pharmaceutical composition comprising at least one EP2 receptor antagonist of Formula I and at least one COX inhibitor and its use for contraception is described.

In the patent application PCT/EP2012/073556 it is shown that the EP2 receptor antagonist according to formula I or Ia has an antagonistic effect on the EP2 receptor (see Biological Examples; Table 1) and is therefore suitable for birth control (see biological examples; 2, 3 and 4). In the present application, according to the present invention, it is possible to unexpectedly achieve an EP2 receptor antagonist or COX by combining an EP2 receptor antagonist according to formula I or Ia with a COX inhibitor even at doses in which the individual active compound is still ineffective. Contraceptive effects of inhibitors (see Biological Examples; Tables 6.1-6.5 and 7.1). Thus, the combination of an EP2 receptor antagonist according to formula I or Ia with a COX inhibitor allows both a reduction in both the COX inhibitor dose and the EP2 receptor antagonist dose, which in turn reduces possible side effects and thus increases the acceptance of the method. Sex and safety.

In addition, contraceptive effects are unexpectedly achieved even after a single administration of an EP2 receptor antagonist according to formula I and a COX inhibitor (see Biological Examples; Sections 6 and 7). This shows that EP2 receptor antagonists and COX inhibitors constitute an effective pharmaceutical composition for emergency contraception that can be administered after unprotected sexual intercourse. Since this pharmaceutical composition is non-hormonal, it represents an alternative to the hormonal method.

In sinusoidal follicles prior to ovulation, oocytes are surrounded by cumulus cells, which form a dense cell crown around the oocyte. After the LH peak (luteinizing hormone), a series of processes are activated which produce significant morphological changes in this cell crown of cumulus cells. During this time, cumulus cells form an extracellular matrix which leads to the so-called cumulus expansion (Vanderhyden et al. Dev Biol.; (1990); 140(2): 307-317). This cumulus extends to an important component of the ovulation process and the likelihood of subsequent fertilization.

Prostaglandins and prostaglandin E ₂ (the synthesis of which is induced by LH peaks) are of decisive importance during cumulus expansion. Prostaglandin EP2 knockout mice (Hizaki et al. Proc Natl Acad Sci US A.; (1999) 96(18): 10501-10506.) show significantly reduced cumulus spread and severe low fertility, which exhibit prostaglandins The importance of EP2-like receptors for this process.

The anti-ovulation effect of COX inhibitors in humans has been demonstrated in clinical studies (as described above). COX inhibitors cause reduced prostaglandin synthesis. In COX-2 knockout mice, prostaglandins have been shown to play a role in ovulation, cumulus expansion and fertilization (Cheng JG and Stewart CL. Biol Reprod.; (2003); 68(2): 401- 4; Lim et al. Cell; (1997) 91(2): 197-208).

Since the EP2 receptor is directly inhibited by the EP2 antagonist in the prostaglandin pathway, the initial action time of this class of substance is earlier than the initial action time of the COX inhibitor, which is triggered by decreasing the prostaglandin concentration.

Emergency contraception

Emergency contraception, which has the same meaning as emergency birth control, emergency pregnancy prevention, and post-intercourse contraception, is understood to be the ingestion of one or more substances to prevent unwanted pregnancies after unprotected sexual intercourse or inadequate use of the contraceptive.

Emergency contraception is different from contraception. Contraception, birth control, or birth control all similarly refers to the continuous routine ingestion of one or more substances at lower doses according to a fixed agreement over a relatively long period of time over a plurality of cycles. Ingestion of pharmacological contraceptives is independent of the frequency and timing of sexual intercourse.

The invention provides the use of a pharmaceutical composition comprising (a) at least one EP2 receptor antagonist according to formula (I) and (b) at least one COX inhibitor for emergency contraception.

EP2 receptor antagonist

An EP2 receptor antagonist for use in accordance with the invention is generally understood to be 2H-carbazole of formula (I)

Wherein R ¹ : means H, C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy; R ² :H or methyl; the restriction is one of two residues R ¹ or R ² Equal to H; X is -(CH ₂ ) _l -, -(CH ₂ ) _k -O-, -CH ₂ -S-, CH ₂ -S(O) ₂ -, -CH(CH ₃ )-, -CH (CH ₃ )-O- or -C(CH ₃ ) ₂ -O-;k: 1 or 2; l: 0, 1 or 2; R ⁴ :H, C ₁ -C ₄ alkyl, C ₃ -C ₄ -cycloalkyl or CH ₂ -C ₃ -C ₄ cycloalkyl; and in the case where X means -(CH ₂ ) _l - and l means 0 or 1 or -CH(CH ₃ )-

R ⁴ : additionally 4-6 membered heterocyclic residue; and in the case where X means -(CH ₂ ) _l - or -CH(CH ₃ )-

R ⁴ : additionally CN; m: 1 or 2; n: 1 or 2; Ar is a 6-10 membered aryl group or a 5-10 membered heteroaryl residue, R ³ : halogen, CN, SF ₅ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ heterocyclyl, OC ₁ -C ₄ alkyl, OC ₃ -C ₆ cycloalkyl, OC ₄ -C ₆ heterocyclic, SC ₁ -C ₄ alkyl, S(O) _2- C ₁ -C ₄ alkyl, Ar', O-Ar', C(CH ₃ ) ₂ -CN or C(CH ₃ ) ₂ -OH; Ar' a 6-membered aryl or a 5-6 membered heteroaryl residue, optionally substituted or unsubstituted; wherein the substituent is selected from the group consisting of F, Cl, CN, C ₁ -C ₄ alkyl, OC ₁ -C ₄ alkane a group, C(CH ₃ ) ₂ -CN, C(CH ₃ ) ₂ -OH and C(O)NH ₂ ; and salts, solvates or solvates thereof, and isomers thereof, diastereomeric Constructs, enantiomers, and salt or cyclodextrin cage compounds are used to produce agents that overcome known disadvantages and have improved properties such as good in vivo efficacy, good solubility, and stability.

The compounds of the invention have an antagonistic effect on the EP ₂ receptor.

C ₁ -C ₂ alkyl or C ₁ -C ₄ alkyl should each be understood to mean a straight or branched alkyl residue such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl. Base, second butyl or tert-butyl.

The alkyl residue may optionally be a single or multiple substituted fluorine.

The hydrogen atom may be replaced by hydrazine as appropriate.

C ₁ -C ₂ alkoxy or C ₁ -C ₄ alkoxy is understood to mean a straight or branched chain residue of the formula alkyl-O-, such as methoxy, ethoxy, n-propoxy. , isopropoxy, n-butoxy, second butoxy, isobutoxy or tert-butoxy.

The alkoxy residue may optionally be a single or multiple substituted fluorine.

C ₃ -C ₆ cycloalkyl is understood to mean a monocyclic alkyl ring such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The cycloalkyl residue may optionally be a single or multiple substituted fluorine.

A 4-6 membered heterocyclic group is understood to mean a monocyclic ring containing one or more heteroatoms such as oxygen, sulfur and/or nitrogen or a hetero group such as -S(O)- or -SO ₂ - Non-carbon atoms. The linkage can be at any carbon or nitrogen atom.

By way of example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, morpholinyl, thiomorpholinyl, oxa Cyclobutane, tetrahydrofuranyl, tetrahydropentanyl, 1,4-dioxanyl and 2-oxo-oxazolidinyl.

The heterocyclyl residue may optionally be mono- or polysubstituted by fluorine, hydroxyl, methoxy or pendant oxy groups.

Halogen should be understood in each case to mean fluoro, chloro, bromo or iodo.

The C ₆ -C ₁₀ member aryl residue in each case contains from 6 to 10 carbon atoms and can be benzocondensed. Mention may be made of phenyl and naphthyl.

The C ₆ -C ₁₀ member aryl residue may be optionally substituted by fluorine, chlorine or methyl.

C ₅ -C ₁₀ heteroaryl residues are understood to mean monocyclic or bicyclic systems which each contain 5 to 10 ring atoms and which may contain one or more identical or different heteroatoms such as oxygen, sulfur or nitrogen. Not carbon. The linkage can be at any carbon or nitrogen atom.

By way of example, mention may be made of thienyl, thiazolyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazepine Azyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, fluorenyl, thiodecyl, decyl, isodecyl, oxazolyl, benzothiazolyl , benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, anthracycline, pyridazinyl, fluorenyl, isoquinolyl, quinolinyl, quinazolyl, quinazoline Lolinyl, quinoxalinyl, Orolinyl, pyridazinyl, 1,7- or 1,8- Pyridyl and acridinyl.

The C ₅ -C ₁₀ member heteroaryl residue may be optionally substituted by fluorine, chlorine or methyl.

Unless otherwise specified, if a group in the compound of the invention is substituted, the group may be mono- or polysubstituted. In the context of the present invention, it applies to all groups which occur multiple times, the meaning of which is independent of one another. Substitution with one, two or three identical or different substituents is preferred. Substitution by a substituent is particularly preferred.

If a basic functional group is included, organic and inorganic acids such as, in particular, physiologically compatible salts of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and tartaric acid are suitable.

Further, the EP2 receptor antagonist used according to the invention is an EP2 receptor antagonist according to formula (I), wherein R ¹ : means H, C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy; R ² : is H or methyl; the restriction is that one of the two residues R ¹ or R ² is equal to H; X: -(CH ₂ ) _l -, -(CH ₂ ) _k -O-, - CH ₂ -S-, CH ₂ -S(O) ₂ -, -CH(CH ₃ )-, -CH(CH ₃ )-O- or -C(CH ₃ ) ₂ -O-; k: 1 or 2 ;l:0, 1 or 2; R ⁴ :H, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ cycloalkyl; and in X means -( CH ₂ ) _l - and l means 0

R ⁴ : additionally a 4-6 membered heterocyclic residue bonded through a ring carbon atom; m: 1 or 2; n: 1 or 2; Ar: 6-10 membered aryl or 5-10 membered heteroaryl residue Base, R ³ : halogen, CN, SF ₅ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ heterocyclic, OC ₁ -C ₄ alkyl, OC ₃ -C ₆ cycloalkyl, OC ₄ -C ₆ heterocyclyl, SC ₁ -C ₄ alkyl, S(O) ₂ -C ₁ -C ₄ alkyl, Ar', O-Ar', C(CH ₃ ) ₂ -CN or C(CH ₃ ) ₂ -OH; Ar': a 6-membered aryl or a 5-6 membered heteroaryl residue, optionally substituted or unsubstituted; wherein the substituent is selected from the group consisting of F, Cl, CN, C ₁ -C ₄ alkyl, OC ₁ -C ₄ alkyl, C(CH ₃ ) ₂ -CN, C(CH ₃ ) ₂ -OH and C(O)NH ₂ ; and salts, solvates or salts thereof Solvates and their isomers, diastereomers, enantiomers and salts or cyclodextrin cage compounds for the production of overcoming known disadvantages and improved properties, such as good in vivo efficacy , good solubility and stability of the agent.

A particularly preferred EP2 receptor antagonist for use according to the invention is a 2H-carbazole of the formula (I), wherein R ¹ , R ² : means H or methyl; the restriction is two residues R ¹ or R ² One of them is equal to H; X: -(CH ₂ ) _l - or -(CH ₂ ) _k -O-; k: 1 or 2; l: 0, 1 or 2; R ⁴ : H, C ₁ - C _4- alkyl, C ₃ -C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ cycloalkyl; m: 1 or 2; n: 1 or 2; Ar: 6-10 member aryl or 5-10 member a heteroaryl residue, R ³ : halogen, CN, SF ₅ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ heterocyclyl, OC ₁ -C ₄ alkyl, OC ₃ -C ₆ cycloalkyl, OC ₄ -C ₆ heterocyclic, SC ₁ -C ₄ alkyl, S(O) ₂ -C ₁ -C ₄ alkyl, Ar', O-Ar', C ( CH ₃ ) ₂ -CN or C(CH ₃ ) ₂ -OH; and Ar': a 6-membered aryl or a 5-6 membered heteroaryl residue which is optionally mono- or disubstituted; wherein the substituent is selected from F , Cl, CN, C ₁ -C ₄ alkyl, OC ₁ -C ₄ alkyl, C(CH ₃ ) ₂ -CN, C(CH ₃ ) ₂ -OH and C(O)NH ₂ ; and salts thereof, a solvate or a solvate of a salt thereof, and isomers, diastereomers, enantiomers thereof and salts or cyclodextrin cage compounds, for use in the production to overcome known disadvantages and to have improved properties , Agents such as good in vivo efficacy, stability and good solubility of the.

Preferred is a compound of formula (I), wherein R ¹ : means methyl; R ² :H; X: -(CH ₂ ) _l - or -(CH ₂ ) _k -O-; k:1; l:0 Or 1; R ⁴ : C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ cycloalkyl; m, n: 2; Ar: phenyl residue; Salts, solvates or solvates of salts and isomers, diastereomers, enantiomers and salts thereof or cyclodextrin cage compounds for use in production to overcome known disadvantages and improved Characteristics, such as good in vivo efficacy, good solubility and stability of the agent.

Also preferred are compounds of formula (I) wherein R ¹ :meaning methyl; R ² :H; X: -(CH ₂ ) _l - or -(CH ₂ ) _k -O-; k:1; 0 or 1; R ⁴ : C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ cycloalkyl; m, n: 1; Ar: phenyl residue; Solvents, solvates or solvates thereof, and isomers, diastereomers, enantiomers and salts thereof or cyclodextrin cage compounds for use in production to overcome known disadvantages and improve Characteristics such as good in vivo efficacy, good solubility and stability.

The following compounds of the invention are particularly preferred: E1 2-{[1-(4-Cyano-2-fluorobenzhydryl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E2 2-{[1-(4-Tertilybutyrylbenzyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H- Oxazole-5-carboxamide

E3 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E4 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-(N-morpholinyl)benzylidene)piperidin-4-yl]methyl}- 2H-carbazole-5-carboxamide

E5 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

E6 2-{[1-(2-Fluoro-4-methylsulfonylbenzylidene)piperidin-4-yl]methyl}-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-carboxamide

E7 2-{[1-(2-Fluoro-4-methoxybenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

E8 2-{[1-(4-Bromo-2-fluorobenzylidinyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H- Oxazole-5-carboxamide

E9 2-{[1-(2-Fluoro-4-methylbenzomethyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E10 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E11 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]piperidin-4-yl}A Base-2H-carbazole-5-carbamide

E12 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-methylbenzylidenyl)piperidin-4-yl]methyl}-2H-carbazole- 5-carbamamine

E13 2-({1-[4-(4-Chlorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E14 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy)benzylidene]piperidin-4-yl}-- Base-2H-carbazole-5-carbamide

E15 2-({1-[4-(4-Tert-butylphenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E16 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E17 N-(2-methoxyethyl)-2-({1-[4-(4-methoxyphenoxy)benzylidenyl]piperidin-4-yl}methyl)-4- methyl-2H-carbazole-5-carbamide

E18 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-phenoxybenzylidinyl)piperidin-4-yl]methyl}-2H-carbazole -5-formamide

E19 2-{[1-(4-Cyclopropylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxy B -4-methyl-2H-carbazole-5-carboxamide

E20 2-{[1-(4-Methoxybenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-formamide

E21 2-{[1-(4-Fluorobenzylidinyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E22 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzylidenyl]piperidin-4-yl}-methyl)- 2H-carbazole-5-carboxamide

E23 2-{[1-(2-Methoxybenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-formamide

E24 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulfonyl]benzylidene]piperidin-4-yl) Methyl]-2H-indazole-5-carboxamide

E25 N-(2-methoxyethyl)-4-methyl-2-({1-[3-(trifluoromethyl)benzylidenyl]piperidin-4-yl}-methyl)- 2H-carbazole-5-carboxamide

E26 N-(2-methoxyethyl)-4-methyl-2-{[1-(3-methylbenzimidyl)piperidin-4-yl]methyl}-2H-carbazole- 5-carbamamine

E27 2-{[1-(3-Chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E28 2-({1-[4-(4-Aminomethylphenylphenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E29 2-({1-[4-(Cyclopentyloxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E30 2-({1-[4-(Difluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E31 2-{[1-(4-Cyanobenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole- 5-carbamamine

E32 2-({1-[4-(1H-imidazol-1-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

E33 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(oxazol-2-yl)benzylidene]piperidin-4-yl}methyl) -2H-carbazole-5-carboxamide

E34 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(oxazol-5-yl)benzylidene]piperidin-4-yl}methyl) -2H-carbazole-5-carboxamide

E35 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(isoxazol-5-yl)benzylidene]piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

E36 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-pyrazol-1-yl)benzylidene]piperidin-4-yl}- Methyl)-2H-carbazole-5-carboxamide

E37 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-1,2,4-triazol-1-yl)benzylidene]piperidine 4-yl}-methyl)-2H-indazole-5-carboxamide

E38 2-({1-[4-(Difluoromethoxy)-2-fluorobenzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)- 4-methyl-2H-indazole-5-carboxamide

E39 2-({1-[2-Fluoro-4-(pyrrolidin-1-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E40 2-({1-[(3,4'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E41 2-({1-[(3-Fluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E42 2-({1-[(3-Fluoro-4'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E43 2-[(1-{[3-Fluoro-3'-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E44 2-[(1-{[3-Fluoro-2'-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxy Base ethyl)-4-methyl-2H-indazole-5-carboxamide

E45 2-({1-[(2'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E46 2-({1-[(2',4'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)- 4-methyl-2H-indazole-5-carboxamide

E47 2-({1-[(2-Fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E48 N-(2-methoxyethyl)-4-methyl-2-({1-[(2'-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}-methyl )-2H-carbazole-5-carbamide

E49 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-pyridyloxy)benzylidene]piperidin-4-yl}methyl)- 2H-carbazole-5-carboxamide

E50 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4H-1,2,4-triazol-4-yl)benzylidene]piperidine 4-yl}-methyl)-2H-indazole-5-carboxamide

E51 2-({1-[2-Fluoro-4-[morpholin-4-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E52 2-{[1-(4-Bromobenzylidenyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E53 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]piperidin-4-yl}-methyl) -2H-carbazole-5-carboxamide

E54 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E55 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidene]piperidin-4-yl)- ]]-2H-carbazole-5-carbamide

E56 4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2,2- Trifluoroethyl)-2H-indazole-5-carboxamide

E57 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indole Oxazol-5-carboxamide

E58 4-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoquinone) Benzylpiperidin-4-yl}methyl)-2H-indazole-5-carboxamide

E59 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H -carbazole-5-carboxamide

E60 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzylidenyl)piperidin-4-yl]-methyl} -2H-carbazole-5-carboxamide

E61 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl}-methyl )-4-methyl-2H-indazole-5-carboxamide

E62 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

E63 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)- 4-methyl-2H-indazole-5-carboxamide

E64 2-{[1-(4-Cyclopropylbenzylidene)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl -2H-carbazole-5-carboxamide

E65 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy) -ethyl]-2H-carbazole-5-carboxamide

E66 4-methyl-2-{[1-(4-methylbenzimidyl)piperidin-4-yl]methyl}-N-[2-(2,2,2-trifluoroethoxy) )-ethyl]-2H-carbazole-5-carboxamide

E67 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2 -trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide

E68 4-Methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzylidene]-periphidine Pyridin-4-yl}methyl)-2H-indazole-5-carboxamide

E69 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2- Trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide

E70 2-{[1-(4-cyclopropylbenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-B Oxy)ethyl]-2H-indazole-5-carboxamide

E71 2-{[1-(4-Chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-isopropoxy B -4-methyl-2H-carbazole-5-carboxamide

E72 N-(2-Isopropoxyethyl)-4-methyl-2-{[1-(4-methylbenzimidyl)piperidin-4-yl]methyl}-2H-carbazole -5-formamide

E73 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl -2-H-carbazole-5-carbamide

E74 N-(2-Isopropoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzylidenyl]piperidin-4-yl}-methyl) -2H-carbazole-5-carboxamide

E75 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E76 2-{[1-(4-Cyclopropylbenzylidene)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

E77 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H- Oxazole-5-carboxamide

E78 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoro-methoxy) Ethyl]-2H-carbazole-5-carboxamide

E79 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy) Ethyl]-2H-carbazole-5-carboxamide

E80 4-methyl-N-[2-(trifluoromethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzylidene] Piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

E81 N-(2-Tertiyloxyethyl)-2-{[1-(4-chlorobenzylidyl)piperidin-4-yl]methyl}-4-methyl-2H-carbazole -5-formamide

E82 N-(2-Tertiyloxyethyl)-2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4- methyl-2H-carbazole-5-carbamide

E83 N-(2-Tertiyloxyethyl)-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-4-methyl -2-H-carbazole-5-carbamide

E84 N-(2-Tertiyloxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy] Benzomethane}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

E85 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-{2-[( ² H3)methoxy]-( ² H4 Ethyl}-2H-carbazole-5-carboxamide

E86 2-({1-[4-(4-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-{2-[( ² H3) A Oxy]( ² H4)ethyl}-2H-indazole-5-carboxamide

E87 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

E88 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidenyl}azetidin-3- Methyl]-2H-carbazole-5-carboxamide

E89 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3-yl}- Methyl)-2H-carbazole-5-carboxamide

E90 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E91 2-{[1-(4-Chloro-2-fluorobenzhydryl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E92 2-({1-[3-Fluoro-4-(trifluoromethyl)benzylidenyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E93 2-({1-[4-Chloro-3-(trifluoromethyl)benzylidenyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E94 2-{[1-(4-Cyclopropylbenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E95 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene} azetidine -3-yl)methyl]-2H-indazole-5-carboxamide

E96 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)- 2H-carbazole-5-carboxamide

E97 4-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzoquinone) Azetidinium-3-yl}-methyl)-2H-indazole-5-carboxamide

E98 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidenyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

E99 4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]azetidin-3-yl}methyl)-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

E100 N-[2-(cyclopropoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3- }]methyl)-2H-carbazole-5-carboxamide

E101 N-[2-(Cyclobutoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3- }]methyl)-2H-carbazole-5-carboxamide

E102 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl -2-H-carbazole-5-carbamide

E103 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzylidene]azetidin-3-yl} -methyl)-4-methyl-2H-indazole-5-carboxamide

E104 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzylidene)azetidin-3-yl]- Methyl}-2H-carbazole-5-carboxamide

E105 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl] -2H-carbazole-5-carboxamide

E106 N-(2-Tertiyloxyethyl)-2-{[1-(4-chlorobenzylidenyl)azetidin-3-yl]methyl}-4-methyl-2H -carbazole-5-carboxamide

E107 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}- -4-methyl-2H-carbazole-5-carboxamide

E108 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E109 2-({1-[4-(4-Fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E110 2-({1-[4-(4-Fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-4- Methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E111 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2- Trifluoroethyl)-2H-indazole-5-carboxamide

E112 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethyl) Oxy)-ethyl]-2H-indazole-5-carboxamide

E113 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy] -benzimidyl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

E114 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}-nitrogen Heterocyclobutane-3-yl)methyl]-2H-indazole-5-carboxamide

E115 2-({1-[4-(4-Chlorophenoxy)benzylidenyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2 -trifluoro-ethyl)-2H-indazole-5-carboxamide

E116 2-({1-[4-(4-Chlorophenoxy)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E117 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene )-azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

E118 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzene Mercapto)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

E119 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-ethyl-4-methyl-2H-indazole-5-carboxamide

E120 2-({1-[4-(4-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro -ethyl)-2H-carbazole-5-carboxamide

E121 2-({1-[4-(4-Chlorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro -ethyl)-2H-carbazole-5-carboxamide

E122 4-methyl-2-({1-[4-(4-methylphenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2,2-three Fluoroethyl)-2H-indazole-5-carboxamide

E123 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N- (2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E124 4-methyl-2-{[1-(4-(N-morpholinyl)benzylidenyl)piperidin-4-yl]methyl}-N-(2,2,2-trifluoroethyl Base-2H-carbazole-5-carbamide

E125 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)thio]benzylidene}-piperidine-4 -yl)methyl]-2H-carbazole-5-carboxamide

E126 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}-peri Pyridin-4-yl)methyl]-2H-indazole-5-carboxamide

E127 4-Methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}- Benzyl hydrazino)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E128 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}- Benzyl hydrazino)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E129 4-Methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}- Benzyl hydrazino)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E130 2-({1-[4-(4-Cyanophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-tri Fluoro-ethyl)-2H-carbazole-5-carbamide

E131 2-({1-[4-(3-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro -ethyl)-2H-carbazole-5-carboxamide

E132 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzylidene}-peri Pyridin-4-yl)methyl]-2H-indazole-5-carboxamide

E133 2-[(1-{4-[(5-Cyanopyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-4-methyl-N-(2 ,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E134 2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzylidene]piperidin-4-yl)methyl]-4-methyl-N-(2, 2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E135 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[5-(trifluoromethyl)pyridin-2-yl]benzylidene) -piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

E136 2-({1-[4-(2,4-Difluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl ke-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E137 2-({1-[4-(3,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

E138 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E139 2-{[1-(4-Bromobenzylidenyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indole Oxazol-5-carboxamide

E140 2-({1-[4-(5-chloropyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2- Trifluoroethyl)-2H-indazole-5-carboxamide

E141 2-({1-[(4'-Methoxy-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2 ,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E142 4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

E143 2-({1-[(4'-Fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2, 2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E144 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzylidene) -piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

E145 2-({1-[4-(6-methoxypyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

E146 2-({1-[4-(6-Methoxypyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

E147 4-methyl-2-({1-[4-(5-methylpyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

E148 2-({1-[4-(5-fluoropyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2- Trifluoroethyl)-2H-indazole-5-carboxamide

E149 2-({1-[4-(5-Methoxypyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)- 4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E150 4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

E151 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzhydryl} -piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

E152 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzylidene) -piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

E153 2-({1-[4-(4-Cyanophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2-H-carbazole-5-carbamide

E154 2-{[1-(4-Bromo-3-methylbenzhydryl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E155 2-{[1-(4-Tertiary benzylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

E156 2-({1-[4-(1-hydroxy-1-methylethyl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

E157 2-{[1-(4-Cyclohexylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole- 5-carbamamine

E158 2-({1-[4-(1-Cyano-1-methylethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E159 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyrimidin-2-yloxy)benzylidene]piperidin-4-yl}-- Base-2H-carbazole-5-carbamide

E160 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzylidene]piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

E161 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene )-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E162 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy))benzhydrazide Benzylpiperidin-4-yl}methyl)-2H-indazole-5-carboxamide

E163 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}-benzamide Basepiperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E164 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzylidene )-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E165 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene )-piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E166 2-({1-[(4'-Methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2-H-carbazole-5-carbamide

E167 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)) Benzyl hydrazino]-piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

E168 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzylidene]piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E169 2-[(1-{4-[(5-Cyanopyridin-2-yl)oxy]benzylidene]piperidin-4-yl)methyl]-N-(2-methoxy- Ethyl)-4-methyl-2H-indazole-5-carboxamide

E170 2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzylidene}piperidin-4-yl)methyl]-N-(2-methoxy-B -4-methyl-2H-carbazole-5-carboxamide

E171 2-({1-[4-(2,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E172 2-({1-[4-(3,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E173 N-(2-methoxyethyl)-4-methyl-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E174 2-({1-[4-(3-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E175 2-{[1-(2-Fluoro-4-isopropoxybenzhydryl)piperidin-4-yl]methyl}-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-carboxamide

E176 2-({1-[(3-Fluoro-3',4'-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E177 2-({1-[(2',3-Difluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Base ethyl)-4-methyl-2H-indazole-5-carboxamide

E178 2-({1-[4-(Difluoromethoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

E179 2-({1-[4-(2-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E180 2-({1-[(4'-Cyano-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

E181 2-({1-[4-(5-chloropyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E182 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzylidene}-piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E183 N-(2-methoxyethyl)-2-({1-[(4'-methoxy-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}A -4-methyl-2H-carbazole-5-carboxamide

E184 2-({1-[(4'-Chloro-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E185 2-[(1-{[4'-(2-Cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxy Base ethyl)-4-methyl-2H-indazole-5-carboxamide

E186 N-(2-methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)- 4-methyl-2H-indazole-5-carboxamide

E187 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzylidene}-piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E188 N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzylidene] Piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

E189 2-({1-[(4'-Fluoro-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E190 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

E191 N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)- 4-methyl-2H-indazole-5-carboxamide

E192 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

E193 2-({1-[(4'-Fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

E194 2-({1-[(4'-Chloro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

E195 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzylidene}-piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E196 2-({1-[(4'-Chloro-2'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

E197 2-({1-[(2'-Chloro-4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

E198 2-({1-[4-(5-chloropyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E199 2-({1-[4-(5-fluoropyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E200 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]benzylidene}-piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E201 2-[(1-{[4'-(2-Hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl) A -N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

E202 2-({1-[(3',5'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)- 4-methyl-2H-indazole-5-carboxamide

E203 2-({1-[(4'-Fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E204 2-({1-[(3',5'-Difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E205 N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzylidene]piperidin-4-yl} -methyl)-2H-carbazole-5-carboxamide

E206 N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzylidene]piperidin-4-yl} -methyl)-2H-carbazole-5-carboxamide

E207 N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}-methyl) -2H-carbazole-5-carboxamide

From 207 compounds, particularly preferred are compounds having an EP2 receptor antagonism of >50 nM: E2 2-{[1-(4-Tertilybutyrylbenzyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H- Oxazole-5-carboxamide

E3 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E5 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

E7 2-{[1-(2-Fluoro-4-methoxybenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

E8 2-{[1-(4-Bromo-2-fluorobenzylidinyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H- Oxazole-5-carboxamide

E9 2-{[1-(2-Fluoro-4-methylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E10 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E11 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]piperidin-4-yl}A Base-2H-carbazole-5-carbamide

E12 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-methylbenzylidenyl)piperidin-4-yl]methyl}-2H-carbazole- 5-carbamamine

E13 2-({1-[4-(4-Chlorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E14 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy)benzylidene]piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

E15 2-({1-[4-(4-Tert-butylphenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E16 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E17 N-(2-methoxyethyl)-2-({1-[4-(4-methoxyphenoxy)benzylidenyl]piperidin-4-yl}methyl)-4- methyl-2H-carbazole-5-carbamide

E18 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-phenoxybenzylidinyl)piperidin-4-yl]methyl}-2H-carbazole -5-formamide

E19 2-{[1-(4-Cyclopropylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-formamide

E20 2-{[1-(4-Methoxybenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-formamide

E21 2-{[1-(4-Fluorobenzylidinyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E22 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzylidene]pipech Pyridin-4-yl}methyl)-2H-indazole-5-carboxamide

E24 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulfonyl]benzylidene]piperidin-4-yl) Methyl]-2H-indazole-5-carboxamide

E25 N-(2-methoxyethyl)-4-methyl-2-({1-[3-(trifluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-2H -carbazole-5-carboxamide

E26 N-(2-methoxyethyl)-4-methyl-2-{[1-(3-methylbenzimidyl)piperidin-4-yl]methyl}-2H-carbazole- 5-carbamamine

E27 2-{[1-(3-Chlorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E29 2-({1-[4-(Cyclopentyloxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E30 2-({1-[4-(Difluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E31 2-{[1-(4-Cyanobenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole- 5-carbamamine

E36 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-pyrazol-1-yl)benzylidene]piperidin-4-yl}A Base-2H-carbazole-5-carbamide

E38 2-({1-[4-(Difluoromethoxy)-2-fluorobenzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E39 2-({1-[2-Fluoro-4-(pyrrolidin-1-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E40 2-({1-[(3,4'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E41 2-({1-[(3-Fluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E42 2-({1-[(3-Fluoro-4'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N- (2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

E43 2-[(1-{[3-Fluoro-3'-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E44 2-[(1-{[3-Fluoro-2'-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxy Base ethyl)-4-methyl-2H-indazole-5-carboxamide

E45 2-({1-[(2'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

E46 2-({1-[(2',4'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E47 2-({1-[(2-Fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E48 N-(2-methoxyethyl)-4-methyl-2-({1-[(2'-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl) -2H-carbazole-5-carboxamide

E51 2-({1-[2-Fluoro-4-(morpholin-4-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E52 2-{[1-(4-Bromobenzylidenyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E53 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidenyl]piperidin-4-yl}methyl)- 2H-carbazole-5-carboxamide

E54 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

E55 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidene]piperidin-4-yl)- ]]-2H-carbazole-5-carbamide

E59 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H -carbazole-5-carboxamide

E60 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzhydryl) Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E61 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl}methyl) -4-methyl-2H-indazole-5-carboxamide

E62 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

E63 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)- 4-methyl-2H-indazole-5-carboxamide

E64 2-{[1-(4-Cyclopropylbenzylidene)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl -2H-carbazole-5-carboxamide

E65 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy) Ethyl]-2H-carbazole-5-carboxamide

E66 4-methyl-2-{[1-(4-methylbenzimidyl)piperidin-4-yl]methyl}-N-[2-(2,2,2-trifluoroethoxy) Ethyl]-2H-carbazole-5-carboxamide

E67 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2 -trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide

E68 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzylidene]piperidine -4-yl}methyl)-2H-indazole-5-carboxamide

E69 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2- Trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide

E70 2-{[1-(4-Cyclopropylbenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy) Ethyl]-2H-carbazole-5-carboxamide

E71 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-carbazole- 5-carbamamine

E72 N-(2-Isopropoxyethyl)-4-methyl-2-{[1-(4-methylbenzimidyl)piperidin-4-yl]methyl}-2H-carbazole -5-formamide

E73 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-iso Propoxyethyl)-4-methyl-2H-indazole-5-carboxamide

E74 N-(2-Isopropoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzylidenyl]piperidin-4-yl}methyl)- 2H-carbazole-5-carboxamide

E75 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E76 2-{[1-(4-Cyclopropylbenzylidene)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

E77 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H- Oxazole-5-carboxamide

E78 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy) Ethyl]-2H-carbazole-5-carboxamide

E79 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy) Ethyl]-2H-carbazole-5-carboxamide

E80 4-methyl-N-[2-(trifluoromethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidin Pyridin-4-yl)methyl]-2H-indazole-5-carboxamide

E81 N-(2-Tertiyloxyethyl)-2-{[1-(4-chlorobenzylidyl)piperidin-4-yl]methyl}-4-methyl-2H-carbazole -5-formamide

E82 N-(2-Tertiyloxyethyl)-2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4- methyl-2H-carbazole-5-carbamide

E83 N-(2-Tertiyloxyethyl)-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-4-methyl -2-H-carbazole-5-carbamide

E84 N-(2-Tertiyloxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidine- 4-yl)methyl]-2H-indazole-5-carboxamide

E85 2-{[1-(4-Chlorobenzoyl)piperidin-4-yl]methyl}-4-methyl-N-{2-[(2H3)methoxy](2H4)ethyl }-2H-carbazole-5-carboxamide

E86 2-({1-[4-(4-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl- N-{2-[(2H3)methoxy](2H4)ethyl}-2H-indazole-5-carboxamide

E87 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

E88 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidenyl}azetidin-3- Methyl]-2H-carbazole-5-carboxamide

E89 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3-yl}A Base-2H-carbazole-5-carbamide

E90 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E91 2-{[1-(4-Chloro-2-fluorobenzhydryl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E92 2-({1-[3-Fluoro-4-(trifluoromethyl)benzylidenyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E93 2-({1-[4-Chloro-3-(trifluoromethyl)benzylidenyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E94 2-{[1-(4-Cyclopropylbenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E95 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene} azetidine -3-yl)methyl]-2H-indazole-5-carboxamide

E100 N-[2-(cyclopropoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3- }]methyl)-2H-carbazole-5-carboxamide

E101 N-[2-(Cyclobutoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3- }]methyl)-2H-carbazole-5-carboxamide

E102 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl -2-H-carbazole-5-carbamide

E103 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzoquinone) Azetidinium-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

E104 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzimidyl)azetidin-3-yl]- }}-2H-carbazole-5-carboxamide

E105 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl] -2H-carbazole-5-carboxamide

E107 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}- -4-methyl-2H-carbazole-5-carboxamide

E108 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E109 2-({1-[4-(4-Fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E112 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethyl) Oxy)ethyl]-2H-indazole-5-carboxamide

E113 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy] Benzyl hydrazino}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

E114 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene} aza Cyclobutane-3-yl)methyl]-2H-indazole-5-carboxamide

E115 2-({1-[4-(4-Chlorophenoxy)benzylidenyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

E116 2-({1-[4-(4-Chlorophenoxy)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E117 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene Azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

E125 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)thio]benzylidene]piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E126 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy] Benzyl hydrazino}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

E127 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzene Mercapto)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E128 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzene Mercapto)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E131 2-({1-[4-(3-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro Ethyl)-2H-carbazole-5-carboxamide

E132 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzylidene]piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E137 2-({1-[4-(3,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

E138 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidine- 4-yl)methyl]-2H-indazole-5-carboxamide

E141 2-({1-[(4'-Methoxy-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2 ,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E143 2-({1-[(4'-Fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2, 2,2-trifluoroethyl)-2H-indazole-5-carboxamide

E153 2-({1-[4-(4-Cyanophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2-H-carbazole-5-carbamide

E154 2-{[1-(4-Bromo-3-methylbenzhydryl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

E155 2-{[1-(4-Tertiary benzylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

E157 2-{[1-(4-Cyclohexylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole- 5-carbamamine

E160 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzoquinone) Benzylpiperidin-4-yl}methyl)-2H-indazole-5-carboxamide

E161 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E162 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzylidene]piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

E163 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}benzylidene Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E164 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzylidene Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E165 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

E166 2-({1-[(4'-Methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2-H-carbazole-5-carbamide

E168 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzylidene]piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E170 2-[(1-{4-[(5-chloropyridin-2-yl)oxy)benzylidenyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

E171 2-({1-[4-(2,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E172 2-({1-[4-(3,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

E173 N-(2-methoxyethyl)-4-methyl-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl )methyl]-2H-carbazole-5-carboxamide

E174 2-({1-[4-(3-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E175 2-{[1-(2-Fluoro-4-isopropoxybenzhydryl)piperidin-4-yl]methyl}-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-carboxamide

E176 2-({1-[(3-Fluoro-3',4'-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E177 2-({1-[(2',3-Difluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Base ethyl)-4-methyl-2H-indazole-5-carboxamide

E178 2-({1-[4-(Difluoromethoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

E179 2-({1-[4-(2-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

E180 2-({1-[(4'-Cyano-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

E181 2-({1-[4-(5-chloropyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E182 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzylidene}piperidine- 4-yl)methyl]-2H-indazole-5-carboxamide

E183 N-(2-methoxyethyl)-2-({1-[(4'-methoxy-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}A -4-methyl-2H-carbazole-5-carboxamide

E184 2-({1-[(4'-Chloro-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E185 2-[(1-{[4'-(2-Cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxy Base ethyl)-4-methyl-2H-indazole-5-carboxamide

E186 N-(2-methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)- 4-methyl-2H-indazole-5-carboxamide

E187 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzylidene]piperidine- 4-yl)methyl]-2H-indazole-5-carboxamide

E188 N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzylidene] Piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

E189 2-({1-[(4'-Fluoro-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

E190 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

E191 N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)- 4-methyl-2H-indazole-5-carboxamide

E193 2-({1-[(4'-Fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

E194 2-({1-[(4'-Chloro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

E195 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzimidyl}piperidine- 4-yl)methyl]-2H-indazole-5-carboxamide

E196 2-({1-[(4'-Chloro-2'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E197 2-({1-[(2'-Chloro-4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E198 2-({1-[4-(5-chloropyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E199 2-({1-[4-(5-fluoropyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

E200 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]benzylidene}piperidine- 4-yl)methyl]-2H-indazole-5-carboxamide

E201 2-[(1-{[4'-(2-Hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E202 2-({1-[(3',5'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-carboxamide

E203 2-({1-[(4'-Fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-carboxamide

E204 2-({1-[(3',5'-Difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

E205 N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

E206 N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

E207 N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)- 2H-carbazole-5-carboxamide

In addition, it is especially preferred for the following compounds: E16 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E126 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E161 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

The daily dose is from 0.1 to 1000 mg, preferably from 50 to 600 mg, wherein the dose can be administered in a single dose or divided into two or more partial doses.

Depending on the body weight, the route of administration, the individual's response to the active compound, the type of preparation, and the time or interval at which the administration is carried out, it may be necessary to deviate from the amount of the EP2 receptor antagonist of formula (I). Therefore, in some cases, it may be sufficient to use less than the minimum amount mentioned above, while in other cases the upper limit mentioned must be exceeded.

COX inhibitor

In general, COX inhibitors suitable for use in accordance with the present invention are all available for their use His indication of COX inhibitors. This means both selective and non-selective COX inhibitors. Particularly suitable inhibitors according to the invention include: C1 indomethacin; C2 diclofenac; C4 naproxen; C5 ibuprofen; C6 meloxicam; C7 piroxicam; C8 nimesulide; C9 ketoprofen; C10 tenoxicam; C11 mefenamic acid; C12 ketorolac; C13 celecoxib (4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide); C14 parecoxib (N- [4-(5-Methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonylpropionamine); C15 rofecoxib (4-(4-methylsulfonyl) Phenyl)-3-phenylfuran-2(5H)-one); C16 valdecoxib (4-[5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide); C17 etoricoxib.

Particularly preferred are: C1 indomethacin; C2 diclofenac; C4 naproxen; C5 ibuprofen; C6 meloxicam; C7 piroxicam; C8 nimesulide.

Particularly preferred are: C1 indomethacin; C2 diclofenac; C6 meloxicam; C7 piroxicam.

Also in the case of COX inhibitors, different doses are used depending on the COX inhibitor used. The amount of COX inhibitor present in the pharmaceutical composition will vary depending upon the inhibitor selected. The dosage range of the COX inhibitor used in accordance with the invention is produced by the daily therapeutic dose (preferably in a single dosage form) of the COX inhibitor. Such therapeutic doses involve relatively long-term treatment and continuous therapy such that, in the case of the invention of emergency contraception, preferably in a single dose, it is also possible to use four times the recommended therapeutic dose. The lower limit is considered to be one quarter of the recommended therapeutic dose. Also in the case of a COX inhibitor, the dose may be administered in the form of a single dose once or divided into two or more partial doses.

According to the invention, the following dosage ranges are suitable for emergency contraception: C1 Indomethacin: 19-800 mg / day (daily therapeutic dose: 75-200 mg / day *)

C2 Diclofenac: 37.5-800 mg / day (daily therapeutic dose: 150-200 mg / day *)

C4 naproxen: 125-4000 mg / day (daily therapeutic dose: 500-1000 mg / day *)

C5 ibuprofen: 200-4800 mg / day (daily therapeutic dose: 800-1200 mg / day *)

C6 Meloxicam: 2-60 mg / day (daily therapeutic dose: 7.5-15 mg / day)

C7 piroxicam: 5-80 mg / day (daily therapeutic dose: 20 mg / day *)

C8 Nimesulide: 25-800 mg / day (daily therapeutic dose: 100-200 mg / day *)

C9 Ketoprofen: 25-1200 mg / day (daily therapeutic dose: 100-300 mg / day *)

C10 tenoxicam: 10-160 mg / day (daily therapeutic dose: 40 mg / day *)

C11 Mefenamic acid: 125-2000 mg / day (daily therapeutic dose: 500 mg / day *)

C12 ketorolac: 2.5-160 mg / day (daily therapeutic dose: 10-40 mg / day *)

C13 senepoxib: 25-800 mg / day (daily therapeutic dose: 100-200 mg / day *)

C14 Parecoxib: 12.5-200 mg / day (daily therapeutic dose: 50 mg / day *)

C15 Rofecoxib: 6-200 mg / day (daily therapeutic dose: 25-50 mg / day *)

C16 Valdecoxib: 10-160 mg / day (daily therapeutic dose: 40 mg / day)

C17 Etoxoxib: 15-360 mg / day (daily therapeutic dose: 60-90 mg / day)

^* Huntjens et al. Rheumatology; (2005); 44: 846-859

Also in the case of a COX inhibitor, the amount mentioned above may be required to deviate from the COX inhibitor if necessary, that is, depending on the body weight, the route of administration, the individual's response to the reaction compound, the type of preparation, and the administration. Time or interval. Therefore, in some cases, it may be sufficient to use less than the minimum amount mentioned above, while in other cases the upper limit mentioned must be exceeded.

Preferred combinations according to the invention comprise an EP2 receptor antagonist according to formula (I) from the following list: E16 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidin-4- Methyl]-2H-carbazole-5-carboxamide

E126 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

E161 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

And COX inhibitors from the following list: C1 indomethacin; C2 diclofenac; C4 naproxen; C5 ibuprofen; C6 meloxicam; C7 piroxicam; C8 nimesulide; Preferred COX inhibitors for use according to the invention: C1 indomethacin; C2 diclofenac; C6 meloxicam; C7 piroxicam.

Investment route

The pharmaceutical compositions of the invention and their use may be systemic and/or topical. For this purpose, it may be administered in a suitable manner, for example, orally, transpulmonarily, nasally, transdermally or transdermally.

Suitable for oral administration are EP2 receptor antagonists and COX inhibitors of the general formula (I) according to the invention which are suitable and comprise crystalline and/or amorphized and/or dissolved forms as described in the prior art. In the form of a tablet, such as a lozenge (uncoated lozenge or coated lozenge, for example having an enteric coating or coating or insoluble coating which dissolves in a delayed manner, which controls the release of the compound of the invention), Tablets or films/powders, films/lyophiles, capsules (such as hard or soft gelatin capsules), dragees, powders, granules, pellets, powders, emulsions, suspensions, aerosols or solutions that dissolve rapidly in the mouth. .

It is also possible to use a liquid form, such as in the form of a syrup, to which a sweetener is added as appropriate. Also, for the oral use of these compounds, a cage compound is also suitable, and for example, a cage compound having α, β or γ cyclodextrin or other β-hydroxypropyl cyclodextrin may be mentioned.

Suitable for other routes of administration are, for example, inhaled pharmaceutical forms (especially powder inhalers, inhalation sprays), nasal drops, solutions, sprays; tablets, sublingual or buccal administration, film/ Powder or capsule; suppository; otic or ophthalmic preparation; aqueous suspension (lotion, turbulent mixture); lipophilic suspension; ointment; cream; transdermal therapeutic system (eg patch); milk; Foam or powder (for spraying).

The pharmaceutical compositions of the invention can be converted to the form of administration. This can be carried out in a manner known per se by mixing with inert, non-toxic pharmaceutically suitable auxiliaries. Such auxiliaries include, inter alia, carriers (eg microcrystalline cellulose, lactose, mannitol), solvents (eg liquid polyethylene glycol), emulsifiers and dispersing or wetting agents (eg sodium lauryl sulfate, poly Oxysorbitol oleate), binders (such as polyvinylpyrrolidone), synthetic and natural polymers (such as albumin), stabilizers (such as antioxidants such as ascorbic acid), colorants (such as inorganic pigments, such as Iron oxide) and taste and / or olfactory correcting agents.

It optionally contains additives which are intended, for example, to act as fillers, binders, disintegrants, lubricants, solvents, solution mediators, taste masking agents, colorants or emulsifiers. The types of additives in the sense of the invention are, for example, saccharides (monosaccharides, disaccharides, trisaccharides, oligosaccharides and/or polysaccharides), fats, waxes, oils, hydrocarbons, anions, nonionics, cations, natural, synthetic or semi Synthetic surfactant. Further, it optionally contains an additive such as a preservative, a stabilizer, a wetting agent or an emulsifier; a salt or a buffer for changing the osmotic pressure.

Investment plan

The present invention further provides a regimen for emergency contraception wherein a single dose administration comprises at least one of the above-mentioned lists (a list of up to 120 hours, preferably up to 72 hours after sexual intercourse) A COX inhibitor of C1 to C17) and at least one pharmaceutical composition according to the EP2 receptor antagonist of the formula (I).

In general, for pharmaceutical compositions, the dosage can be administered in a single dosage form or divided into two or more partial doses. A partial dose may be distributed under this condition for a period of up to 120 hours, preferably 72 hours, after unprotected sexual intercourse.

Process for producing a compound of the invention having the formula:

The following description of the production process is contained in the patent application PCT/EP2012/073556, which is hereby incorporated by reference.

In this regard, for example, a carboxylic acid of formula VIII is reacted with an amine of formula XI by methods known to those skilled in the art to obtain a compound of the invention of formula I (Scheme 1).

This reaction occurs because, for example, the carboxylic acid of formula VIII and isobutyl chloroformate are converted to a mixed anhydride in the presence of a tertiary amine such as triethylamine, which is at -30 ° C with the alkali metal salt of the appropriate amine XI. Reaction with an inert solvent or solvent mixture such as tetrahydrofuran, N,N-dimethylformamide or dimethoxyethane at a temperature between +60 ° C to obtain the target compound of formula I.

It is also possible to use, for example, dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N-hydroxybenzotriazole ( HOBT) or N-[(dimethylamino)-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N hexafluorophosphate - A reagent of methylmethylammonium (HATU) activates the carboxylic acid VIII. For example, in the presence of a suitable amine XI and a tertiary amine such as triethylamine or diisopropylamine in an inert solvent such as N,N-dimethylmethyl at a temperature between -30 ° C and +60 ° C The reaction with HATU occurs in guanamine or dimethyl hydrazine.

It is also possible to convert the carboxylic acid of formula VIII to the corresponding carboxylic acid chloride by means of a mineral acid chloride such as phosphorus pentachloride, phosphorus trichloride or sulphide chloride and then between -30 ° C and +60 ° C Conversion to the target compound of formula I in the presence of the appropriate amine XI and a tertiary amine such as triethylamine in pyridine or an inert solvent such as N,N-dimethylformamide.

It can also be used at a temperature between 80 ° C and 160 ° C (as appropriate with microwave irradiation between 80-200 watts) (and in the case of carbon monoxide, at a CO pressure of 5-15 bar) Catalyzed by palladium (0) with a suitable amine XI and a carbon monoxide (CO) or carbon monoxide source, such as molybdenum hexacarbonyl, in a suitable solvent or solvent mixture, such as 1,4-dioxane/water or tetrahydrofuran, such as carbonic acid a base of sodium or 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) and, for example, palladium(II) acetate or trans-bis(acetate) bis[o(di-o-tolylphosphine) Compound of the invention of formula I is obtained from a bromocarbazole of formula VI by a catalyst-ligand mixture of benzyl]di-palladium(II)/trifluoroborate tributylphosphonate (Scheme 1) .

The carboxylic acid (Y=OH), chloride (Y=Cl) or anhydride (e.g., Y=OC(O)-O-CH) of formula IX can also be used in the manner described for the production of compound I from compounds VIII and XI. ₂ (CH) ₃ CH ₃ ) The compound of the invention of formula I is obtained from the amine of formula XV (Scheme 2).

Likewise, a compound of formula I can be obtained by reacting a compound of formula XVIII from a compound of formula XVI wherein LG' means, for example, Br or I (Scheme 2).

The compound of formula XVIII is, for example, a (hetero)aryl group Acid (R ³ -Met=(Het)Ar-B(OH) ₂ ) or Tetramethylethylene glycolate (R ³ -Met=(Het)Ar-BPin), which is at a temperature between 20 ° C and 120 ° C in a suitable solvent by methods known to those skilled in the art, for example N,N-dimethylformamide, tetrahydrofuran, dimethoxyethane and optionally in water with the addition of a base such as triethylamine, potassium carbonate, cesium carbonate and a catalyst-ligand mixture such as palladium acetate (II)/Triphenylphosphine, bis(diphenylphosphino)ferrocene palladium(II) chloride/(1,1'-bis(diphenylphosphino)ferrocene/copper (I) Conversion to the biaryl compound of formula I by Cl).

The compound of formula XVIII may also be a (hetero)aryl alcohol (R ³ -Met=(Het)ArO-H) which is at a temperature between 60 ° C and 120 ° C by methods known to those skilled in the art. Adding a base such as potassium carbonate or cesium carbonate (under copper-(I) catalysis, for example by copper (I) bromide) in a suitable solvent such as N,N-dimethylformamide or two Conversion to a aryl ether of formula I in methyl hydrazine.

It can be mixed, for example, at a temperature between 20 ° C and 60 ° C with an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide by a suitable solvent or solvent. The carboxylic acid of the formula VIII is obtained by saponification of an ester such as methanol, ethanol or tetrahydrofuran or water from the ester of the formula VII (Scheme 1).

In the same manner, the carboxylic acid XIII can be obtained from the ester XII (Scheme 2, PG: for example Boc (tert-butyloxycarbonyl) and the carboxylic acid XXI can be obtained from the ester XX (Scheme 3, LG': eg Br or I) .

The ester of formula VII can be at a temperature between 20 ° C and 140 ° C (optional microwave irradiation between 80-200 watts as needed) (and in the case of carbon monoxide, 5-15 bar CO) Under pressure, in a suitable solvent, such as dimethyl hydrazine, N, N-dimethylformamide or tetrahydrofuran and adding a base such as triethylamine or 1,8-diazabicyclo (5.4.0) Undec-7-ene and catalyst-ligand mixtures, such as palladium(II) acetate/bis1,3-diphenylphosphino-propane or trans-bis(acetate) bis[o-(di-o-tolylphosphine) Benzophenyl]dipalladium(II)/tris-tert-butylphosphine tetrafluoroborate reacted with a carbon monoxide or carbon monoxide source, such as hexacarbonyl molybdenum and methanol, under palladium (0) catalysis from bromocarbazole of formula VI Obtained (Process 1).

This method is not limited to methyl esters, that is, methanol is used, and it is also possible to extend to other esters. Thus, for example, by using ethanol instead of methanol in this manner, the corresponding ethyl ester can be synthesized.

In the same manner, ester XII can be obtained from bromide IV (Scheme 2, -PG: for example -Boc).

The guanamine of the formula VII can also be obtained from an amine of the formula XIX by reacting a compound of the formula IX (Scheme 2) with a compound of the formula IX (Scheme 3).

The compound of formula VII can also be obtained from the compound of formula XVI to the conversion of compound of formula X (Scheme 2) and from the compound of formula XVIII (Scheme 3) from the compound of formula XX.

The guanamine of the formula VI can be reacted with a carboxylic acid (Y=OH), a chloride (Y=Cl) or an anhydride of the formula IX as described in relation to the conversion of the amine XV to the guanamine I (Scheme 2) (for example Y= The OC(O)-O-CH ₂ (CH) ₃ CH ₃ ) reaction (Scheme 1) is obtained from an amine of formula V.

The indoleamine of the formula XVI can be similarly derived from the amine XV and the carboxylic acid or the carboxylic acid derivative XVII (Y: eg OH, Cl or OC(O)-O-CH ₂ (CH) ₃ CH ₃ ; LG': eg Br Or I) get (flow 2).

Similarly, the amine XX (LG': for example Br or I) can be derived from the amine XIX and the carboxylic acid or the carboxylic acid derivative XVII (Y: eg OH, Cl or OC(O)-O-CH ₂ (CH) ₃ CH ₃ ; LG': for example Br or I) is obtained (flow 3).

Also, in this manner, the carboxylic acid XIII (PG: for example, Boc) can be converted to the guanamine XIV by the amine XI (Scheme 2), and the carboxylic acid XXI (LG': for example, Br, I) can be converted to Indoleamine XVI (Scheme 3).

The secondary amine V can be obtained from the corresponding carbamate IV (PG: e.g., Boc) by methods known to those skilled in the art (Scheme 1).

Thus, for example, the third butyl carbamate can be used in an acidic medium by using, for example, trifluoroacetic acid or hydrochloric acid in a suitable solvent or solvent mixture such as dichloromethane, dioxane or acetone/water. Conversion to the amine V. In an anhydrous medium, the amine V is formed as a corresponding salt.

Similarly, the amine XV can be obtained from the carbamate XIV (Scheme 2) and the amine XIX can be obtained from the carbamate XII (Scheme 3).

2H -carbazoles of the formula IV and VI can be produced in a variety of ways.

For example, 2H -carbazole IV can be suitably used at a temperature between 25 ° C and 100 ° C (or in the case of sodium bis(trimethyldecyl) amination, between 0 ° C and 25 ° C). a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylhydrazine or THF, 1,4-dioxane and a base such as potassium carbonate or carbonic acid铯 (addition of tetrabutylammonium iodide as needed) or sodium bis(trimethyldecyl)amide by compound with formula III (PG: eg Boc, LG: eg Br, I, O-Ts (toluene) The alkylation of decyloxy) or O-Ms (methylsulfonyloxy)) is obtained from 1H-carbazole of formula II (Scheme 1).

Similarly, 2H -carbazole of formula VI can be obtained from 1H-carbazole of formula II and compounds of formula X (LG: such as Br, I, O-Ts or O-MS) (Scheme 1).

2H -carbazole of the formula IV can also be obtained by adding a reducing agent such as triethyl phosphite in a suitable solvent such as 1,4-dioxane at a temperature between 100 ° C and 160 ° C (possibly Obtained with o-nitrobenzaldehyde of the formula XXVII by reaction with an appropriate amine XXVIII (PG: eg Boc) with the addition of potassium carbonate or cesium carbonate or a powdered molecular sieve (Scheme 4).

Similarly, 2H -carbazole of formula VI can be obtained from o-nitrobenzaldehyde XXVII by reaction with amine XXIX (Scheme 4).

The compound of the formula XIV (PG: for example Boc) can also be obtained by a process analogous to that relating to the conversion of bromocarbazole VI to a compound of the formula I (Scheme 1) with a suitable amine XI and a carbon monoxide or carbon monoxide source, such as The hexacarbonyl molybdenum reaction (Scheme 2) is obtained from palladium(0) catalyzed from bromo-carbazole of the formula IV (PG: eg Boc).

The o-nitrobenzaldehyde of the formula XXVII can be produced from the o-nitrotoluene of the formula XXVI in two reaction steps by a method known to those skilled in the art (Scheme 4).

In this regard, o-nitrotoluene XXVI is dissolved in a suitable solvent such as N,N-dimethylformamide and at a temperature of 100-140 ° C by N,N-dimethylformamide Conversion of the acetal to the corresponding enamine, which is followed by a suitable aqueous solvent mixture such as water/N,N-dimethylformamide and optionally a base such as triethylamine, N,N-di Propylethylamine, sodium bicarbonate or sodium carbonate is oxidized to the corresponding o-nitrobenzaldehyde by a suitable oxidizing agent such as NaIO ₄ at a temperature between 0 ° C and 20 ° C.

The o-nitrotoluene of formula XXVI can be produced from o-toluidine of formula XXV by a method known to those skilled in the art (Scheme 4).

In this regard, o-toluidine XXV is dissolved in a suitable solvent such as dichloromethane or chloroform, treated with zirconium tert-butoxide (IV), ground molecular sieve 3Å and tributyl hydroperoxide and at 20- The reaction was carried out at a temperature of 40 °C.

The 1H-carbazole of formula II can be released from the acetamide of formula XXIV by methods known to those skilled in the art (Scheme 4).

In this connection, for example, the acetamide XXIV is reacted at a temperature of 40 to 80 ° C in a suitable solvent such as methanol or ethanol with the addition of 37% hydrochloric acid.

Similarly, the aniline of formula XXV can be released from the acetophenone of formula XXIII (Scheme 4).

The indoleamine of formula XXIV can be produced from o-methylacetanilide of formula XXIII by a method known to those skilled in the art (Scheme 4).

In this regard, o-methylacetanilide XXIII is dissolved in a suitable solvent such as chloroform or toluene with acetic anhydride, isoamyl nitrite or butyl nitrite and, if appropriate, potassium acetate and 18 - Crown-6 treatment and reaction at a temperature of 60-100 °C.

o-Methylacetanilide XXIII can be produced from acetophenone of formula XXII by bromination by methods known to those skilled in the art (Scheme 4).

In this connection, acetanilide XXII (which can be obtained, for example, by reaction with acetic anhydride at a temperature of 80-110 ° C in a suitable solvent (for example toluene) from the corresponding aniline) and bromine at a temperature of 10-25 ° C. Reacted in glacial acetic acid.

Compounds of formula III wherein LG means -OTs or -OMs can be produced from the corresponding alcohol by methods known to those skilled in the art.

In this connection, the alcohol is mixed with p-toluenesulfonyl chloride or methanesulfonate chloride at a temperature between 0 ° C and 40 ° C in a suitable solvent such as dichloromethane or tetrahydrofuran or toluene and a suitable base such as pyridine or Triethylamine is reacted.

Compounds of formula X (wherein LG means -OTs or -OMs) can be produced from the corresponding amino alcohol XXX (Scheme 4) by methods known to those skilled in the art.

In this connection, in the first step, the amino alcohol XXX is subjected to the formula Cl-C(O)-Ar-R ³ in a suitable solvent such as dichloromethane at a temperature between 0 ° C and 25 ° C. The aryl carboxylic acid chloride is converted to the corresponding guanamine XXXI by the addition of a suitable base, such as triethylamine. If desired, the corresponding ester formed as a by-product may be isolated or otherwise saponified to the corresponding alcohol XXXI under standard conditions, for example by use in a suitable solvent mixture, such as ethanol/water, at a temperature between 20 ° C and 40 ° C. A base such as potassium hydroxide.

The N-protected alcohol XXXI thus obtained can be converted into a compound of the formula X having LG:-OTs or -OMs analogously to the process described for the synthesis of compound III. The compound of formula X having LG:-Br can be added as an oxophilic agent by a method known to those skilled in the art by adding a PPh ₃ at a temperature between 20 ° C and 40 ° C with a brominating agent such as CBr ₄ . In the case of a suitable solvent such as chloroform, it is obtained from the corresponding alcohol XXXI.

Compounds of formula XXIX can be produced by methods known to those skilled in the art, for example, from amines of formula XXXII (Scheme 4).

In this regard, in the first step, the amine XXXII is converted to the corresponding guanamine XXXIII analogously to the synthesis of the compound I from the compound XV.

The third butyloxycarbonyl group in the compound of the formula XXXIII is cleaved similarly to the conversion of the compound IV to the compound V, whereby a compound of the formula XXIX can be obtained.

Process 2

Process 4

Production of the compounds of the invention

The following description of the production of the compounds of the present invention is included in the patent application PCT/EP2012/073556, which is hereby incorporated by reference.

The following examples illustrate the production of the compounds of the invention of formula (I) without limiting the scope of the claimed compounds to such examples.

The compounds of the invention of formula (I) can be prepared and characterized as described below.

LC-MS: Waters Acquity HPLC/MS 100-800 Dalton (Dolton); 20 V (Micromass/Waters ZQ 4000); Column: BEHC 18 (Waters), 2.1×50 mm, BEH 1.7 μm; Action Phase: A: H ₂ O/0.05% HCOOH, B: CH ₃ CN/0.05% HCOOH. Gradient: 10-90% B in 1.7 min, 90% B for 0.2 min, 98-2% B in 0.6 min; flow rate: 1.3 ml/min, detection: UV = 200-400 nm.

For palm HPLC separation method A: Preparative palmar HPLC: System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 Column: Chiralpak AD-H 5 μm 250 x 20 mm; Solvent: Hexane/Ethanol 50: 50; flow rate: 15 ml / min; injection volume: 0.5 ml; detection: UV 254 nm.

Analytical versus palm HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak AD-H 5 μm 150 x 4.6 mm Solvent: hexane/ethanol 50:50; flow rate: 1.0 ml/min ; temperature: 25 ° C; injection: 5 μl; detection: DAD 254 nm.

For palm HPLC separation method B: preparative palmitic HPLC: system: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 column: Chiralpak IC 5 μm 250 × 30 mm; solvent: Ethanol/methanol 50:50; flow rate: 30 ml/min; injection volume: 0.5 ml; detection: UV 254 nm.

Analytical versus palm HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak IC 5 μm 150 x 4.6 mm Solvent: ethanol/methanol 50:50; flow rate: 1.0 ml/min; 25 ° C; injection: 5 μl; detection: DAD 254 nm.

For palmar HPLC separation method C: preparative palmitic HPLC: system: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 column: Chiralpak AD-H 5 μm 250 × 20 mm; Solvent: hexane/2-propanol 50:50; flow rate: 15 ml/min; injection volume: 0.25 ml; detection: UV 254 nm.

Analytical versus palm HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak AD-H 5 μm 150 x 4.6 mm Solvent: Hexane/2-propanol 50:50; Flow rate: 1.0 Ml/min; temperature: 25 ° C; injection: 5 μl; detection: DAD 254 nm.

For palmar HPLC separation method D: preparative palmitic HPLC: system: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 column: Chiralpak IB 5 μm 250 × 20 mm; solvent: Hexane/ethanol 70:30; flow rate: 20 ml/min; injection volume: 0.1 ml; detection: UV 210 nm.

Analytical versus palm HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak IB 5 μm 150 x 4.6 mm Solvent: hexane/ethanol 70:30; flow rate: 1.0 ml/min; : 25 ° C; injection: 5 μl; detection: DAD 230 nm.

For palm HPLC separation method E: preparative palmitic HPLC: system: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 column: Chiralpak IC 5 μm 250 × 20 mm; solvent: Ethanol/methanol 50:50; flow rate: 15 ml/min; injection volume: 0.3 ml; detection: UV 230 nm.

Analytical versus palm HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak IC 5 μm 150 x 4.6 mm Solvent: ethanol/methanol 50:50; flow rate: 1.0 ml/min; 25 ° C; injection: 5 μl; detection: DAD 230 nm.

abbreviation

Example 1 : 2-{[1-(4-Cyano-2-fluorobenzylidenyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

To 33.7 mg of 4-cyano-2-fluorobenzoic acid in 1.0 ml of dimethyl hydrazine, 85.5 mg of HATU, 75 mg of the amine prepared in Example 1a and 0.071 ml of N,N-diisopropylethylamine were added. This was stirred at 25 ° C for 1 hour. The mixture was concentrated in vacuo and the residue thus obtained was purified by HPLC. Yield: 43.3 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.07-1.28 (2H), 1.30- 1.44 (1H), 1.47-1.61 (1H), 2.18-2.34 (1H), 2.49 (3H) , 2.71-2.83 (1H), 2.92-3.08 (1H), 3.32 (4H), 3.36 (2H), 3.42 (2H), 4.31 (2H), 4.39-4.51 (1H), 7.14 (1H), 7.38 (1H) ), 7.50-7.63 (1H), 7.71-7.79 (1H), 7.95 (1H), 8.09-8.15 (1H), 8.47 (1H).

The starting materials of the above title compounds were prepared as follows:

Example 1a : N-(2-methoxyethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

To 855.1 mg of 1b was added 4.5 ml of 4 M hydrochloric acid in dioxane and 1 ml of dioxane. An oily mass is formed which dissolves upon vigorous agitation and gentle warming. The mixture was stirred at about 30 ° C for 1 hour. The reaction mixture was concentrated. Yield: 764.7 mg of the title compound, which was further purified without further purification.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.33-1.50 (2H), 1.52-1.62 (2H), 2.17-2.31 (1H), 2.32-2.38 (1H), 2.49 (3H) , 2.67-2.86 (2H), 3.13 - 3.28 (5H), 3.31-3.46 (4H), 4.33 (2H), 7.16 (1H), 7.38 (1H), 8.13 (1H), 8.53 (1H), 8.71-8.88 (1H), 8.99-9.11 (1H).

Example 1b : 4-({5-[N-(2-methoxyethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidin-1- Tert-butyl formate

Version A: 2820 mg 1c, 1556 mg 2-methoxyethylamine, 1823 mg hexacarbonyl molybdenum, 200.4 mg tetrafluoro Acid tri-tert-butylphosphine and 647.5 mg of anti-bis(acetate)-bis[o-(tert-tolylphosphino)benzyl]dipalladium (II) were placed in three microwave tubes and suspended in 56 ml of THF. . Subsequently, 3.1 ml of DBU was added and the mixture was stirred in a microwave at 125 ° C and 200 watts for 20 minutes. The reaction mixture was combined, filtered and diluted with EtOAc EtOAc. This was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP4. Gradient: ethyl acetate / methanol 0-10%. Yield: 885.1 mg of the title compound.

Version B: 780 mg 1d and 1747 mg HATU were first dissolved in 10 ml DMSO. Then, 314 mg of 2-methoxyethylamine and 1080 mg of N,N-diisopropylethylamine were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium The residue was purified by chromatography on Biotage SP4. Gradient: ethyl acetate / methanol 0-10%. Yield: 740 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.01-1.13 (2H), 1.34 (9H), 1.36-1.43 (2H), 2.06-2.19 (1H), 2.49 (3H), 2.59 -2.70 (2H), 3.29 (3H), 3.33-3.39 (2H), 3.40-3.45 (2H), 3.82-3.93 (2H), 4.28 (2H), 7.14 (1H), 7.38 (1H), 8.09-8.14 (1H), 8.46 (1H).

Example 1c : 4-[(5-Bromo-4-methyl-2H-indazol-2-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester

5 g of 5-bromo-4-methyl-1H-indazole was dissolved in 110 ml of DMF and treated with 11.5 g of cesium carbonate and 7.9 g of N-Boc-4-(bromomethyl)piperidine. The mixture was stirred at 60 ° C for 3 hours and at room temperature overnight. The reaction mixture was then diluted with EtOAc (EtOAc)EtOAc. The residue was chromatographed on a Biotage SP4 by means of a 65i-Si column. Gradient: hexane/ethyl acetate 0-100%. Yield: 3.53 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 0.99-1.12 (2H), 1.34 (9H), 1.36-1.44 (2H), 2.04-2.19 (1H), 2.47 (3H), 2.54 -2.72 (2H),

3.82-3.93 (2H), 4.27 (2H), 7.29 (1H), 7.34 (1H), 8.46 (1H).

Example 1d : 2-{[1-(Tertibutoxycarbonyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxylic acid

1080 mg of 1e was dissolved in 8 ml of methanol and treated with 1235 mg of lithium hydroxide in 10 ml of water. An additional 2 ml of THF was added as a solubilizer. The mixture was stirred at room temperature for 24 hours. Subsequently, methanol and THF were distilled off. The aqueous residue was diluted with water and washed once with ethyl acetate. The aqueous phase was acidified with 10% sulfuric acid and extracted twice with ethyl acetate. The combined organic phases were dried with sodium sulfate, filtered and evaporated. Yield: 880 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 0.99-1.18 (2H), 1.37-1.48 (2H), 1.34 (9H), 2.05-2.21 (1H), 2.53-2.70 (2H) , 2.73 (3H), 3.81-3.94 (2H), 4.29 (2H), 7.39 (1H), 7.62 (1H), 8.62 (1H), 11.92-12.31 (1H).

Example 1e : methyl 2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl)}-4-methyl-2H-indazole-5-carboxylate

666 mg 1c, 156.8 mg methanol, 645.8 mg molybdenum hexacarbonyl, 47.3 mg tetrafluoro Acid tri-tert-butylphosphine and 123.5 mg of trans-bis(acetate)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) were placed in a microwave tube and suspended in 15 ml of THF. Subsequently, 0.7 ml of DBU was added and the mixture was stirred in a microwave at 125 ° C and 150 watts for 20 minutes. Then, it was concentrated, dissolved in ethyl acetate and the organic phase was washed twice with water and once with a saturated sodium chloride solution. It was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP4. Gradient: hexane/ethyl acetate 0-100%. Yield: 363 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.01-1.12 (2H), 1.34 (9H), 1.37-1.45 (2H), 2.08-2.19 (1H), 2.53-2.69 (2H) , 2.73 (3H), 3.79 (3H), 3.83-3.93 (2H), 4.30 (2H), 7.42 (1H), 7.62 (1H), 8.67 (1H).

Example 2 : 2-({1-[4-Thr-(butoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

Analogously to Example 1, 35.9 mg of the title compound was obtained from 75 mg of the amine of Example 1a and 39.7 mg of 4-(t-butoxy)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.09-1.26 (2H), 1.29 (9H), 1.35-1.58 (2H), 2.15-2.35 (1H), 2.49 (3H), 2.69 - 2.97 (2H), 3.24 (3H), 3.32-3.47 (4H), 4.23-4.40 (2H), 6.98 (2H), 7.14 (1H), 7.23 (2H), 7.38 (1H), 8.10 (1H), 8.47 (1H).

Example 3 : 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

Analogously to Example 1, 51.6 mg of the title compound was obtained from 75 mg of the title compound of Example 1a and 47.5 mg of 4-(4-fluorophenoxy)benzoic acid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.10 - 1.30 (2H), 1.32-1.58 (2H), 2.19-2.35 (1H), 2.49 (3H), 2.71-3.02 (2H) , 3.25 (3H), 3.32 - 3.39 (2H), 3.40-3.47 (2H), 4.32 (2H), 6.95 (2H), 7.06-7.14 (3H), 7.15-7.27 (3H), 7.31-7.42 (3H) , 8.07-8.15 (1H), 8.47 (1H).

Example 4 : N-(2-methoxyethyl)-4-methyl-2-{[1-(4-(N-morpholinyl)benzylidene)piperidin-4-yl]methyl }-2H-carbazole-5-carboxamide

Analogously to Example 1, 48.1 mg of the title compound was obtained from 75 mg of the compound of Example 1a and 42.3 mg of 4-(N-morpholinyl)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=1.09-1.29 (2H), 1.36-1.53 (2H), 2.16-2.34 (1H), 2.49 (3H), 2.72-2.94 (2H) , 3.13 (4H), 3.24 (3H), 3.42 (4H), 3.64-3.75 (4H), 3.92-4.15 (1H), 4.32 (2H), 6.92 (2H), 7.14 (1H), 7.20 (2H), 7.38 (1H), 8.07-8.15 (1H), 8.47 (1H).

Example 5 : 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4- methyl-2H-carbazole-5-carbamide

Analogously to Example 1, 50.1 mg of the title compound was obtained from 75 mg of the compound of Example 1a and 44.2 mg of 4-(4-fluorophenyl)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.11-1.32 (2H), 1.32-1.64 (2H), 2.20-2.36 (1H), 2.49 (3H), 2.63-3.08 (2H) , 3.24 (3H), 3.42 (4H), 3.50-3.73 (1H), 4.24 - 4.55 (3H), 7.10-7.20 (1H), 7.27 2H), 7.41 (3H), 7.67 (4H), 8.03-8.16 ( 1H), 8.48 (1H).

Example 6 : 2-{[1-(2-Fluoro-4-methylsulfonylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

Analogously to Example 1, 40.1 mg of the title compound was obtained from 75 mg of the title compound of Example 1a and 44.6 mg of 2-fluoro-4-methanesulfonylbenzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.06-1.30 (2H), 1.31-1.45 (1H), 1.51-1.64 (1H), 2.20-2.37 (1H), 2.49 (3H) , 2.71-2.85 (1H), 2.91-3.10 (1H), 3.24 (3H), 3.26 (3H), 3.33-3.39 (2H), 3.42 (2H), 4.24-4.39 (2H), 4.40-4.51 (1H) , 7.14 (1H), 7.38 (1H), 7.59-7.69 (1H), 7.76-7.89 (2H), 8.07-8.14 (1H), 8.47 (1H).

Example 7 : 2-{[1-(2-Fluoro-4-methoxybenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2-H-carbazole-5-carbamide

Analogously to Example 1, 43.1 mg of the title compound was obtained from 75 mg of the compound of Example 1a and 34.8 mg of 2-fluoro-4-methoxybenzoic acid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.05-1.25 (2H), 1.32-1.44 (1H), 1.48-1.61 (1H), 2.18-2.33 (1H), 2.49 (3H) , 2.63-2.79 (1H), 2.88-3.05 (1H), 3.24 (3H), 3.42 (d, 5H), 3.75 (3H), 4.27-4.35 (2H), 4.37-4.49 (1H), 6.77-6.89 ( 2H), 7.14 (1H), 7.24 (1H), 7.38 (1H), 8.07-8.15 (1H), 8.47 (1H).

Example 8 : 2-{[1-(4-Bromo-2-fluorobenzylidinyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

Analogously to Example 1, 51.8 mg of the title compound was obtained from 75 mg of the compound of Example 1a and 44.7 mg of 4-bromo-2-fluorobenzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.04-1.27 (2H), 1.32-1.43 (1H), 1.49-1.61 (1H), 2.20-2.33 (1H), 2.48 (3H) , 2.67-2.80 (1H), 2.91-3.05 (1H), 3.24 (3H), 3.33-3.46 (5H), 4.24-4.36 (2H), 4.38-4.49 (1H), 7.15 (1H), 7.27-7.34 ( 1H), 7.35-7.41 (1H), 7.44-7.50 (1H), 7.60-7.66 (1H), 8.07-8.15 (1H), 8.47 (1H).

Example 9 : 2-{[1-(2-Fluoro-4-methylbenzylidenyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

Analogously to Example 1, 38.3 mg of the title compound was obtained from 75 mg of the compound of Example 1a and 31.5 mg of 2-fluoro-4-methylbenzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.04-1.26 (2H), 1.31-1.43 (1H), 1.48-1.60 (1H), 2.18-2.35 (4H), 2.48 (3H) , 2.64-2.79 (1H), 2.89-3.04 (1H), 3.24 (3H), 3.33-3.39 (3H), 3.39-3.45 (2H), 4.23-4.36 (2H), 4.39-4.49 (1H), 7.01- 7.10(2H), 7.13(1H), 7.16-7.24(1H), 7.38(1H), 8.07-8.14(1H), 8.47(1H).

Example 10 : 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 57.8 mg of the title compound was obtained from 75 mg of the compound of Example 1a and 42.5 mg of 2-fluoro-4-(trifluoromethyl)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.07-1.29 (2H), 1.32-1.44 (1H), 1.52-1.62 (1H), 2.20-2.36 (1H), 2,49 ( 3H), 2.67-2.84 (1H), 2.93-3.07 (1H), 3.24 (3H), 3.32-3.39 (3H), 3.39-3.46 (2H), 4.24-4.39 (2H), 4.40-4.51 (1H), 7.14 (1H), 7.38 (1H), 7.56-7.68 (2H), 7.76 (1H), 8.07-8.14 (1H), 8.47 (1H).

Example 11 : N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]piperidin-4-yl }methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1, 135.1 mg of the title compound was obtained from 150 mg of the compound of Example 1a and 101.5 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.10-1.30 (2H), 1.31-1.42 (1H), 1.50-1.62 (1H), 2.20-2.33 (1H), 2.49 (3H) , 2.67-2.83 (1H), 2.91-3.06 (1H), 3.24 (3H), 3.32-3.39 (2H), 3.41 (3H), 4.32 (2H), 4.37-4.48 (1H), 7.14 (1H), 7.38 (1H), 7.55 (2H), 7.94 (2H), 8.12 (1H), 8.47 (1H).

The following compounds were prepared similarly:

Example 55 : N-(2-Methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

150 mg of the amine prepared in Example 1a was first dissolved in 1.5 ml of pyridine. Then 101 mg of 4-(trifluoromethoxy)benzimidium chloride was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then treated with some toluene and concentrated. The residue was dissolved in ethyl acetate and washed twice with water, twice with saturated sodium hydrogen carbonate (pH 9) and once with saturated sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on Biotage SP4. Gradient: ethyl acetate / methanol 0-10%. Yield: 118.2 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.17 - 1.30 (2H), 1.30 - 1.45 (1H), 1.45-1.62 (1H), 2.19 - 2.35 (1H), 2.49 (3H) , 2.64-2.86 (1H), 2.86-3.07 (1H), 3.24 (3H), 3.31-3.56 (5H), 4.31 (2H), 4.36- 4.49 (1H), 7.14 (1H), 7.35-7.42 (3H) , 7.43-7.50 (2H), 8.11 (1H), 8.47 (1H).

Example 56 : 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-formamide

Analogously to Example 55, 183 mg of the title compound was obtained from 300 mg of the compound of Example 1a and 157.4 mg of 4-chlorobenzamide.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.10-1.29 (2H), 1.29-1.43 (1H), 1.44-1.61 (1H), 2.20-2.34 (1H), 2.49 (3H) , 2.66-2.83 (1H), 2.84-3.06 (1H), 3.25 (3H), 3.32-3.39 (2H), 3.40-3.45 (2H), 3.45-3.55 (1H), 4.26-4.35 (2H), 4.35- 4.46(1H), 7.14(1H), 7.32-7.41(3H), 7.47(2H), 8.09-8.15(1H), 8.47(1H).

Example 57 : N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidene]piperidin-4-yl )methyl]-2H-carbazole-5-carboxamide

60 mg of the amine prepared in Example 1a was first dissolved in 2 ml of DCM at 0 °C. Subsequently, 0.034 ml of triethylamine and 43.2 mg of 4-[(trifluoromethyl)thio]benzamide chloride were added and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was then diluted with DCM and washed with 1 M aqueous hydrochloric acid, saturated sodium hydrogen carbonate (pH 9) and saturated sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on Biotage SP4. Gradient: DCM/methanol 0-10%. Dissolve the product in ethyl acetate and saturate The sodium bicarbonate solution was extracted twice. The organic phase was concentrated and the residue was purified again by HPLC. Yield: 26.5 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14-1.30 (2H), 1.31-1.42 (1H), 1.49-1.61 (1H), 2.21-2.32 (1H), 2.49 (3H) , 2.67-2.80(1H), 2.93-3.05(1H), 3.25(3H), 3.36(2H), 3.42(3H), 4.27-4.36(2H), 4.38-4.48(1H), 7.14(1H), 7.38 (1H), 7.48 (2H), 7.75 (2H), 8.09-8.14 (1H), 8.47 (1H).

Example 58 : 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2-(N -morpholinyl)ethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 34.6 mg of the title compound was obtained from 75 mg of the title compound of Example 58a and 37.0 mg of 2-fluoro-4-(trifluoromethyl)benzoic acid.

¹ H-NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.24-1.43 (2H), 1.50-1.59 (1H), 1.65-1.73 (1H), 2.33 - 2.45 (1H), 2.65 (3H) , 2.80-2.91 (1H), 3.05-3.18 (1H), 3.19-3.26 (2H), 3.39-3.44 (2H), 3.45-3.52 (1H), 3.63-3.70 (2H), 3.71-3.82 (4H), 4.06-4.14(2H), 4.39(2H), 4.62-4.70(1H), 7.39(1H), 7.47(1H), 7.54-7.62(3H), 8.45(1H).

The starting materials were prepared as follows:

Example 58a : 4-Methyl-N-(2-(N-morpholinyl)ethyl)-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

Add 2.9 ml of 4 M hydrochloric acid and 0.5 ml dioxane to 624.4 mg 58b alkyl. An oily mass is formed which dissolves upon vigorous agitation and gentle warming. The mixture was stirred at about 30 ° C for 1 hour. The reaction mixture was concentrated. Yield: 980 mg of the title compound, which was taken further without further purification.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.33-1.51 (2H), 1.58-1.64 (1H), 2.17-2.31 (1H), 2.55 (3H), 2.70-2.86 (2H) , 3.02-3.31 (7H), 3.43-3.51 (2H), 3.61-3.71 (2H), 3.72-3.88 (3H), 3.89-3.99 (2H), 4.30-4.36 (2H), 7.29 (1H), 7.40 ( 1H), 8.46-8.52 (1H), 8.54-8.58 (1H), 8.69-8.85 (1H), 8.96-9.10 (1H).

Example 58b : 4-({4-Methyl-5-[N-(2-(N-morpholinyl)ethyl)aminemethanyl]-1H-indazol-2-yl}-methyl)piperidin Pyridin-1-carboxylic acid tert-butyl ester

896 mg 1c, 857 mg 2-(N-morpholinyl)ethylamine, 579.3 mg hexacarbonyl molybdenum, 63.6 mg tetrafluoro Acid tri-tert-butylphosphine and 205.8 mg of trans-bis(acetate)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) were placed in a microwave tube and suspended in 18 ml of THF. Then 1.0 ml of DBU was added and the mixture was stirred in a microwave at 125 ° C and 200 watts for 20 minutes. The reaction mixture was diluted with some ethyl acetate and filtered first over Celite. The filtrate was diluted with ethyl acetate and the organic phase was washed twice with water and once with saturated sodium chloride. It was then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP4. Gradient: ethyl acetate / methanol 0-10%. Yield: 624.4 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.98-1.13 (2H), 1.34 (11H), 2.05-2.27 (2H), 2.33-2.41 (5H), 2.51 (3H), 2.56 -2.73 (2H), 3.25-3.37 (2H), 3.51-3.57 (4H), 3.81-3.93 (2H), 4.28 (2H), 7.14 (1H), 7.36-7.41 (1H), 7.95-8.02 (1H) , 8.46 (1H).

Example 59 : 4-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Analogously to Example 55, 10.1 mg of the title compound was obtained from &lt

¹ H-NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.24-1.44 (2H), 1.44-1.58 (1H), 1.59-1.74 (1H), 2.32-2.44 (1H), 2.51-2.58 ( 4H), 2.59-2.65 (5H), 2.77-2.90 (1H), 3.02-3.17 (1H), 3.53 (2H), 3.62-3.72 (5H), 4.35-4.41 (2H), 4.55-4.67 (1H), 7.29 (1H), 7.34 (2H), 7.43 (1H), 7.49 (2H), 8.39 (1H).

Example 60 : 4-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]-periphidine Pyridin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 14.0 mg of the title compound was obtained from 75 mg of the compound of Example 58a and 44.1 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid.

¹ H-NMR (400 MHz, chloroform-d): δ [ppm] = 1.16-1.32 (1H), 1.33-1.48 (1H), 1.50-1.63 (1H), 1.71-1.83 (1H), 1.84-2.08 (2H), 2.44 (1H), 2.55 (4H), 2.60-2.71 (5H), 2.72-2.85 (1H), 2.96-3.10 (1H), 3.60 (2H), 3.67-3.78 (4H), 4.33 (2H) ), 4.71-4.81 (1H), 6.45 (1H), 7.34 (1H), 7.47 (2H), 7.54 (1H), 7.79 (2H), 7.96 (1H).

Example 61 : 4-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[3-(trifluoromethoxy)benzylidene]piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Analogously to Example 55, 18.1 mg of the title compound was obtained from <RTI ID=0.0>>

¹ H-NMR (400 MHz, chloroform-d): δ [ppm] = 1.18-1.46 (2H), 1.49-1.63 (1H), 1.66-1.82 (1H), 2.37-2.49 (1H), 2.62 (3H) ), 2.67 (3H), 2.70-2.78 (4H), 2.79-2.86 (2H), 2.93-3.09 (1H), 3.66-3.74 (2H), 3.83 (4H), 4.32 (2H), 4.66-4.82 (1H) ), 6.83-6.96 (1H), 7.23-7.29 (2H), 7.29-7.34 (1H), 7.39 (1H), 7.43 (1H), 7.54 (1H), 7.96 (1H).

Example 62 : 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-4-methyl-N-(2-(N-morpholinyl)ethyl)- 2H-carbazole-5-carboxamide

Analogously to Example 55, 14.9 mg of the title compound was obtained from &lt

¹ H-NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.24-1.42 (2H), 1.46-1.58 (1H), 1.58-1.71 (1H), 2.31-2.43 (1H), 2.63 (5H) , 2.65 (3H), 2.73-2.91 (1H), 3.00-3.15 (1H), 3.25-3.33 (2H), 3.63-3.77 (3H), 3.79-4.03 (3H), 4.38 (2H), 4.54-4.67 ( 1H), 7.38 (3H), 7.42-7.49 (3H), 8.44 (1H).

Example 63 : 4-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[4-(trifluoromethyl)benzylidene]piperidin-4-yl }methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1, 31.7 mg of the title compound was obtained from 75 mg of the title compound of Example 58a and 33.8 mg of 4-(trifluoromethyl)benzoic acid.

¹ H-NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.24-1.43 (2H), 1.45-1.57 (1H), 1.63-1.73 (1H), 2.33 - 2.45 (1H), 2.66 (3H) , 2.79-2.90 (1H), 3.04-3.17 (1H), 3.18-3.27 (2H), 3.39-3.45 (2H), 3.56-3.70 (3H), 3.76 (4H), 4.06-4.14 (2H), 4.36- 4.42 (2H), 4.59-4.68 (1H), 7.39 (1H), 7.47 (1H), 7.57 (2H), 7.73 (2H), 8.45 (1H).

Example 64 : 4-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]-periphidine Pyridin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 24.7 mg of the title compound was obtained from 75 mg of the compound of Example 58a and 44.1 mg of 3-(pentafluoro-λ ⁶ -thio)benzoic acid.

¹ H-NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.27-1.47 (2H), 1.48-1.60 (1H), 1.60-1.74 (1H), 2.31-2.46 (1H), 2.66 (3H) , 2.78-2.93 (1H), 3.04-3.18 (1H), 3.18-3.26 (2H), 3.39-3.43 (2H), 3.57-3.70 (3H), 3.72-3.82 (4H), 4.06-4.14 (2H), 4.39 (2H), 4.55-4.67 (1H), 7.38 (1H), 7.47 (1H), 7.60-7.67 (2H), 7.82-7.86 (1H), 7.89-7.94 (1H), 8.45 (1H).

Example 65 : 4-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[3-(trifluoromethyl)benzylidene]piperidin-4-yl }methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1, 14.0 mg of the title compound was obtained from 75 mg of the compound of Example 58a and 33.8 mg of 3-(trifluoromethyl)benzoic acid.

¹ H-NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.28-1.45 (2H), 1.47-1.59 (1H), 1.59-1.73 (1H), 2.32-2.45 (1H), 2.66 (3H) , 2.79-2.93 (1H), 3.05-3.18 (1H), 3.19-3.27 (2H), 3.39-3.45 (2H), 3.58-3.70 (3H), 3.72-3.82 (4H), 4.06-4.14 (2H), 4.39(2H), 4.57-4.68(1H), 7.39(1H), 7.47(1H), 7.64(2H), 7.67-7.70(1H), 7.73-7.78(1H), 8.45(1H).

The following compounds were prepared similarly:

Example 68 : N-[2-(3,3-Difluoropyrrolidin-1-yl)ethyl]-4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)) Benzyl hydrazino]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogous to Example 57, from the amine prepared in Example 68a in 266.5mg of and 150.3mg 4- (pentafluoro -λ ⁶ - thio) benzoyl chloride to obtain 61.7mg of the title compound.

¹ H-NMR (300 MHz, chloroform-d): δ [ppm] = 1.13-1.46 (2H), 1.48-1.65 (1H), 1.66-1.87 (1H), 2.26-2.50 (3H), 2.66 (3H) ), 2.71-3.23 (8H), 3.57-3.72 (3H), 4.25-4.42 (2H), 4.67-4.84 (1H), 6.40-6.61 (1H), 7.38 (1H), 7.47 (2H), 7.53 (1H) ), 7.79 (2H), 7.96 (1H).

The starting materials were prepared as follows:

Example 68a : N- [2-(3,3-Difluoropyrrolidin-1-yl)ethyl]-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5- Formamide hydrochloride

To 41.6 mg of 68b was added 1.85 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane. An oily mass is formed which dissolves upon vigorous agitation and gentle warming. The mixture was stirred at about 30 ° C for 1 hour. The reaction mixture was concentrated. Yield: 439.2 mg of the title compound, which was taken further without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.36-1.48 (2H), 1.54-1.63 (2H), 2.18-2.28 (1H), 2.40-2.45 (2H), 2.55 (3H) , 2.72-2.83 (2H), 3.14-3.22 (2H), 3.38-3.44 (2H), 3.56-3.63 (2H), 3.65-3.95 (2H), 4.11-4.21 (2H), 7.32 (1H), 7.40 ( 1H), 8.43-8.48 (1H), 8.57 (1H), 8.68-8.82 (1H), 8.96-9.07 (1H).

Example 68b : 4-[(5-{N-[2-(3,3-Difluoropyrrolidin-1-yl)ethyl]aminemethanyl}-4-methyl-2H-indazole-2- Methyl]-piperidine-1-carboxylic acid tert-butyl ester

220 mg 1c, 242.7 mg 2-(3,3-difluoro-pyrrolidin-1-yl)ethylamine, 142.2 mg hexacarbonyl molybdenum, 15.6 mg tetrafluoro Acid tri-tert-butylphosphine and 50.5 mg of trans-bis(acetate)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) were placed in a microwave tube and suspended in 4.4 ml of THF. . Then 0.24 ml of DBU was added and the mixture was stirred in a microwave at 125 ° C and 200 watts for 20 minutes. The reaction mixture was diluted with some ethyl acetate and filtered first over Celite. The filtrate was diluted with ethyl acetate and the organic phase was washed twice with water and once with saturated sodium chloride. It was dried over sodium sulfate, filtered and concentrated. The residue (209.3 mg) was chromatographed on Biotage SP4. Gradient: DCM/methanol 0-10%. Yield: 53.4 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.00 - 1.12 (2H), 1.32-1.42 (2H), 1.34 (9H), 2.07-2.25 (3H), 2.50 (3H), 2.57 (2H), 2.60-2.68 (2H), 2.72 (2H), 2.91 (2H), 3.30-3.35 (2H), 3.83-3.92 (2H), 4.28 (2H), 7.15 (1H), 7.39 (1H), 8.04-8.09 (1H), 8.47 (1H).

Example 69 : 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl ]-4-methyl-2H-carbazole-5-carboxamide

Analogously to Example 57, 79.9 mg of the title compound was obtained from 125.0 mg of the compound of Example 68a and 54.5 mg of 4-chlorobenzamide.

¹ H-NMR (300 MHz, chloroform-d): δ [ppm] = 1.13-1.35 (2H), 1.46-1.84 (2H), 2.27-2.50 (3H), 2.66 (3H), 2.80-3.26 (8H ), 3.59-3.83 (3H), 4.25-4.39 (2H), 4.62-4.85 (1H), 6.41-6.69 (1H), 7.30-7.40 (6H), 7.55 (1H), 7.96 (1H).

Example 70 : N-[2-(3,3-Difluoropyrrolidin-1-yl)ethyl]-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]] Benzyl hydrazino}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 15.2 mg of the title compound was obtained from 23.4 mg of the compound of Example 68a and 14.0 mg of 4-[(trifluoromethyl)thio]benzhydrin chloride.

¹ H-NMR (400 MHz, chloroform-d): δ [ppm] = 1.23-1.26 (1H), 1.33-1.46 (1H), 1.48-1.61 (1H), 1.77 (1H), 2.20-2.35 (2H) ), 2.36-2.49 (1H), 2.64 (3H), 2.73-2.85 (5H), 2.90-3.10 (3H), 3.56 (2H), 3.63-3.76 (1H), 4.26-4.39 (2H), 4.70-4.82 (1H), 6.28 (1H), 7.33 (1H), 7.42 (2H), 7.53 (1H), 7.68 (2H), 7.96 (1H).

Example 71 : 4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 126.9 mg of the title compound was obtained from 146.9 mg of the compound of Example 71a and 93.3 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.12-1.31 (2H), 1.31-1.45 (1H), 1.47-1.63 (1H), 2.20-2.36 (1H), 2.50 (3H) , 2.67-2.83 (1H), 2.91-3.07 (1H), 3.36-3.47 (1H), 3.96-4.10 (2H), 4.29-4.37 (2H), 4.37-4.48 (1H), 7.17 (1H), 7.43 ( 1H), 7.56 (2H), 7.94 (2H), 8.50- 8.54 (1H), 8.75-8.83 (1H).

The starting materials were prepared as follows:

Example 71a : 4-Methyl-2-(4-piperidinylmethyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide hydrochloride

To 425.2 mg of 71b was added 2.35 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane. An oily mass is formed which dissolves upon vigorous agitation and gentle warming. The mixture was stirred at about 30 ° C for 1 hour. The reaction mixture was concentrated. Yield: 440.6 mg of the title compound, which was further purified without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.35-1.49 (2H), 1.53-1.62 (2H), 2.20-2.32 (1H), 2.51 (3H), 2.72-2.85 (2H) , 3.14 - 3.23 (2H), 3.97 - 4.09 (2H), 4.34 (2H), 7.18 (1H), 7.43 (1H), 8.58 (1H), 8.64 - 8.77 (1H), 8.78-8.85 (1H), 8.93 -9.08(1H).

Example 71b : 4-({4-Methyl-5-[N-(2,2,2-trifluoroethyl)amine-carbamoyl]-2H-indazol-2-yl}-methyl)piperidine 1-butylic acid tert-butyl ester

2820 mg 1c, 2052 mg 2,2,2-trifluoroethylamine, 1823.2 mg hexacarbonyl molybdenum, 200.4 mg tetrafluoro Acid tri-tert-butylphosphine and 647.5 mg of trans-bis(acetate)-bis[o-(di-tolylphosphino)-benzyl]dipalladium (II) were placed in a microwave tube and suspended in 56 ml of THF. . Then 3.1 ml of DBU was added and the mixture was stirred in a microwave at 125 ° C and 200 watts for 20 minutes. The reaction mixture was diluted with some ethyl acetate, washed twice with water and once with saturated sodium chloride. It was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP4. Gradient: hexane/ethyl acetate 0-100%. Yield: 475.2 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 0.99-1.17 (2H), 1.30-1.44 (11H), 2.05-2.21 (1H), 2.50 (3H), 2.54-2.73 (2H) , 3.81-3.94 (2H), 3.95-4.10 (2H), 4.29 (2H), 7.18 (1H), 7.43 (1H), 8.51 (1H), 8.74-8.83 (1H).

Example 72 : 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H -carbazole-5-carboxamide

Analogously to Example 1, 97.8 mg of the title compound was obtained from 146.9 mg of the compound of Example 71a and 58.8 mg of 4-chlorobenzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.11-1.29 (2H), 1.31-1.45 (1H), 1.45-1.61 (1H), 2.20-2.35 (1H), 2.50 (3H) , 2.63-2.84 (1H), 2.85-3.08 (1H), 3.42-3.59 (1H), 3.96-4.10 (2H), 4.29-4.47 (3H), 7.17 (1H), 7.36 (2H), 7.40-7.50 ( 3H), 8.52 (1H), 8.75-8.82 (1H).

Example 73 : 4-Methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]piperidin-4-yl }methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1, 106.9 mg of the title compound was obtained from 146.9 mg of the compound obtained in Example 71a and 77.5 mg of 4-(trifluoromethoxy)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.12-1.30 (2H), 1.31 - 1.46 (1H), 1.47-1.64 (1H), 2.20-2.36 (1H), 2.50 (3H) , 2.66-2.85 (1H), 2.86-3.09 (1H), 3.40-3.55 (1H), 3.96-4.10 (2H), 4.29-4.48 (3H), 7.17 (1H), 7.36-7.50 (5H), 8.52 ( 1H), 8.75-8.82 (1H).

Example 74 : 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-6-methyl-N-(2-(N-morpholinyl)ethyl)- 2H-carbazole-5-carboxamide

Analogously to Example 55, 30 mg of the title compound was obtained from 79 mg of the title compound of Example 74a and 26 mg of 4-chlorobenzamide.

¹ NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.31 (2H), 1.50 (1H), 1.65 (1H), 2.35 (1H), 2.47 (3H), 2.63 (6H), 2.81 (1H) , 3.07 (1H), 3.53 (2H), 3.71 (5H), 4.34 (2H), 4.59 (1H), 7.36 (2H), 7.43 (3H), 7.75 (1H), 8.24 (1H).

The starting materials were prepared as follows:

Example 74a : 6-Methyl-N-(2-(N-morpholinyl)ethyl)-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

768 mg (1.58 mmol) of the third butyl carbazate 74b was dissolved in 4 ml of hydrochloric acid in 4.0 ml of dioxane and stirred at room temperature under nitrogen. Further, 4 ml of hydrochloric acid in 0.8 ml of dioxane was added and the mixture was stirred at room temperature. The reaction solution was concentrated to give EtOAc (EtOAc):

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.34-1.50 (2H), 1.53-1.67 (2H), 2.21-2.30 (1H), 2.41 (3H), 2.74-2.89 (2H) , 3.07-3.33 (8H), 3.62-3.71 (2H), 3.77-3.90 (2H), 3.90-4.03 (2H), 4.35 (2H), 7.39 (1H), 7.88 (1H), 8.44 (1H), 8.57 (1H), 8.62-8.79 (1H), 8.87-9.02 (1H), 11.17 (1H).

Example 74b : 4-({6-Methyl-5-[N-(2-(N-morpholinyl)ethyl)aminemethanyl]-2H-indazol-2-yl}-methyl)piperidin Pyridin-1-carboxylic acid tert-butyl ester

3.00 g (7.35 mmol) of 5-bromocarbazole 74c and 2.87 g (22.04 mmol) of 2-(N-morpholinyl)-ethylamine were dissolved in 134 ml of dioxane and 1.94 g (7.35 mmol) of hexacarbonyl molybdenum was added. 167 mg (1.47 mmol) palladium acetate, 213 mg (0.74 mmol) tetrafluoro Tributylphosphine, 2.34 g (22.0 mmol) sodium carbonate and 2 drops of water. The reaction mixture was heated at 125 ° C under nitrogen and stirred at this temperature for 2.5 hours. For the treatment, the suspension was filtered through celite, washed with dioxane, concentrated in vacuo and dried. The crude product was separated by column chromatography. Yield: 518 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.93-1.16 (2H), 1.26-1.37 (2H), 1.34 (9H), 1.99-2.17 (1H), 2.32-2.43 (10H) , 2.54-2.72 (2H), 3.34 (1H), 3.48-3.59 (4H), 3.86 (2H), 4.26 (2H), 7.35 (1H), 7.63 (1H), 8.09 (1H), 8.32 (1H).

Example 74c : tert-butyl 4-[(5-bromo-6-methyl-2H-indazol-2-yl)methyl]piperidine-1-carboxylate

10.0 g (47.4 mmol) of 5-bromo-4-methyl-1H-indazole and 21.0 g (56.9 mmol) of tert-butyl 4-[(toluenesulfonyloxy)methyl]piperidine-1-carboxylate Dissolved in 726 ml DMF. 21.0 g (56.9 mmol) of tetrabutylammonium iodide and 18.5 g (56.9 mmol) of cesium carbonate were added thereto and the reaction mixture was heated at 80 ° C for 1.5 hours under nitrogen. In terms of treatment, water and B This was treated with ethyl acetate, the organic phase was separated with ethyl acetate and the aqueous phase was extracted several times. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated. This resulted in a yield of 5 g of the title compound after purification by column chromatography.

¹ H-NMR (600 MHz, chloroform-d): δ [ppm] = 1.16 - 1.30 (2H), 1.45 (9H), 1.54 (2H), 2.22 - 2.33 (1H), 2.51 (3H), 2.67 ( 2H), 4.03-4.17 (2H), 4.27-4.32 (2H), 7.60 (1H), 7.81 (1H), 7.90 (1H).

The following compounds were prepared similarly:

Example 77 : 6-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzimidyl]piperidine -4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 23 mg of the title compound was obtained from 79 mg of the title compound of y.

¹ H-NMR (400 MHz, methanol-d ₄ ): δ [ppm] = 1.34 (2H), 1.52 (1H), 1.66 (1H), 2.37 (1H), 2.49 (3H), 2.84 (1H), 3.10 ( 1H), 3.25 (2H), 3.42 (2H), 3.63 (3H), 3.75 (4H), 4.10 (2H), 4.36 (2H), 4.62 (1H), 7.43 (1H), 7.56 (2H), 7.89 ( 3H), 8.28 (1H).

The following compounds were prepared similarly:

Example 84 : 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl -2H-carbazole-5-carboxamide

Analogously to Example 1, 38 mg of the title compound was obtained from &lt

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.14 (2H), 0.42 (2H), 0.97 (1H), 1.21 (2H), 1.36 (1H), 1.52 (1H), 2.27 ( 1H), 2.50 (3H), 2.72 (1H), 2.97 (1H), 3.23 (2H), 3.36 (2H), 3.48 (3H), 4.31 (2H), 4.40 (1H), 7.14 (1H), 7.36 ( 3H), 7.46 (2H), 8.12 (1H), 8.47 (1H).

The starting materials were prepared as follows:

Example 84a : N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

To 781 mg of 84b, 3.7 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane were added. The mixture was stirred at about 30 ° C for 30 minutes. The reaction mixture was concentrated, taken up in some toluene and concentrated again. Yield: 751 mg of the title compound which was taken further without further purification.

^{1 H-NMR (400MHz, DMSO} -d6): δ [ppm] = 0.14 (2H), 0.42 (2H), 0.97 (1H), 1.43 (2H), 1.58 (2H), 2.26 (1H), 2.50 (3H ), 2.65 (1H), 2.78 (2H), 3.18 (2H), 3.22 (2H), 3.36 (2H), 3.49 (2H), 4.33 (2H), 7.16 (2H), 7.38 (1H), 8.11 (1H) ), 8.53 (1H), 8.80 (1H), 9.06 (1H).

Example 84b : 4-[(5-{N-[2-(cyclopropylmethoxy)ethyl]aminemethanyl}-4-methyl-2H-indazol-2-yl)methyl]piperidin Pyridin-1-carboxylic acid tert-butyl ester

500 mg of 1d reacted with 203 mg of amine similar to 1b version B. Yield: 781 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.98-1.13 (2H), 1.34 (11H), 2.05-2.27 (2H), 2.33-2.41 (5H), 2.51 (3H), 2.56 -2.73 (2H), 3.25-3.37 (2H), 3.51-3.57 (4H), 3.81-3.93 (2H), 4.28 (2H), 7.14 (1H), 7.36-7.41 (1H), 7.95-8.02 (1H) , 8.46 (1H).

The following compounds were prepared similarly:

Example 90 : 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-B Oxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 40 mg of the title compound was obtained from 75 mg of the title compound of Example 90a and 27 mg of 4-chlorobenzoic acid.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.20 (2H), 1.36 (1H), 1.53 (1H), 2.27 (1H), 2.49 (3H), 2.72 (1H), 2.97 ( 1H), 3.40 (2H), 3.49 (1H), 3.69 (2H), 4.07 (2H), 4.31 (2H), 4.40 (1H), 7.15 (1H), 7.37 (3H), 7.46 (2H), 8.19 ( 1H), 8.48 (1H).

The starting materials were prepared as follows:

Example 90a : 4-Methyl-2-(4-piperidinylmethyl)-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-A Guanamine

To 610 mg of 90b was added 3.0 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane. The mixture was stirred at about 30 ° C for 30 minutes. The reaction mixture was concentrated, taken up in some toluene and concentrated again. Yield: 619 mg of the title compound, which was further purified without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.42 (2H), 1.59 (2H), 2.26 (1H), 2.50 (3H), 2.64 (1H), 2.79 (2H), 3.20 ( 2H), 3.40 (2H), 3.70 (2H), 4.07 (2H), 4.33 (2H), 5.67 (1H), 7.16 (1H), 7.39 (1H), 8.18 (1H), 8.53 (1H), 8.69 ( 1H), 8.94 (1H).

Example 90b : 4-[(4-Methyl-5-{N-[2-(2,2,2-trifluoroethoxy)ethyl]aminemethylmercapto}-2H-indazol-2-yl Methyl] piperidine-1-carboxylic acid tert-butyl ester

500 mg of 1d reacted with 240 mg of amine similar to 1b version B. Yield: 670 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.07 (2H), 1.34 (9H), 1.37 (2H), 2.14 (1H), 2.49 (3H), 2.63 (2H), 3.40 ( 2H), 3.70 (2H), 3.88 (2H), 4.06 (2H), 4.29 (2H), 7.15 (1H), 7.39 (1H), 8.16 (1H), 8.47 (1H).

The following compounds were prepared similarly:

Example 96 : 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

Analogously to Example 1, 36 mg of the title compound was obtained from 75 mg of the title compound of Example 96a and 30 mg of 4-chlorobenzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.07 (6H), 1.22 (2H), 1.39 (1H), 1.51 (1H), 2.26 (1H), 2.50 (3H), 2.75 ( 1H), 2.97 (1H), 3.33 (2H), 3.45 (3H), 3.55 (1H), 4.31 (2H), 4.39 (1H), 7.14 (1H), 7.36 (3H), 7.47 (2H), 8.05 ( 1H), 8.46 (1H).

The starting materials were prepared as follows:

Example 96a : N-(2-Isopropoxyethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

To 650 mg of 96b was added 3.2 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane. The mixture was stirred at about 30 ° C for 30 minutes. The reaction mixture was concentrated, taken up in some toluene and concentrated again. Yield: 529 mg of the title compound which was taken further without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.06 (3H), 1.07 (3H), 1.42 (2H), 1.57 (2H), 2.25 (1H), 2.50 (3H), 2.65 ( 1H), 2.78 (2H), 3.19 (2H), 3.32 (2H), 3.45 (2H), 3.55 (1H), 4.32 (1H), 6.61 (1H), 7.15 (1H), 7.38 (1H), 8.11 ( 1H), 8.53 (1H), 8.78 (1H), 9.04 (1H).

Example 96b : 4-({5-[N-(2-Isopropoxyethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidine-1 -T-butyl formate

500 mg of 1d reacted with 138 mg of amine similar to 1b version B. Yield: 650 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.07 (8H), 1.34 (9H), 1.38 (2H), 2.13 (1H), 2.50 (3H), 2.63 (2H), 3.33 ( 2H), 3.46 (2H), 3.55 (1H), 3.87 (2H), 4.28 (2H), 7.14 (1H), 7.38 (1H), 8.05 (1H), 8.46 (1H).

The following compounds were prepared similarly:

Example 102 : (+/-)-2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)propyl ]-4-methyl-2H-carbazole-5-carboxamide

Analogously to Example 1, 41 mg of the title compound was obtained from 100 mg of the compound obtained in Example 102a and 37 mg of 4-chlorobenzoic acid.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 0.16 (2H), 0.43 (2H), 0.97 (1H), 1.10 (3H), 1.23 (2H), 1.40 (1H), 1.55 ( 1H), 2.29 (1H), 2.53 (3H), 2.75 (1H), 2.99 (1H), 3.23 (2H), 3.20 (2H), 3.51 (1H), 3.59 (1H), 4.34 (2H), 4.43 ( 1H), 7.17 (1H), 7.39 (3H), 7.49 (2H), 8.09 (1H), 8.49 (1H).

The starting materials were prepared as follows:

Example 102a : (+/-)-N-[2-(cyclopropylmethoxy)propyl]-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5- Formamide

To 632 mg of 102b, 2.9 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane were added. The mixture was stirred at about 30 ° C for 30 minutes. The reaction mixture was concentrated, taken up in some toluene and concentrated again. Yield: 561 mg of the title compound which was taken further without further purification.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.13 (2H), 0.40 (2H), 0.94 (1H), 1.07 (3H), 1.44 (2H), 1.57 (2H), 2.26 ( 1H), 2.50 (3H), 2.77 (2H), 3.20 (6H), 3.57 (1H), 4.33 (2H), 6.33 (1H), 7.16 (1H), 7.39 (1H), 8.11 (1H), 8.53 ( 1H), 8.79 (1H), 9.06 (1H).

Example 102b : (+/-)-4-[(5-{N-[2-(cyclopropylmethoxy)propyl]aminemethanyl}-4-methyl-2H-indazole-2- Methyl] piperidine-1-carboxylic acid tert-butyl ester

500 mg of 1d reacted with 222 mg of amine similar to 1b version B. Yield: 631 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 0.13 (2H), 0.40 (2H), 0-94 (1H), 1.07 (3H), 1.14 (2H), 1.34 (9H), 1.38(2H), 2.13(1H), 2.50(3H), 3.24(6H), 3.57(1H), 3.87(2H), 4.28(2H), 7.15(1H), 7.39(1H), 8.09(1H), 8.46 (1H).

The following compounds were prepared similarly:

Example 107 : 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]- 2H-carbazole-5-carboxamide

Analogously to Example 1, 26 mg of the title compound was obtained from 75 mg of the title compound of Example 107a and 28 mg of 4-chlorobenzoic acid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.20 (2H), 1.36 (1H), 1.52 (1H), 2.27 (1H), 2.49 (3H), 2.72 (1H), 2.97 ( 1H), 3.51 (3H), 4.17 (2H), 4.33 (3H), 7.15 (1H), 7.41 (5H), 8.37 (1H), 8.49 (1H).

The starting materials were prepared as follows:

Example 107a : 4-methyl-2-(4-piperidinylmethyl)-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide

To 648 mg of 107b was added 3.0 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane. The mixture was stirred at about 30 ° C for 30 minutes. The reaction mixture was concentrated, taken up in some toluene and concentrated again. Yield: 766 mg of the title compound which was taken further without further purification.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.43 (2H), 1.57 (2H), 2.24 (1H), 2.50 (3H), 2.78 (2H), 3.19 (2H), 3.50 ( 1H), 4.17 (2H), 4.33 (2H), 6.49 (1H), 7.17 (2H), 7.40 (1H), 8.39 (1H), 8.55 (1H), 8.70 (1H), 8.98 (1H).

Example 107b : 4-[(4-Methyl-5-{N-[2-(trifluoromethoxy)ethyl]aminemethanyl}-2H-indazol-2-yl)methyl]piperidine 1-butylic acid tert-butyl ester

500 mg 1d was reacted with 293 mg of amine similar to 1b version B. Yield: 748 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.07 (2H), 1.34 (9H), 1.37 (2H), 2.12 (1H), 2.50 (3H), 2.63 (1H), 3.52 ( 2H), 3.87 (2H), 4.17 (2H), 4.29 (2H), 7.16 (2H), 7.41 (1H), 8.37 (1H), 8.48 (1H).

The following compounds were prepared similarly:

Example 111 : N-(2-Tertiyloxyethyl)-2-{[1-(4-chlorobenzylidyl)piperidin-4-yl]methyl}-4-methyl-2H- Oxazole-5-carboxamide

Analogously to Example 1, 8 mg of the title compound was obtained from 75 mg of the title compound of the compound 111a and 28 mg of 4-chlorobenzoic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.12 (9H), 1.21 (2H), 1.36 (1H), 1.53 (1H), 2.27 (1H), 2.50 (3H), 2.72 ( 1H), 2.97 (1H), 3.29 (2H), 3.43 (3H), 4.31 (2H), 4.40 (1H), 7.14 (1H), 7.36 (3H), 7.46 (2H), 8.04 (1H), 8.46 ( 1H).

The starting materials were prepared as follows:

Example 111a : N-(2-Tertiethoxyethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

To 743 mg of 111b, 3.5 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane were added. The mixture was stirred at about 30 ° C for 30 minutes. The reaction mixture was concentrated, taken up in some toluene and concentrated again. Yield: the title compound in a mixture of 677 mg of N-(2-hydroxyethyl)-4-methyl-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide. The reaction was further carried out by further purification.

Example 111b : 4-({5-[N-(2-Tertiyloxyethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}methyl)piperidine-1 -T-butyl formate

500 mg of 1d was reacted with 206 mg of amine similar to 1b version B. Yield: 743 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 1.06 (2H), 1.11 (9H), 1.34 (9H), 1.39 (2H), 2.13 (1H), 2.50 (3H), 2.65 ( 2H), 3.27 (2H), 3.40 (2H), 3.87 (2H), 4.28 (2H), 7.14 (1H), 7.38 (1H), 8.05 (1H), 8.46 (1H).

The following compounds were prepared similarly:

Example 115 : 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(2-[ ² H ₃ ]methoxy[ ² H ₄ ]ethyl) -4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 1 mg of the title compound was obtained from 54 mg of the title compound of Example 115a and 22 mg of 4-chlorobenzoic acid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.20 (2H), 1.40 (1H), 1.51 (1H), 2.27 (1H), 2.49 (3H), 2.75 (1H), 2.96 ( 1H), 3.50 (1H), 4.31 (2H), 4.40 (1H), 7.15 (1H), 7.36 (3H), 7.47 (2H), 8.07 (1H), 8.46 (1H).

The starting materials were prepared as follows:

Example 115a : 4-Methyl-N-(2-[ ² H ₃ ]methoxy[ ² H ₄ ]ethyl)-2-(4-piperidinylmethyl)-2H-indazole-5-A Guanamine

To 131 mg of 115b was added 0.7 ml of 4 M hydrochloric acid in dioxane and 0.5 ml of dioxane. The mixture was stirred at about 30 ° C for 30 minutes. The reaction mixture was concentrated, taken up in some toluene and concentrated again. Yield: 108 mg of the title compound which was further purified without further purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.42 (2H), 1.58 (2H), 2.26 (1H), 2.49 (3H), 2.78 (2H), 3.19 (2H), 4.33 ( 2H), 5.55 (1H), 7.16 (1H), 7.38 (1H), 8.12 (1H), 8.53 (1H), 8.70 (1H), 8.97 (1H).

Example 115b : 4-({4-methyl-5-[N-(2-[ ² H ₃ ]methoxy[ ² H ₄ ]ethyl)aminemethanyl]-2H-indazol-2-yl }methyl) piperidine-1-carboxylic acid tert-butyl ester

500 mg of 1d and 110 mg of the amine prepared in 115c were reacted similarly to 1b version B. Yield: 131 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.07 (2H), 1.34 (9H), 1.37 (2H), 2.13 (1H), 2.49 (3H), 2.62 (2H), 3.88 ( 2H), 4.28 (2H), 7.15 (1H), 7.38 (1H), 8.07 (1H), 8.46 (1H).

Example 115c : 2-[ ² H ₃ ]Methoxy[ ² H ₄ ]Ethyl-1-amine

110 mg (0.51 mmol) of 115d was first placed in 2.2 ml of toluene. After adding 11 mg of palladium/charcoal (10%) and hydrogen under normal pressure, the mixture was stirred at room temperature for 50 minutes. The reaction mixture was filtered through celite and washed with toluene. A colorless filtrate was used as the solution in the subsequent reaction.

Example 115d : Benzyl N- (2-[ ² H ₃ ]methoxy[ ² H ₄ ]ethyl)carbamate

1.32 g (6.6 mmol) of 115e was dissolved in 23 ml of acetonitrile. Subsequently, 2.3 g (9.9 mmol) of silver oxide and 1.64 ml (3.8 g, 26 mmol) of methyl iodide were added. The reaction mixture was stirred at 40 ° C for 1.5 hours, at 72 ° C for 7.5 hours and then at room temperature overnight. Further 2.3 g (9.9 mmol) of silver oxide was added and the mixture was stirred at 72 ° C for 1.5 hours. For processing, the black solid was filtered off at the pump and the clear filtrate was concentrated. Chromatography by column chromatography (hexane/B Ethyl acetate 0-10%) purified residue. Yield: 1.13 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 4.97 (2H), 7.31 (5H).

Example 115e : Benzyl N- (2-hydroxy[ ² H ₄ ]ethyl)carbamate

1.0 g (15 mmol) of deuterated aminoethanol was first dissolved in 29 ml of dichloromethane. Then 2.5 ml (1.8 g, 18 mmol) of triethylamine were added and the reaction mixture was cooled to 0 °C. At this temperature, 2.75 ml (3.34 g, 19.6 mmol) of benzyl chloroformate was now carefully added dropwise. After the addition was completed, the mixture was stirred for an additional hour without an ice bath and warmed to room temperature during the process. The reaction mixture was diluted once with some dichloromethane and once with a saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified twice by column chromatography (dichloromethane / methanol 0-10% ethyl acetate). Yield: 1.32 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 4.54 (1H), 4.97 (2H), 7.12 (1H), 7.81 (5H).

The following compounds were prepared similarly:

Example 117: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

Similar to Example 55, from 500 mg of the compound prepared in Example 117e and 287 mg 4-Chlorobenzylidene chloride gave 471 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.49 (3H), 3.22 (1H), 3.25 (3H), 3.32-3.46 (4H), 3.89 (1H), 4.09 (1H), 4.19 (1H) , 4.37 (1H), 4.67 (2H), 7.15 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 8.12 (1H), 8.54 (1H).

The starting materials were prepared as follows:

Example 117a: 3-[(5-Bromo-4-methyl-2H-indazol-2-yl)methyl]-azetidine-1-carboxylic acid tert-butyl ester

To 21.1 g of 5-bromo-4-methyl-1H-carbazole and 37.6 g of 3-[(toluenesulfonyloxy)-methyl]azetidin-1-carboxylic acid tributyl at 25 ° C To a solution of the ester in 100 ml of dioxane was added 150 ml of a 1 M solution of sodium bis(trimethyldecyl)amide in tetrahydrofuran and the solution was stirred at 90 ° C for 6 hours. After cooling, the reaction mixture was taken with ethyl acetate and water, and the organic phase was separated and the aqueous phase was extracted twice with 100 ml of ethyl acetate. The combined organic phases were washed with aq. The residue thus obtained was purified by chromatography (hexane/ethyl acetate 1:0-0:1) on Flash. 15.0 g of the title compound was obtained.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.48 (3H), 3.07 (1H), 3.69 (2H), 3.87 (2H), 4.59 (2H), 7.28 (1H), 7.35 (1H), 8.53 (1H).

Example 117b: methyl 2-{[1-(t-butoxycarbonyl)azetidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxylate

To a solution of 8.16 g of bromide prepared in Example 117a in 65.4 ml of methanol was added 6.5 g of 1,1 bis(diphenylphosphino)ferrocene-palladium(II) chloride and 15 g at 25 °C. Acetic acid Potassium and the mixture was stirred in an autoclave under a CO at 10.15 bar and 120 ° C for 24 hours. The reaction mixture was then cooled, filtered through celite at a pump and concentrated in vacuo. The residue thus obtained was purified by chromatography (hexane/ethyl acetate 1:0-0:1) on Flash. 6.97 g of the title compound were obtained.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.73 (3H), 3.09 (1H), 3.71 (2H), 3.79 (3H), 3.87 (2H), 4.62 (2H), 7.42 (1H), 7.63 (1H), 8.74 (1H).

Example 117c: 2-{[1-( Tertidinoxycarbonyl )azetidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxylic acid

Analogously to Example 1d, 5.2 g of the title compound was obtained from 15.1 g of the ester of Example 117b.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.73 (3H), 3.09 (1H), 3.71 (2H), 3.87 (2H), 4.61 (2H), 7.39 (1H), 7.64 (1H), 8.70 (1H), 12.57 (1H).

Example 117d: 3-({5-[N-(2-methoxyethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}-methyl)azetidine 1-butylic acid tert-butyl ester

Similar to Example 1, a crude product was obtained from 2.5 g of the acid from the compound of 117c and 0.54 g of 2-methoxyethylamine, which was purified by Biotage unit (ethyl acetate: 0 to 30% methanol) to yield 2.69. g title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.32 (9H), 2.49 (3H), 3.08 (1H), 3.25 (3H), 3.32-3.46 (4H), 3.70 (2H), 3.86 (2H) , 4.60 (2H), 7.15 (1H), 7.38 (1H), 8.11 (1H), 8.54 (1H).

Example 117e: 2-(Azetidin-3-ylmethyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 2.59 g of the title compound was obtained from the title compound from </RTI>

Example 118: N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidene] azetidine- 3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 29 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

¹ H-NMR (300MHz, DMSO-d6): δ=2.49 (3H), 3.22 (1H), 3.25 (3H), 3.36 (2H), 3.42 (2H), 3.92 (1H), 4.11 (1H), 4.20 (1H), 4.39 (1H), 4.67 (2H), 7.15 (1H), 7.38 (1H), 7.69 (2H), 7.76 (2H), 8.12 (1H), 8.54 (1H).

Example 119: N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidenyl]azetidin-3-yl }methyl)-2H-carbazole-5-carboxamide

Analogously to Example 55, 27 mg of the title compound was obtained from &lt

¹ H-NMR (300MHz, DMSO-d6): δ=2.49 (3H), 3.20 (1H), 3.24 (3H), 3.32-3.46 (4H), 3.91 (1H), 4.10 (1H), 4.20 (1H) , 4.39 (1H), 4.67 (2H), 7.15 (1H), 7.35-7.44 (3H), 7.70 (2H), 8.12 (1H), 8.54 (1H).

Example 120: 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxy- Ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 17 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.48 (3H), 3.23 (1H), 3.25 (3H), 3.36 (2H), 3.42 (2H), 3.94 (2H), 4.11 (2H), 4.66 (2H), 7.15 (1H), 7.38 (1H), 7.64 (2H), 7.79 (1H), 8.12 (1H), 8.54 (1H).

Example 121: 2-{[1-(4-Chloro-2-fluorobenzhydryl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

Analogously to Example 55, 19 mg of the title compound was obtained from 42 mg of the compound of Example 117e and 26 mg of 4-chloro-2-fluorobenzamide.

¹ H-NMR (300 MHz, DMSO-d6): δ = 2.48 (3H), 3.21 (1H), 3.24 (3H), 3.33 - 3.46 (4H), 3.86 - 3.97 (2H), 4.08 (2H), 4.65 ( 2H), 7.15 (1H), 7.34 (1H), 7.37 (1H), 7.44 (1H), 7.52 (1H), 8.12 (1H), 8.53 (1H).

Example 122: 2-({1-[3-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxy- Ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 15 mg of the title compound was obtained from 42 mg of the compound of Example 117e and 31 mg of 3-fluoro-4-(trifluoromethyl) benzindole.

¹ H-NMR (300MHz, DMSO-d6): δ=2.49 (3H), 3.21 (1H), 3.25 (3H), 3.36 (2H), 3.42 (2H), 3.93 (1H), 4.12 (1H), 4.22 (1H), 4.40 (1H), 4.67 (2H), 7.15 (1H), 7.37 (1H), 7.57 (1H), 7.64 (1H), 7.85 (1H), 8.12 (1H), 8.54 (1H).

Example 123: 2-({1-[4-Chloro-3-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxy- Ethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 6 mg of the title compound was obtained from 42 mg of the compound of Example 117e and 33 mg of 4-chloro-3-(trifluoromethyl) benzindole.

¹ H-NMR (300MHz, DMSO-d6): δ=2.49 (3H), 3.21 (1H), 3.25 (3H), 3.31-3.46 (4H), 3.92 (1H), 4.11 (1H), 4.22 (1H) , 4.41 (1H), 4.67 (2H), 7.15 (1H), 7.37 (1H), 7.79 (1H), 7.86 (1H), 7.94 (1H), 8.12 (1H), 8.53 (1H).

Example 124: 2-{[1-(4-Cyclopropylbenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

Similar to Example 1, from 163 mg of the compound prepared in Example 117e and 78 mg of 4- Cyclopropylbenzoic acid afforded 76 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.71 (2H), 0.99 (2H), 1.95 (1H), 2.52 (3H), 3.24 (1H), 3.34-3.41 (5H), 3.45 (2H) , 3.90 (1H), 4.09 (1H), 4.20 (1H), 4.38 (1H), 4.68 (2H), 7.12 (2H), 7.18 (1H), 7.41 (1H), 7.48 (2H), 8.12 (1H) , 8.57 (1H).

Example 125: N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}N-heterocyclic ring Butane-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, the compound of Example 117e and 850 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid were obtained from 1.20 g.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.52 (3H), 3.25 (1H), 3.27 (3H), 3.39 (2H), 3.45 (2H), 3.94 (1H), 4.12 (1H), 4.24 (1H), 4.42 (1H), 4.70 (2H), 7.14 (2H), 7.18 (1H), 7.22 (2H), 7.41 (1H), 7.69 (2H), 7.77 (2H), 8.12 (1H), 8.57 (1H).

Example 126: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-N-[2-(3,3-difluoropyrrolidin-1-yl) Ethyl]-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 38 mg of the title compound was obtained from 43 mg of the compound of Example 126a and 20 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.10-2.27 (3H), 2.49 (3H), 2.57 (2H), 2.72 (2H), 2.91 (2H), 3.17-3.36 (2H), 3.89 ( 1H), 4.08 (1H), 4.19 (1H), 4.36 (1H), 4.67 (2H), 7.14 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 8.05 (1H), 8.54 ( 1H).

Example 126a: 2-(Azetidin-3-ylmethyl)-N-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-4-methyl-2H-indole Zol-5-carbamidine hydrochloride

Analogously to Example 1a, 43 mg of the title compound was obtained from 50 mg of the title compound.

Example 126b: 3-[(5-{N-[2-(3,3-Difluoropyrrolidin-1-yl)ethyl]aminemethanyl}-4-methyl-2H-indazole-2- Methyl]azetidin-1-carboxylic acid tert-butyl ester

Analogously to Example 1b, 71 mg of the title compound was obtained from 70 mg of the compound of Example 117a and 83 mg of 2-(3,3-difluoropyrrolidin-1-yl)ethylamine.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.10-2.28 (2H), 2.50 (3H), 2.57 (2H), 2.66-2.77 (2H), 2.84-2.98 (2H), 3.08 (1H), 3.23 - 3.36 (2H), 3.69 (2H), 3.86 (2H), 4.60 (2H), 7.14 (1H), 7.39 (1H), 8.05 (1H), 8.55 (1H).

Example 127: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-{2-[(trifluoromethyl)sulfide Ethyl}ethyl}-2H-carbazole-5-carboxamide

Analogously to Example 55, 143 mg of the title compound was obtained from yd.

¹ H-NMR (300MHz, DMSO-d6): δ=2.51 (3H), 3.13-3.29 (3H), 3.50 (2H), 3.90 (1H), 4.09 (1H), 4.19 (1H), 4.37 (1H) , 4.67 (2H), 7.19 (1H), 7.40 (1H), 7.48 (2H), 7.59 (2H), 8.38 (1H), 8.57 (1H).

The starting materials were prepared as follows:

Example 127a: 3-{[4-Methyl-5-(N-{2-[(trifluoromethyl)thio]ethyl}aminecarbazyl)-oxazol-2-yl]methyl}nitrogen Heterocyclic butane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 674 mg of the title compound was obtained from 500 mg of compound obtained in Example 117c.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.52 (3H), 3.08 (1H), 3.17 (2H), 3.50 (2H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.19 (1H), 7.41 (1H), 8.38 (1H), 8.57 (1H).

Example 127b: 2-(Azetidin-3-ylmethyl)-4-methyl-N-{2-[(trifluoromethyl)thio]ethyl}-2H-indazole-5- Formamide hydrochloride

Analogously to Example 1a, 130 mg of the title compound was obtained from 150 mg.

Example 128: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-4-methyl-N-(2-(N-morpholinyl)B Base-2H-carbazole-5-carbamide

Analogously to Example 55, 30 mg of the title compound was obtained from 50 mg of the compound of Example 128b and 24 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=2.34-2.45 (6H), 2.51 (3H), 3.22 (1H), 3.33 (2H), 3.54 (4H), 3.89 (1H), 4.08 (1H) , 4.19 (1H), 4.36 (1H), 4.67 (2H), 7.15 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 7.99 (1H), 8.54 (1H).

The starting materials were prepared as follows:

Example 128a: 3-({4-Methyl-5-[N-(2-(N-morpholinyl)ethyl)aminemethanyl]-2H-indazol-2-yl}methyl)aza Cyclobutane-1-carboxylic acid tert-butyl ester

Analogously to Example 1b, 59 mg of the title compound was obtained from 200 mg of the compound of Example 117a and 205 mg of 2-(N-morpholinyl)ethylamine.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.32 (9H), 2.34-2.44 (6H), 2.52 (3H), 3.08 (1H), 3.33 (2H), 3.54 (4H), 3.69 (2H) , 3.86 (2H), 4.61 (2H), 7.15 (1H), 7.39 (1H), 7.98 (1H), 8.55 (1H).

Example 128b: 2-(Azetidin-3-ylmethyl)-4-methyl-N-(2-(N-morpholinyl)ethyl)-2H-indazole-5-carboxamide Hydrochloride

Analogously to Example 1a, 63 mg of the title compound was obtained from 59 mg of the compound obtained in Example 128a, which was carried out without further purification.

Example 129: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl )-2H-carbazole-5-carbamide

Analogously to Example 55, 127 mg of the title compound was obtained from 128 mg of the compound of Example 129b and 68 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.50 (3H), 3.22 (1H), 3.90 (1H), 3.96-4.13 (3H), 4.19 (1H), 4.37 (1H), 4.68 (2H) , 7.18 (1H), 7.42 (1H), 7.48 (2H), 7.59 (2H), 8.59 (1H), 8.79 (1H).

The starting materials were prepared as follows:

Example 129a: 3-({4-Methyl-5-[N-(2,2,2-trifluoroethyl)aminemethanyl]-2H-indazol-2-yl}methyl)aza heterocycle Butane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 1.02 g of the title compound was obtained from 1.0 g of the compound of Example 117c and 287 mg of 2,2,2-trifluoroethylamine.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.51 (3H), 3.09 (1H), 3.70 (2H), 3.86 (2H), 4.03 (2H), 4.62 (2H), 7.17 (1H), 7.43 (1H), 8.60 (1H), 8.79 (1H).

Example 129b: 2-(Azetidin-3-ylmethyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide Acid salt

Analogously to Example 1a, 852 mg of the title compound was obtained from 1.0 g of the compound obtained in Example 129a, which was carried out without further purification.

Example 130: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]azetidine- 3-yl}methyl)-2H-indazole-5-carboxamide

Similar to Example 55, from 128 mg of the compound prepared in Example 129b and 87 mg of 4- (Trifluoromethoxy)benzimidium chloride gave 113 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.50 (3H), 3.23 (1H), 3.92 (1H), 3.96-4.14 (3H), 4.20 (1H), 4.39 (1H), 4.68 (2H) , 7.18 (1H), 7.36-7.46 (3H), 7.70 (2H), 8.59 (1H), 8.79 (1H).

Example 131: 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-4-methyl-N-(2 ,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 128 mg of the title compound was obtained from 128 mg of the compound of Example 129b and 88 mg of 2-fluoro-4-(trifluoromethyl) benzindole.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.49 (3H), 3.23 (1H), 3.89-4.16 (6H), 4.67 (2H), 7.17 (1H), 7.42 (1H), 7.60-7.67 ( 2H), 7.79 (1H), 8.58 (1H), 8.80 (1H).

Example 132: 4-Methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]azetidin-3-yl}methyl)-N-(2 ,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, from 128 mg of the compound obtained in Example 129b and 96 mg of 4-(pentafluoro-(6-sufanyl)benzoic acid, 121 mg of the title compound was obtained.

¹ H-NMR (300MHz, DMSO-d6): δ=2.50 (3H), 3.24 (1H), 3.94 (1H), 3.98-4.08 (2H), 4.12 (1H), 4.20 (1H), 4.39 (1H) , 4.69 (2H), 7.18 (1H), 7.42 (1H), 7.76 (2H), 7.95 (2H), 8.59 (1H), 8.80 (1H).

Example 133: 4-Methyl-2-({1-[4-(trifluoromethoxy)benzylidenyl]azetidin-3-yl}methyl)-N-{2-[( Trifluoromethyl)thio]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 178 mg of the title compound was obtained from yd.

¹ H-NMR (300MHz, DMSO-d6): δ=2.51 (3H), 3.13-3.28 (3H), 3.51 (2H), 3.91 (1H), 4.10 (1H), 4.20 (1H), 4.39 (1H) , 4.67 (2H), 7.19 (1H), 7.40 (3H), 7.70 (2H), 8.38 (1H), 8.57 (1H).

Example 134: 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-4-methyl-N-{2 -[(trifluoromethyl)thio]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 128 mg of the title compound was obtained from 130 mg of the compound of Example 127b and 79 mg of 2-fluoro-4-(trifluoromethyl) benzindole.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.51 (3H), 3.12-3.25 (3H), 3.50 (2H), 3.89-3.98 (2H), 4.06-4.16 (2H), 4.67 (2H), 7.19(1H), 7.40(1H), 7.64(2H), 7.79(1H), 8.39(1H), 8.56(1H).

Example 135: 4-Methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]azetidin-3-yl}methyl)-N-{2 -[(trifluoromethyl)thio]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 1, from 130 mg of the compound obtained in Example 127b and 87 mg of 4-(pentafluoro-(6-thio)benzoic acid afforded 84 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.51 (3H), 3.18 (2H), 3.23 (1H), 3.51 (2H), 3.94 (1H), 4.12 (1H), 4.20 (1H), 4.39 (1H), 4.68 (2H), 7.19 (1H), 7.41 (1H), 7.76 (2H), 7.95 (2H), 8.39 (1H), 8.56 (1H).

Example 136: N-[2-(Cyclopropoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidine- 3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 172 mg of the title compound was obtained from 161 mg of the compound of Example 136b and 109 mg of 4-(trifluoromethoxy) benzhydrin chloride.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.36-0.48 (4H), 2.48 (3H), 3.22 (1H), 3.27 (1H), 3.35 (2H), 3.53 (2H), 3.91 (1H) , 4.10 (1H), 4.20 (1H), 4.39 (1H), 4.67 (2H), 7.14 (1H), 7.35-7.44 (3H), 7.71 (2H), 8.11 (1H), 8.54 (1H).

The starting materials were prepared as follows:

Example 136a: 3-[(5-{N-[2-(Cyclopropoxy)ethyl]aminemethanyl}-4-methyl-2H-indazol-2-yl)methyl]azacyclocycle Butane-1-carboxylic acid tert-butyl ester

Similar to Example 1, from 150 mg of the compound prepared in Example 118c and 140 mg of 2-cyclopropoxy-ethylamine trifluoroacetate (may be similar to Example 1a according to Examples 154a and 154b, with cyclopropanol and bromoacetamide as The starting material was prepared by Boc cleavage with trifluoroacetic acid to give 189 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.36-0.48 (4H), 1.33 (9H), 2.49 (3H), 3.08 (1H), 3.25-3.39 (3H), 3.53 (2H), 3.70 ( 2H), 3.87 (2H), 4.61 (2H), 7.14 (1H), 7.38 (1H), 8.10 (1H), 8.54 (1H).

Example 136b: 2-(Azetidin-3-ylmethyl)-N-[(2-cyclopropoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide Acid salt

Analogously to Example 1a, 161 mg of the title compound was obtained from 189 mg of the compound obtained in Example 136a, which was carried out without further purification.

Example 137: N-[2-(Cyclobutoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidine- 3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 207 mg of the title compound was obtained from 254 mg of the compound of Example 137b and 166 mg of 4-(trifluoromethoxy) benzhydrin chloride.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.42 (1H), 1.59 (1H), 1.80 (2H), 2.11 (2H), 2.50 (3H), 3.17-3.28 (1H), 3.31-3.41 ( 4H), 3.85-3.95 (2H), 4.10 (1H), 4.20 (1H), 4.39 (1H), 4.67 (2H), 7.15 (1H), 7.35-7.44 (3H), 7.71 (2H), 8.11 (1H) ), 8.54 (1H).

The starting materials were prepared as follows:

Example 137a: 3-[(5-{N-[2-(Cyclobutoxy)ethyl]aminemethanyl}-4-methyl-2H-indazol-2-yl)methyl]azacyclocycle Butane-1-carboxylic acid tert-butyl ester

Similar to Example 1, from 220 mg of the compound prepared in Example 117c and 143 mg of 2-(cyclobutoxy)ethylamine trifluoroacetate (may be similar to Example 1a according to Examples 154a and 154b, with cyclobutanol and bromoacetamide Prepared as starting material, followed by Boc cleavage with trifluoroacetic acid to afford 297 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.33 (9H), 1.35-1.49 (1H), 1.59 (1H), 1.80 (2H), 2.11 (2H), 2.50 (3H), 3.08 (1H) , 3.30-3.41 (4H), 3.69 (2H), 3.82-3.95 (3H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.10 (1H), 8.54 (1H).

Example 137b: 2-(Azetidin-3-ylmethyl)-N-[(2-(cyclobutoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide Hydrochloride

Analogously to Example 1a, 254 mg of the title compound was obtained from 297 mg of the compound of Example 137a.

Example 138: (+/-)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxypropyl)- 4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 166 mg of the title compound was obtained from 237 mg of the compound of Example 138b and 129 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.07 (3H), 2.49 (3H), 3.14-3.28 (3H), 3.43 (1H), 3.89 (1H), 4.08 (1H), 4.19 (1H) , 4.36 (1H), 4.67 (2H), 7.15 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 8.11 (1H), 8.54 (1H).

The starting materials were prepared as follows:

Example 138a: (+/-)-3-({5-[N-(2-methoxypropyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}methyl) Azetidine-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 331 mg of the title compound was obtained from 323 mg of the compound of the compound of Example 117c and 117 mg of 2-methoxyethylamine.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.08 (3H), 1.33 (9H), 2.50 (3H), 3.09 (1H), 3.16-3.31 (2H), 3.44 (1H), 3.69 (2H) , 3.85 (2H), 4.61 (2H), 7.15 (1H), 7.39 (1H), 8.08 (1H), 8.54 (1H).

Example 138b: (+/-)-2-(azetidin-3-ylmethyl)-N-(2-methoxypropyl)-4-methyl-2H-indazole-5-A Indoleamine hydrochloride

Analogously to Example 1a, 247 mg of the title compound was obtained from 280 mg of the compound obtained in Example 138a.

Example 139: (R or S)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxypropyl)- 4-methyl-2H-indazole-5-carboxamide

52 mg of the title compound was obtained along with 48 mg of the slower enantiomer (by Example 140) by preparatively preparative-p-HPLC (Method A). ).

Analytical versus palm HPLC: 14.5 min.

Example 140: (S or R)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxypropyl)- 4-methyl-2H-indazole-5-carboxamide

Separation of 158 mg by racemization by means of preparative palmitic HPLC (Method A) The racemate was prepared in Example 138 to afford 48 mg of the title compound as well as 52.

Analytical versus palm HPLC: 17.1 min.

Example 141: (+/-)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(1,4-dioxane-2 -ylmethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 177 mg of the title compound was obtained from 269 mg of the compound of Example 141b and 136 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.49 (3H), 3.13-3.28 (4H), 3.38-3.66 (4H), 3.67-3.77 (2H), 3.89 (1H), 4.08 (1H), 4.19(1H), 4.37(1H), 4.67(2H), 7.15(1H), 7.38(1H), 7.48(2H), 7.59(2H), 8.17(1H), 8.55(1H).

The starting materials were prepared as follows:

Example 141a: (+/-)-3-({5-[N-(1,4-dioxan-2-ylmethyl)aminemethanyl]-4-methyl-2H-indazole-2 -yl}methyl)azetidin-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 364 mg of the title compound was obtained from 323 mg of the compound of Example 117c and 110 mg of 1,4-dioxane-2-ymethylamine.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.33 (9H), 2.50 (3H), 3.09 (1H), 3.16-3.29 (3H), 3.40-3.77 (8H), 3.86 (2H), 4.61 ( 2H), 7.16 (1H), 7.39 (1H), 8.14 (1H), 8.55 (1H).

Example 141b: (+/-)-2-(azetidin-3-ylmethyl)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2H- Oxazole-5-carbamide hydrochloride

Analogously to Example 1a, 314 mg of the title compound was obtained from 314 mg of the compound obtained in Example 141a.

Example 142: (R or S)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(1,4-dioxane-2 -yl-methyl)-4-methyl-2H-indazole-5-carboxamide

60 mg of the title compound was obtained along with 60 mg of the slower enantiomer (by Example 143) by preparatively preparative versus HPLC (Method B). ).

Analytical versus palm HPLC: 5.84 min.

Example 143: (S or R)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(1,4-dioxane-2 -yl-methyl)-4-methyl-2H-indazole-5-carboxamide

60 mg of the title compound was obtained along with 60 mg of the faster-dissolved enantiomer by means of preparative-type palmitic HPLC (Method B) racemic separation from 172 mg of the racemate prepared in Example 141 (Example 142 ).

Analytical versus palm HPLC: 6.28 min.

Example 144: (+/-)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-(3,4, 5,6-tetrahydro-2H-piperidin-2-ylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 144 mg of the title compound was obtained from 254 mg of the compound of Example 144b and 130 mg of 4-chlorobenzamide.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.10-1.23 (1H), 1.35-1.47 (3H), 1.61 (1H), 1.71-1.81 (1H), 2.48 (3H), 3.15-3.27 (4H ), 3.37 (1H), 3.80-3.93 (2H), 4.08 (1H), 4.19 (1H), 4.36 (1H), 4.66 (2H), 7.14 (1H), 7.37 (1H), 7.48 (2H), 7.59 (2H), 8.09 (1H), 8.54 (1H).

The starting materials were prepared as follows:

Example 144a: (+/-)-3-({4-methyl-5-[N-(3,4,5,6-tetrahydro-2H-piperidin-2-ylmethyl)-amine formazan) Tert-butyl]-2H-carbazol-2-yl}methyl)azetidin-1-carboxylate

Analogously to Example 1, 323 mg of the compound obtained in Example 117c and 141 mg of 3,4,5,6-tetrahydro-2H-pyran-2-ylmethylamine hydrochloride gave 342 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.14-1.21 (1H), 1.33 (9H), 1.37-1.49 (3H), 1.61 (1H), 1.71-1.80 (1H), 2.49 (3H), 3.09 (1H), 3.21 (2H), 3.27-3.43 (2H), 3.69 (2H), 3.81-3.91 (3H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.06 (1H), 8.53 (1H).

Example 144b: (+/-)-2-(azetidin-3-ylmethyl)-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2 -yl-methyl)-2H-carbazole-5-carbamide hydrochloride

Analogously to Example 1a, 261 mg of the title compound was obtained from 298 mg.

Example 145: (R or S)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-(3,4, 5,6-tetrahydro-2H-piperidin-2-ylmethyl)-2H-indazole-5-carboxamide

43 mg of the title compound was obtained along with 35 mg of the slower enantiomer by the preparation of the racemate from the preparative type of palmitic HPLC (Method C). ).

Analytical versus palm HPLC: 4.38 min.

Example 146: (S or R)-2-{[1-(4-chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-(3,4, 5,6-tetrahydro-2H-piperidin-2-ylmethyl)-2H-indazole-5-carboxamide

35 mg of the title compound was obtained along with 43 mg of the faster-dissolving enantiomer by means of preparative-type palmitic HPLC (Method C) racemic separation from 140 mg of the racemate prepared in Example 144 (Example 145 ).

Analytical versus palm HPLC: 4.88 min.

Example 147: (+/-)-2-({1-[4-(4-Fluorophenoxy)benzylidenyl]azetidin-3-yl}methyl)-N-(2- Methoxy-propyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 1, a material that was still contaminated after HPLC purification was obtained from 42 mg of the compound prepared in Example 138b and 28 mg of 4-(4-fluorophenoxy)benzoic acid, by additional This was further purified by preparative thick layer chromatography (ethyl acetate/methanol in a ratio of 9:1). Yield in this way: 15 mg of the title compound.

¹ H-NMR (300MHz, CDCl3): δ = 1.22 (3H), 2.64 (3H), 3.28 (1H), 3.36 (3H), 3.40 (1H), 3.57 (1H), 3.76 (1H), 3.97-4.46 (4H), 4.66 (2H), 6.14 (1H), 6.93 (2H), 6.97-7.11 (4H), 7.32 (1H), 7.51 (1H), 7.60 (2H), 8.00 (1H).

Example 148: (+/-)-N-(1,4-dioxan-2-ylmethyl)-2-({1-[4-(4-fluorophenoxy)benzylidene]Nitrogen Heterocyclobutane-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 18 mg of the title compound was obtained from 43 mg of the compound obtained in Example 141b and 26 mg of 4-(4-fluorophenoxy)benzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.49 (3H), 3.13-3.28 (4H), 3.38-3.66 (4H), 3.67-3.77 (2H), 3.89 (1H), 4.07 (1H), 4.19(1H), 4.37(1H), 4.66(2H), 6.94(2H), 7.08-7.18(3H), 7.24(2H), 7.38(1H), 7.60(2H), 8.17(1H), 8.55(1H ).

Example 149: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4 -methyl-2H-carbazole-5-carboxamide

Analogously to Example 55, 72 mg of the title compound was obtained from 127 mg of the compound of Example 149b and 65 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.17 (2H), 0.45 (2H), 0.99 (1H), 2.51-2.54 (3H), 3.20-3.28 (3H), 3.38 (2H), 3.51 ( 2H), 3.92 (1H), 4.11 (1H), 4.21 (1H), 4.39 (1H), 4.69 (2H), 7.18 (1H), 7.40 (1H), 7.50 (2H), 7.62 (2H), 8.12 ( 1H), 8.56 (1H).

The starting materials were prepared as follows:

Example 149a: 3-[(5-{N-[2-(cyclopropylmethoxy)ethyl]aminemethanyl}-4-methyl-2H-indazol-2-yl)methyl]nitrogen Heterocyclic butane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 448 mg of the title compound was obtained from 400 mg of the compound of Example 117c and 133 mg of 2-(cyclopropylmethoxy)ethylamine hydrochloride.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.14 (2H), 0.42 (2H), 0.97 (1H), 1.33 (9H), 2.50 (3H), 3.09 (1H), 3.24 (2H), 3.36 (2H), 3.49 (2H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.08 (1H), 8.54 (1H).

Example 149b: 2-(Azetidin-3-ylmethyl)-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamidine Amine hydrochloride

Analogously to Example 1a, 390 mg of the title compound was obtained from 448 mg of the compound obtained in Example 149a.

Example 150: N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzylidene]azetidin-3- }methyl)-4-methyl-2H-carbazole-5-carboxamide

Similar to Example 1, from 102 mg of the compound prepared in Example 149b and 63 mg of 4- (4-Fluorophenoxy)benzoic acid afforded 48 mg of the title compound.

¹ H-NMR (300MHz, CDCl3): δ = 0.20 (2H), 0.54 (2H), 1.05 (1H), 2.65 (3H), 3.32 (2H), 3.35-3.45 (1H), 3.63-3.75 (4H) , 3.99-4.50 (4H), 4.66 (2H), 6.22 (1H), 6.93 (2H), 6.97-7.11 (4H), 7.34 (1H), 7.51 (1H), 7.61 (2H), 8.00 (1H).

Example 151: N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzylidenyl)azetidin-3-yl ]methyl}-2H-carbazole-5-carboxamide

Analogously to Example 1, 55 mg of the title compound was obtained from 127 mg of the compound of Example 149b and 46 mg of 4-methylbenzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.17 (2H), 0.45 (2H), 0.99 (1H), 2.33 (3H), 2.53 (3H), 3.19-3.28 (3H), 3.38 (2H) , 3.51 (2H), 3.90 (1H), 4.09 (1H), 4.20 (1H), 4.38 (1H), 4.69 (2H), 7.18 (1H), 7.24 (2H), 7.41 (1H), 7.50 (2H) , 8.11 (1H), 8.57 (1H).

Example 152: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)B ]]-2H-carbazole-5-carbamide

Analogously to Example 55, 122 mg of the title compound was obtained from 234 mg of the compound of Example 152b and 115 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.52 (3H), 3.25 (1H), 3.54 (2H), 3.93 (1H), 4.11 (1H), 4.17-4.25 (3H), 4.40 (1H) , 4.70 (2H), 7.19 (1H), 7.43 (1H), 7.50 (2H), 7.61 (2H), 8.38 (1H), 8.58 (1H).

The starting materials were prepared as follows:

Example 152a: 3-[(4-Methyl-5-{N-[2-(trifluoromethoxy)ethyl]aminemethanyl}-2H-indazol-2-yl)methyl]aza Cyclobutane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 272 mg of the title compound was obtained from 250 mg of the compound obtained in Example 117c and 120 mg of 2-(trifluoromethoxy)ethylamine hydrochloride.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.32 (9H), 2.50 (3H), 3.08 (1H), 3.51 (2H), 3.70 (2H), 3.86 (2H), 4.17 (2H), 4.61 (2H), 7.16 (1H), 7.41 (1H), 8.36 (1H), 8.56 (1H).

Example 152b: 2-(Azetidin-3-ylmethyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide Hydrochloride

Analogously to Example 1a, 240 mg of the title compound was obtained from 272 mg of the compound obtained in Example 152a, which was carried out without further purification.

Example 153: N-(2-Tertioxyethyl)-2-{[1-(4-chlorobenzylidenyl)azetidin-3-yl]methyl}-4-methyl -2H-carbazole-5-carboxamide

Analogously to Example 55, 12 mg of the title compound was obtained from 160 mg of the compound of Example 153b and 81 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.14 (9H), 2.53 (3H), 3.19-3.34 (3H), 3.43 (2H), 3.92 (1H), 4.11 (1H), 4.21 (1H) , 4.39 (1H), 4.69 (2H), 7.18 (1H), 7.40 (1H), 7.50 (2H), 7.62 (2H), 8.05 (1H), 8.56 (1H).

The starting materials were prepared as follows:

Example 153a: 3-({5-[N-(2-Tertibutoxyethyl)amine-carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)azacyclocycle Butane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 284 mg of the title compound was obtained from 250 mg of the compound obtained in Example 117c and 111 mg of 2-t-butoxyethylamine hydrochloride.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.11 (9H), 1.32 (9H), 2.50 (3H), 3.08 (1H), 3.27 (2H), 3.40 (2H), 3.69 (2H), 3.86 (2H), 4.60 (2H), 7.15 (1H), 7.38 (1H), 8.04 (1H), 8.54 (1H).

Example 153b: 2-(Azetidin-3-ylmethyl)-N-(2-tert-butoxyethyl)-4-methyl-2H-indazole-5-carboxamide hydrochloride salt

Analogously to Example 1a, 240 mg of the title compound was obtained from 284 mg of the compound obtained in Example 153a.

Example 154: (+/-)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-[2-(cyclobutoxy)propane 4-methyl-2H-carbazole-5-carboxamide

Analogously to Example 55, 135 mg of the title compound was obtained from 222 mg of the compound of Example 154d and 109 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.05 (3H), 1.39 (1H), 1.55 (1H), 1.80 (2H), 2.11 (2H), 2.50 (3H), 3.08-3.23 (3H) , 3.55 (1H), 3.89 (1H), 4.03-4.13 (1H), 4.19 (1H), 4.37 (1H), 4.67 (2H), 7.15 (1H), 7.38 (1H), 7.48 (2H), 7.59 ( 2H), 8.07 (1H), 8.53 (1H).

The starting materials were prepared as follows:

Example 154a: (+/-)-2-(cyclobutoxy)-propanamide

To a suspension of 732 mg of sodium hydride in 15 ml of THF was added dropwise 2.0 g of cyclobutanol in 0.5 ml of THF and stirred at 25 ° C for 30 minutes. The reaction mixture was then cooled to 0 ° C and 2.11 g (+/-) 2-bromopropionamide in 0.5 ml of tetrahydrofuran was added dropwise and then stirred at 25 ° C for 18 hours. The reaction mixture was poured onto ice water and extracted once with 75 mL dichloromethane. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The crude product thus obtained was purified by column chromatography on silica gel eluting with hexane / 0-50% ethyl acetate. Yield: 0.79 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.14 (3H), 1.38 (1H), 1.56 (1H), 1.83 (2H), 2.08 (2H), 3.62 (1H), 3.90 (1H), 7.07 (2H).

Example 154b: (+/-)-N-[2-(cyclobutoxy)propyl]carbamic acid tert-butyl ester

6.5 g of the guanamine prepared in Example 154a was carefully added dropwise to a suspension of 6.9 g of lithium aluminum hydride in 250 ml of THF at 0 °C. Subsequently, the mixture was first stirred at 0 ° C for 30 minutes and then heated under reflux for 5 hours. After cooling, the mixture was carefully treated with 20 g of sodium sulfate decahydrate and 20 g of potassium fluoride and the solid matter was removed by filtration later. The filtrate was concentrated in vacuo. The residue thus obtained (5.8 g) was dissolved in 174 ml of dichloromethane and treated with 11.9 g of di-t-butyl-dicarbonate, without further purification. After stirring at 25 ° C for 16 hours, this was concentrated in vacuo and EtOAc EtOAc EtOAc EtOAc Yield: 8.54 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.94 (3H), 1.28-1.42 (10H), 1.53 (1H), 1.76 (2H), 2.07 (2H), 2.76 (1H), 2.90 (1H) , 3.34 (1H), 3.92 (1H), 6.72 (1H).

Example 154c: (+/-)-3-[(5-{N-[2-(cyclobutoxy)propyl]aminemethanyl}-4-methyl-2H-indazol-2-yl) Methyl]azetidin-1-carboxylic acid tert-butyl ester

Analogously to Example 1a, 2-(cyclobutoxy)propylamine as the hydrochloride salt was obtained from 200 mg of the compound obtained in Example 154b, which was produced without further purification, together with 250 mg of the compound of Example 117c. 259 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.05 (3H), 1.32 (9H), 1.39 (1H), 1.55 (1H), 1.80 (2H), 2.11 (2H), 2.50 (3H), 3.02 -3.17(2H), 3.22(1H), 3.54(1H), 3.69(2H), 3.86(2H), 3.99(1H), 4.61(2H), 7.15(1H), 7.39(1H), 8.09(1H) , 8.55 (1H).

Example 154d: (+/-)-2-(azetidin-3-ylmethyl)-N-[2-(cyclobutoxy)propyl]-4-methyl-2H-indazole- 5-methanamine hydrochloride

Analogously to Example 1a, 225 mg of the title compound was obtained from 259 mg of the compound of Example 154c.

Example 155: (S or R)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-[2-(cyclobutoxy)- Propyl]-4-methyl-2H-indazole-5-carboxamide

41 mg of the title compound was obtained by dissolving the racemate in 154 mg from 135 mg by preparative palmer HPLC (Method A). Slow enantiomer (Example 156).

Analytical versus palm HPLC: 10.05 min.

Example 156: (R or S)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-[2-(cyclobutoxy)- Propyl]-4-methyl-2H-indazole-5-carboxamide

21 mg of the title compound was obtained along with 41 mg of the faster-dissolved enantiomer by means of preparative-type palmitic HPLC (Method A) racemic separation from 135 mg of the racemate prepared in Example 154 (Example 155 ).

Analytical versus palm HPLC: 13.14 min.

Example 157 : N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)azetidin-3-yl }Methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 54 mg of the title compound was obtained from 102 mg of the compound of Example 149b and 58 mg of 4'-fluorobiphenyl-4-carboxylic acid.

^{1 H-NMR (300MHz, CDCl3} ): δ = 0.20 (2H), 0.54 (2H), 1.05 (1H), 2.66 (3H), 3.32 (2H), 3.42 (1H), 3.61-3.73 (4H), 4.09 (1H), 4.28 (1H), 4.38 (1H), 4.49 (1H), 4.69 (2H), 6.22 (1H), 7.10-7.18 (2H), 7.26 (2H), 7.35 (1H), 7.50-7.59 ( 3H), 7.70 (2H), 8.01 (1H).

Example 158: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 54 mg of the title compound was obtained from 108 mg of the compound obtained in Example 117e and 69 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (300MHz, DMSO-d6): δ=2.49 (3H), 3.17-3.29 (4H), 3.36 (2H), 3.43 (2H), 3.92 (1H), 4.11 (1H), 4.24 (1H) , 4.42 (1H), 4.68 (2H), 7.15 (1H), 7.29 (2H), 7.39 (1H), 7.63-7.78 (6H), 8.12 (1H), 8.56 (1H).

Example 159: 2-({1-[4-(4-Fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 28 mg of the title compound was obtained from 108 mg of the compound obtained in Example 117e and 74 mg of 4-(4-fluorophenoxy)benzoic acid.

¹ H-NMR (300 MHz, CDCl 3 ): δ = 2.65 (3H), 3.31-3.46 (4H), 3.58 (2H), 3.67 (2H), 4.06 (1H), 4.24 (1H), 4.40 (2H), 4.66 (2H), 6.15 (1H), 6.89-7.13 (6H), 7.33 (1H), 7.51 (1H), 7.61 (2H), 8.00 (1H).

Example 160: 2-({1-[4-(4-Fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-4-methyl-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 47 mg of the title compound was obtained from 115 mg of the compound obtained in Example 129b and 74 mg of 4-(4-fluorophenoxy)benzoic acid.

¹ H-NMR (300MHz, CDCl3): δ = 2.65 (3H), 3.39 (1H), 3.97-4.52 (6H), 4.67 (2H), 6.04 (1H), 6.89-7.12 (6H), 7.31 (1H) , 7.53 (1H), 7.60 (2H), 8.03 (1H).

Example 161: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 28 mg of the title compound was obtained from 115 mg of the compound of Example 129b and 69 mg of 4'-fluorobiphenyl-4-carboxylic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.65 (3H), 3.42 (1H), 4.01-4.54 (6H), 4.69 (2H), 6.02 (1H), 7.15 (2H), 7.32 (1H) , 7.51-7.62 (5H), 7.69 (2H), 8.04 (1H).

Example 162: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-[2-(2,2,2-tri) Fluoro-ethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 197 mg of the title compound was obtained from 252 mg of the compound of Example 162a and 108 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=2.49 (3H), 3.22 (1H), 3.40 (2H), 3.69 (2H), 3.90 (1H), 4.03-4.13 (3H), 4.19 (1H) , 4.37 (1H), 4.67 (2H), 7.15 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 8.19 (1H), 8.55 (1H).

The starting materials were prepared as follows:

Example 162a: 2-(Azetidin-3-ylmethyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-carbazole -5-methionine hydrochloride

Similar to Example 1a, 505 was obtained from 583 mg of the compound prepared in Example 162b. Mg title compound which was subjected to further reaction without purification.

Example 162b: 3-[(4-Methyl-5-{N-[2-(2,2,2-trifluoroethoxy)ethyl]aminemethanyl}-2H-indazol-2-yl )methyl]azetidin-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 580 mg of the title compound was obtained from 500 mg of the compound of Example 117c and 260 mg of 2-(2,2,2-trifluoroethoxy)ethylamine hydrochloride.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.32 (9H), 2.50 (3H), 3.08 (1H), 3.40 (2H), 3.61-3.76 (4H), 3.86 (2H), 4.07 (2H) , 4.61 (2H), 7.15 (1H), 7.39 (1H), 8.18 (1H), 8.55 (1H).

Example 163: 4-Methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy) Benzomethane}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 89 mg of the title compound was obtained from 252 mg of the compound of Example 162a and 175 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.49 (3H), 3.23 (1H), 3.40 (2H), 3.69 (2H), 3.90 (1H), 4.01-4.14 (3H), 4.21 (1H) , 4.40 (1H), 4.68 (2H), 7.11 (2H), 7.15 (1H), 7.20 (2H), 7.39 (1H), 7.66 (2H), 7.75 (2H), 8.19 (1H), 8.56 (1H) .

Example 164: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene] Azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, from 225 mg of the compound obtained in Example 129b and 149 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid afforded the title compound.

¹ H-NMR (300MHz, DMSO-d6): δ=2.50 (3H), 3.24 (1H), 3.91 (1H), 3.95-4.15 (3H), 4.22 (1H), 4.40 (1H), 4.69 (2H) , 7.11 (2H), 7.15-7.23 (3H), 7.43 (1H), 7.66 (2H), 7.75 (2H), 8.60 (1H), 8.79 (1H).

Example 165: 2-({1-[4-(4-Chlorophenoxy)benzylidenyl]azetidin-3-yl}methyl)-4-methyl-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 97 mg of the title compound was obtained from 225 mg of the compound of Example 129b and 131 mg of 4-(4-chlorophenoxy)benzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.50 (3H), 3.23 (1H), 3.90 (1H), 3.96-4.12 (3H), 4.20 (1H), 4.38 (1H), 4.68 (2H) , 7.00 (2H), 7.09 (2H), 7.18 (1H), 7.40-7.48 (3H), 7.62 (2H), 8.60 (1H), 8.79 (1H)

Example 166: 2-({1-[4-(4-Chlorophenoxy)benzylidenyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

Similar to Example 1, from 225 mg of the compound prepared in Example 117e and 140 mg of 4- (4-Chlorophenoxy)benzoic acid afforded 99 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.49 (3H), 3.16-3.27 (4H), 3.36 (2H), 3.42 (2H), 3.89 (1H), 4.08 (1H), 4.19 (1H) , 4.38 (1H), 4.67 (2H), 7.00 (2H), 7.09 (2H), 7.15 (1H), 7.38 (1H), 7.45 (2H), 7.62 (2H), 8.12 (1H), 8.55 (1H) .

Example 167: 2-({1-[(5-Fluoro-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl- N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 48 mg of the title compound was obtained from 180 mg of the compound obtained in Example 129b and 82 mg of 5-fluoro-1-methyl-1H-indole-2-carboxylic acid.

¹ H-NMR (300MHz, CDCl3): δ=2.66 (3H), 2.80 (3H), 3.36-3.51 (1H), 4.01 (3H), 4.04-4.63 (6H), 4.70 (2H), 6.03 (1H) , 6.68 (1H), 7.08 (1H), 7.22-7.36 (3H), 7.55 (1H), 8.05 (1H),

Example 168: 2-({1-[(5-Methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl ke-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, from 180 mg of the compound obtained in Example 129b and 87 mg of 5-methoxy-1-methyl-1H-indole-2-carboxylic acid gave 15 mg of the title compound.

¹ H-NMR (300MHz, CDCl3): δ = 2.66 (3H), 3.43 (1H), 3.84 (3H), 4.00 (3H), 4.03-4.59 (6H), 4.70 (2H), 6.02 (1H), 6.66 (1H), 7.02 (1H), 7.27-7.35 (3H), 7.56 (1H), 8.06 (1H).

Example 169: 2-({1-[(6-Methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl ke-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 57 mg of the title compound was obtained from 180 mg of the compound obtained in Example 129b and 87 mg of 6-methoxy-1-methyl-1H-indole-2-carboxylic acid.

¹ H-NMR (300MHz, CDCl3): δ = 2.66 (3H), 3.43 (1H), 3.89 (3H), 3.99 (3H), 4.05-4.60 (6H), 4.70 (2H), 6.01 (1H), 6.69 (1H), 6.77 (1H), 6.81 (1H), 7.32 (1H), 7.48 (1H), 7.56 (1H), 8.05 (1H).

Example 170: 2-({1-[(5-Fluoro-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 95 mg of the title compound was obtained from 180 mg of the compound obtained in Example 117e and 87 mg of 5-fluoro-1-methyl-1H-indole-2-carboxylic acid.

¹ H-NMR (300MHz, CDCl3): δ=2.65 (3H), 3.35-3.51 (4H), 3.58 (2H), 3.67 (2H), 4.01 (3H), 4.02-4.62 (4H), 4.69 (2H) , 6.15 (1H), 6.68 (1H), 7.08 (1H), 7.21-7.38 (3H), 7.53 (1H), 8.02 (1H).

Example 171: 2-({1-[(5-Chloro-1-methyl-1H-indol-2-yl)carbonyl]azetidin-3-yl}methyl)-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 90 mg of the title compound was obtained from 180 mg of the compound obtained in Example 117e and 95 mg of 5-chloro-1-methyl-1H-indole-2-carboxylic acid.

¹ H-NMR (300MHz, CDCl3): δ = 2.66 (3H), 3.37-3.49 (4H), 3.58 (2H), 3.67 (2H), 4.00 (3H), 4.08 (1H), 4.37 (2H), 4.56 (1H), 4.70 (2H), 6.15 (1H), 6.66 (1H), 7.27-7.38 (3H), 7.53 (1H), 7.58 (1H), 8.02 (1H).

Example 172: N-(2-Methoxyethyl)-2-({1-[(5-methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidine -3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 86 mg of the title compound was obtained from 180 mg of the compound obtained in Example 117e and 93 mg of 5-methoxy-1-methyl-1H-indole-2-carboxylic acid.

¹ H-NMR (300MHz, CDCl3): δ = 2.65 (3H), 3.36-3.50 (4H), 3.58 (2H), 3.67 (2H), 3.84 (3H), 4.00 (3H), 4.07 (1H), 4.35 (2H), 4.55 (1H), 4.69 (2H), 6.15 (1H), 6.66 (1H), 6.97-7.06 (2H), 7.28 (1H), 7.34 (1H), 7.53 (1H), 8.02 (1H) .

Example 173: N-(2-Methoxyethyl)-2-({1-[(6-methoxy-1-methyl-1H-indol-2-yl)carbonyl]azetidine -3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 97 mg of the title compound was obtained from 180 mg of the compound obtained in Example 117e and 93 mg of 6-methoxy-1-methyl-1H-indole-2-carboxylic acid.

¹ H-NMR (300MHz, CDCl3): δ = 2.66 (3H), 3.37-3.47 (4H), 3.58 (2H), 3.67 (2H), 3.89 (3H), 3.99 (3H), 4.02-4.60 (4H) , 4.69 (2H), 6.15 (1H), 6.69 (1H), 6.77 (1H), 6.81 (1H), 7.34 (1H), 7.48 (1H), 7.53 (1H), 8.02 (1H).

Example 174: N-(2-Methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl Indenyl)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 66 mg of the title compound was obtained from 135 mg of the compound obtained in Example 117e and 96 mg of 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzoic acid.

¹ H-NMR (300MHz, DMSO-d6): δ=2.50 (3H), 3.18-3.27 (4H), 3.36 (2H), 3.42 (2H), 3.91 (1H), 4.10 (1H), 4.24 (1H) , 4.42 (1H), 4.68 (2H), 7.15 (1H), 7.24 (2H), 7.28 (1H), 7.39 (1H), 7.67 (2H), 8.12 (1H), 8.24 (1H), 8.56 (2H) .

Example 175: N-(2-Methoxyethyl)-2-{[1-(7-methoxy-2-naphthylmethyl)azetidin-3-yl]methyl}-4 -methyl-2H-carbazole-5-carboxamide

Analogously to Example 1, 72 mg of the title compound was obtained from 135 mg of the compound of Example 117e and 69 mg of 7-methoxy-naphthalene-2-carboxylic acid.

¹ H-NMR (300 MHz, DMSO-d6): δ=2.50 (3H), 3.21-3.28 (4H), 3.36 (2H), 3.42 (2H), 3.85 (3H), 3.93-3.99 (1H), 4.14 ( 1H), 4.26 (1H), 4.47 (1H), 4.69 (2H), 7.15 (1H), 7.22 (1H), 7.38 (1H), 7.43 (1H), 7.50 (1H), 7.81-7.88 (2H), 8.05 (1H), 8.12 (1H), 8.56 (1H).

Example 176: N-(2-Methoxyethyl)-2-{[1-(6-methoxy-2-naphthylmethyl)azetidin-3-yl]methyl}-4 -methyl-2H-carbazole-5-carboxamide

Similar to Example 1, from 135 mg of the compound prepared in Example 117e and 69 mg of 6- Methoxynaphthalene-2-carboxylic acid gave 72 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ = 2.49 (3H), 3.21-3.28 (4H), 3.33 - 3.39 (2H), 3.42 (2H), 3.86 (3H), 3.91-3.98 (1H), 4.13(1H), 4.27(1H), 4.48(1H), 4.69(2H), 7.15(1H), 7.19(1H), 7.34(1H), 7.38(1H), 7.63(1H), 7.82(1H), 7.92 (1H), 8.08-8.14 (2H), 8.56 (1H).

Example 177: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy }benzylidene)azetidin-3-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 68 mg of the title compound was obtained from 170 mg of the compound of Example 129b and 113 mg of 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid.

¹ H-NMR (300 MHz, DMSO-d6): δ= 2.35 (3H), 3.21 (1H), 3.89 (1H), 3.96-4.13 (3H), 4.21. (1H), 4.40 (1H), 4.68 (2H) , 7.24 (2H), 7.28 (1H), 7.40 (1H), 7.66 (2H), 7.72 (1H), 8.24 (1H), 8.48 (1H), 8.56 (1H), 8.89 (1H).

Example 178: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H -carbazole-5-carboxamide

Analogously to Example 55, 154 mg of the title compound was obtained from 210 mg of the compound of Example 178e and 119 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.19 (1H), 3.24 (3H), 3.34 (2H), 3.42 (2H), 3.87 (1H), 4.07 (1H), 4.16 (1H), 4.34 (1H), 4.65 (2H), 7.35 (1H), 7.48 (2H), 7.59 (2H), 7.63 (1H), 8.21 (1H), 8.41 (1H).

The starting materials were prepared as follows:

Example 178a: 3-[(5-Bromo-6-methyl-2H-indazol-2-yl)methyl]azetidin-1-carboxylic acid tert-butyl ester

To 6.18 g of 5-bromo-6-methyl-1H-indazole and 15 g of tert-butyl 3-[(tosyloxy)methyl]azetidin-1-carboxylate at 25 ° C To the solution in 200 ml of DMF, 9.54 g of cesium carbonate and 10.8 g of tetrabutylammonium iodide were added, and then this was heated under reflux for 1.5 hours. After cooling, the reaction mixture was treated with 1:1 hexanes / ether and water, and the phases were separated and the aqueous phase was extracted twice with 250 ml of 1:1 hexanes / ether. The combined organic phases were washed with aq.

The residue thus obtained was purified by double column chromatography on silica gel eluting with hexane/0-20% ethyl acetate. 2.88 g of the title compound were obtained.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.32 (9H), 2.37 (3H), 3.05 (1H), 3.67 (2H), 3.85 (2H), 4.59 (2H), 7.56 (1H), 7.97 (1H), 8.33 (1H).

Example 178b: methyl 2-{[1-(t-butoxycarbonyl)azetidin-3-yl]methyl}-6-methyl-2H-indazole-5-carboxylate

To a solution of 730 mg of the bromide prepared in Example 178a in 17.5 ml of tetrahydrofuran, 0.23 ml of methanol, 145 mg of trans-bis(acetate)-bis[o-(tert-tolylphosphino)-benzyl]dipalladium ( II), 877 mg DBU and 760 mg hexacarbonyl molybdenum. The reaction mixture was then heated in a microwave (120 watts) at 125 °C for 20 minutes. Seven more preparations were made in the same manner and all were processed together. In this regard, it was concentrated in vacuo and the residue was dissolved in water and ethyl acetate. After phase separation, the aqueous phase was used with 75 ml of acetic acid per serving. The ethyl ester was extracted three times and the combined organic phases were washed with sat. The residue thus obtained was purified by double column chromatography on silica gel eluting with hexane / 0-30% ethyl acetate. Yield: 4.0 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.52 (3H), 3.07 (1H), 3.69 (2H), 3.86 (2H), 3.78 (3H), 4.62 (2H), 7.43 (1H), 8.33 (1H), 8.53 (1H).

Example 178c: 2-{[1-( Tertibutoxycarbonyl )azetidin-3-yl]methyl}-6-methyl-2H-indazole-5-carboxylic acid

Analogously to Example 1d, 3.2 g of the title compound was obtained from 4.0 g of the compound obtained in Example 178b.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.53 (3H), 3.07 (1H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.39 (1H), 8.31 (1H), 8.50 (1H), 12.48 (1H).

Example 178d: 3-({5-[N-(2-methoxyethyl) aminemethanyl ]-6-methyl-2H-indazol-2-yl}-methyl)azetidine 1-butylic acid tert-butyl ester

Analogously to Example 1, 603 mg of the title compound was obtained from 500 mg of the acid from 178c.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.34 (3H), 3.06 (1H), 3.25 (3H), 3.32-3.45 (4H), 3.67 (2H), 3.84 (2H) , 4.59 (2H), 7.35 (1H), 7.64 (1H), 8.21 (1H), 8.41 (1H).

Example 178e: 2-(Azetidin-3-ylmethyl)-N-(2-methoxyethyl)-6-methyl-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 275 mg of the title compound was obtained from 250 mg of the title compound of y.

Example 179: 2-{[1-(3,5-Difluorobenzimidyl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6-A -2-H-carbazole-5-carbamide

Analogously to Example 55, 51 mg of the title compound was obtained from &lt

¹ H-NMR (300MHz, DMSO-d6): δ=2.33 (3H), 3.18 (1H), 3.24 (3H), 3.34 (2H), 3.42 (2H), 3.87 (1H), 4.03-4.11 (1H) , 4.20 (1H), 4.38 (1H), 4.65 (2H), 7.20-7.28 (2H), 7.34 (1H), 7.36-7.45 (2H), 7.64 (1H), 8.22 (1H), 8.42 (1H).

Example 180: N-(2-Methoxyethyl)-6-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidene] azetidine- 3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 30 mg of the title compound was obtained from 43 mg of the compound of Example 178e and 34 mg of 4-[(trifluoromethyl)thio]benzhydryl chloride.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.20 (1H), 3.24 (3H), 3.34 (2H), 3.42 (2H), 3.89 (1H), 4.09 (1H), 4.17 (1H), 4.36 (1H), 4.65 (2H), 7.34 (1H), 7.63 (1H), 7.69 (2H), 7.76 (2H), 8.21 (1H), 8.41 (1H).

Example 181: N-(2-Methoxyethyl)-6-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3-yl }methyl)-2H-carbazole-5-carboxamide

Analogously to Example 55, 221 mg of the title compound was obtained from 294 mg of the compound of Example 178e and 214 mg of 4-(trifluoromethoxy) benzindole chloride.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.20 (1H), 3.25 (3H), 3.34 (2H), 3.42 (2H), 3.89 (1H), 4.08 (1H), 4.18 (1H), 4.36 (1H), 4.65 (2H), 7.35 (1H), 7.40 (2H), 7.64 (1H), 7.70 (2H), 8.21 (1H), 8.42 (1H).

Example 182: 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidenyl]azetidin-3-yl}methyl)-N-(2-methoxy- Ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 11 mg of the title compound was obtained from 43 mg of the compound of Example 178e and 32 mg of 2-fluoro-4-(trifluoromethyl) benzindole.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.33 (3H), 3.20 (1H), 3.24 (3H), 3.35 (2H), 3.42 (2H), 3.86-3.95 (2H), 4.02-4.16 ( 2H), 4.65 (2H), 7.34 (1H), 7.61-7.69 (3H), 7.79 (1H), 8.21 (1H), 8.41 (1H).

Example 183: 2-{[1-(4-Chloro-2-fluorobenzhydryl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6- methyl-2H-carbazole-5-carbamide

Similar to Example 55, a material that was still contaminated after HPLC purification was obtained from 70 mg of the compound prepared in Example 178e and 44 mg of 4-chloro-2-fluorobenzhydrin chloride by additional preparative thick layer chromatography (in ratio) It was further purified by a 9:1 ethyl acetate/methanol as the mobile phase. This gave 12 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ= 2.34 (3H), 3.19 (1H), 3.25 (3H), 3.34 (2H), 3.42 (2H), 3.84-3.93 (2H), 4.02-4.10 ( 2H), 4.64 (2H), 7.32-7.36 (2H), 7.46 (1H), 7.53 (1H), 7.63 (1H), 8.22 (1H), 8.41 (1H).

Example 184: 2-({1-[3-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxy- Ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, from &lt;RTI ID=0.0&gt;&gt;&gt;&gt;

¹ H-NMR (300MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.24 (3H), 3.30-3.38 (2H), 3.42 (2H), 3.90 (1H), 4.10 (1H) , 4.19 (1H), 4.38 (1H), 4.66 (2H), 7.34 (1H), 7.57 (1H), 7.60-7.67 (2H), 7.85 (1H), 8.21 (1H), 8.41 (1H).

Example 185: 2-({1-[4-Chloro-3-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxy- Ethyl)-6-methyl-2H-indazole-5-carboxamide

Analogously to Example 55, 30 mg of the title compound was obtained from 70 mg of the compound of Example 178e and 55 mg of 4-chloro-3-(trifluoromethyl) benzindole.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.19 (1H), 3.24 (3H), 3.34 (2H), 3.42 (2H), 3.89 (1H), 4.10 (1H), 4.20 (1H), 4.35-4.43 (1H), 4.65 (2H), 7.33 (1H), 7.64 (1H), 7.78 (1H), 7.85 (1H), 7.93 (1H), 8.21 (1H), 8.40 (1H) .

Example 186: N-(2-Methoxyethyl)-6-methyl-2-({1-[4-(trifluoromethyl)benzylidene]azetidin-3-yl} Methyl)-2H-carbazole-5-carboxamide

Analogously to Example 55, 31 mg of the title compound was obtained from 70 mg of the compound of Example 178e and 47 mg of 4-(trifluoromethyl) benzindole.

¹ H-NMR (300MHz, DMSO-d6): δ=2.34 (3H), 3.20 (1H), 3.24 (3H), 3.35 (2H), 3.42 (2H), 3.90 (1H), 4.06-4.21 (2H) , 4.35 (1H), 4.66 (2H), 7.34 (1H), 7.63 (1H), 7.73-7.82 (4H), 8.21 (1H), 8.41 (1H).

Example 187: 6-Methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]azetidin-3-yl}methyl)-N-{2 -[(trifluoromethyl)thio]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 35 mg of the title compound was obtained from 170 mg of the compound of Example 187b and 103 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid.

¹ H-NMR (300 MHz, DMSO-d6): δ= 2.36 (3H), 3.12-3.23 (3H), 3.49 (2H), 3.91 (1H), 4.06-4.21 (2H), 4.36 (1H), 4.66 ( 2H), 7.36 (1H), 7.69 (1H), 7.76 (2H), 7.95 (2H), 8.44 (1H), 8.46 (1H).

The starting materials were prepared as follows:

Example 187a: 3-{[6-Methyl-5-(N-{2-[(trifluoromethyl)thio]ethyl}aminecarboxy)-2H-indazol-2-yl]methyl }Azetidine-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 998 mg of the title compound was obtained from 800 mg of the acid from 178 s.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.32 (9H), 2.36 (3H), 3.06 (1H), 3.13 - 3.21 (2H), 3.49 (2H), 3.67 (2H), 3.84 (2H) , 4.59 (2H), 7.37 (1H), 7.70 (1H), 8.44 (1H), 8.47 (1H).

Example 187b: 2-(Azetidin-3-ylmethyl)-6-methyl-N-{2-[(trifluoromethyl)thio]ethyl}-2H-indazole-5- Formamide hydrochloride

Analogously to Example 1a, 402 mg of the title compound was obtained from 395 g.

Example 188: 6-Methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]azetidin-3-yl}methyl)-N-(2 ,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1, from 136 mg of the compound obtained in Example 188b and 93 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid afforded 25 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.20 (1H), 3.91 (1H), 3.95-4.21 (4H), 4.36 (1H), 4.67 (2H), 7.38 (1H) , 7.71 (1H), 7.76 (2H), 7.95 (2H), 8.45 (1H), 8.86 (1H).

The starting materials were prepared as follows:

Example 188a: 3-({6-Methyl-5-[N-(2,2,2-trifluoroethyl)aminemethanyl]-2H-indazol-2-yl}methyl)azacyclocycle Butane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 560 mg of the title compound was obtained from 560 mg of the acid from 178c, and 160 mg of 2,2,2-trifluoroethylamine.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.34 (3H), 3.06 (1H), 3.67 (2H), 3.84 (2H), 3.93-4.10 (2H), 4.60 (2H) , 7.40 (1H), 7.71 (1H), 8.46 (1H), 8.88 (1H).

Example 188b: 2-(Azetidin-3-ylmethyl)-6-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide Acid salt

Analogously to Example 1a, 530 mg of the title compound was obtained from 550 mg of dec.

Example 189: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-6-methyl-N-{2-[(trifluoromethyl)sulfide Ethyl}ethyl}-2H-carbazole-5-carboxamide

Analogously to Example 55, 45 mg of the title compound was obtained from 170 mg of the compound of Example 187b and 80 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.39 (3H), 3.17-3.27 (3H), 3.52 (2H), 3.90 (1H), 4.10 (1H), 4.19 (1H), 4.37 (1H) , 4.68 (2H), 7.39 (1H), 7.50 (2H), 7.61 (2H), 7.72 (1H), 8.47 (1H), 8.49 (1H).

Example 190: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-6-methyl-N-(2,2,2-trifluoroethyl )-2H-carbazole-5-carbamide

Analogously to Example 55, 60 mg of the title compound was obtained from 136 mg of the compound of Example 188b and 72 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.20 (1H), 3.87 (1H), 3.94-4.11 (3H), 4.16 (1H), 4.35 (1H), 4.66 (2H) , 7.39 (1H), 7.48 (2H), 7.59 (2H), 7.71 (1H), 8.46 (1H), 8.89 (1H).

Example 191: (+/-)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-6-methyl-N-(3,4, 5,6-tetrahydro-2H-piperidin-2-ylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 49 mg of the title compound was obtained from 120 mg of the compound of Example 191b and 61 mg of 4-chlorobenzamide.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.08-1.23 (1H), 1.36-1.49 (3H), 1.62 (1H), 1.72-1.80 (1H), 2.34 (3H), 3.10-3.43 (5H) ), 3.80-3.92 (2H), 4.07 (1H), 4.16 (1H), 4.34 (1H), 4.65 (2H), 7.34 (1H), 7.47 (2H), 7.59 (2H), 7.63 (1H), 8.16 (1H), 8.40 (1H).

The starting materials were prepared as follows:

Example 191a: (+/-)-3-({6-methyl-5-[N-(3,4,5,6-tetrahydro-2H-piperidin-2-ylmethyl)-amine-carboxamidine Tert-butyl]-2H-carbazol-2-yl}methyl)azetidin-1-carboxylate

Similar to Example 1, from 300 mg of the acid prepared in Example 178c and 105 mg of 3,4,5,6- Tetrahydro-2H-piperidin-2-ylmethylamine gave 140 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.07-1.24 (1H), 1.27-1.49 (12H), 1.62 (1H), 1.76 (1H), 2.33 (3H), 3.06 (1H), 3.20 ( 2H), 3.29-3.45 (2H), 3.67 (2H), 3.78-3.90 (3H), 4.59 (2H), 7.35 (1H), 7.63 (1H), 8.16 (1H), 8.40 (1H).

Example 191b: (+/-)-2-(azetidin-3-ylmethyl)-6-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2 -ylmethyl)-2H-carbazole-5-carbamide hydrochloride

Analogously to Example 1a, 132 mg of the title compound was obtained from EtOAc (m.

Example 192: (+/-)-2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxypropyl)- 6-methyl-2H-carbazole-5-carboxamide

Analogously to Example 55, 89 mg of the title compound was obtained from 151 mg of the compound of Example 192b and 82 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ = 1.08 (3H), 2.34 (3H), 3.13-3.32 (6H), 3.43 (1H), 3.87 (1H), 4.07 (1H), 4.16 (1H) , 4.34 (1H), 4.65 (2H), 7.35 (1H), 7.48 (2H), 7.59 (2H), 7.63 (1H), 8.18 (1H), 8.41 (1H).

The starting materials were prepared as follows:

Example 192a: (+/-)-3-({5-[N-(2-methoxypropyl)aminemethanyl]-6-methyl-2H-indazol-2-yl}methyl) Azetidine-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 358 mg of the title compound was obtained from 300 mg of the acid from 178c and 77 mg of 2-methoxypropan-1-amine.

¹ H-NMR (300MHz, DMSO-d6): δ = 1.08 (3H), 1.32 (9H), 2.34 (3H), 3.06 (1H), 3.13-3.31 (5H), 3.43 (1H), 3.67 (2H) , 3.84 (2H), 4.59 (2H), 7.35 (1H), 7.64 (1H), 8.18 (1H), 8.40 (1H).

Example 192b: (+/-)-2-(azetidin-3-ylmethyl)-N-(2-methoxypropyl)-6-methyl-2H-indazole-5-A Indoleamine hydrochloride

Analogously to Example 1a, 319 mg of the title compound was obtained from 358 mg of the title compound of </RTI>

Example 193: (+/-)-N-(2-methoxypropyl)-6-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]-aza Cyclobutane-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 87 mg of the title compound was obtained from 151 mg of the compound of Example 192b and 106 mg of 4-(trifluoromethoxy) benzhydrin chloride.

¹ H-NMR (300MHz, DMSO-d6): δ = 1.08 (3H), 2.34 (3H), 3.13-3.31 (6H), 3.43 (1H), 3.88 (1H), 4.08 (1H), 4.17 (1H) , 4.36 (1H), 4.65 (2H), 7.35 (1H), 7.40 (2H), 7.64 (1H), 7.70 (2H), 8.18 (1H), 8.41 (1H).

Example 194: 6-Methyl-2-({1-[4-(trifluoromethoxy)benzylidenyl]azetidin-3-yl}methyl)-N-{2-[( Trifluoromethyl)thio]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 87 mg of the title compound was obtained from 173 mg of the compound of Example 187b and 105 mg of 4-(trifluoromethoxy) benzindole.

¹ H-NMR (300 MHz, DMSO-d6): δ= 2.36 (3H), 3.11-3.24 (3H), 3.49 (2H), 3.89 (1H), 4.09 (1H), 4.17 (1H), 4.36 (1H) , 4.66 (2H), 7.36 (1H), 7.40 (2H), 7.66-7.74 (3H), 8.44 (1H), 8.46 (1H).

Example 195: 6-Methyl-N-(2,2,2-trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]azetidine- 3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 55, 70 mg of the title compound was obtained from 170 mg of the compound of Example 188b and 116 mg of 4-(trifluoromethoxy) benzhydrin chloride.

¹ H-NMR (300 MHz, DMSO-d6): δ= 2.35 (3H), 3.21 (1H), 3.89 (1H), 3.95-4.13 (3H), 4.18 (1H), 4.36 (1H), 4.67 (2H) , 7.40 (3H), 7.66-7.75 (3H), 8.45 (1H), 8.86 (1H).

Example 196: 6-Methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3-yl}methyl)-N-[2-(III Fluoromethoxy)ethyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 22 mg of the title compound was obtained from 179 mg of the compound of Example 196b and 113 mg of 4-(trifluoromethoxy) benzindole.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.20 (1H), 3.50 (2H), 3.89 (1H), 4.08 (1H), 4.14-4.21 (3H), 4.36 (1H) , 4.66 (2H), 7.36 (1H), 7.40 (2H), 7.66 (1H), 7.70 (2H), 8.44 (1H), 8.46 (1H).

The starting materials were prepared as follows:

Example 196a: 3-[(6-Methyl-5-{N-[2-(trifluoromethoxy)ethyl]aminemethanyl}-2H-indazol-2-yl)methyl]aza Cyclobutane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 741 mg of the title compound was obtained from EtOAc (EtOAc: EtOAc)

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 2.34 (3H), 3.06 (1H), 3.50 (2H), 3.68 (2H), 3.84 (2H), 4.16 (2H), 4.59 (2H), 7.37 (1H), 7.66 (1H), 8.44 (1H), 8.46 (1H).

Example 196b: 2-(Azetidin-3-ylmethyl)-6-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide Hydrochloride

Analogously to Example 1a, 369 mg of the title compound was obtained from </ RTI> </ RTI>

Example 197: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-6-methyl-N-[2-(trifluoromethoxy)B ]]-2H-carbazole-5-carbamide

Analogously to Example 55, 41 mg of the title compound was obtained from 179 mg of the compound of Example 196b and 88 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.19 (1H), 3.50 (2H), 3.87 (1H), 4.07 (1H), 4.13-4.21 (3H), 4.34 (1H) , 4.65 (2H), 7.36 (1H), 7.48 (2H), 7.59 (2H), 7.66 (1H), 8.44 (1H), 8.46 (1H).

Example 198: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-6 -methyl-2H-carbazole-5-carboxamide

Analogously to Example 55, 107 mg of the title compound was obtained from </RTI>

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.14 (2H), 0.42 (2H), 0.97 (1H), 2.34 (3H), 3.12-3.26 (3H), 3.34 (2H), 3.47 (2H) , 3.87 (1H), 4.07 (1H), 4.16 (1H), 4.34 (1H), 4.65 (2H), 7.35 (1H), 7.48 (2H), 7.59 (2H), 7.63 (1H), 8.21 (1H) , 8.42 (1H).

The starting materials were prepared as follows:

Example 198a: 3-[(5-{N-[2-(cyclopropylmethoxy)ethyl]aminemethanyl}-6-methyl-2H-indazol-2-yl)methyl]nitrogen Heterocyclic butane-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 245 mg of the title compound was obtained from 245 mg of yd.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.14 (2H), 0.43 (2H), 0.97 (1H), 1.32 (9H), 2.35 (3H), 3.06 (1H), 3.23 (2H), 3.34 (2H), 3.48 (2H), 3.67 (2H), 3.85 (2H), 4.59 (2H), 7.35 (1H), 7.64 (1H), 8.18 (1H), 8.41 (1H).

Example 198b: 2-(Azetidin-3-ylmethyl)-N-[2-(cyclopropylmethoxy)ethyl]-6-methyl-2H-indazole-5-carboxamidine Amine hydrochloride

Similar to Example 1a, 214 mg was obtained from 247 mg of the decylamine prepared in Example 198a. The title compound was reacted without further purification.

Example 199: 2-({1-[4-(4-Fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-6-methyl-N-{2-[ (trifluoromethyl)thio]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 56 mg of the title compound was obtained from 173 mg of the compound obtained in Example 187b and 98 mg of 4-(4-fluorophenoxy)benzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.38 (3H), 3.16-3.27 (3H), 3.52 (2H), 3.90 (1H), 4.08 (1H), 4.19 (1H), 4.38 (1H) , 4.68 (2H), 6.97 (2H), 7.14 (2H), 7.27 (2H), 7.39 (1H), 7.62 (2H), 7.72 (1H), 8.47 (1H), 8.49 (1H).

Example 200: 2-{[1-(4-Cyclopropylbenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-6-methyl -2H-carbazole-5-carboxamide

Analogously to Example 1, 86 mg of the title compound was obtained from 168 mg of the compound of Example 178e and 80 mg of 4-cyclopropylbenzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.71 (2H), 0.99 (2H), 1.95 (1H), 2.37 (3H), 3.21 (1H), 3.27 (3H), 3.37 (2H), 3.45 (2H), 3.88 (1H), 4.07 (1H), 4.17 (1H), 4.35 (1H), 4.67 (2H), 7.12 (2H), 7.38 (1H), 7.47 (2H), 7.66 (1H), 8.22 (1H), 8.44 (1H).

Example 201: 6-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene] Azetidin-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 71 mg of the title compound was obtained from 180 mg of the compound of Example 188b and 95 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.21 (1H), 3.88 (1H), 3.95-4.13 (3H), 4.19 (1H), 4.37 (1H), 4.67 (2H) , 7.11 (2H), 7.19 (2H), 7.39 (1H), 7.65 (2H), 7.69-7.79 (3H), 8.47 (1H), 8.88 (1H).

Example 202: N-(2-Methoxyethyl)-6-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}-aza Cyclobutane-3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 108 mg of the title compound was obtained from 180 mg of the compound of Example 178e and 102 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.34 (3H), 3.14-3.26 (4H), 3.34 (2H), 3.42 (2H), 3.88 (1H), 4.07 (1H), 4.19 (1H) , 4.37 (1H), 4.66 (2H), 7.11 (2H), 7.19 (2H), 7.35 (1H), 7.61-7.68 (3H), 7.75 (2H), 8.21 (1H), 8.42 (1H).

Example 203: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-6-methyl-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1, from 180 mg of the compound prepared in Example 188b and 73 mg of 4'- Fluorine biphenyl-4-carboxylic acid gave 104 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d6): δ=2.34 (3H), 3.22 (1H), 3.90 (1H), 3.95-4.14 (3H), 4.21 (1H), 4.40 (1H), 4.68 (2H) , 7.28 (2H), 7.40 (1H), 7.60-7.77 (7H), 8.48 (1H), 8.89 (1H).

Example 204: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxy-ethyl) -6-methyl-2H-carbazole-5-carboxamide

Analogously to Example 1, 73 mg of the title compound was obtained from 180 mg of the compound of Example 178e and 78 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (300MHz, DMSO-d6): δ=2.34 (3H), 3.14-3.26 (4H), 3.34 (2H), 3.41 (2H), 3.89 (1H), 4.09 (1H), 4.21 (1H) , 4.39 (1H), 4.66 (2H), 7.28 (2H), 7.35 (1H), 7.61-7.77 (7H), 8.21 (1H), 8.43 (1H).

Example 205: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-6-methyl-2H-carbazole -5-formamide

Similar to Example 55, a material that was still contaminated after column chromatography was obtained from 85 mg of the compound prepared in Example 205c and 45 mg of 4-chlorobenzhydrin chloride by additional preparative thick layer chromatography (with a ratio of 95). Further purification was carried out using :5 dichloromethane/methanol as the mobile phase. Yield: 48 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d6): δ = 1.09-1.53 (4H), 2.24 (1H), 2.34 (3H), 2.71 (1H), 2.97 (1H), 3.24 (3H), 3.34 (2H) , 3.38-3.54 (3H), 7.31-7.37 (3H), 7.46 (2H), 7.63 (1H), 8.21 (1H), 8.33 (H).

The starting materials were prepared as follows:

Example 205a: 4-[(5-Bromo-6-methyl-2H-indazol-2-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester

Similar to Example 1c, 2.99 g was obtained from 5.7 g of 5-bromo-6-methyl-1H-indazole and 15.0 g of tert-butyl 4-[(toluenesulfonyloxy)methyl]piperidine-1-carboxylate. Title compound.

¹ H-NMR (300MHz, CDCl3): δ=1.14-1.30 (2H), 1.44 (9H), 1.53 (2H), 2.24 (1H), 2.50 (3H), 2.66 (2H), 4.11 (2H), 4.23 (2H), 7.55 (1H), 7.77 (1H), 7.87 (1H).

Example 205b: 4-({5-[N-(2-methoxyethyl)aminemethanyl]-6-methyl-2H-indazol-2-yl}-methyl)piperidin-1- Tert-butyl formate

Similar to Example 1b, 3.56 g of the title compound was obtained from EtOAc (m.

¹ H-NMR (300 MHz, DMSO-d6): δ=0.96-1.15 (2H), 1.29-1.42 (10H), 2.03-2.18 (1H), 2.34 (3H), 2.51-2.73 (3H), 3.25 (3H) ), 3.31-3.45 (4H), 3.86 (2H), 4.26 (2H), 7.35 (1H), 7.63 (1H), 8.21 (1H), 8.32 (1H).

Example 205c: N-(2-Methoxyethyl)-6-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 85 mg of the title compound was obtained from 100 mg of the title compound from </RTI>

Example 206: 2 - ({1- [2-fluoro-4- (trifluoromethyl) benzoyl-yl] piperidin-4-yl} methyl) -N- (2- methoxy-ethyl) - -6-methyl-2H-carbazole-5-carboxamide

Similar to Example 55, a material that was still contaminated after column chromatography was obtained from 85 mg of the compound prepared in Example 205c and 58 mg of 2-fluoro-4-(trifluoromethyl)benzhydrin chloride by additional preparation. This was further purified by thick layer chromatography (methylene chloride/methanol in a ratio of 95:5). Yield: 40 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.03-1.28 (2H), 1.37 (1H), 1.53 (1H), 2.23 (1H), 2.34 (3H), 2.77 (1H), 3.00 (1H) , 3.26-3.49 (11H), 4.30 (2H), 4.44 (1H), 7.35 (1H), 7.54-7.67 (3H), 7.78 (1H), 8.21 (1H), 8.34 (1H).

Example 207: 2-{[1-(4-Chloro-2-fluorobenzylidinyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-6-methyl- 2H-carbazole-5-carboxamide

Analogously to Example 55, 68 mg of the title compound was obtained from &lt

¹ H-NMR (300 MHz, DMSO-d6): δ=1.04-1.25 (2H), 1.37 (1H), 1.51 (1H), 2.23 (1H), 2.34 (3H), 2.73 (1H), 2.98 (1H) , 3.21-3.48 (3H), 3.30-3.38 (3H), 3.42 (2H), 4.29 (2H), 4.42 (1H), 7.29-7.42 (3H), 7.51 (1H), 7.63 (1H), 8.21 (1H) ), 8.33 (1H).

Example 208: 2-({1-[3-Fluoro-4-(trifluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 6-methyl-2H-carbazole-5-carboxamide

Analogously to Example 55, 70 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.13-1.27 (2H), 1.35 (1H), 1.51 (1H), 2.23 (1H), 2.34 (3H), 2.74 (1H), 2.98 (1H) , 3.22-3.45 (8H), 4.29 (2H), 4.40 (1H), 7.32-7.38 (2H), 7.52 (1H), 7.63 (1H), 7.82 (1H), 8.21 (1H), 8.33 (1H).

Example 209: 2-({1-[4-Chloro-3-(trifluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 6-methyl-2H-carbazole-5-carboxamide

Analogously to Example 55, 92 mg of the title compound was obtained from EtOAc (m.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.14-1.28 (2H), 1.35 (1H), 1.44-1.53 (1H), 2.25 (1H), 2.34 (3H), 2.74 (1H), 3.01 ( 1H), 3.24 (3H), 3.34 (2H), 3.39-3.50 (3H), 4.29 (2H), 4.39 (1H), 7.35 (1H), 7.61-7.68 (2H), 7.74-7.80 (2H), 8.21. (1H), 8.33 (1H).

Example 210: N-(2-Methoxyethyl)-6-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzomethyl]-piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Similar to Example 1, from 85 mg of the compound prepared in Example 205c and 58 mg of 4-(five Fluorine-(6-thio)benzoic acid gave 126 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.12-1.27 (2H), 1.35 (1H), 1.51 (1H), 2.24 (1H), 2.34 (3H), 2.74 (1H), 2.99 (1H) , 3.24 (3H), 3.34-3.46 (5H), 4.30 (2H), 4.41 (1H), 7.35 (1H), 7.55 (2H), 7.63 (1H), 7.94 (2H), 8.21 (1H), 8.33 ( 1H).

Example 211: N-(2-Methoxyethyl)-6-methyl-2-({1-[4-(trifluoromethyl)benzylidenyl]piperidin-4-yl}-methyl )-2H-carbazole-5-carbamide

Analogously to Example 55, 69 mg of the title compound was obtained from mp.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.10-1.26 (2H), 1.35 (1H), 1.51 (1H), 2.19-2.30 (1H), 2.34 (3H), 2.74 (1H), 2.98 ( 1H), 3.21-3.47 (8H), 4.30 (2H), 4.42 (1H), 7.35 (1H), 7.54 (2H), 7.63 (1H), 7.77 (2H), 8.21 (1H), 8.33 (1H).

Example 212: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-ethyl-N-(2-methoxyethyl)-2H-carbazole -5-formamide

Analogously to Example 55, 61 mg of the title compound was obtained from 91 mg of the compound of Example 212i and 46 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=1.14-1.28 (5H), 1.31-1.60 (2H), 2.27 (1H), 2.63-3.04 (4H), 3.24 (3H), 3.31-3.56 (5H) ), 4.31 (2H), 4.39 (1H), 7.10 (1H), 7.32-7.41 (3H), 7.46 (2H), 8.11 (1H), 8.50 (1H).

The starting materials were prepared as follows:

Example 212a : 4-bromo-3-ethyl-2-toluidine

A suspension of 3 g of 3-ethyl-2-toluidine hydrochloride in 200 ml of ethyl acetate was washed twice with 30 ml portions of saturated sodium carbonate solution and twice with 20 ml portions of saturated sodium chloride solution. Dry over sodium sulfate and concentrate in vacuo after filtration. This gave 2.69 g of ethyl-2-toluidine which was subjected to further reaction without purification.

To a solution of 2.36 g of the above prepared amine in 29 ml of DMF was added dropwise a solution of 3.1 g of N-bromosuccinimide in 14.5 ml of DMF at 0 ° C and stirred at 0 ° C for 30 minutes. The reaction mixture was then diluted with 400 ml of ethyl acetate and washed once with 30 ml of 10% aqueous sodium carbonate and once with 30 ml of water. After drying over sodium sulfate and filtration, this was concentrated in vacuo. The crude product thus obtained (3.86 g) was used in the next step without purification.

Example 212b : N-(4-bromo-3-ethyl-2-methylphenyl)acetamide

To a solution of 3.86 g of the bromide in Example 212a in 48 ml of pyridine was added dropwise 2.04 ml of acetic anhydride at 0 ° C and stirred at 25 ° C for 20 hours. The reaction mixture was concentrated in vacuo and EtOAc EtOAc m. In this way, 3.73 g of the title compound was obtained.

^{1 H-NMR (300MHz, CDCl3} ): δ = 1.13 (3H), 2.20 (3H), 2.25 (3H), 2.86 (2H), 6.91 (1H), 7.33 (1H), 7.40 (1H).

Example 212c : 1-(5-Bromo-4-ethyl-1H-indazol-1-yl)ethan-1-one

To 3.72 g of the solution of the acetamide prepared in Example 212b in 31.5 ml of chloroform, 4.1 ml of acetic anhydride and 2.85 g of potassium acetate were added, and then 192 mg of 18-crown-6 and 3.4 g of nitrous acid were added dropwise. Amyl ester. The reaction mixture was heated at reflux for 20 h and then diluted with EtOAc EtOAc. The organic phase was washed with 20 ml of sodium carbonate solution and once with saturated sodium chloride solution. After drying over sodium sulfate and filtration, this was concentrated in vacuo and purified eluting with EtOAc EtOAc. Yield: 3.78 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.18 (3H), 2.68 (3H), 3.04 (2H), 7.73 (1H), 8.03 (1H), 8.64 (1H).

Example 212d : 5-bromo-4-ethyl-1H-carbazole

A mixture of 3.78 g of the compound obtained in Example 212c in 7.3 ml of methanol and 26.3 ml of 37% hydrochloric acid was heated under reflux for 2 hours. This was then diluted with 400 ml of ethyl acetate. The organic phase was washed three times with 50 mL portions of sodium bicarbonate solution and once with 50 mL of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained was purified by column chromatography on silica gel eluting with hexane / 0-50% ethyl acetate. Yield: 2.97 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.17 (3H), 2.98 (2H), 7.30 (1H), 7.41 (1H), 8.16 (1H), 13.17 (1H).

Example 212e: 4-[(5-Bromo-4-ethyl-2H-indazol-2-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester

Analogously to Example 1c, from 2.9 g of the carbazole prepared in Example 212d and 7.3 g of the tert-butyl 4-[(toluenesulfonyloxy)methyl]piperidine-1-carboxylate afforded 961 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.01-1.13 (2H), 1.16 (3H), 1.34 (9H), 1.41 (2H), 2.12 (1H), 2.63 (2H), 2.90 (2H) , 3.87 (2H), 4.27 (2H), 7.27 (1H), 7.35 (1H), 8.49 (1H).

Example 212f: methyl 2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-4-ethyl-2H-indazole-5-carboxylate

Analogously to Example 1e, 571 mg of the title compound was obtained from 347 mg of br.

¹ H-NMR (300MHz, DMSO-d6): δ=1.02-1.15 (2H), 1.7-1.24 (3H), 1.34 (9H), 1.42 (2H), 2.14 (1H), 2.63 (2H), 3.17 ( 2H), 3.79 (3H), 3.88 (2H), 4.30 (2H), 7.43 (1H), 7.60 (1H), 8.68 (1H).

Example 212g: 2-{[1-(Tertibutoxycarbonyl)piperidin-4-yl]methyl}-4-ethyl-2H-indazole-5-carboxylic acid

Analogously to Example 1d, 427 mg of the title compound was obtained from 371 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d6): δ=1.00-1.15 (2H), 1.20 (3H), 1.34 (9H), 1.42 (2H), 2.14 (1H), 2.64 (2H), 3.19 (2H) , 3.88 (2H), 4.29 (2H), 7.39 (1H), 7.61 (1H), 8.63 (1H), 12.33 (1H).

Example 212h: 4-({4-Ethyl-5-[N-(2-methoxyethyl)aminemethanyl]-2H-indazol-2-yl}-methyl)piperidine-1- Tert-butyl formate

Analogously to Example 1, 215 mg of the title compound was obtained from 427 mg of yd.

¹ H-NMR (300 MHz, DMSO-d6): δ=0.98-1.14 (2H), 1.19 (3H), 1.30-1.47 (11H), 2.13 (1H), 2.65 (2H), 2.90 (2H), 3.24 ( 3H), 3.32-3.45 (4H), 3.87 (2H), 4.28 (2H), 7.10 (1H), 7.38 (1H), 8.12 (1H), 8.50 (1H).

Example 212i: 4-Ethyl-N-(2-methoxyethyl)-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 258 mg of the title compound was obtained from 215 mg of the title compound.

Example 213: 4-Ethyl-N-(2-methoxyethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

Analogously to Example 55, 32 mg of the title compound was obtained from 91 mg of the compound of Example 212i and 59 mg of 4-(trifluoromethoxy) benzindole.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.14-1.29 (5H), 1.31-1.61 (2H), 2.20-2.35 (1H), 2.66-3.06 (4H), 3.24 (3H), 3.30-3.56 (5H), 431 (2H), 4.41 (1H), 7.10 (1H), 7.34-7.43 (3H), 7.47 (2H), 8.11 (1H), 8.50 (1H).

Example 214: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methoxy-N-(2-methoxyethyl)- 2H-carbazole-5-carboxamide

Analogously to Example 55, 691 mg of the title compound was obtained from 68 mg of the compound of Example 214c and 37 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=3.22 (1H), 3.27 (3H), 3.40-3.47 (4H), 3.92 (1H), 4.10 (1H), 4.16 (3H), 4.19 (1H) , 4.38 (1H), 4.66 (2H), 7.21 (1H), 7.48 (2H), 7.55-7.67 (3H), 8.18 (1H), 8.87 (1H).

The starting materials were prepared as follows:

Example 214a: 3-[(5-Bromo-4-methoxy-2H-indazol-2-yl)methyl]azetidin-1-carboxylic acid tert-butyl ester

To a solution of 1.94 g of 3-[(toluenesulfonyloxy)methyl]azetidin-1-carboxylic acid tert-butyl ester in 15.5 ml of acetone was added 837 mg of lithium iodide and the reaction mixture was at 35 ° C Stir for 16 hours. After cooling, it was diluted with 200 ml of ethyl acetate and the organic phase was washed twice with 30 ml portions of water and once with 20 ml of saturated sodium chloride solution. After drying over sodium sulfate and filtration, this was concentrated in vacuo. In this way, 1.6 g of tributyl butyl 3-(iodomethyl)azetidin-1-carboxylate was obtained, which was further reacted without purification.

To a solution of 620 mg of 5-bromo-7-methoxy-1H-indazole in 24 ml of DMF was added 1.11 g of potassium carbonate and the mixture was stirred at 25 ° C for 30 min. Then add 1.25g of the above system The iodide was prepared and the reaction mixture was stirred at 60 ° C for 3 hours. After cooling, it was diluted with 200 ml of 1:1 tert-butyl methyl ether/hexane, washed once with 20 ml portions of water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Column chromatography on silica gel The crude product thus obtained was purified by hexane/ethyl acetate gradient. Yield: 263 mg of the title compound.

^{1 H-NMR (300MHz, CDCl3} ): δ = 1.43 (9H), 3.23 (1H), 3.78 (2H), 4.07 (2H), 4.10 (3H), 4.59 (2H), 7.28 (1H), 7.36 (1H ), 8.03 (1H).

Example 214b: 3-({4-Methoxy-5-[N-(2-methoxyethyl)aminemethanyl]-2H-indazol-2-yl}methyl)azetidine 1-butylic acid tert-butyl ester

Similar to Example 1b, a total of 193 mg of the title compound was obtained from 110 and 252 mg of the compound of Example 214a, respectively, and 63 and 143 mg of 2-methoxyethylamine, respectively.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.32 (9H), 3.10 (1H), 3.27 (3H), 3.38-3.48 (4H), 3.72 (2H), 3.82-3.94 (2H), 4.17 ( 3H), 4.60 (2H), 7.21 (1H), 7.63 (1H), 8.18 (1H), 8.87 (1H).

Example 214c: 2-(Azetidin-3-ylmethyl)-4-methoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 42 mg of the title compound was obtained from 50 mg of the compound obtained in Example 214b, which was further reacted without purification.

Example 215: 4-Methoxy-N-(2-methoxyethyl)-2-[(1-{4-[(trifluoromethyl)thio]benzylidenyl}azetidine -3-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 55, 56 mg of the title compound was obtained from 42 mg of the compound of Example 214c and 32 mg of 4-[(trifluoromethyl)thio]benzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=3.21 (1H), 3.27 (3H), 3.38-3.49 (4H), 3.95 (1H), 4.12 (1H), 4.16 (3H), 4.21 (1H) , 4.40 (1H), 4.67 (2H), 7.20 (1H), 7.63 (1H), 7.69 (2H), 7.76 (2H), 8.18 (1H), 8.87 (1H).

Example 216: 2-{[1-(4-Bromobenzylidenyl)azetidin-3-yl]methyl}-4-methoxy-N-(2-methoxyethyl)- 2H-carbazole-5-carboxamide

Analogously to Example 55, 48 mg of the title compound was obtained from 42 mg of the compound of Example 214c and 29 mg of 4-bromobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=3.23 (1H), 3.26 (3H), 3.38-3.48 (4H), 3.92 (1H), 4.09 (1H), 4.16 (3H), 4.19 (1H) , 4.38 (1H), 4.66 (2H), 7.20 (1H), 7.51 (2H), 7.58-7.68 (3H), 8.18 (1H), 8.86 (1H).

Example 217: 2-{[(R)-1-(4-Chlorobenzylidene)pyrrolidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

Analogously to Example 55, 50 mg of the title compound was obtained from 106 mg of the compound of Example 217e and 58 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=1.57-1.73 (1H), 1.81-1.97 (1H), 2.47/2.51 (3H), 2.78-2.93 (1H), 3.25 (3H), 3.19-3.61 (8H), 4.39/4.51 (2H), 7.11-7.18 (1H), 7.33-7.43 (1H), 7.45 (2H), 7.50 (2H), 8.09-8.16 (1H), 8.47/8.55 (1H).

The starting materials were prepared as follows:

Example 217a: (R)-3-[(5-Bromo-4-methyl-2H-indazol-2-yl)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of 9.0 g of (R) 3-butyl(3-hydroxymethyl)pyrrolidine-1-carboxylic acid in 100 ml of pyridine at 0 ° C under nitrogen, 12.8 g of p-toluenesulfonyl chloride was added at 25 Stir at ° C for 3 hours. The reaction mixture was diluted with ethyl acetate and stirred with sodium hydrogen sulfate for 30 min. The phases were separated and the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The residue thus obtained was purified by column chromatography on silica gel using hexane / 0-100% ethyl acetate. Yield: 11.4 g of (R)-3-[(toluenesulfonyloxy)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester.

Similar to Example 1c, from 4.53 g of 5-bromo-4-methyl-1H-indazole and 11.4 g of (R)-3-[(tosulphonyloxy)methyl]pyrrolidine-1- The third butyl formate was added with 7.9 g of tetrabutylammonium iodide to obtain 1.97 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.34 (9H), 1.50-1.66 (1H), 1.81 (1H), 2.48 (3H), 2.78 (1H), 3.01 (1H), 3.16 (1H) , 3.25-3.37 (2H), 4.41 (2H), 7.29 (1H), 7.36 (1H), 8.51 (1H).

Example 217b: Methyl 2-{[(R)-1-(t-butoxycarbonyl)pyrrolidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxylate

Analogously to Example 1e, 820 mg of the title compound was obtained from 563 mg of the bromide of Example 217a and 0.17 ml of methanol after two runs.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.34 (9H), 1.58 (1H), 1.83 (1H), 2.73 (3H), 2.80 (1H), 3.03 (1H), 3.17 (1H), 3.25 -3.37(2H), 3.79(3H), 4.37-4.49(2H), 7.44(1H), 7.64(1H), 8.72(1H).

Example 217c: 2-{[(R)-1-(T-Butoxycarbonyl)pyrrolidin-3-yl]methyl}-4-methyl-2H-indazole-5-carboxylic acid

Analogously to Example 1d, 701 mg of the title compound was obtained from </ RTI> </RTI>

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.34 (9H), 1.50-1.69 (1H), 1.82 (1H), 1.75-1.86 (1H), 2.69-2.88 (4H), 3.03 (1H), 3.17(1H), 3.24-3.38(1H), 4.42(2H), 7.40(1H), 7.65(1H), 8.68(1H), 12.28(1H).

Example 217d: (R)-3-({5-[N-(2-methoxyethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}methyl)pyrrolidine 1-butylic acid tert-butyl ester

Analogously to Example 1, 376 mg of the title compound was obtained from 350 mg of the acid of y.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.35 (9H), 1.57 (1H), 1.80 (1H), 2.50 (3H), 2.73-2.86 (1H), 3.01 (1H), 3.11-3.22 ( 1H), 3.25 (3H), 3.26-3.39 (3H), 3.39-3.46 (2H), 4.42 (2H), 7.15 (1H), 7.39 (1H), 8.13 (1H), 8.52 (1H).

Example 217e: N-(2-methoxyethyl)-4-methyl-2-[(R)-pyrrolidin-3-ylmethyl]-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 465 mg of the title compound was obtained from 376 mg of the title compound.

Example 218: N-(2-Methoxyethyl)-4-methyl-2-({(R)-1-[4-(trifluoromethoxy)benzylidene]-pyrrolidine-3 -yl}methyl)-2H-carbazole-5-carboxamide

Analogously to Example 55, 61 mg of the title compound was obtained from 106 mg of the compound of Example 217e and 74 mg of 4-(trifluoromethoxy) benzindole.

¹ H-NMR (300MHz, DMSO-d6): δ=1.57-1.74 (1H), 1.81-1.97 (1H), 2.47/2.51 (3H), 2.77-2.94 (1H), 3.25-3.62 (11H), 4.40 /4.51(2H), 7.09-7.19(1H), 7.31-7.44(3H), 7.61(2H), 8.08-8.16(1H), 8.47/8.55(1H).

Example 219: N-(2-Methoxyethyl)-4-methyl-2-({(3R)-1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]-pyrrole Pyridin-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 29 mg of the title compound was obtained from 106 mg of the compound obtained in Example 217e and 75 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid.

1H-NMR (300MHz, DMSO-d6): δ=1.57-1.76 (1H), 1.81-1.99 (1H), 2.50 (3H), 2.77-2.94 (1H), 3.16-3.62 (11H), 4.39/4.52 ( 2H), 7.09-7.19 (1H), 7.32-7.44 (1H), 7.68 (2H), 7.90-7.97 (2H), 8.10-8.17 (1H), 8.46/8.55 (1H).

Example 220: 2-{[(R)-1-(4-Chlorobenzylidyl)pyrrolidin-3-yl]methyl}-4-methyl-N-{2-[(trifluoro-methyl) )thio]ethyl}-2H-carbazole-5-carboxamide

Analogously to Example 55, 29 mg of the title compound was obtained from 106 mg of the compound of Example 220b and 48 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=1.57-1.73 (1H), 1.81-1.96 (1H), 2.48/2.53 (3H), 2.79-2.93 (1H), 3.13-3.60 (8H), 4.40 /4.51(2H), 7.14-7.23(1H), 7.33-7.53(5H), 8.35-8.42(1H), 8.49/8.58(1H).

The starting materials were prepared as follows:

Example 220a: (R) -Tertiary Butyl 3-{[4-Methyl-5-(N-{2-[(trifluoromethyl)thio]ethyl}-aminecarbamyl)-2H- Oxazol-2-yl]methyl}pyrrolidine-1-carboxylate

Analogously to Example 1, 245 mg of the title compound was obtained from 350 mg of yd.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.35 (9H), 1.52-1.64 (1H), 1.81 (1H), 2.52 (3H), 2.71-2.96 (2H), 2.97-3.05 (12H), 3.18(2H), 3.23-3.28(1H), 3.51(2H), 4.42(2H), 7.19(1H), 7.42(1H), 8.39(1H), 8.54 (1H).

Example 220b: 4-Methyl-2-[(R)-pyrrolidin-3-ylmethyl]-N-{2-[(trifluoromethyl)thio]-ethyl}-2H-carbazole- 5-methanamine hydrochloride

Analogously to Example 1a, 410 mg of the title compound was obtained from 245 mg of dec.

Example 221: 4-Methyl-2-({(R)-1-[4-(trifluoromethoxy)benzylidene]pyrrolidin-3-yl}methyl)-N-{2-[ (trifluoromethyl)thio]ethyl}-2H-indazole-5-carboxamide

Analogously to Example 55, 49 mg of the title compound was obtained from 106 mg of the compound of Example 220b and 62 mg of 4-(trifluoromethoxy) benzindole.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.58-1.74 (1H), 1.81-1.98 (1H), 2.48/2.53 (3H), 2.78-2.94 (1H), 3.12-3.62 (8H), 4.40 /4.52(2H), 7.14-7.23(1H), 7.32-7.49(3H), 7.61(2H), 8.35-8.43(1H), 8.49/8.58(1H).

Example 222: 2-{[(S)-1-(4-Chlorobenzylidene)pyrrolidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carboxamide

Analogously to Example 55, 67 mg of the title compound was obtained from 134 mg of the compound of Example 222a and 73 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, CDCl3): δ=1.72-1.86 (1H), 1.99-2.20 (1H), 2.64 (3H), 2.93-3.13 (1H), 3.29-3.36 (1H), 3.39 (3H), 3.45-3.71(6H), 3.76-3.86(1H), 4.31-4.57(2H), 6.12-6.20(1H), 7.30-7.42(3H), 7.43-7.56(3H), 7.90/8.02(1H).

The starting materials were prepared as follows:

Example 222a: (S)-3-({5-[N-(2-methoxyethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}methyl)pyrrolidine 1-butylic acid tert-butyl ester

Analogously to Examples 217a to 217d, the title compound was prepared in an amount of 760 mg starting from (S)-3-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.35 (9H), 1.52-1.64 (1H), 1.77-1.87 (1H), 1.76-1.82 (1H), 2.50 (3H), 2.74-2.86 (1H) ), 3.02 (1H), 3.12-3.20 (1H), 3.25 (3H), 3.31 (1H), 3.36 (2H), 3.43 (2H), 4.42 (2H), 7.16 (1H), 7.39 (1H), 8.10 (1H), 8.51 (1H).

Example 222b: N-(2-Methoxyethyl)-4-methyl-2-[(S)-pyrrolidin-3-ylmethyl]-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 134 mg of the title compound was obtained from 159 mg of the title compound.

Example 223: 2-({(S)-1-[(4'-Flutabiphenyl-4-yl)carbonyl]pyrrolidin-3-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 128 mg of the title compound was obtained from 230 mg of the compound of Example 222b and 141 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (300MHz, CDCl3): δ = 1.73-1.89 (1H), 1.98-2.24 (1H), 2.60/2.67 (3H), 2.94-3.18 (1H), 3.37/3.39 (3H), 3.49-3.76 (6H), 3.79-3.91 (2H), 4.32-4.61 (2H), 6.08-6.21 (1H), 7.09-7.20 (2H), 7.28-7.38 (1H), 7.46-7.62 (7H), 7.91/8.04 ( 1H).

Example 224: N-(2-Methoxyethyl)-4-methyl-2-{[(S)-1-{4-[4-(trifluoromethyl)phenoxy]benzylidene }pyrrolidin-3-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1, 102 mg of the title compound was obtained from 230 mg of the compound of Example 222b and 184 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹ H-NMR (300MHz, CDCl3): δ = 1.70-2.25 (2H), 2.63/2.66 (3H), 2.94-3.17 (1H), 3.39 (3H), 3.47-3.92 (8H), 4.33-4.59 (2H ), 6.15 (1H), 7.00-7.11 (4H), 7.30-7.40 (1H), 7.47-7.65 (5H), 7.91/8.03 (1H).

Example 225: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-(difluoromethoxy)-N-(2-methoxyethyl) -2H-carbazole-5-carboxamide

Analogously to Example 55, 90 mg of the title compound was obtained from &lt

¹ H-NMR (300 MHz, DMSO-d6): δ=1.14-1.58 (4H), 2.19-2.34 (1H), 2.67-2.81 (1H), 2.97 (1H), 3.22-3.53 (9H), 4.37 (2H) ), 7.13 (1H), 7.31-7.39 (3H), 7.47 (2H), 7.54 (1H), 8.21 (1H), 8.50 (1H).

The starting materials were prepared as follows:

Example 225a : N-[4-bromo-3-(difluoromethoxy)-2-methylphenyl]acetamide

To a solution of 5.0 g of 3-difluoromethoxy-2-toluidine in 48 ml of DMF, a solution of 5.1 g of N-bromosuccinimide in 24 ml of DMF was added dropwise at 0 ° C and Stir at 0 ° C for 1 hour. The reaction mixture was then diluted with 400 ml of hexane/ethyl acetate and washed once with 50 ml of 10% aqueous sodium carbonate and three times with 50 ml of water. After drying over sodium sulfate and filtration, this was concentrated in vacuo. The crude product thus obtained (6.68 g) was used in the next step without purification.

To a solution of 6.39 g of the bromide prepared above in 70 ml of pyridine was added dropwise 3.0 ml of acetic anhydride at 0 ° C and stirred at 25 ° C for 20 hours. The reaction mixture was concentrated in vacuo and EtOAc EtOAc m. The material itself is then recrystallized. In this way, 6.39 g of the title compound was obtained.

^{1 H-NMR (300MHz, CDCl3} ): δ = 2.22 (3H), 2.27 (3H), 6.51 (1H), 6.95 (1H), 7.46 (1H), 7.71 (1H).

Example 225b : 1-[5-Bromo-4-(difluoromethoxy)-1H-indazol-1-yl]ethan-1-one

Similar to Example 212c, 5.32 g of the title compound was obtained from 6.38 g of the decylamine of Example 225a.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.70 (3H), 7.34 (1H), 7.90 (1H), 8.16 (1H), 8.46 (1H).

Example 225c : 5-bromo-4-(difluoromethoxy)-1H-carbazole

Similar to Example 212d, from 4.32 g of the carbazole prepared in Example 225b, 4.12 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 7.30 (1H), 7.44 (1H), 7.56 (1H), 8.06 (1H), 13.54 (1H).

Example 225d: 4-{[5-Bromo-4-(difluoromethoxy)-2H-indazol-2-yl]methyl}-piperidine-1-carboxylic acid tert-butyl ester

Analogously to Example 212e, oxazole prepared in Example 225c and 8.7 g of tert-butyl 4-[(toluenesulfonyloxy)methyl]piperidine-1-carboxylate from 4.1 g afforded the title compound.

¹ H-NMR (300MHz, CDCl3): δ=1.19-1.28 (2H), 1.45 (9H), 1.51-1.59 (2H), 2.25 (1H), 2.68 (2H), 4.12 (2H), 4.27 (2H) , 6.61 (1H), 7.41 (1H), 7.50 (1H), 7.95 (1H).

Example 225e: methyl 2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-4-(difluoromethoxy)-2H-indazole-5-carboxylate

Analogously to Example 1e, 1.28 g of the title compound was obtained from </RTI> </ RTI> </ RTI>

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.96-1.22 (2H), 1.28-1.47 (11H), 2.14 (1H), 2.54-2.74 (2H), 3.81 (3H), 3.87 (2H), 4.36(2H), 7.17(1H), 7.58(1H), 7.65(1H), 8.62(1H).

Example 225f: 2-{[1-( Tertibutoxycarbonyl )piperidin-4-yl]methyl}-4-(difluoromethoxy)-2H-indazole-5-carboxylic acid

Analogously to Example 1d, 1.05 g of the title compound was obtained from 1.28 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.97-1.16 (2H), 1.28-1.47 (11H), 2.13 (1H), 2.63 (2H), 3.87 (2H), 4.35 (2H), 7.14 ( 1H), 7.54 (1H), 7.65 (1H), 8.58 (1H), 13.05 (1H).

Example 225g: 4-({4-(Difluoromethoxy)-5-[N-(2-methoxyethyl)aminemethanyl]-2H-indazol-2-yl}methyl)piperidin Pyridin-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 503 mg of the title compound was obtained from 520 mg of the compound of Example 225f and 92 mg of 2-methoxyethylamine.

¹ H-NMR (300MHz, DMSO-d6): δ=1.01-1.13 (2H), 1.34 (9H), 1.38 (2H), 2.13 (1H), 2.59-2.71 (6H), 3.24 (3H), 3.34 3.44 (2H), 3.87 (2H), 4.34 (2H), 7.14 (1H), 7.33 (1H), 7.54 (1H), 8.21 (1H), 8.50 (1H).

Example 225h: 4-(Difluoromethoxy)-N-(2-methoxyethyl)-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

Similar to Example 1a, 106 mg was obtained from 122 mg of the decylamine prepared in Example 225g. The title compound was reacted without further purification.

Example 226: 4-(Difluoromethoxy)-2-({1-[4-(4-fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2 -methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 11 mg of the title compound was obtained from 106 mg of the compound obtained in Example 225h and 59 mg of 4-(4-fluorophenoxy)benzoic acid.

¹ H-NMR (300MHz, DMSO-d6): δ=1.10-1.59 (4H), 2.23-2.33 (1H), 2.75-3.01 (2H), 3.24 (3H), 3.33-3.51 (5H), 3.51-3.72 (1H), 4.37 (2H), 6.95 (2H), 7.07-7.12 (2H), 7.13 (1H), 7.17-7.26 (2H), 7.28-7.39 (3H), 7.54 (1H), 8.21 (1H), 8.50 (1H).

Example 227: 4-(Difluoromethoxy)-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2- Methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 38 mg of the title compound was obtained from 106 mg of the compound obtained in Example 225h and 55 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.14-1.62 (4H), 2.23-2.35 (1H), 2.68-2.85 (1H), 2.91-3.09 (1H), 3.24 (3H), 3.32-3.48 (5H), 3.50-3.70(1H), 4.38(2H), 7.14(1H), 7.28(2H), 7.33(1H), 7.40(2H), 7.55(1H), 7.64-7.75(4H), 8.21( 1H), 8.51 (1H).

Example 228: 2-{[1-(4-Cyclopropylbenzimidyl)piperidin-4-yl]methyl}-4-(difluoromethoxy)-N-(2-methoxyB Base-2H-carbazole-5-carbamide

Analogously to Example 1, 75 mg of the title compound was obtained from 106 mg of the compound obtained in Example 225h and 41 mg of 4-cyclopropylbenzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.66 (2H), 0.94 (2H), 1.10-1.54 (4H), 1.90 (1H), 2.14-2.31 (1H), 2.72-3.02 (2H), 3.03-3.18(1H), 3.24(3H),3.33-3.47(4H), 3.49-3.68(1H), 4.37(2H),7.07(2H),7.13(1H),7.19(2H),7.33(1H) , 7.54 (1H), 8.21 (1H), 8.50 (1H).

Example 229: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)-ethyl]-4-( Difluoromethoxy)-2H-indazole-5-carboxamide

Analogously to Example 55, 170 mg of the title compound was obtained from 127 mg of the compound of Example 229b and 53 mg of 4-chlorobenzamide.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.14 (2H), 0.42 (2H), 0.96 (1H), 1.10-1.27 (2H), 1.37 (1H), 1.51 (1H), 2.26 (1H) , 2.71 (1H), 2.97 (1H), 3.20-3.55 (8H), 4.37 (2H), 7.14 (1H), 7.31-7.38 (3H), 7.47 (2H), 7.55 (1H), 8.21 (1H), 8.51 (1H).

The starting materials were prepared as follows:

Example 229a: 4-{[5-{N-[2-(cyclopropylmethoxy)ethyl]aminemethanyl}-4-(difluoro-methoxy)-2H-indazole-2- Tert-butyl]methyl}piperidine-1-carboxylic acid

Analogously to Example 1, 453 mg of the title compound was obtained from 520 mg of the compound of Example 225f and 185 mg of 2-(cyclopropylmethoxy)ethylamine.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.14 (2H), 0.42 (2H), 0.97 (1H), 1.07 (2H), 1.34 (9H), 1.39 (2H), 2.13 (1H), 2.56 -2.72 (2H), 3.23 (2H), 3.37 (2H), 3.48 (2H), 3.87 (2H), 4.34 (2H), 7.15 (1H), 7.34 (1H), 7.55 (1H), 8.21 (1H) , 8.50 (1H).

Example 229b: N-[(2-Cyclopropylmethoxy)ethyl]-4-(difluoromethoxy)-2-(4-piperidinylmethyl)-2H-indazole-5-A Indoleamine hydrochloride

Analogously to Example 1a, 127 mg of the title compound was obtained from 145 mg of the title compound.

Example 230: N-[2-(Cyclopropylmethoxy)ethyl]-4-(difluoromethoxy)-2-({1-[4-(4-fluoro-phenoxy)phenyl) Mercapto]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 156 mg of the title compound was obtained from 127 mg of the compound of Example 229b and 64 mg of 4-(4-fluorophenoxy)benzoic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.14 (2H), 0.42 (2H), 0.96 (1H), 1.10-1.54 (4H), 2.18-2.33 (1H), 2.71-3.02 (2H), 3.03-3.16(1H), 3.22(2H), 3.37(2H), 3.47(2H), 3.55-3.68(1H), 4.37(2H), 6.95(2H), 7.10(2H), 7.14(1H), 7.22 (2H), 7.34 (3H), 7.55 (1H), 8.21 (1H), 8.51 (1H).

Example 231: N-[2-(Cyclopropylmethoxy)ethyl]-4-(difluoromethoxy)-2-({1-[(4'-fluoro-biphenyl-4-yl)) Carbonyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 164 mg of the title compound was obtained from 127 mg of the compound of Example 229b and 60 mg of 4'-fluorobiphenyl-4-carboxylic acid.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.14 (2H), 0.42 (2H), 0.96 (1H), 1.14-1.60 (4H), 2.27 (1H), 2.70-3.04 (1H), 2.87 ( 1H), 3.03-3.15(1H), 3.22(2H), 3.37(2H), 3.47(2H), 3.60(1H), 4.38(2H), 7.14(1H), 7.28(2H), 7.34(1H), 7.41(2H), 7.55(1H), 7.64-7.75(4H), 8.21(1H), 8.52(1H).

Example 232: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-(2,2,2- Trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 55, 113 mg of the title compound was obtained from 109 mg of the compound of compound 232h and 46 mg of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=1.12-1.61 (3H), 2.19-2.34 (1H), 2.67-3.07 (2H), 3.23 (3H), 3.33-3.56 (4H), 4.28-4.47 (3H), 4.95 (2H), 7.31-7.39 (3H), 7.40-7.50 (3H), 7.99 (1H), 8.65 (1H).

The starting materials were prepared as follows:

Example 232a : N-[4-bromo-2-methyl-3-(2,2,2-trifluoroethoxy)phenyl]acetamide

Similar to Example 225a, 6.13 g of the title compound was obtained from 5.0 g of 2-methyl-3-(2,2,2-trifluoroethoxy)aniline.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.07 (3H), 2.18 (3H), 4.55 (2H), 7.29 (1H), 7.45 (1H), 9.42 (1H).

Example 232b : 1-[5-Bromo-4-(2,2,2-trifluoroethoxy)-1H-indazol-1-yl]ethan-1-one

Similar to Example 212c, the title compound was obtained from 6.13 g of the decylamine from Example 232a.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 2.69 (3H), 5.14 (2H), 7.80 (1H), 7.99 (1H), 8.64 (1H).

Example 232c : 5-Bromo-4-(2,2,2-trifluoroethoxy)-1H-carbazole

Similar to Example 212d, 3.57 g of the title compound was obtained from 5.08 g of the carbazole prepared in Example 232b.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 5.05 (2H), 7.24 (1H), 7.45 (1H), 8.26 (1H), 13.38 (1H).

Example 232d: 4-{[5-Bromo-4-(2,2,2-trifluoroethoxy)-2H-indazol-2-yl]methyl}-piperidine-1-carboxylic acid tert-butyl ester

Analogously to Example 212e, oxazole prepared in Example 232c and 6.7 g of &lt;RTI ID=0.0&gt;&gt;

¹ H-NMR (300MHz, CDCl3): δ=1.16-1.31(2H), 1.45(9H), 1.54(2H), 2.25(1H), 2.68(2H), 4.05-4.21(2H), 4.27(2H) , 4.54 (2H), 7.35 (1H), 7.41 (1H), 7.91 (1H).

Example 232e: methyl 2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-4-(2,2,2-trifluoro-ethoxy)-2H-indole Azole-5-formate

Analogously to Example 1e, 857 mg of the title compound was obtained from 590 mg of br.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.00-1.17 (2H), 1.34 (9H), 1.37-1.47 (2H), 2.13 (1H), 2.55-2.74 (2H), 3.79 (3H), 3.87(2H), 4.32(2H), 4.89(2H), 7.39(1H), 7.56(1H), 8.67(1H).

Example 232f: 2-{[1-( Tertibutoxycarbonyl )piperidin-4-yl]methyl}-4-(2,2,2-trifluoroethoxy)-2H-indazole-5 -formic acid

Analogously to Example 1d, 724 mg of the title compound was obtained from EtOAc.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.01-1.17 (2H), 1.34 (9H), 1.40 (2H), 2.13 (1H), 2.53-2.75 (2H), 3.87 (2H), 4.32 ( 2H), 4.84 (2H), 7.37 (1H), 7.58 (1H), 8.60 (1H), 12.74 (1H).

Example 232g: 4-({5-[N-(2-methoxyethyl)aminemethanyl]-4-(2,2,2-trifluoroethoxy)-2H-indazole-2- Tert-butyl ester

Analogously to Example 1, 386 mg of the title compound was obtained from 360 mg of the compound of Example 232f and 59 mg of 2-methoxyethylamine.

¹ H-NMR (300 MHz, DMSO-d6): δ=0.98-1.18 (2H), 1.34 (9H), 1.43 (2H), 2.14 (1H), 2.65 (2H), 3.23 (3H), 3.35-3.47 ( 4H), 3.88 (2H), 4.30 (2H), 4.96 (2H), 7.35 (1H), 7.43 (1H), 7.99 (1H), 8.65 (1H).

Example 232h: N-(2-Methoxyethyl)-2-(4-piperidinylmethyl)-4-(2,2,2-trifluoroethoxy)-2H-indazole-5- Formamide hydrochloride

Analogously to Example 1a, 113 mg of the title compound was obtained from EtOAc (m.

Example 233: 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- (2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 51 mg of the title compound was obtained from 109 mg of the compound of Example 232h and 56 mg of 4-(4-fluorophenoxy)benzoic acid.

¹ H-NMR (300MHz, DMSO-d6): δ=1.10-1.31 (1H), 1.48 (2H), 2.18-2.37 (1H), 2.69-3.04 (2H), 3.23 (3H), 3.37-3.48 (4H ), 3.56-3.71 (1H), 4.33 (2H), 4.95 (2H), 6.95 (2H), 7.06-7.15 (2H), 7.18-7.27 (2H), 7.31-7.38 (3H), 7.40-7.47 (1H) ), 7.99 (1H), 8.66 (1H).

Example 234: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4- (2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 61 mg of the title compound was obtained from 109 mg of the compound obtained in Example 232h and 52 mg of 4-(4-fluorophenyl)benzoic acid.

¹ H-NMR (300MHz, DMSO-d6): δ=1.14-1.63 (3H), 2.19-2.37 (1H), 2.68-3.09 (2H), 3.23 (3H), 3.34-3.48 (4H), 3.62 (1H) ), 4.28-4.42 (2H), 4.96 (2H), 7.22-7.47 (6H), 7.64-7.76 (4H), 7.99 (1H), 8.66 (1H).

Example 235: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)-ethyl]-4-( 2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 55, 122 mg of the title compound was obtained from EtOAc (m.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.13 (2H), 0.41 (2H), 0.95 (1H), 1.11-1.62 (3H), 2.19-2.34 (1H), 2.73 (1H), 2.98 ( 1H), 3.21 (2H), 3.33-3.57 (5H), 4.33 (2H), 4.95 (2H), 7.31-7.51 (6H), 8.00 (1H), 8.65 (1H).

The starting materials were prepared as follows:

Example 235a: 4-{[5-{N-[2-(cyclopropylmethoxy)ethyl]aminemethylmercapto}-4-(2,2,2-trifluoroethoxy)-2H- Benzazol-2-yl]methyl}piperidine-1-carboxylic acid tert-butyl ester

Analogously to Example 1, 429 mg of the title compound was obtained from 360 mg of the compound of Example 232f and 119 mg of 2-(cyclopropylmethoxy)ethylamine.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.13 (2H), 0.42 (2H), 0.95 (1H), 1.08 (2H), 1.34 (9H), 1.41 (2H), 2.14 (1H), 3.22 (2H), 3.41 (2H), 3.48 (2H), 3.88 (2H), 4.30 (2H), 4.95 (2H), 7.35 (1H), 7.42 (1H), 8.00 (1H), 8.65 (1H).

Example 235b: N-[2-(cyclopropylmethoxy)ethyl]-2-(4-piperidinylmethyl)-4-(2,2,2-trifluoro-ethoxy)-2H -carbazole-5-carbamide hydrochloride

Analogously to Example 1a, from 138 mg of the title compound of </ RTI>

Example 236: N-[2-(Cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl}A 4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 95 mg of the title compound was obtained from yd.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.13 (2H), 0.41 (2H), 0.95 (1H), 1.09-1.60 (3H), 2.17-2.36 (1H), 2.68-3.06 (2H), 3.22(2H), 3.34-3.76(5H), 4.33(2H), 4.95(2H), 6.95(2H), 7.06-7.14(2H), 7.17-7.27(2H), 7.30-7.38(3H), 7.42( 1H), 7.99 (1H), 8.65 (1H).

Example 237: N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl )-4-(2,2,2-trifluoroethoxy)-2H-indazole-5-carboxamide

Analogously to Example 1, 98 mg of the title compound was obtained from yd.

¹ H-NMR (300MHz, DMSO-d6): δ = 0.12 (2H), 0.41 (2H), 0.95 (1H), 1.15-1.64 (3H), 2.21-2.36 (1H), 2.70-3.10 (2H), 3.21(2H), 3.35-3.69(5H), 4.35(2H), 4.95(2H), 7.22-7.46(6H), 7.63-7.77(4H), 7.99(1H), 8.66(1H).

Example 238: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-[2-(3-methoxyazetidin-1-yl)B 4-methyl-2H-carbazole-5-carboxamide

Analogously to Example 1, from 120 mg of the compound obtained in Example 238c and 40 mg of 2-(3-methoxyazetidin-l-yl)ethylamine (prepared to WO2006/104406) gave 33 mg of the title compound.

¹ H-NMR (300MHz, CDCl3): δ = 0.83 (1H), 1.20-2.01 (4H), 2.38 (1H), 2.66 (3H), 2.69-3.09 (2H), 3.31 (3H), 3.43 (2H) , 3.56-3.90 (5H), 4.18-4.32 (3H), 4.43 (2H), 6.91 (1H), 7.30-7.41 (5H), 7.52 (1H), 7.95 (1H).

The starting materials were prepared as follows:

Example 238a: 4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxylic acid methyl ester hydrochloride

Analogously to Example 1a, 2.51 g of the title compound was obtained from 3.0 g of the title compound of Example 1e, which was carried out without further purification.

Example 238b: Methyl 2-{[1-(4-chlorobenzylidenyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxylate

Analogously to Example 55, 3.27 g of the title compound was obtained from 2.5 g of the compound of Example 238a and 1.5 g of 4-chlorobenzamide.

¹ H-NMR (300MHz, DMSO-d6): δ=1.16-1.63 (4H), 2.21-2.33 (1H), 2.73 (4H), 2.90-3.05 (1H), 3.44-3.55 (1H), 3.79 (3H) ), 4.32 (2H), 4.36-4.47 (1H), 7.36 (2H), 7.42 (1H), 7.46 (2H), 7.63 (1H), 8.67 (1H).

Example 238c: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carboxylic acid

Analogously to Example 1d, 470 mg of the title compound was obtained from 485 mg of the title compound of Example 238b.

Example 239: (+/-)-2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-4-methyl-N-(3,4,5,6 -tetrahydro-2H-piperidin-2-ylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, from 300 mg of the compound obtained in Example 238c, and 92 mg of 3,4,5,6-tetrahydro-2H-pyran-2-ylmethylamine hydrochloride gave 188 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.01-1.27 (3H), 1.29-1.64 (7H), 2.19-2.32 (1H), 2.48 (3H), 2.66-2.80 (1H), 2.89-3.00 (1H), 3.00-3.08 (1H), 3.16-3.25 (2H), 3.34-3.42 (1H), 3.43-3.55 (1H), 3.77-3.88 (1H), 4.31 (2H), 4.39 (1H), 7.14 (1H), 7.32-7.40 (2H), 7.46 (2H), 7.83 (1H), 8.09 (1H), 8.46 (1H).

Example 240: (R or S)-2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-4-methyl-N-(3,4,5,6 -tetrahydro-2H-piperidin-2-ylmethyl)-2H-indazole-5-carboxamide

51 mg of the title compound was obtained along with 53 mg of the slower enantiomer (by Example 241) by preparatively separated from the mp. ).

Analytical versus palm HPLC: 7.02 min.

Example 241: (S or R)-2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-4-methyl-N-(3,4,5,6 -tetrahydro-2H-piperidin-2-ylmethyl)-2H-indazole-5-carboxamide

The title compound was obtained along with 51 mg of the faster-dissolving enantiomer by means of preparative-type palmitic HPLC (Method B) racemic separation from 185 mg of the racemate prepared in Example 239 (Example 240 ).

Analytical versus palm HPLC: 8.24 min.

Example 242: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-ethyl-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 85 mg of the title compound was obtained from 300 mg of the compound obtained in Example 238c and 43 mg of ethylamine 2M in THF.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.08 (3H), 1.16-1.60 (4H), 2.20-2.33 (1H), 2.48 (3H), 2.63-3.07 (2H), 3.22 (2H), 3.48 (1H), 4.24-4.46 (3H), 7.14 (1H), 7.31-7.42 (3H), 7.46 (2H), 8.08 (1H), 8.46 (1H).

Example 243: 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-N-isobutyl-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1, 92 mg of the title compound was obtained from 300 mg of the compound of Example 238c and 69 mg of isobutylamine.

¹ H-NMR (300MHz, DMSO-d6): δ = 0.85-0.90 (6H), 1.13-1.57 (4H), 1.75-1.83 (1H), 2.21-2.34 (1H), 2.49 (3H), 3.03 (4H) ), 3.48 (1H), 4.27-4.45 (3H), 7.14 (1H), 7.31-7.41 (3H), 7.46 (2H), 8.11 (1H), 8.47 (1H).

Example 244: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(2-methylsulfonylethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

Analogously to Example 1, from 300 mg of the compound obtained in Example 238c and 151 mg of 2-methanesulfonylethylamine hydrochloride afforded 132 mg of the title compound.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.19-1.62 (4H), 2.24-2.36 (1H), 2.54 (3H), 2.70-3.05 (2H), 3.05 (3H), 3.38 (2H), 3.52 (1H), 3.65 (2H), 4.30-4.49 (3H), 7.22 (1H), 7.38 (2H), 7.42 (1H), 7.49 (2H), 8.33 (1H), 8.52 (1H).

Example 245: N-(2-Methylsulfonylethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}-peripipeline Pyridin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 67 mg of the title compound was obtained from 137 mg of the compound obtained in Example 245b and 41 mg of 2-methanesulfonylethylamine hydrochloride.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.15-1.62 (4H), 2.22-2.33 (1H), 2.50 (3H), 2.68-3.01 (2H), 3.02 (2H), 3.35 (1H), 3.52-3.69(3H), 4.28-4.47(2H), 7.12(1H), 7.15-7.22(2H), 7.37-7.44(2H), 7.73(1H), 8.32(1H), 8.50(1H).

The starting materials were prepared as follows:

Example 245a: 4-Methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)methyl]-2H-carbazole -5-methyl formate

Analogously to Example 1, 2.76 g of the compound obtained in Example 238a and 3.28 g of 4-[4-(trifluoromethyl)phenoxy]benzoic acid afforded 2.73 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d6): δ = 1.25 (2H), 1.35-1.70 (2H), 2.20-2.37 (1H), 2.65-2.70 (3H), 2.75-3.10 (2H), 3.52-3.72 (1H), 3.82 (4H), 4.36 (2H), 7.14 (2H), 7.20 (2H), 7.39-7.48 (3H), 7.66 (1H), 7.75 (2H), 8.70 (1H).

Example 245b: 4-Methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)-methyl]-2H-indole Oxazol-5-formic acid

Analogously to Example 1d, 1.1 g of the title compound was obtained from 2.73 g of the title compound.

Example 246: N-(2-Cyanoethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidin-4 -yl)methyl]-2H-carbazole-5-carboxamide

Analogously to Example 1, 144 mg of the title compound was obtained from 137 mg of the compound of Example 245b and 18 mg of 3-aminopropionitrile.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.13-1.58 (4H), 2.21-2.33 (1H), 2.52 (3H), 2.75 (2H), 2.80-3.16 (2H), 3.44 (2H), 3.59(1H), 4.27-4.50(3H), 7.12(2H), 7.15-7.21(3H), 7.37-7.44(3H), 7.73(2H), 8.46(1H), 8.51(1H)

Example 247: N-(Cyanomethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene]piperidin-4-yl )methyl]-2H-carbazole-5-carboxamide

Analogously to Example 1, 125 mg of the title compound was obtained from 137 mg of the compound obtained in Example 245b and 24 mg of 2-aminoacetonitrile hydrochloride.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.16-1.60 (4H), 2.23-2.34 (1H), 2.53 (3H), 2.69-3.06 (2H), 3.59 (1H), 4.26 (2H), 4.29-4.50(3H), 7.08-7.23(5H), 7.38-7.46(3H), 7.73(2H), 8.54(1H), 8.83(1H).

Example 248: (+/-)-4-Methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2-[(1-{4-[ 4-(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 231 mg of the title compound was obtained from 254 mg of the compound of Example 245b and 72 mg of 3,4,5,6-tetrahydro-2H-pyran-2-ylmethylamine.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.01-1.66 (10H), 2.24-2.32 (1H), 2.70-3.15 (4H), 3.21 (3H), 3.34-3.43 (1H), 3.54-3.64 (1H), 3.76-3.89 (2H), 4.32 (3H), 7.09-7.21 (5H), 7.35-7.44 (3H), 7.73 (2H), 8.09 (1H), 8.47 (1H).

Example 249: (+/-)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)) Phenoxy]benzhydryl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1, 280 mg of the title compound was obtained from 254 mg of the compound of Example 245b and 73 mg of 1,4-dioxane-2-ymethylamine.

¹ H-NMR (300MHz, DMSO-d6): δ=1.13-1.61 (4H), 2.23-2.32 (1H), 2.49 (3H), 2.75 (1H), 2.94-3.27 (4H), 3.38-3.77 (8H) ), 4.32 (2H), 7.09-7.21 (5H), 7.36-7.44 (3H), 7.73 (2H), 8.16 (1H), 8.48 (1H).

Example 250: 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-N-(cyclobutylmethyl)-4-methyl-2H-indazole-5-A Guanamine

Analogously to Example 1, 79 mg of the title compound was obtained from 300 mg of the compound obtained in Example 238c and 115 mg of cyclobutylmethylamine hydrochloride.

¹ H-NMR (300 MHz, DMSO-d6): δ=1.16-1.58 (4H), 1.64-1.86 (4H), 1.90-2.01 (2H), 2.19-2.32 (1H), 2.48 (3H), 2.50 (1H) ), 2.66-3.05(2H), 3.19-3.25(2H), 3.48(1H), 4.27-4.47(3H), 7.12(1H), 7.31-7.40(3H), 7.46(2H), 8.09(1H), 8.46 (1H).

Example 251: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2,2-dimethylpropyl)-4-methyl-2H- Oxazole-5-carboxamide

Analogously to Example 1, 108 mg of the title compound was obtained from 300 mg of the compound of Example 238c and 83 mg of 2,2-dimethylpropan-1-amine.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 0.91 (9H), 1.17-1.63 (4H), 2.24-2.36 (1H), 2.52 (3H), 2.70-3.04 (2H), 3.07 (2H), 3.52 (1H), 4.30-4.50 (3H), 7.17 (1H), 7.38 (2H), 7.42 (1H), 7.49 (2H), 8.07 (1H), 8.49 (1H).

Example 252: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(2-hydroxyethyl)-4-methyl-2H-indazole-5 -Procarbamide

Analogously to Example 1, 84 mg of the title compound was obtained from 370 mg of the compound obtained in Example 238c and 54 mg of 2-aminoethanol.

¹ H-NMR (300MHz, DMSO-d6): δ=1.14-1.64 (4H), 2.24-2.35 (1H), 2.53 (3H), 2.69-3.09 (2H), 3.30 (2H), 3.43-3.58 (3H) ), 4.27-4.50 (3H), 4.67 (1H), 7.20 (1H), 7.35-7.43 (3H), 7.49 (2H), 8.02 (1H), 8.49 (1H).

Example 253: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(3-hydroxypropyl)-4-methyl-2H-indazole-5 -Procarbamide

Analogously to Example 1, 95 mg of the title compound was obtained from 370 mg of the compound obtained in Example 238c and 66 mg of 3-aminopropan-1-ol.

^{1 H-NMR (300MHz, DMSO} -d6): δ = 1.17-1.60 (4H), 1.66 (2H), 2.22-2.35 (1H), 2.53 (3H), 2.70-3.09 (2H), 3.27 (2H), 3.47 (2H), 3.47-3.67 (1H), 4.34 (2H), 4.41 (1H), 4.45 (1H), 7.17 (1H), 7.35-7.43 (3H), 7.49 (2H), 8.07 (1H), 8.49 (1H).

Example 254: 4-Methoxy-N-(2-methoxyethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3- }]methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1, 90 mg of the title compound was obtained from 100 mg of the compound obtained in Example 214c and 97 mg of 4-(trifluoromethoxy)benzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.24 - 3.29 (1H), 3.29 - 3.32 (3H), 3.43 - 3.51 (4H), 3.91-4.04 (1H), 4.10 - 4.18 ( 1H), 4.20 (3H), 4.22-4.29 (1H), 4.44 (1H), 4.70 (2H), 7.24 (1H), 7.37-7.51 (2H), 7.66 (1H), 7.70-7.80 (2H), 8.22 (1H), 8.91 (1H).

Example 255: 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-4-methoxy-N-( 2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 40 mg of the title compound was obtained from 100 mg of the compound obtained in Example 214c and 98 mg of 2-fluoro-4-(trifluoromethyl)benzoic acid in DMF.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 3.30 (4H), 3.44 - 3.50 (4H), 3.94 - 4.04 (2H), 4.15 (2H), 4.20 (3H), 4.70 (2H) ), 7.24 (1H), 7.60-7.75 (3H), 7.78-7.89 (1H), 8.16-8.27 (1H), 8.90 (1H).

Example 256: 2-({1-[4-Chloro-3-(trifluoromethyl)benzylidenyl]azetidin-3-yl}methyl)-4-methoxy-N-( 2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1, 40 mg of the title compound was obtained from 100 mg of the compound obtained in Example 214c and 106 mg of 4-chloro-3-(trifluoromethyl)benzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.30 (4H), 3.43-3.53 (4H), 3.95-4.05 (1H), 4.20 (4H), 4.23-4.31 (1H), 4.47 (1H), 4.71 (2H), 7.23 (1H), 7.67 (1H), 7.78-7.85 (1H), 7.86-7.93 (1H), 7.96 (1H), 8.22 (1H), 8.90 (1H).

Example 257: 2-{[1-(4-Chloro-2-fluorobenzylidenyl)azetidin-3-yl]methyl}-4-methoxy-N-(2-methoxy Ethyl)-2H-carbazole-5-carboxamide

Analogously to Example 1, 20 mg of the title compound was obtained from 100 mg of the compound obtained in Example 214c and 82 mg of 4-chloro-2-fluorobenzoic acid in DMF.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 3.30 (4H), 3.42-3.51 (4H), 3.98 (2H), 4.14 (2H), 4.20 (3H), 4.69 (2H), 7.24 (1H), 7.38 (1H), 7.48 (1H), 7.56 (1H), 7.66 (1H), 8.15-8.30 (1H), 8.90 (1H).

Example 258: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methoxy-N-(2-(N-morpholinyl) -ethyl)-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 67 mg of the title compound was obtained from 66 mg of the compound of Example 258d and 32 mg of 2-(N-morpholinyl)ethylamine in DMF.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 2.44 (4H), 3.21-3.36 (3H), 3.42 (2H), 3.61 (4H), 3.88-4.04 (1H), 4.07-4.18 (1H), 4.23 (4H), 4.35-4.50 (1H), 4.70 (2H), 7.25 (1H), 7.41-7.56 (2H), 7.59-7.66 (2H), 7.70 (1H), 8.32 (1H), 8.91 (1H).

The starting materials were prepared as follows:

Example 258a: methyl 2-{[1-(t-butoxycarbonyl)azetidin-3-yl]methyl}-4-methoxy-2H-indazole-5-carboxylate

Similar to Example 1e, from 750 mg of the compound prepared in Example 214a and 546 mg. The alcohol obtained 448 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27-1.44 (9H), 3.01-3.22 (1H), 3.78 (5H), 3.85-3.99 (2H), 4.14 (3H), 4.64 (2H), 7.24 (1H), 7.51 (1H), 8.94 (1H).

Example 258b: Methyl 2-(azetidin-3-ylmethyl)-4-methoxy-2H-indazole-5-carboxylate

800 mg of 258a was first placed in 40 ml of acetone, treated with 40 ml of semi-concentrated hydrochloric acid, stirred until complete conversion and concentrated to dryness. Yield: 414 mg of the title compound.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 3.39 (1H), 3.79 (3H), 3.84-3.95 (2H), 3.96-4.07 (2H), 4.15 (3H), 4.72 (2H) ), 7.25 (1H), 7.52 (1H), 8.92 (1H).

Example 258c: Methyl 2-{[1-(4-chlorobenzylidenyl)azetidin-3-yl]methyl}-4-methoxy-2H-indazole-5-carboxylate

404 mg of 258b was first placed in 30 ml of DCM at 0 ° C, treated with 0.21 ml of 4-chloro-benzhydryl chloride and 0.75 ml of N-ethyldiisopropylamine and stirred at room temperature until complete conversion. For the treatment, the reaction solution was treated with aq. This gave 608 mg of the title compound which was used in the next step without further purification.

Example 258d: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-methoxy-2H-indazole-5-carboxylic acid

550 mg of 258c was first placed in 20 ml of ethanol, treated with 20 ml of 2N sodium hydroxide and stirred until complete conversion. For the treatment, the reaction solution was adjusted to pH 3 with 1N hydrochloric acid, extracted with ethyl acetate and the combined organic phases dried over sodium sulfate and concentrated to dry. Yield after purification by column chromatography on silica gel eluting with hexane / ethyl acetate gradient: 213 mg of the title compound.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 3.27 (1H), 3.97 (1H), 4.07-4.17 (4H), 4.24 (1H), 4.42 (1H), 4.70 (2H), 7.22(1H), 7.46-7.57(3H), 7.59-7.68(2H), 8.88(1H), 12.61(m,1H).

Example 259: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-ethoxyethyl)-4-methoxy- 2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 30 mg of the title compound was obtained from 66 mg of the compound of Example 258d and 22 mg of 2-ethoxyethylamine in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.07-1.21 (3H), 3.30 (1H), 3.40-3.57 (6H), 3.90-4.02 (1H), 4.08-4.17 (1H) , 4.21 (4H), 4.34 - 4.48 (1H), 4.70 (2H), 7.24 (1H), 7.45-7.57 (2H), 7.60-7.74 (3H), 8.24 (1H), 8.91 (1H).

Example 260: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-N-[2-(3,3-difluoropyrrolidin-1-yl) Ethyl]-4-methoxy-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 58 mg of the title compound was obtained from 66 mg of the compound of Example 258d and 37 mg of 2-(3,3-difluoropyrrolidin-1-yl)ethylamine.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 2.27 (2H), 2.64 (2H), 2.77 (2H), 2.96 (2H), 3.22-3.30 (1H), 3.41 (2H), 3.92-4.01(1H), 4.11(1H), 4.19(4H), 4.35-4.48(1H), 4.70(2H), 7.24(1H), 7.51(2H), 7.57-7.75(3H), 8.32(1H) , 8.90 (1H).

Example 261: 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-4-methoxy-N-(2-(N-morpholinyl)-ethyl )-2H-carbazole-5-carbamide

Analogously to Example 1b, version B, 77 mg of the title compound was obtained from 100 mg of the compound of Example 261e and 46 mg of 2-(N-morpholinyl)ethylamine.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.11-1.33 (2H), 1.35-1.75 (2H), 2.18-2.39 (1H), 2.65-2.88 (2H), 2.90-3.23 ( 3H), 3.41-3.82 (8H), 3.84-4.12 (2H), 4.24 (3H), 4.35 (3H), 7.26 (1H), 7.33-7.44 (2H), 7.46-7.58 (2H), 7.69 (1H) , 8.27-8.52 (1H), 8.87 (1H).

The starting materials were prepared as follows:

Example 261a : tert-butyl 4-[(5-bromo-4-methoxy-2H-indazol-2-yl)methyl]piperidine-1-carboxylate

Similar to Example 1c, 5.65 g of 5-bromo-4-methoxy-1H-indazole and 23.55 g of 4-[(toluenesulfonyloxy)methyl]piperidine-1-carboxylic acid tert-butyl ester were obtained 5.57. g title compound.

¹ H-NMR (400 MHz, chloroform-d): δ [ppm] = 1.16-1.31 (2H), 1.39- 1.49 (9H), 1.52-1.64 (2H), 2.16-2.36 (1H), 2.56-2.80 (2H), 4.11 (5H), 4.26 (2H), 7.28-7.33 (1H), 7.34-7.39 (1H), 7.99 (1H).

Example 261b: methyl 2-{[1-(t-butoxycarbonyl)piperidin-4-yl]methyl}-4-methoxy-2H-indazole-5-carboxylate

Analogously to Example 1e, 1.1 g of the title compound was obtained from 2.4 g of the compound of Example 261a and 1.63 g of methanol.

Example 261c: Methyl 4-methoxy-2-(4-piperidinylmethyl)-2H-indazole-5-carboxylate

Analogously to Example 258b, 1.1 g of the title compound was obtained from the title compound from </ RTI>

Example 261d: methyl 2-{[1-(4-chlorobenzylidinyl)piperidin-4-yl]methyl}-4-methoxy-2H-indazole-5-carboxylate

Similar to Example 258c, 980 mg of the title compound was obtained from 1.1 g of the compound of Example 261c and 762 mg of 4-chlorobenzhydrin chloride after purification by column chromatography on silica gel.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (2H), 1.36-1.76 (2H), 2.18-2.40 (1H), 2.65-2.88 (1H), 2.91-3.12 (1H) , 3.42-3.67 (1H), 3.78 (3H), 4.05-4.21 (3H), 4.35 (3H), 7.24 (1H), 7.34-7.43 (2H), 7.45-7.56 (3H), 8.86 (1H).

Example 261e: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methoxy-2H-indazole-5-carboxylic acid

Analogously to Example 258d, 547 mg of the title compound was obtained from 980 mg of the compound of Example 261d.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.12-1.35 (2H), 1.35 - 1.73 (2H), 2.21-2.40 (1H), 2.63 - 3.12 (2H), 3.14 - 3.70 ( 3H), 4.34 (3H), 5.76 (s, 1H), 7.21 (1H), 7.32-7.45 (2H), 7.46-7.58 (3H), 8.76 (1H).

Example 262: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methoxy-N-(2-methoxyethyl)-2H-indole Oxazol-5-carboxamide

Similar to Example 1b, version B, 50 mg of the title compound was obtained from 100 mg of the compound of Example 261e and 26 mg of 2-methoxyethylamine in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.11-1.35 (2H), 1.35-1.72 (2H), 2.21-2.39 (1H), 2.69-2.88 (1H), 2.92-3.11 ( 1H), 3.30 (s, 3H), 3.38-3.64 (5H), 4.20 (3H), 4.34 (3H), 7.25 (1H), 7.34-7.43 (2H), 7.45-7.57 (2H), 7.66 (1H) , 8.22 (1H), 8.83 (1H).

Example 263: 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-4-methoxy-N-(2,2,2-trifluoro-ethyl) -2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 68 mg of the title compound was obtained from 100 mg of the compound of Example 261e and 35 mg of 2,2,2-trifluoroethylamine in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.09-1.35 (2H), 1.37-1.75 (2H), 2.21-2.41 (1H), 2.69-2.88 (1H), 2.92-3.19 ( 1H), 3.42-3.69 (1H), 4.13 (2H), 4.23 (3H), 4.35 (3H), 7.26 (1H), 7.34-7.45 (2H), 7.46-7.55 (2H), 7.61 (1H), 8.59 (1H), 8.88 (1H).

Example 264: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(2-ethoxyethyl)-4-methoxy-2H-indole Oxazol-5-carboxamide

Similar to Example 1b, version B, 60 mg of the title compound was obtained from 100 mg of the compound of Example 261e and 31 mg of 2-ethoxyethylamine in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14 (3H), 1.19-1.35 (2H), 1.37-1.72 (2H), 2.23 - 2.43 (1H), 2.68-2.88 (1H) , 2.91-3.15 (1H), 3.41-3.56 (m, 7H), 4.20 (3H), 4.34 (3H), 7.25 (1H), 7.33-7.45 (2H), 7.46-7.55 (2H), 7.67 (1H) , 8.23 (1H), 8.83 (1H).

Example 265: 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-4-methoxy-N-{2-[(trifluoro-methyl)thio ]ethyl}-2H-carbazole-5-carboxamide

Similar to Example 1b, Revision B, from 100 mg of the compound prepared in Example 261e and 51 mg of 2-[(trifluoromethyl)thio]-ethylamine in DMF gave 68 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14-1.35 (2H), 1.36-1.72 (2H), 2.18-2.40 (1H), 2.66-2.87 (1H), 2.91-3.11 ( 1H), 3.21 (2H), 3.42-3.70 (3H), 4.22 (3H), 4.34 (3H), 7.24 (1H), 7.32-7.45 (2H), 7.46-7.55 (2H), 7.64 (1H), 8.45 (1H), 8.85 (1H).

Example 266: 4-Methoxy-N-(2-methoxyethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]piperidin-4-yl}A Base-2H-carbazole-5-carbamide

Analogously to Example 1b, version B, 84 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 89 mg of 4-(trifluoromethoxy)benzoic acid in DMF.

_{LC-MS: R t = 1.16min} , MS (ES +): m / z = 435 (M + H) +.

The starting materials were prepared as follows:

Example 266a : 4-({4-Methoxy-5-[N-(2-methoxyethyl)aminemethanyl]-2H-indazol-2-yl}methyl)piperidine-1- Tert-butyl formate

3 g of compound 261a, 1.59 g of 2-methoxyethylamine, 1.87 g of hexacarbonyl molybdenum, 204 mg of tetrafluoro The acid tri-tert-butylphosphine and 316 mg of palladium(II) acetate were first suspended in 100 ml of 1,4-dioxane. Subsequently, 2.25 g of sodium carbonate and a few drops of water were added, and the mixture was stirred in a microwave at 140 ° C and 150 watts for 25 minutes. The reaction mixture was concentrated and the residue was purified eluting with EtOAc EtOAc Yield: 1.3 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 0.95-1.22 (2H), 1.29-1.55 (11H), 2.03-2.33 (1H), 2.60-2.83 (2H), 3.28-3.31 ( 3H), 3.43-3.52 (4H), 3.82-4.03 (2H), 4.20 (3H), 4.31 (2H), 7.25 (1H), 7.66 (1H), 8.21 (1H), 8.82 (1H).

Example 266b : 4-methoxy-N-(2-methoxyethyl)-2-(4-piperidylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, 1.38 g of the title compound was obtained from the title compound </RTI>

Example 267: 2-({1-[2-Fluoro-4-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-4-methoxy-N-(2-A Oxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 20 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 90 mg of 2-fluoro-4-(trifluoromethyl)benzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.05-1.36 (2H), 1.39-1.53 (1H), 1.56-1.72 (1H), 2.21-2.40 (1H), 2.75-2.90 ( 1H), 2.92-3.15 (1H), 3.27-3.35 (4H), 3.44-3.53 (4H), 4.20 (3H), 4.27-4.43 (2H), 4.44-4.58 (1H), 7.25 (1H), 7.54 7.74 (3H), 7.81 (1H), 8.20 (1H), 8.83 (1H).

Example 268: 4-Methoxy-N-(2-methoxyethyl)-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]-piperidine-4 -yl}methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 39 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 107 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid in DMF.

_{LC-MS: R t = 1.18min} , MS (ES +): m / z = 577 (M + H) +.

Example 269: 4-Methoxy-N-(2-methoxyethyl)-2-[(1-{4-[(trifluoromethyl)thio]benzylidenyl}-piperidine-4 -yl)methyl]-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 25 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 96 mg of 4-[(trifluoromethyl)thio]benzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.09-1.37 (2H), 1.38-1.72 (2H), 2.23-2.39 (1H), 2.70-2.93 (1H), 2.95-3.16 ( 1H), 3.30 (3H), 3.40-3.55 (5H), 4.20 (3H), 4.35 (d, 3H), 7.25 (1H), 7.46-7.58 (2H), 7.66 (1H), 7.78 (2H), 8.20 (1H), 8.82 (1H).

Example 270: 2-({1-[4-Chloro-3-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-4-methoxy-N-(2-A Oxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 27 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 97 mg of 4-chloro-3-(trifluoromethyl)benzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.15 - 1.37 (2H), 1.38 - 1.73 (2H), 2.14 - 2.41 (1H), 2.70 - 2.88 (1H), 2.95 - 3.18 ( 1H), 3.30 (3H), 3.39-3.62 (5H), 4.20 (3H), 4.35 (3H), 7.25 (1H), 7.59-7.73 (2H), 7.75-7.86 (2H), 8.20 (1H), 8.82 (1H).

Example 271: 2-{[1-(4-Chloro-2-fluorobenzylidinyl)piperidin-4-yl]methyl}-4-methoxy-N-(2-methoxyethyl) -2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 17 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 75 mg of 4-chloro-2-fluorobenzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.08-1.33 (2H), 1.37-1.52 (1H), 1.53-1.70 (1H), 2.20-2.42 (1H), 2.72-2.88 ( 1H), 2.94-3.12 (1H), 3.30 (3H), 3.37 (1H), 3.43-3.51 (4H), 4.20 (3H), 4.34 (2H), 4.42-4.55 (1H), 7.25 (1H), 7.31 -7.48(2H), 7.55(1H), 7.66(1H), 8.20(1H), 8.83(1H).

Example 272: 2-({1-[3-Fluoro-4-(trifluoromethoxy)benzylidene]piperidin-4-yl}methyl)-4-methoxy-N-(2- Methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 12 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 97 mg of 3-fluoro-4-(trifluoromethoxy)benzoic acid in DMF.

_{LC-MS: R t = 1.18min} , MS (ES +): m / z = 553 (M + H) +.

Example 273: 4-Methoxy-N-(2-methoxyethyl)-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]-piperidin-4 -yl}methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 19 mg of the title compound was obtained from 100 mg of the compound of Example 266b and 76 mg of 1-methyl-1H-indole-3-carboxylic acid in DMF.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.11-1.40 (2H), 1.54 (2H), 2.18-2.42 (1H), 2.93 (2H), 3.30 (3H), 3.40-3.45 (4H), 3.70-3.91 (3H), 4.12-4.48 (7H), 7.00-7.34 (3H), 7.48 (1H), 7.66 (3H), 8.22 (1H), 8.84 (1H).

Example 274: 2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-4-ethoxy-N-(2-methoxyethyl)-2H-indole Oxazol-5-carboxamide

Analogously to Example 1b, version B, 47 mg of the title compound was obtained from 110 mg of the compound of Example 274c and 72 mg of 4-chlorobenzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.10-1.33 (2H), 1.44 (5H), 2.20-2.39 (1H), 2.68-2.85 (1H), 2.92-3.12 (1H) , 3.32 (7H), 3.51-3.62 (1H), 4.20-4.59 (5H), 7.26 (1H), 7.33-7.44 (2H), 7.47-7.55 (2H), 7.70 (1H), 8.30 (1H), 8.79 (1H).

The starting materials were prepared as follows:

Example 274a : 4-[(5-Bromo-4-ethoxy-2H-indazol-2-yl)methyl]piperidine-1-carboxylic acid tert-butyl ester

Analogous to Example 74c, from 484 mg of 5-bromo-4-ethoxy-1H-carbazole and 1.11 g of 4-[(5-bromo-4-ethoxy-2H-indazol-2-yl)-methyl Piperidine-1-carboxylic acid tert-butyl ester gave 285 mg of the title compound.

¹ H-NMR (400 MHz, chloroform-d): δ [ppm] = 1.13-1.34 (2H), 1.46 (9H), 1.49 (3H), 1.56-1.63 (2H), 2.16-2.37 (1H), 2.54-2.80(2H), 4.02-4.21(2H), 4.26(2H), 4.33(2H), 7.28-7.43(2H), 7.93(1H).

Example 274b: 4-({4-Ethoxy-5-[N-(2-methoxyethyl)aminemethanyl]-2H-indazol-2-yl}-methyl)piperidine-1 -T-butyl formate

Analogously to Example 266a, 235 mg of the title compound was obtained from 285 mg of the compound of Example 274a and 146 mg of 2-methoxyethylamine.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.97-1.22 (2H), 1.29-1.56 (14H), 2.06-2.31 (1H), 2.59-2.86 (2H), 3.33 (3H) , 3.49 (4H), 3.80-4.02 (2H), 4.30 (2H), 4.51 (2H), 7.26 (1H), 7.71 (1H), 8.31 (1H), 8.79 (1H).

Example 274c: 4-Ethoxy-N-(2-methoxyethyl)-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, 237 mg of the title compound was obtained from br.

Example 275: 4-Ethoxy-N-(2-methoxyethyl)-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]-piperidine-4 -yl}methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 30 mg of the title compound was obtained from 110 mg of the compound of Example 274c and 113 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.10-1.36 (2H), 1.44 (4H), 1.54-1.69 (1H), 2.22-2.40 (1H), 2.70-2.87 (1H) , 2.93-3.13(1H), 3.30(3H), 3.48(5H), 4.34(2H),4.41-4.63(3H), 7.26(1H), 7.59(2H), 7.70(1H), 7.98(2H), 8.30 (1H), 8.79 (1H).

Example 276: 2-{[1-(4-Chlorobenzylidene)azetidin-3-yl]methyl}-4-ethoxy-N-(2-methoxyethyl)- 2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 25 mg of the title compound was obtained from 50 mg of the compound of Example 276c and 35 mg of 4-chlorobenzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.44 (3H), 3.21-3.29 (1H), 3.31 (3H), 3.49 (4H), 3.96 (1H), 4.06-4.30 (2H) ), 4.34 - 4.59 (3H), 4.69 (2H), 7.25 (1H), 7.51 (2H), 7.62 (2H), 7.71 (1H), 8.30 (1H), 8.86 (1H).

The starting materials were prepared as follows:

Example 276a: 3-[(5-Bromo-4-ethoxy-2H-indazol-2-yl)methyl]azetidin-1-carboxylic acid tert-butyl ester

Analogously to Example 74c, from 500 mg of 5-bromo-4-ethoxy-1H-carbazole and 1.06 g of tert-butyl 3-[(toluenesulfonyloxy)methyl]azetidin-1-carboxylate Obtained 204 mg of the title compound.

¹ H-NMR (600 MHz, chloroform-d): δ [ppm] = 1.44 (9H), 1.49 (3H), 3.14-3.30 (1H), 3.72-3.83 (2H), 4.07 (2H), 4.33 ( 2H), 4.59 (2H), 7.29 (1H), 7.37 (1H), 7.98 (1H).

Example 276b: 3-({4-Ethoxy-5-[N-(2-methoxyethyl)aminemethanyl]-2H-indazol-2-yl}-methyl)azetidine Alkyl-1-carboxylic acid tert-butyl ester

Analogously to Example 266a, from 191 mg of EtOAc Compound:

Example 276c: 2-(Azetidin-3-ylmethyl)-4-ethoxy-N-(2-methoxyethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, 93 mg of the title compound was obtained from the title compound 129b.

Example 277: 4-Ethoxy-N-(2-methoxyethyl)-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]-azetidine Alkyl-3-yl}methyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 35 mg of the title compound was obtained from 50 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid in 50 mg of 276c and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.37-1.50 (3H), 3.26 (1H), 3.31 (3H), 3.43-3.57 (4H), 3.92-4.05 (1H), 4.10 -4.31(2H), 4.38-4.57(3H), 4.70(2H), 7.25(1H), 7.66-7.87(3H), 7.98(2H), 8.30(1H),8.86(1H).

Example 278: 2-{[1-(4-Chlorobenzylidenyl)azetidin-3-yl]methyl}-6-methyl-N-(2-(N-morpholinyl) Base-2H-carbazole-5-carbamide

Similar to Example 1b, version B, 23 mg of the title compound was obtained from 66 mg of 4-chlorobenzoic acid in 100 mg of 278b and DMF.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 2.42 (s, 3H), 3.09-3.27 (m, 3H), 3.29-3.33 (2H), 3.49-3.73 (m, 6H), 3.84-3.96 (m, 1H), 3.97-4.15 (m, 3H), 4.16-4.27 (m, 1H), 4.31-4.45 (m, 1H), 4.62-4.80 (m, 2H), 7.36-7.47 (1H ), 7.48-7.57 (2H), 7.58-7.70 (2H), 7.77-7.89 (1H), 8.41-8.58 (2H).

The starting materials were prepared as follows:

Example 278a: 3-({6-Methyl-5-[N-(2-(N-morpholinyl)ethyl)aminemethanyl]-2H-indazol-2-yl}methyl)aza Cyclobutane-1-carboxylic acid tert-butyl ester

Analogously to Example 1b, version B, 418 mg of the title compound was obtained from 232 mg of 2-(N-morpholinyl)ethylamine from 410 mg of 178c.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.36 (9H), 2.39 (3H), 2.44 (4H), 2.95-3.17 (1H), 3.24-3.43 (4H), 3.58 (4H ), 3.64-3.79 (2H), 3.88 (2H), 4.62 (2H), 7.39 (1H), 7.68 (1H), 8.04-8.22 (1H), 8.45 (1H).

Example 278b: 2-(Azetidin-3-ylmethyl)-6-methyl-N-(2-(N-morpholinyl)ethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, 372 mg of the title compound was obtained from the title compound.

Example 279: 6-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]azetidine -3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 44 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 2.42 (3H), 3.07-3.27 (5H), 3.48-3.74 (6H), 3.85-4.17 (4H), 4.18-4.29 (1H) , 4.33-4.48 (1H), 4.61-4.82 (2H), 7.30-7.54 (3H), 7.68-7.78 (2H), 7.79-7.88 (1H), 8.43-8.60 (2H).

Example 280: 6-Methyl-N-(2-(N-morpholinyl)ethyl)-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzimidyl]-nitrogen Heterocyclobutane-3-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 37 mg of the title compound was obtained from 104 mg of 4-(pentafluoro-λ ⁶ -thio)benzoic acid in 100 mg of 278b and DMF.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 2.42 (3H), 3.06-3.27 (5H), 3.47-3.75 (6H), 3.87-4.08 (3H), 4.09-4.29 (2H) , 4.33-4.49 (1H), 4.61-4.80 (2H), 7.34-7.52 (1H), 7.71-7.88 (3H), 7.92-8.07 (2H), 8.39-8.59 (2H).

Example 281: N-(2-Methoxyethyl)-6-methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl)-piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 4.2 mg of the title compound was obtained from 119 mg of 1-methyl-1H-indole-3-carboxylic acid from 150 mg of 205c and DMF.

_{LC-MS: R t = 1.01min} , MS (ES +): m / z = 489 (M + H) +.

Example 282: N-(2-Methoxyethyl)-4-methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]azetidine- 3-yl}methyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 35 mg of the title compound was obtained from 175 mg of 117e and 122 mg of 1-methyl-1H-indole-3-carboxylic acid in DMF.

_{LC-MS: R t = 0.95min} , MS (ES +): m / z = 460 (M + H) +.

Example 283: 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2- Trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 267 mg of the title compound was obtained from 246 mg of 4-(4-fluorophenoxy)benzoic acid in 250 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.32 (2H), 1.35-1.69 (2H), 2.20-2.39 (1H), 2.54 (3H), 2.70-3.15 (2H) , 3.50-3.83 (1H), 4.07 (2H), 4.36 (3H), 6.91-7.05 (2H), 7.08-7.31 (5H), 7.34-7.42 (2H), 7.46 (1H), 8.56 (1H), 8.83 (1H).

Example 284: 2-({1-[4-(4-Chlorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2- Trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 55 mg of the title compound was obtained from 105 mg of 4-(4-chlorophenoxy)benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.34-1.72 (2H), 2.21-2.41 (1H), 2.54 (3H), 2.67-3.20 (2H), 3.51 -3.83 (1H), 4.07 (2H), 4.36 (3H), 6.92-7.15 (4H), 7.20 (1H), 7.35-7.53 (5H), 8.56 (1H), 8.84 (1H).

Example 285: 4-Methyl-2-({1-[4-(4-methylphenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

60 mg of the title compound was obtained from 97 mg of 4-(4-methylphenoxy)benzoic acid from 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.36-1.71 (2H), 2.30 (4H), 2.54 (3H), 2.64 - 3.17 (2H), 3.49-3.82 (1H), 4.07 (2H), 4.36 (3H), 6.85-7.04 (4H), 7.21 (3H), 7.29-7.41 (2H), 7.46 (1H), 8.56 (1H), 8.84 (s1H).

Example 286: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-tri Fluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 39 mg of the title compound was obtained from EtOAc (EtOAc)

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14-1.36 (2H), 1.36-1.73 (2H), 2.18-2.41 (1H), 2.54 (3H), 2.70-3.16 (2H) , 3.51-3.82 (1H), 4.07 (2H), 4.38 (3H), 7.21 (1H), 7.31 (2H), 7.40-7.53 (3H), 7.64-7.85 (4H), 8.56 (1H), 8.81 (1H) ).

Example 287: 4-Methyl-2-{[1-(4-(N-morpholinyl)benzylidenyl)piperidin-4-yl]methyl}-N-(2,2,2-tri Fluoro-ethyl)-2H-carbazole-5-carbamide

Similar to Example 1b, Revision B, 88 mg of 4-(N-morpholine) from 100 mg of 71a and DMF Benzoic acid afforded 45 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (2H), 1.40-1.60 (2H), 2.20-2.40 (1H), 2.54 (3H), 2.73-3.01 (2H), 3.38 (4H), 3.64-3.81 (5H), 4.07 (3H), 4.36 (2H), 6.94 (2H), 7.16-7.30 (3H), 7.46 (1H), 8.55 (1H), 8.81 (1H).

Example 288: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[(trifluoromethyl)thio]benzylidene}-piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 67 mg of the title compound was obtained from 94 mg of 4-[(trifluoromethyl)thio]benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.12-1.35 (2H), 1.35-1.70 (2H), 2.21-2.40 (1H), 2.54 (3H), 2.70-2.88 (1H) , 2.94 - 3.12 (1H), 3.38 - 3.61 (1H), 4.07 (2H), 4.36 (3H), 7.21 (1H), 7.37-7.60 (3H), 7.78 (2H), 8.55 (1H), 8.81 (1H) ).

Example 289: 4-Methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl)piperidin-4-yl}methyl)-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 43 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.27 (2H), 1.52 (2H), 2.20-2.40 (1H), 2.54 (3H), 2.92 (2H), 3.82 (3H), 4.07(2H), 4.27(2H), 4.38(2H), 6.92-7.33(3H), 7.47(2H), 7.61-7.76(2H), 8.56(1H), 8.81 (1H).

Example 290: 4-Methyl-2-({1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 51 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.41 (2H), 1.43-1.73 (2H), 2.19-2.43 (1H), 2.54 (3H), 2.74-3.23 (2H) , 3.73 (3H), 4.07 (3H), 4.39 (3H), 6.60 (s, 1H), 7.03-7.14 (1H), 7.16-7.30 (2H), 7.48 (2H), 7.59 (1H), 8.57 (1H) ), 8.81 (1H).

Example 291: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzhydryl) }piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similarly to Example 1b, version B, 156 mg of the title compound was obtained from 179 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid from 150 mg of 71a.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.36-1.68 (2H), 2.20-2.43 (1H), 2.54 (3H), 2.68-3.17 (2H), 3.50 -3.79 (1H), 4.07 (2H), 4.37 (3H), 7.09-7.28 (5H), 7.35-7.51 (3H), 7.76 (2H), 8.56 (1H), 8.83 (1H).

Example 292: 2-({1-[(5-Fluoro-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N- ( 2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 28 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.18-1.38 (2H), 1.39-1.72 (2H), 2.25-2.42 (1H), 2.54 (3H), 2.74-3.25 (2H) , 3.73 (3H), 4.07 (3H), 4.38 (3H), 6.58 (1H), 7.09 (1H), 7.21 (1H), 7.36 (1H), 7.47 (2H), 8.57 (1H), 8.83 (1H) .

Example 293: 2-({1-[(5-Methoxy-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N -(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 37 mg of the title compound was obtained from 87 mg of 5-methoxy-1-methyl-1H-indole-2-carboxylic acid from 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.30 (2H), 1.41-1.71 (2H), 2.26-2.43 (1H), 2.54 (3H), 2.71-3.22 (2H), 3.69 (3H), 3.75 (3H), 4.07 (3H), 4.39 (3H), 6.51 (1H), 6.88 (1H), 7.07 (1H), 7.21 (1H), 7.34-7.54 (2H), 8.57 (1H) , 8.83 (1H).

Example 294: 2-({1-[(5-Chloro-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N- ( 2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, Revision B, 89 mg 5-chloro-1-A from 100 mg 71a and DMF Base-1H-indole-2-carboxylic acid afforded 43 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.29 (2H), 1.38-1.72 (2H), 2.26-2.43 (1H), 2.54 (3H), 2.71-3.21 (2H), 3.73 (3H), 3.84-4.18 (3H), 4.38 (3H), 6.59 (1H), 7.15-7.28 (2H), 7.47 (1H), 7.55 (1H), 7.65 (1H), 8.57 (1H), 8.83 ( 1H).

Example 295: 2-({1-[(6-Methoxy-1-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N -(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 36 mg of the title compound was obtained from 87 mg of 6-methoxy-1-methyl-1H-indole-2-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (2H), 1.52 (2H), 2.25-2.43 (1H), 2.54 (3H), 2.78-3.16 (2H), 3.70 (3H) ), 3.82 (3H), 3.97-4.63 (6H), 6.54 (1H), 6.73 (1H), 7.01 (1H), 7.21 (1H), 7.39-7.53 (2H), 8.57 (1H), 8.83 (t1H) .

Example 296: 2-{[1-(1H-indol-2-ylcarbonyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl) -2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 43 mg of the title compound was obtained from &lt

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.40 (2H), 1.58 (2H), 2.27-2.44 (1H), 2.55 (3H), 2.77-3.24 (2H), 4.07 (2H), 4.30-4.59 (4H), 6.74 (1H), 6.95-7.08 (1H), 7.10-7.26 (2H), 7.40 (1H), 7.48 (1H), 7.59 (1H), 8.58 (1H), 8.84 (1H), 11.54 (1H).

Example 297: 4-Methyl-2-({1-[(1-methyl-1H-benzimidazol-2-yl)carbonyl]piperidin-4-yl}-methyl)-N-(2, 2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 26 mg of the title compound was obtained from 75 mg of 1-methyl-1H-benzimidazole-2-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.42 (2H), 1.46 (1H), 1.57-1.75 (1H), 2.27-2.44 (1H), 2.54 (3H), 2.87 (1H), 3.11 (1H), 3.83 (3H), 4.07 (3H), 4.40 (2H), 4.48-4.62 (1H), 7.13-7.41 (3H), 7.47 (1H), 7.58-7.76 (2H), 8.58 (1H), 8.83 (1H).

Example 298: 4-Methyl-2-({1-[(2-phenylthiazol-5-yl)carbonyl)piperidin-4-yl}methyl)-N-(2,2,2-trifluoro Ethyl)-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 53 mg of the title compound was obtained from 87 mg of 2-phenylthiazole-5-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.18-1.41 (2H), 1.56 (2H), 2.27-2.44 (1H), 2.54 (3H), 2.73-3.29 (2H), 3.93 -4.53 (6H), 7.21 (1H), 7.42-7.61 (4H), 7.93-8.03 (2H), 8.14 (1H), 8.57 (1H), 8.83 (1H).

Example 299: 2-{[1-(Benzoxazol-2-ylcarbonyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl) -2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 20 mg of the title compound was obtained from 69 mg of benzoxazole-2-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.19-1.44 (2H), 1.48-1.72 (2H), 2.29-2.46 (1H), 2.54 (3H), 2.82-3.01 (1H) , 3.12-3.31 (1H), 4.07 (2H), 4.40 (4H), 7.21 (1H), 7.42-7.61 (3H), 7.78-7.95 (2H), 8.58 (1H), 8.83 (1H).

Example 300: 4-Methyl-2-({1-[(2-phenyloxazol-5-yl)carbonyl)piperidin-4-yl}methyl)-N-(2,2,2-tri Fluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 20 mg of the title compound was obtained from 100 mg of 2-phenyloxazole-5-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.15-1.43 (2H), 1.59 (2H), 2.31-2.45 (1H), 2.55 (3H), 2.70-3.35 (2H), 4.07 (2H), 4.39 (4H), 7.21 (1H), 7.48 (1H), 7.53-7.67 (3H), 7.80 (1H), 7.94-8.07 (2H), 8.58 (1H), 8.83 (1H).

Example 301: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]-oxy Benzomethyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 23 mg of the title compound was obtained from 90 mg of 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in 75 mg of 71a and DMF.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.13-1.35 (2H), 1.37.72 (2H), 2.19-2.42 (1H), 2.54 (3H), 2.69-3.17 (2H) , 3.55-3.82 (1H), 3.91-4.18 (2H), 4.26-4.60 (3H), 7.28 (4H), 7.38-7.56 (3H), 8.16-8.33 (1H), 8.49-8.63 (2H), 8.75- 8.91 (1H).

Example 302: 2-{[1-(Benzothiazol-2-ylcarbonyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)- 2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 35 mg of the title compound was obtained from 57 mg of benzothiazole-2-carboxylic acid in 75 mg of 71a and DMF.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.36 (2H), 1.59 (2H), 2.31-2.46 (1H), 2.55 (3H), 2.91 (1H), 3.26 (1H), 4.07 (2H), 4.31-4.61 (3H), 4.95-5.23 (1H), 7.21 (1H), 7.41-7.69 (3H), 8.05-8.28 (2H), 8.58 (1H), 8.83 (1H).

Example 303: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]-oxy Benzomethyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 90 mg of the formic acid from Example 303b from 90 mg of 71a and DMF afforded 42 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.33 (2H), 1.34 - 1.67 (2H), 2.21-2.39 (1H), 2.54 (3H), 2.68-3.16 (2H) , 3.52-3.76 (1H), 3.95-4.16 (2H), 4.28-4.61 (3H), 7.13-7.31 (3H), 7.46 (3H), 7.59-7.71 (1H), 7.92 (1H), 8.52-8.65 ( 2H), 8.84 (1H).

The starting materials were prepared as follows:

Example 303a: 4-{[6-(Trifluoromethyl)pyridin-3-yl]oxy}benzonitrile

2.77 g of molybdenum hexacarbonyl in 2.5 g of 5-bromo-2-(trifluoromethyl)pyridine, 5.8 g of 4-hydroxybenzonitrile, 10.8 g of cesium carbonate and 100 ml of 1,4-dioxane were heated under reflux Until complete conversion. The reaction mixture was diluted with water, extracted with EtOAc EtOAc EtOAc. The residue was purified by column chromatography using hexane/ethyl acetate gradient. Yield: 1.35 g of the title compound.

^{1 H-NMR (300MHz, DMSO} -d 6): δ [ppm] = 7.35 (2H), 7.75-7.84 (1H), 7.89-8.03 (3H), 8.66 (1H).

Example 303b: 4-{[6-(Trifluoromethyl)pyridin-2-yl]oxy}benzoic acid

1.33 g of the compound prepared in Example 303a in 64 ml of ethanol was treated with 32 ml of 40% potassium hydroxide solution and heated under reflux until complete conversion. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated. Yield: 1.32 g of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.19-7.33 (2H), 7.68-7.81 (1H), 7.90-8.08 (3H), 8.64 (1H), 12.71-13.28 (1H) .

Example 304: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]-oxy Benzomethyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

48 mg of the title compound were obtained from 90 mg of 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid from 75 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.15 - 1.34 (2H), 1.35 - 1.71 (2H), 2.23 - 2.41 (1H), 2.54 (3H), 2.67 - 3.17 (2H) , 3.51-3.77 (1H), 3.97-4.18 (2H), 4.22-4.65 (3H), 7.13-7.31 (3H), 7.37 (1H), 7.41-7.53 (3H), 7.67 (1H), 8.07-8.20 ( 1H), 8.57 (1H), 8.75-8.92 (1H).

Example 305: 4-Methyl-2-({1-[(3-phenyl-1,2,4-oxadiazol-5-yl)carbonyl)piperidin-4-yl}methyl)-N- (2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 40 mg of the title compound was obtained from 73 mg of 3-phenyl-1,2,4-oxadiazol-5-carboxylic acid in 90 mg of 71a and DMF.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.18-1.43 (2H), 1.48-1.72 (2H), 2.33-2.47 (1H), 2.54 (3H), 2.95 (1H), 3.24 (1H), 3.94-4.17 (3H), 4.33-4.53 (3H), 7.21 (1H), 7.47 (1H), 7.55-7.70 (3H), 7.96-8.12 (2H), 8.57 (1H), 8.83 (1H) ).

Example 306: 2-({1-[4-(4-Cyanophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2 -trifluoroethyl)-2H-indazole-5-carboxamide

59 mg of the title compound was obtained from 101 mg of 4-(4-cyanophenoxy)benzoic acid in 110 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.34 (2H), 1.35-1.70 (2H), 2.18-2.41 (1H), 2.54 (3H), 2.70-3.18 (2H) , 3.54-3.79 (1H), 4.07 (2H), 4.37 (3H), 7.10-7.28 (5H), 7.41-7.52 (3H), 7.79-7.94 (2H), 8.56 (s1H), 8.81 (s1H).

Example 307: 2-({1-[4-(3-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2- Trifluoroethyl)-2H-indazole-5-carboxamide

40 mg of the title compound was obtained from 89 mg of 4-(3-fluorophenoxy)benzoic acid from 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14-1.34 (2H), 1.36-1.70 (2H), 2.22-2.44 (1H), 2.54 (3H), 2.70-3.13 (2H) , 3.52-3.86 (1H), 4.07 (2H), 4.37 (3H), 6.79-7.12 (5H), 7.21 (1H), 7.35-7.52 (4H), 8.55 (1H), 8.81 (1H).

Example 308: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]-benzylidene) }piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 47 mg of the title compound was obtained from 119 mg of 4-[3-(trifluoromethyl)phenoxy]benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.34 (2H), 1.37-1.66 (2H), 2.22-2.38 (1H), 2.54 (3H), 2.69-3.14 (2H) , 3.50-3.83 (1H), 4.07 (2H), 4.37 (3H), 7.10 (2H), 7.21 (1H), 7.36 (1H), 7.39-7.50 (4H), 7.54 (1H), 7.61-7.75 (1H) ), 8.55 (1H), 8.81 (1H).

Example 309: 4-Methyl-2-({1-[(5-phenyloxazol-2-yl)carbonyl)piperidin-4-yl}methyl)-N-(2,2,2-tri Fluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 10 mg of the title compound was obtained from 73 mg of 5-phenyloxazole-2-carboxylic acid in 100 mg of 71a and DMF.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.24 (2H), 1.58 (2H), 2.29-2.45 (1H), 2.55 (3H), 2.86 (1H), 3.21 (1H), 4.07(2H),4.31-4.52(3H),4.62(1H),7.21(1H),7.39-7.57(4H),7.74-7.83(2H),7.88(1H),8.57(1H),8.81(1H) .

Example 310: 2-[(1-{4-[(5-Cyanopyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-4-methyl-N- (2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 47 mg of the title compound was obtained from 119 mg of 4-[3-(trifluoromethyl)phenoxy]benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.34 (2H), 1.37-1.66 (2H), 2.22-2.38 (1H), 2.54 (3H), 2.69-3.14 (2H) , 3.50-3.83 (1H), 4.07 (2H), 4.37 (3H), 7.10 (2H), 7.21 (1H), 7.36 (1H), 7.39-7.50 (4H), 7.54 (1H), 7.61-7.75 (1H) ), 8.55 (1H), 8.81 (1H).

Example 311: 2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-4-methyl-N-( 2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 72 mg of the title compound was obtained from 96 mg of 4-[(5-chloropyridin-2-yl)oxy]benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.34 (2H), 1.36- 1.73 (2H), 2.22-2.41 (1H), 2.54 (3H), 2.69-3.18 (2H) , 3.47-3.88(1H), 4.07(2H), 4.37(3H), 7.06-7.28(4H),7.34-7.52(3H),7.99(1H),8.22(1H),8.56(1H),8.81(1H ).

Example 312: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[5-(trifluoromethyl)pyridin-2-yl]-benzene Mercapto}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 83 mg of the title compound was obtained from 103 mg of 4-[5-(trifluoromethyl)pyridin-2-yl]benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (2H), 1.36-1.73 (2H), 2.33 (1H), 2.54 (3H), 2.70-3.18 (2H), 3.47-3.76 (1H), 3.96-4.16(2H), 4.38(3H), 7.21(1H), 7.41-7.60(3H), 8.17-8.40(4H), 8.56(1H), 8.81(1H), 9.07(1H).

Example 313: 2-({1-[4-(2,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 87 mg of the title compound was obtained from 96 mg of 4-(2,4-difluorophenoxy)benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.34-1.72 (2H), 2.18-2.42 (1H), 2.52-2.58 (3H), 2.69-3.20 (2H) , 3.43-3.84 (1H), 4.07 (2H), 4.36 (3H), 6.92-7.06 (2H), 7.09-7.25 (2H), 7.28-7.42 (3H), 7.43-7.61 (2H), 8.55 (1H) , 8.81 (1H).

Example 314: 2-({1-[4-(3,4-Difluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

48 mg of the title compound was obtained from 96 mg of 4-(3,4-difluorophenoxy)benzoic acid from 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (2H), 1.36-1.72 (2H), 2.19-2.42 (1H), 2.54 (3H), 2.70-3.17 (2H), 3.44 -3.86(1H), 3.99-4.17(2H), 4.36(3H), 6.86-6.97(1H), 7.01-7.11(2H), 7.21(1H), 7.29(1H), 7.35-7.55(4H),8.55 (1H), 8.81 (1H).

Example 315: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]-carbonyl} Piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 32 mg of the title compound was obtained from 102 mg of 4'-(trifluoromethyl)biphenyl-4-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (2H), 1.37-1.71 (2H), 2.24 - 2.29 (1H), 2.53 (3H), 2.70-3.18 (2H), 3.43 -3.51 (2H), 3.54-3.86 (1H), 4.37 (3H), 7.18 (1H), 7.38-7.57 (3H), 7.72-7.88 (4H), 7.89-7.98 (2H), 8.13 (1H), 8.51 (1H).

Example 316: 2-{[1-(4-Bromobenzylidenyl)piperidin-4-yl]methyl}-4-methyl-N-(2,2,2-trifluoro-ethyl)- 2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 6.96 g of the title compound was obtained from 5.61 g of 71a and 2.89 g of 4-bromobenzoic acid.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.32 (2H), 1.34-1.74 (2H), 2.19-2.41 (1H), 2.54 (3H), 2.88-3.22 (2H) , 3.42-3.74 (1H), 3.94-4.18 (2H), 4.36 (3H), 7.20 (1H), 7.32 (2H), 7.46 (1H), 7.64 (2H), 8.55 (1H), 8.83 (1H).

Example 317: 2-({1-[4-(5-chloropyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

80 mg of the aryl bromide prepared in Example 316 along with 32 mg (5-chloropyridin-2-yl) The acid was first placed in 1 ml of tetrahydrofuran, treated with 17.3 mg of 1,1'-bis(diphenylphosphino)ferrocene palladium (II) chloride and 0.17 ml of 1 M potassium carbonate solution in a microwave at 120 ° C. Heat (100 watts) for 10 minutes. Adding 11mg (5-chloropyridin-2-yl) in a new addition After acid and 17.3 mg of palladium (II) catalyst, the reaction mixture was heated again in the microwave at 120 ° C (100 watts) for 10 minutes until complete conversion. The reaction mixture was concentrated. This gave 15 mg of the title compound after HPLC purification.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.18-1.36 (2H), 1.37.75 (2H), 2.28-2.38 (1H), 2.54 (3H), 2.73-3.18 (2H) , 3.49-3.74 (1H), 3.95-4.16 (2H), 4.28-4.62 (3H), 7.22 (1H), 7.33-7.65 (5H), 7.98-8.22 (3H), 8.56 (1H), 8.77-8.91 ( 1H).

Example 318: 2-({1-[(4'-Methoxy-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N- (2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 53 mg (4-methoxy-2-methyl-phenyl) The acid gave 50 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.36 (2H), 1.37-1.74 (2H), 2.23 (3H), 2.29-2.38 (1H), 2.54 (3H), 2.72 -3.12(2H), 3.77(4H), 3.97-4.17(2H), 4.38(3H), 6.75-6.94(2H), 7.07-7.26(2H), 7.29-7.56(5H), 8.56(1H),8.81 (1H).

Example 319: 4-Methyl-2-({1-[4-(6-methylpyridin-3-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 44 mg (6-methylpyridin-3-yl) under reflux The acid gave 37 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.15 - 1.35 (2H), 1.37.71 (2H), 2.20-2.40 (1H), 2.52 (3H), 2.54 (3H), 2.74 -3.15(2H), 3.52-3.82(1H), 4.07(2H), 4.38(3H), 7.20(1H), 7.37(1H), 7.47(3H), 7.77(2H), 8.01(1H), 8.57( 1H), 8.72-8.92 (2H).

Example 320: 2-({1-[(4'-Fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N- ( 2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 75 g (4-fluoro-2-methoxyphenyl) under reflux The acid gave 60 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.37 (2H), 1.38-1.75 (2H), 2.25-2.37 (1H), 2.54 (3H), 2.72-3.17 (2H) , 3.79 (4H), 4.07 (2H), 4.38 (3H), 6.87 (1H), 7.04 (1H), 7.21 (1H), 7.27-7.58 (6H), 8.56 (1H), 8.81 (1H).

Example 321: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]-benzene Mercapto}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 84 mg [6-(trifluoromethyl)pyridin-3-yl] under reflux The acid gave 45 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.15 - 1.37 (2H), 1.37-7.11 (2H), 2.22-2.41 (1H), 2.54 (3H), 2.73-3.20 (2H) , 3.45-3.74 (1H), 3.93-4.17 (2H), 4.29-4.62 (3H), 7.21 (1H), 7.39-7.62 (4H), 7.89 (2H), 8.01 (1H), 8.57 (1H), 8.73 -8.92 (1H), 9.13 (1H).

Example 322: 2-({1-[4-(6-Methoxypyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2, 2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 68 mg (6-methoxypyridin-3-yl) under reflux The acid gave 54 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.13-1.35 (2H), 1.36-1.71 (2H), 2.20-2.40 (1H), 2.54 (3H), 2.73-3.16 (2H) , 3-5. ), 8.47-8.63 (2H), 8.83 (1H).

Example 323: 2-({1-[4-(6-Methoxypyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2, 2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 49 mg (6-methoxypyridin-2-yl) under reflux The acid gave 55 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.36 (2H), 1.37-1.69 (2H), 2.20-2.41 (1H), 2.54 (3H), 2.74-3.16 (2H) , 3.47-3.81 (1H), 3.96 (3H), 4.06 (2H), 4.38 (3H), 6.81 (1H), 7.21 (1H), 7.47 (3H), 7.60 (1H), 7.74-7.90 (1H), 8.15(2H), 8.56(1H), 8.81(1H).

Example 324: 4-Methyl-2-({1-[4-(5-methylpyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 44 mg (5-methylpyridin-2-yl) under reflux The acid gave 9 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.36 (2H), 1.37-1.71 (2H), 2.24-2.30 (1H), 2.34 (3H), 2.54 (3H), 2.74 -3.16(2H), 3.52-3.79(1H), 3.93-4.17(2H), 4.38(3H), 7.20(1H), 7.37-7.54(3H), 7.66-7.78(1H), 7.89(1H), 8.11 (2H), 8.45-8.61 (2H), 8.74-8.88 (1H).

Example 325: 2-({1-[4-(5-fluoropyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 45 mg (5-fluoropyridin-2-yl) under reflux The acid gave 35 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.34 (2H), 1.35-1.69 (2H), 2.22-2.41 (1H), 2.54 (3H), 2.69-3.19 (2H) , 3.51-3.78 (1H), 4.07 (2H), 4.38 (3H), 7.20 (1H), 7.40-7.53 (3H), 7.85 (1H), 8.04-8.17 (3H), 8.57 (1H), 8.68 (1H) ), 8.83 (1H).

Example 326: 2-({1-[4-(5-Methoxypyridin-2-yl)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2, 2,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 49 mg (5-methoxypyridin-2-yl) under reflux The acid gave 94 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=1.19-1.36 (2H), 1.37-1.69 (2H), 2.28-2.40 (1H), 2.54 (3H), 2.73-3.19 (2H) , 3.48-3.79 (1H), 3.88 (3H), 4.07 (2H), 4.38 (3H), 7.20 (1H), 7.38-7.55 (4H), 7.96 (1H), 8.07 (2H), 8.39 (1H), 8.57 (1H), 8.82 (1H).

Example 327: 4-Methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2,2 ,2-trifluoroethyl)-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 102 mg (2-methylpyrimidin-5-yl) under reflux Acid tetramethyl glycol ester gave 46 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.35 (2H), 1.35-1.67 (2H), 2.21-2.42 (1H), 2.54 (3H), 2.67 (3H), 2.71 -2.89 (1H), 2.93-3.20 (1H), 3.50-3.73 (1H), 4.07 (2H), 4.37 (3H), 7.20 (1H), 7.40-7.57 (3H), 7.85 (2H), 8.57 (1H) ), 8.84 (1H), 9.05 (2H).

Example 328: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]-benzene Mercapto}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 89 mg [2-(trifluoromethyl)pyrimidin-5-yl] under reflux The acid gave 34 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.35 (2H), 1.36-1.71 (2H), 2.23-2.41 (1H), 2.54 (3H), 2.71-2.89 (1H) , 2.94-3.17 (1H), 3.48-3.72 (1H), 4.05 (2H), 4.28-4.61 (3H), 7.21 (1H), 7.47 (1H), 7.57 (2H), 7.98 (2H), 8.57 (1H) ), 8.84 (1H), 9.44 (2H).

Example 329: 4-Methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]-benzene Mercapto}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 317, from 125 mg 316 and 121 mg [6-(trifluoromethyl)pyridin-2-yl] under reflux Acid tetramethyl glycol ester gave 70 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.36 (2H), 1.37-1.72 (2H), 2.23-2.39 (1H), 2.54 (3H), 2.68-2.90 (1H) , 2.92-3.16 (1H), 3.50-3.73 (1H), 4.06 (2H), 4.38 (3H), 7.20 (1H), 7.41-7.60 (3H), 7.89 (1H), 8.11-8.27 (3H), 8.33 (1H), 8.56 (1H), 8.81 (1H).

Example 330: 2-({1-[4-(4-Cyanophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4 -methyl-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 151 mg of the title compound was obtained from 153 mg of 4-(4-cyanophenoxy)benzoic acid from 213 mg of 71A and DMF.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=1.22 (2H), 1.31-1.66 (2H), 2.15-2.36 (1H), 2.49 (3H), 2.70-3.12 (2H), 3.24 (3H), 3.36 (2H), 3.39-3.46 (2H), 3.50-3.79 (1H), 4.32 (3H), 7.00-7.23 (5H), 7.30-7.49 (3H), 7.75-7.91 (2H), 8.12 (1H), 8.48 (1H).

Example 331: N-(2-Methoxyethyl)-4-methyl-2-({1-[(1-methyl-1H-indol-3-yl)carbonyl]-piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 26 mg of the title compound was obtained from 36 mg of 1-methyl-1H-indole-3-carboxylic acid in 38 mg of 71a and DMF.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=1.23 (2H), 1.43-1.64 (2H), 2.20-2.39 (1H), 2.53 (3H), 2.80-3.03 (2H), 3.28 (3H), 3.37-3.50(4H), 3.81(3H), 4.37(4H), 7.18(3H), 7.36-7.53(2H), 7.67(2H), 8.04-8.25(1H), 8.52(1H).

Example 332: 2-{[1-(4-Bromo-3-methylbenzylidenyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 498 mg of the title compound was obtained from 788 mg of 4-bromo-3-methylbenzoic acid in 807 mg of 71a and DMF.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.20 - 1.32 (2H), 1.33-1.67 (2H), 2.24 - 2.33 (1H), 2.36 (3H), 2.52 (3H), 2.73 (1H), 2.91-3.13 (1H), 3.28 (3H), 3.35-3.63 (5H), 4.34 (3H), 7.03-7.23 (2H), 7.30-7.49 (2H), 7.63 (1H), 8.15 (1H) ), 8.51 (1H).

Example 333: 2-{[1-(4-Tertiarybenzylbenzyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carboxamide

Similar to Example 1b, version B, 50 mg of the title compound was obtained from 81 mg of 4-t-butylbenzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20-1.33 (11H), 1.33-1.67 (2H), 2.21-2.37 (1H), 2.52 (3H), 2.68-3.10 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.45 (2H), 3.52-3.74 (1H), 4.35 (3H), 7.18 (1H), 7.25-7.35 (2H), 7.36-7.52 (3H), 8.15 (1H), 8.50 (1H).

Example 334: 2-({1-[4-(1-hydroxy-1-methylethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 28 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;0&gt;

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.24 (2H), 1.42 (8H), 2.20-2.40 (1H), 2.52 (3H), 2.64-3.11 (2H), 3.28 (3H ), 3.34-3.43 (2H), 3.43-3.51 (2H), 3.53-3.71 (1H), 4.35 (3H), 4.76-5.43 (1H), 7.18 (1H), 7.28 (2H), 7.42 (1H), 7.46-7.56(2H), 8.15(1H), 8.51(1H).

Example 335: 2-{[1-(4-Cyclohexylbenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

Similar to Example 1b, Revision B, 93 mg of 4-cyclohexyl from 100 mg of 71a and DMF Benzoic acid gave 75 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.10-1.63 (9H), 1.64-1.89 (5H), 2.17-2.40 (1H), 2.52 (3H), 2.69-3.08 (2H) , 3.28 (3H), 3.38-3.43 (2H), 3.43-3.49 (2H), 3.53-3.73 (1H), 4.35 (3H), 7.18 (1H), 7.27 (4H), 7.42 (1H), 8.15 (1H) ), 8.50 (1H).

Example 336: N-(2-methoxyethyl)-2-{[1-(6-methoxy-2-naphthylmethyl)piperidin-4-yl]methyl}-4-methyl -2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 23 mg of the title compound was obtained from <RTI ID=0.0># </ RTI> </ RTI> <RTIgt;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.37-1.72 (2H), 2.23-2.39 (1H), 2.52 (3H), 2.72-3.12 (2H), 3.28 (3H), 3.36-3.42 (2H), 3.43-3.49 (2H), 3.59-3.81 (1H), 3.89 (3H), 4.36 (3H), 7.09-7.27 (2H), 7.33-7.49 (3H), 7.79 -7.95(3H), 8.15(1H), 8.51(1H).

Example 337: N-(2-methoxyethyl)-4-methyl-2-({1-[(2-phenylthiazol-5-yl)carbonyl)piperidin-4-yl}methyl) -2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 36 mg of the title compound was obtained from 93 mg of 2-phenylthiazole-5-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.55 (2H), 2.19-2.45 (1H), 2.52-2.56 (3H), 2.70-3.24 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.44-3.49 (2H), 4.37 (4H), 7.19 (1H), 7.43 (1H), 7.49-7.62 (3H), 7.90-8.03 (2H), 8.08-8.25 (2H), 8.52 (1H).

Example 338: N-(2-Methoxyethyl)-4-methyl-2-({1-[(1-methyl-1H-benzimidazol-2-yl)carbonyl]-piperidin-4 -yl}methyl)-2H-carbazole-5-carboxamide

39 mg of the title compound was obtained from 1-methyl-1H-benzimidazole-2-carboxylic acid in 100 mg of 71a and 80 mg of DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22-1.43 (2H), 1.43-1.53 (1H), 1.59-1.70 (1H), 2.27-2.44 (1H), 2.53 (3H) , 2.87 (1H), 3.11 (1H), 3.28 (3H), 3.36-3.42 (2H), 3.43-3.48 (2H), 3.83 (3H), 4.00-4.14 (1H), 4.39 (2H), 4.48-4.61 (1H), 7.18 (1H), 7.23-7.46 (3H), 7.58-7.74 (2H), 8.10-8.20 (1H), 8.53 (1H).

Example 339: N-(2-methoxyethyl)-4-methyl-2-({1-[(2-phenyloxazol-5-yl)carbonyl)piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

Similar to Example 1b, version B, 30 mg of the title compound was obtained from 2-phenyloxazol-5-carboxylic acid in 100 mg of 71a and 86 mg of DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14-1.48 (2H), 1.59 (2H), 2.24-2.46 (1H), 2.52-2.56 (3H), 2.71-3.01 (1H) , 3.11-3.26(1H), 3.28(3H), 3.36-3.43(2H), 3.43-3.50(2H), 4.38(4H), 7.19(1H), 7.43(1H), 7.52-7.67(3H), 7.80 (1H), 7.97-8.05 (2H), 8.16 (1H), 8.53 (1H).

Example 340: 2-{[1-(Benzoxazol-2-ylcarbonyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H- Oxazole-5-carboxamide

Analogously to Example 1b, version B, 37 mg of the title compound was obtained from 84 mg of benzoxazole-2-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.43 (2H), 1.48-1.73 (2H), 2.28-2.45 (1H), 2.53 (3H), 2.91 (1H), 3.22 (1H), 3.33-3.57 (m, 7H), 4.25-4.60 (4H), 7.18 (1H), 7.36-7.62 (3H), 7.78-7.95 (2H), 8.16 (1H), 8.53 (1H).

Example 341: 2-({1-[4-(1-Cyano-1-methylethyl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxy- Ethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 20 mg of the title compound was obtained from 86 mg of 4-(1-cyano-1-methylethyl)benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.7-1.34 (2H), 1.35-1.64 (2H), 1.70 (6H), 2.16-2.40 (1H), 2.52 (3H), 2.64 -3.13(2H), 3.28(3H), 3.40(2H), 3.43-3.49(2H), 3.49-3.67(1H), 4.35(3H), 7.18(1H), 7.42(3H), 7.58(2H), 8.15 (1H), 8.50 (1H).

Example 342: N-(2-Methoxyethyl)-4-methyl-2-({1-[4-(pyrimidin-2-yloxy)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 37 mg of the title compound was obtained from 98 mg of 4-(2-pyrimidinyloxy)benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.26 (2H), 1.38-1.66 (2H), 2.20-2.40 (1H), 2.52-2.56 (3H), 2.70-3.16 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.43-3.49 (2H), 3.64-3.77 (m, 1H), 4.36 (3H), 7.18 (1H), 7.22-7.33 (3H), 7.39-7.49 ( 3H), 8.15 (1H), 8.43 - 8.57 (1H), 8.66 (2H).

Example 343: N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-3-yloxy)benzylidene]piperidin-4-yl} Methyl)-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 7 mg of the title compound was obtained from 73 mg of 4-(3-pyridyloxy)benzoic acid from 75 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.32 (2H), 1.35- 1.69 (2H), 2.19-2.38 (1H), 2.52 (3H), 2.70-3.14 (2H) , 3.28 (3H), 3.34-3.43 (2H), 3.43-3.51 (2H), 3.55-3.70 (1H), 4.35 (3H), 7.04-7.13 (2H), 7.18 (1H), 7.37-7.46 (3H) , 7.47-7.54 (1H), 7.58 (1H), 8.15 (1H), 8.38-8.55 (3H).

Example 344: N-(2-Methoxyethyl)-2-{[1-(7-methoxy-2-naphthylmethyl)piperidin-4-yl]methyl}-4-methyl -2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 69 mg of the formic acid from Example 344c from &lt

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.35 (2H), 1.37-1.75 (2H), 2.23-2.39 (1H), 2.2 (3H), 2.73-3.13 (2H) , 3.28 (3H), 3.35-3.42 (2H), 3.45 (2H), 3.53-3.74 (1H), 3.88 (3H), 4.37 (3H), 7.13-725 (2H), 7.29 (1H), 7.36-7.48 (2H), 7.77-7.93 (3H), 8.15 (1H), 8.52 (1H).

The starting materials were prepared as follows:

Example 344a: 1,1,2,2,3,3,4,4,4-perfluorobutyl-1-sulfonic acid 7-methoxynaphthalen-2-ester

5.12 g of 7-methoxy-2-naphthol was dissolved in 50 ml of toluene and cooled to 0 °C. 30.7 ml of N,N-diisopropylethylamine and 17.6 ml of perfluorobutylsulfonyl chloride were added dropwise thereto in this order and then the reaction mixture was stirred at room temperature until complete conversion. The reaction mixture was poured into 600 mL of a saturated aqueous solution of ammonium chloride. The combined organic phases were washed with water and a saturated sodium chloride solution, dried and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate gradient. Yield: 11.45 g of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.89 (3H), 7.28 (1H), 7.41 (1H), 7.52 (1H), 7.90-8.00 (2H), 8.05 (1H).

Example 344b: Methyl 7-methoxynaphthalene-2-carboxylate

Similar to Example 1e, 2.34g of title compound was obtained from 11.0g of 344a and 8.8ml of methanol. Things.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 3.89 (3H), 3.91 (3H), 7.31 (1H), 7.57 (1H), 7.82 (1H), 7.94 (2H), 8.54 ( 1H).

Example 344c: 7- Methoxynaphthalene -2-carboxylic acid

Similar to Example 258d, 1.27 g of the title compound was obtained from 2.0 g 344b.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 3.89 (3H), 7.30 (1H), 7.53 (1H), 7.78-7.86 (1H), 7.87-8.01 (2H), 8.50 (1H) ), 12.99 (1H).

Example 345: N-(2-Methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-benzene Mercapto)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Similarly to Example 1b, version B, 221 mg of the title compound was obtained from 232 mg of 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in 200 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.34 (2H), 1.36-1.72 (2H), 2.23-2.39 (1H), 2.53 (3H), 2.89 (2H), 3.31 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.53-3.86 (1H), 4.36 (3H), 7.18 (1H), 7.23-7.33 (3H), 7.37-7.50 (3H), 8.13 (1H), 8.25 (1H), 8.51 (1H), 8.55-8.63 (1H).

Example 346: N-(2-Methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzylidene]piperidin-4-yl} -methyl)-2H-carbazole-5-carboxamide

29 mg of the title compound was obtained from 98 mg of 4-(2-pyridinyloxy)benzoic acid from 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.39-1.68 (2H), 2.24 - 2.39 (1H), 2.52-2.56 (3H), 2.71-3.13 (2H) , 3.28(3H), 3.36-3.43(2H), 3.45(2H), 3.53-3.87(1H), 4.36(3H), 7.08(1H), 7.13-7.26(4H),7.34-7.52(3H),7.88 (1H), 8.07-8.23 (2H), 8.51 (1H).

Example 347: N-(2-Methoxyethyl)-4-methyl-2-{[1-(4-{[4-(trifluoromethyl)pyrimidin-2-yl]-oxy}benzene Mercapto)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 11 mg of the title compound was obtained from 97 mg of 4-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}benzoic acid in 75 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.37-1.69 (2H), 2.19-2.39 (1H), 2.53 (3H), 2.68-3.18 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.45 (2H), 3.51-3.79 (1H), 4.36 (3H), 7.18 (1H), 7.31-7.39 (2H), 7.39-7.53 (3H), 7.81 (1H) ), 8.15 (1H), 8.51 (1H), 9.00 (1H).

Example 348: 2-{[1-(Benzothiazol-2-ylcarbonyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

Similar to Example 1b, Revision B, 61 mg of benzothiazole from 75 mg of 71a and DMF - 2-carboxylic acid gave 28 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.34 (2H), 1.62 (2H), 2.32 - 2.45 (1H), 2.53 (3H), 2.82-3.00 (1H), 3.26 (1H) ), 3.28 (3H), 3.40 (2H), 3.43-3.50 (2H), 4.38 (3H), 4.98-5.23 (1H), 7.19 (1H), 7.43 (1H), 7.59 (2H), 8.01-8.30 ( 3H), 8.53 (1H).

Example 349: N-(2-Methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-benzene Mercapto)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 34 mg of the title compound was obtained from 96 mg of 303b from 75 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (2H), 1.37-1.68 (2H), 2.22-2.38 (1H), 2.53 (3H), 2.71-3.14 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.44-3.49 (2H), 3.52-3.84 (1H), 4.36 (3H), 7.09-7.29 (3H), 7.35-7.53 (3H), 7.65 (1H), 7.92 (1H), 8.13 (1H), 8.51 (1H), 8.60 (1H).

Example 350: N-(2-Methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-benzene Mercapto)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 36 mg of the title compound was obtained from 129 mg of 4-{[6-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20 - 1.34 (2H), 1.36 - 1.66 (2H), 2.24 - 2.39 (1H), 2.53 (3H), 2.70 - 3.16 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.44 - 3.49 (2H), 3.53-3.82 (1H), 4.36 (3H), 7.18 (1H), 7.22-7.30 (2H), 7.32-7.50 (4H) , 7.67 (1H), 8.06-8.21 (2H), 8.51 (1H).

Example 351: 2-({1-[(4'-Methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)- 4-methyl-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 15 mg of the title compound was obtained from 104 mg of 4'-methoxy-biphenyl-4-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (2H), 1.37-1.64 (2H), 2.19-2.32 (1H), 2.53 (3H), 2.74-3.10 (2H), 3.28 (3H), 3.40 (2H), 3.45 (2H), 3.67-3.91 (4H), 4.21-4.64 (3H), 7.04 (2H), 7.19 (1H), 7.41 (2H), 7.66 (5H), 8.04 8.22 (1H), 8.51 (1H).

Example 352: N-(2-Methoxyethyl)-4-methyl-2-({1-[(3-phenyl-1,2,4-oxadiazol-5-yl)carbonyl]- Piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 12 mg of the title compound was obtained from 78 mg of 3-phenyl-1,2,4-oxadiazol-5-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.33 (2H), 1.50-1.72 (2H), 2.31-2.45 (1H), 2.53 (3H), 2.86-3.04 (1H), 3.16 -3.26(1H), 3.28(3H), 3.41(2H), 3.43-3.51(2H), 3.94-4.13(1H), 4.28-4.55(3H), 7.19(1H),7.43(1H),7.52-7.72 (3H), 7.96-8.09 (2H), 8.13 (1H), 8.52 (1H).

Example 353: N-(2-Methoxyethyl)-4-methyl-2-({1-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy) Benzyl)-benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 21 mg of the title compound was obtained from 91 mg of 4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzoic acid in 100 mg of 71a.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.38-1.70 (4H), 1.97 (2H), 2.18-2.41 (1H), 2.53 (3H), 2.75-3.02 (2H), 3.28 (3H), 3.35-3.54 (8H), 3.84 (2H), 4.35 (2H), 4.52-4.77 (1H), 7.00 (2H), 7.18 (1H), 7.30 (2H), 7.42 ( 1H), 8.13 (1H), 8.50 (1H).

Example 354: N-(2-Methoxyethyl)-4-methyl-2-({1-[(5-phenyloxazol-2-yl)carbonyl)piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

Similar to Example 1b, version B, 10 mg of the title compound was obtained from 77 mg of 5-phenyl-oxazole-2-carboxylic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.41 (2H), 1.59 (2H), 2.28-2.45 (1H), 2.52-2.56 (3H), 2.85 (1H), 3.20 (1H), 3.28 (3H), 3.36-3.43 (2H), 3.44-3.50 (2H), 4.38 (3H), 4.57-4.74 (1H), 7.19 (1H), 7.39-7.57 (4H), 7.74-7.82 (2H), 7.88 (1H), 8.13 (1H), 8.52 (1H).

Example 355: N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzylidene}-piperidine 4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 40 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;0&gt;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.35-1.65 (2H), 2.19-2.38 (1H), 2.52-2.56 (3H), 2.71-3.12 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.53-3.87 (1H), 4.35 (3H), 7.07-7.15 (2H), 7.18 (1H), 7.30-7.48 (5H) , 7.54 (1H), 7.64 (1H), 8.13 (1H), 8.50 (1H).

Example 356: 2-[(1-{4-[(5-Cyanopyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-N-(2-methoxy Base ethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 15 mg of the title compound was obtained from 98 mg of 4-[(5-cyanopyridin-2-yl)oxy]benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.35 (2H), 1.36-1.75 (2H), 2.23-2.39 (1H), 2.53 (3H), 2.69-3.19 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.46 (2H), 3.53-3.85 (1H), 4.36 (3H), 7.18 (1H), 7.23-7.33 (3H), 7.36-7.53 (3H), 8.13 (1H), 8.34 (1H), 8.51 (1H), 8.66 (1H).

Example 357: 2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

40 mg of the title compound was obtained from 102 mg of 4-[(5-chloropyridin-2-yl)oxy]benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.25 (2H), 1.36-1.70 (2H), 2.20-2.39 (1H), 2.53 (3H), 2.66-3.15 (2H), 3.28 (3H), 3.40 (2H), 3.43-3.50 (2H), 3.55-3.90 (1H), 4.36 (3H), 7.08-7.28 (4H), 7.42 (3H), 7.99 (1H), 8.10-8.30 (2H ), 8.51 (1H).

Example 358: 2-({1-[4-(2,4-Difluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl )-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 22 mg of the title compound was obtained from 102 mg of 4-(2,4-difluorophenoxy)benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21 (2H), 1.33-1.76 (2H), 2.20-2.39 (1H), 2.52 (3H), 2.69-3.13 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.53-3.90 (1H), 4.35 (3H), 6.91-7.04 (2H), 7.11-7.22 (2H), 7.30-7.46 (4H) , 7.51 (1H), 8.13 (1H), 8.50 (1H).

Example 359: 2-({1-[4-(3,4-Difluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl )-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 23 mg of the title compound was obtained from 102 mg of 4-(3,4-difluorophenoxy)benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.17 - 1.30 (2H), 1.35 - 1.70 (2H), 2.20 - 2.40 (1H), 2.52 (3H), 2.74 - 3.14 (2H) , 3.28 (3H), 3.40 (2H), 3.43-3.51 (2H), 3.52-3.89 (1H), 4.35 (3H), 6.94 (1H), 7.05 (2H), 7.18 (1H), 7.30 (1H), 7.36-7.59 (4H), 8.15 (1H), 8.51 (1H).

Example 360: N-(2-Methoxyethyl)-4-methyl-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]-carbonyl}piperidine- 4-yl)methyl]-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 44 mg of the title compound was obtained from 109 mg of 4'-(trifluoromethyl)biphenyl-4-carboxylic acid in 100 mg of 71a and DMF.

_{LC-MS: R t = 1.28min} , MS (ES +): m / z = 579 (M + H) +.

Example 361: 2-({1-[4-(3-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

Analogously to Example 1b, version B, 43 mg of the title compound was obtained from 95 mg of 4-(3-fluorophenoxy)benzoic acid in 100 mg of 71a and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17-1.31 (2H), 1.33-1.69 (2H), 2.19-2.38 (1H), 2.52 (3H), 2.70-3.11 (2H) , 3.28 (3H), 3.36- 3.43 (2H), 3.43-3.49 (2H), 3.54-3.85 (1H), 4.35 (3H), 6.85-7.13 (5H), 7.18 (1H), 7.35-7.55 (4H) , 8.15 (1H), 8.51 (1H).

Example 362: 2-{[1-(2-Fluoro-4-isopropoxybenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxy-ethyl)-4 -methyl-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 31 mg of the title compound was obtained from 75 mg of 71a and 41 mg of 2-fluoro-4-isopropoxybenzoic acid.

¹ H-NMR (300MHz, chloroform -d): δ [ppm] = 1.21-1.42 (8H), 1.51 (1H), 1.69 (1H), 2.38 (1H), 2.56-2.80 (4H), 2.87- 3.08 (1H), 3.36 (3H), 3.48-3.73 (4H), 4.28 (2H), 4.51 (1H), 4.74 (1H), 5.28 (1H), 6.19 (1H), 6.54 (1H), 6.67 (1H) ), 7.13 - 7.38 (2H), 7.50 (1H), 7.94 (1H).

Example 363: 2-({1-[(3-Fluoro-3',4'-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 35 mg of the title compound was obtained from 75 mg of 71a and 50 mg of 3-fluoro-3',4'-dimethylbiphenyl-4-carboxylic acid.

¹ H-NMR (300MHz, chloroform-d): δ [ppm] = 1.25-1.51 (2H), 1.57 (1H), 1.76 (1H), 2.25-2.37 (6H), 2.45 (1H), 2.61 2.71 (3H), 2.79 (1H), 3.06 (1H), 3.40 (3H), 3.53-3.77 (5H), 4.34 (2H), 4.83 (1H), 6.04-6.30 (1H), 7.15-7.47 (7H) , 7.55 (1H), 7.98 (1H).

Example 364: 2-({1-[(2',3-Difluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Analogously to Example 1b, version B, 28 mg of the title compound was obtained from 90 mg of 71a and 65 mg of 3,2'-difluoro-4'-methoxybiphenyl-4-carboxylic acid.

¹ H-NMR (300 MHz, chloroform-d): δ [ppm] = 1.25-1.50 (2H), 1.50-1.84 (2H), 2.44 (1H), 2.66 (3H), 2.78 (1H), 3.03 ( 1H), 3.39 (3H), 3.53-3.76 (5H), 3.85 (3H), 4.23-4.45 (2H), 4.83 (1H), 6.17 (1H), 6.64-6.92 (2H), 7.18-7.48 (5H) , 7.54 (1H), 7.97 (1H).

Example 365: 2-({1-[4-(Difluoromethoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2-H-carbazole-5-carbamide

Analogously to Example 1b, version B, 23 mg of the title compound was obtained from 75 mg of 71a and 38 mg of 4-(difluoromethoxy)benzoic acid.

¹ H-NMR (300MHz, chloroform-d): δ [ppm] = 1.26 (2H), 1.59 (2H), 2.26-2.49 (1H), 2.62 (3H), 2.84 (2H), 3.36 (3H) , 3.43 (1H), 3.50-3.96 (4H), 4.29 (2H), 4.46-5.02 (1H), 6.13-6.25 (1H), 6.26-6.82 (1H), 7.11 (2H), 7.22-7.43 (3H) , 7.50 (1H), 7.93 (1H).

Example 366: 2-({1-[4-(2-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- methyl-2H-carbazole-5-carbamide

120 mg of compound 54, 26 mg of o-fluorophenol, 152 mg of cesium carbonate, 6.7 mg of copper (I) bromide and 3.2 mg of (2-pyridyl)acetone were suspended in 6 ml of dimethyl hydrazine at 80 ° C. Stir for 3 days. The reaction mixture was filtered, and the cake was washed with water and ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by HPLC to afford 12 mg of the title compound.

¹ H-NMR (300 MHz, chloroform-d): δ [ppm] = 1.16-1.47 (2H), 1.62 (2H), 2.43 (1H), 2.66 (3H), 2.85 (2H), 3.39 (3H) , 3.53-3.74(4H), 3.79-4.19(1H), 4.33(2H), 4.47-5.02(1H), 6.15(1H), 6.96(2H), 7.07-7.23(3H), 7.30-7.45(3H) , 7.54 (1H), 7.96 (1H).

Example 367: 2-({1-[(4'-Cyano-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 80 mg of 54 and 38 mg (2-methyl-4-cyanophenyl) under reflux The acid gave 40 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20-1.34 (2H), 1.36-1.69 (2H), 2.28 (4H), 2.53 (3H), 2.69-3.19 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.54-3.77 (1H), 4.37 (3H), 7.18 (1H), 7.37-7.50 (6H), 7.74 (1H), 7.83 (1H) ), 8.15 (1H), 8.52 (1H).

Example 368: 2-({1-[4-(5-chloropyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

200 mg of the aryl bromide prepared in Example 54 together with 187 mg of (5-chloropyridin-2-yl)-2- Acid tetramethyl glycol ester was first placed in 3 ml of DMF, using 48 mg of 1,1'-bis(diphenylphosphino)ferrocene palladium (II) chloride, 39 mg of copper (I) chloride, 254 mg of cesium carbonate and 22 mg of 1,1 '-bis(diphenylphosphino)ferrocene were treated and heated at 70 ° C for about 1 day until no further progress of the reaction was observed. The reaction mixture was treated with EtOAc (EtOAc)EtOAc. This gave 92 mg of the title compound after HPLC purification.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.19-1.36 (2H), 1.37.72 (2H), 2.23-2.41 (1H), 2.52-2.57 (3H), 2.70-3.13 ( 2H), 3.28 (3H), 3.39 (2H), 3.45 (2H), 3.51-3.80 (1H), 4.36 (3H), 7.18 (1H), 7.36-7.52 (3H), 8.05 (2H), 8.09-8.22 (3H), 8.51 (1H), 8.73 (1H).

Example 369: N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]-benzoguanidinyl} Piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 80 mg of [6-(trifluoromethyl)pyridin-2-yl] under reflux Acid tetramethyl glycol ester gave 33 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.18-1.35 (2H), 1.36-1.67 (2H), 2.25-2.41 (1H), 2.53 (3H), 2.70-3.15 (2H) , 3.28 (3H), 3.35-3.43 (2H), 3.43-3.51 (2H), 3.53-3.73 (1H), 4.37 (3H), 7.18 (1H), 7.42 (1H), 7.53 (2H), 7.89 (1H) ), 8.06-8.26 (4H), 8.33 (1H), 8.51 (1H).

Example 370: N-(2-Methoxyethyl)-2-({1-[(4'-methoxy-2'-methylbiphenyl-4-yl)carbonyl]-piperidin-4- }methyl)-4-methyl-2H-carbazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 48 mg (4-methoxy-2-methylphenyl) under reflux The acid gave 52 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.35 (2H), 1.37-1.67 (2H), 2.23 (3H), 2.26-2.42 (1H), 2.53 (3H), 2.70 -3.12(2H), 3.28(3H), 3.36-3.43(2H), 3.43-3.50(2H), 3.77(4H), 4.36(3H), 6.77-6.92(2H), 7.10-7.22(2H), 7.39 (5H), 8.15 (1H), 8.52 (1H).

Example 371: 2-({1-[(4'-Chloro-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy B -4-methyl-2H-carbazole-5-carboxamide

Similar to Example 317, from 100 mg 54 and 50 mg (4-chloro-2-methylphenyl) under reflux The acid gave 43 mg of the title compound.

^{1 H-NMR (400MHz, DMSO} -d 6): δ [ppm] = 1.27 (2H), 1.38-1.70 (2H), 2.23 (4H), 2.53 (3H), 2.70-3.15 (2H), 3.28 (3H ), 3.36-3.43 (2H), 3.43-3.49 (2H), 3.55-3.84 (1H), 4.36 (3H), 7.12-7.27 (2H), 7.28-7.35 (1H), 7.36-7.47 (6H), 8.15 (1H), 8.52 (1H).

Example 372: 2-[(1-{[4'-(2-Cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)-methyl]-N-(2 -methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 55 mg of [4-(1-cyano-1-methylethyl)phenyl] under reflux The acid gave 67 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (2H), 1.36-1.65 (2H), 1.72 (6H), 2.24-2.40 (1H), 2.53 (3H), 2.70-3.14 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.49 (2H), 3.54-3.77 (1H), 4.36 (3H), 7.18 (1H), 7.38-7.50 (3H), 7.62 (2H) ), 7.75 (4H), 8.15 (1H), 8.52 (1H).

Example 373: N-(2-Methoxyethyl)-2-({1-[4-(5-methoxypyridin-2-yl)benzylidene]piperidin-4-yl}- -4-methyl-2H-carbazole-5-carboxamide

Similar to Example 368, from 200 mg of 54 and 183 mg of (5-methoxypyridin-2-yl) under reflux Acid tetramethyl glycol ester gave 12 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.22-1.33 (2H), 1.36-1.66 (2H), 2.23-2.38 (1H), 2.53 (3H), 2.68-3.12 (2H) , 3.28 (3H), 3.35-3.42 (2H), 3.43-3.50 (2H), 3.54-3.78 (1H), 3.88 (3H), 4.36 (3H), 7.18 (1H), 7.36-7.55 (4H), 7.96 (1H), 8.07 (2H), 8.13 (1H), 8.39 (1H), 8.51 (1H).

Example 374: N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]-benzhydryl} Piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 56 mg of [2-(trifluoromethyl)pyridin-5-yl] under reflux The acid gave 37 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.19-1.36 (2H), 1.36-1.69 (2H), 2.21-2.42 (1H), 2.53 (3H), 2.70-3.14 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.53-3.72 (1H), 4.36 (3H), 7.18 (1H), 7.42 (1H), 7.53 (2H), 7.89 (2H) ), 8.01 (1H), 8.15 (1H), 8.41 (1H), 8.52 (1H), 9.13 (1H).

Example 375: N-(2-Methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzylidene]piperidin-4-yl}-- -4-methyl-2H-carbazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 47 mg (2-methoxypyridin-5-yl) under reflux The acid gave 50 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.26 (2H), 1.34-1.70 (2H), 2.21-2.40 (1H), 2.53 (3H), 2.69-3.15 (2H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.49 (2H), 3.51-3.79 (1H), 3.90 (3H), 4.36 (3H), 6.93 (1H), 7.18 (1H), 7.36-7.52 (3H) ), 7.72 (2H), 8.05 (1H), 8.15 (1H), 8.46-8.57 (2H).

Example 376: 2-({1-[(4'-Fluoro-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy B -4-methyl-2H-carbazole-5-carboxamide

Similar to Example 317, from 300 mg of 54 and 135 mg of (4-fluoro-2-methylphenyl) under reflux The acid gave 261 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (2H), 1.37-1.70 (2H), 2.24 (4H), 2.53 (3H), 2.71-3.14 (2H), 3.28 (3H) ), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.55-3.83 (1H), 4.37 (3H), 7.05-7.12 (1H), 7.18 (2H), 7.22-7.30 (1H), 7.40 (5H) ), 8.14 (1H), 8.52 (1H).

Example 377: N-(2-Methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzylidene]piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Similar to Example 317, from 80 mg of 54 and 32 mg of (2-methylpyridin-5-yl) under reflux The acid gave 45 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (2H), 1.37-7.11 (2H), 2.18-2.39 (1H), 2.52-2.58 (3H), 2.73-3.16 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.45 (2H), 3.54-3.79 (1H), 4.36 (3H), 7.18 (1H), 7.30-7.54 (4H), 7.76 (2H), 8.00 (1H) ), 8.15 (1H), 8.51 (1H), 8.78 (1H).

Example 378: N-(2-Methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzylidene]piperidin-4-yl}methyl )-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 45 mg of (6-methoxypyridin-2-yl) under reflux The acid gave 30 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (2H), 1.35-1.68 (2H), 2.32 (1H), 2.52 (3H), 2.70-3.13 (2H), 3.28 (3H) ), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.53-3.74 (1H), 3.96 (3H), 4.36 (3H), 6.81 (1H), 7.18 (1H), 7.37-7.67 (4H), 7.81 (1H), 8.15 (3H), 8.51 (1H).

Example 379: N-(2-Methoxyethyl)-4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzylidene]-piperidine-4 -yl}methyl)-2H-carbazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 64 mg (2-methylpyrimidin-5-yl) under reflux Acid tetramethyl glycol ester gave 36 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (2H), 1.38-1.70 (2H), 2.21-2.40 (1H), 2.53 (3H), 2.67 (3H), 2.73-3.16 (2H), 3.28 (3H), 3.40 (2H), 3.43-3.50 (2H), 3.53-3.76 (1H), 4.36 (3H), 7.18 (1H), 7.42 (1H), 7.51 (2H), 7.84 ( 2H), 8.13 (1H), 8.51 (1H), 9.05 (2H).

Example 380: 2-({1-[(4'-Fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 50 mg of (4-fluoro-2-methoxyphenyl) under reflux The acid gave 47 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.34 (2H), 1.37-1.71 (2H), 2.22-2.40 (1H), 2.53 (3H), 2.70-3.15 (2H) , 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.56-3.75 (1H), 3.79 (3H), 4.36 (3H), 6.87 (1H), 6.99-7.10 (1H), 7.18 (1H), 7.30-7.46 (4H), 7.50 (2H), 8.13 (1H), 8.51 (1H).

Example 381: 2-({1-[(4'-Chloro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 54 mg (4-fluoro-2-methoxyphenyl) under reflux The acid gave 87 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (2H), 1.39-1.69 (2H), 2.19-2.39 (1H), 2.53 (3H), 2.75-3.14 (2H), 3.28 (3H), 3.40 (2H), 3.45 (2H), 3.57-3.74 (1H), 3.81 (3H), 4.36 (3H), 7.04-7.25 (3H), 7.28-7.62 (6H), 8.13 (1H), 8.51 (1H).

Example 382: N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]-benzhydryl} Piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 56 mg of [2-(trifluoromethyl)pyrimidin-5-yl] under reflux The acid gave 14 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (2H), 1.38-1.73 (2H), 2.22-2.41 (1H), 2.53 (3H), 2.70-2.89 (1H), 2.94 -3.18(1H), 3.28(3H), 3.36-3.43(2H), 3.44-3.49(2H), 3.51-3.70(1H), 4.37(3H), 7.18(1H), 7.42(1H), 7.57(2H ), 7.97 (2H), 8.13 (1H), 8.51 (1H), 9.43 (2H).

Example 383: 2-({1-[(4'-Chloro-2'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 51 mg (4-chloro-2-fluorophenyl) under reflux The acid gave 51 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (2H), 1.38-1.68 (2H), 2.32 (1H), 2.53 (3H), 2.71-2.91 (1H), 2.93-3.16 (1H), 3.28(3H), 3.40(2H), 3.45(2H), 3.53-3.78(m,1H), 4.37(3H),7.18(1H),7.33-7.52(4H),7.53-7.74(4H ), 8.13 (1H), 8.51 (1H).

Example 384: 2-({1-[(2'-Chloro-4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 51 mg (2-chloro-4-fluorophenyl) under reflux The acid gave 26 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.28 (2H), 1.38-1.67 (2H), 2.23-2.39 (1H), 2.53 (3H), 2.71-2.91 (1H), 2.94 -3.15(1H), 3.28(3H), 3.36-3.43(2H), 3.43-3.50(2H), 3.54-3.74(1H), 4.37(3H), 7.18(1H),7.33(1H),7.39-7.63 (7H), 8.13 (1H), 8.51 (1H).

Example 385: 2-({1-[4-(5-chloropyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 46 mg (5-chloropyridin-3-yl) under reflux The acid gave 22 mg of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.35 (2H), 1.36-1.69 (2H), 2.23-2.40 (1H), 2.53 (3H), 2.69-2.90 (1H) , 2.92-3.16(1H), 3.28(3H), 3.40(2H), 3.45(2H), 3.53-3.73(1H), 4.36(3H), 7.18(1H), 7.35-7.57(3H),7.86(2H ), 8.15 (1H), 8.30 (1H), 8.52 (1H), 8.65 (1H), 8.90 (1H).

Example 386: 2-({1-[4-(5-fluoropyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl) -4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 41 mg (5-fluoropyridin-3-yl) under reflux The acid gave 57 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.27 (2H), 1.37-1.70 (2H), 2.24-2.40 (1H), 2.52-2.55 (3H), 2.70-2.89 (1H) , 2.93-3.15 (1H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.53-3.73 (1H), 4.36 (3H), 7.18 (1H), 7.42 (1H), 7.50 (2H), 7.86 (2H), 8.07-8.18 (2H), 8.51 (1H), 8.61 (1H), 8.84 (1H).

Example 387: N-(2-Methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl]-benzoguanidinyl} Piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 56 mg of [5-(trifluoromethyl)pyridin-3-yl] under reflux The acid gave 73 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20-1.35 (2H), 1.36-1.67 (2H), 2.23-2.40 (1H), 2.53 (3H), 2.69-2.92 (1H) , 2.93-3.17 (1H), 3.28 (3H), 3.35-3.43 (2H), 3.43-3.49 (2H), 3.53-3.75 (1H), 4.37 (3H), 7.18 (1H), 7.42 (1H), 7.52 (2H), 7.93 (2H), 8.07-8.20 (1H), 8.45-8.58 (2H), 9.00 (1H), 9.24 (1H).

Example 388: 2-[(1-{[4'-(2-Hydroxypropyl-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)-methyl]-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 77 mg (4-hydroxy-tert-butylphenyl) under reflux Acid tetramethyl glycol ester gave 46 mg of the title compound.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (2H), 1.45 (8H), 2.22, 2.42 (1H), 2.53 (3H), 2.71-2.90 (1H), 2.91-3.14 (1H), 3.28 (3H), 3.40 (2H), 3.43-3.50 (2H), 3.56-3.80 (1H), 4.36 (3H), 5.06 (1H), 7.18 (d, 1H), 7.37-7.50 (3H) ), 7.50-7.67 (4H), 7.71 (2H), 8.15 (1H), 8.52 (1H).

Example 389: 2-({1-[(3',5'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 100 mg of 54 and 46 mg of (3,5-difluorophenyl) under reflux The acid gave 22 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.18-1.35 (2H), 1.36-1.70 (2H), 2.19-2.39 (1H), 2.52-2.56 (3H), 2.71-2.92 ( 1H), 2.93-3.17 (1H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.49 (2H), 3.52-3.71 (1H), 4.36 (3H), 7.11-7.33 (2H), 7.37- 7.54 (5H), 7.81 (2H), 8.13 (1H), 8.51 (1H).

Example 390: 2-({1-[(4'-Fluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl )-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 60 mg 332 and 19 mg (4-fluorophenyl) under reflux The acid gave 25 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.25 (2H), 1.37-1.67 (2H), 2.24 (4H), 2.53 (3H), 2.69-2.87 (1H), 2.92-3.14 (1H), 3.28 (3H), 3.36-3.43 (2H), 3.43-3.50 (2H), 3.56-3.81 (1H), 4.36 (3H), 7.11-7.34 (6H), 7.36-7.46 (3H), 8.15 (1H), 8.52 (1H).

Example 391: 2-({1-[(3',5'-Difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 317, from 60 mg 332 and 27 mg (3,5-difluorophenyl) under reflux The acid gave 30 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.23 (2H), 1.36-1.69 (2H), 2.27 (4H), 2.53 (3H), 2.69-2.90 (1H), 2.92-3.15 (1H), 3.28 (3H), 3.36-3.43 (2H), 3.45 (2H), 3.53-3.76 (1H), 4.36 (3H), 7.08-7.21 (3H), 7.22-7.34 (4H), 7.42 (1H) ), 8.15 (1H), 8.52 (1H).

Example 392: N-(2-Methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzylidene]piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Similar to Example 317, from 60 mg of 332 and 21 mg of pyridin-3-yl under reflux The acid gave 19 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.20-1.33 (2H), 1.37.71 (2H), 2.26 (4H), 2.53 (3H), 2.70-2.88 (1H), 2.94 -3.17(1H), 3.28(3H), 3.36-3.43(2H), 3.43-3.49(2H), 3.56-3.82(1H), 4.36(3H), 7.18(1H), 7.23-7.37(3H),7.39 -7.56(2H), 7.83(1H), 8.15(1H), 8.52(1H), 8.56-8.65(2H).

Example 393: N-(2-Methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzylidene]piperidin-4- }]methyl)-2H-carbazole-5-carboxamide

Similar to Example 317, from 60 mg 332 and 21 mg pyridin-4-yl under reflux The acid gave 19 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.18-1.33 (2H), 1.37-1.67 (2H), 2.27 (4H), 2.52-2.56 (3H), 2.70-2.86 (1H) , 2.93-3.13(1H), 3.28(3H), 3.36-3.43(2H), 3.43-3.49(2H), 3.55-3.75(1H), 4.36(3H), 7.18(1H), 7.23-7.36(3H) , 7.38-7.48 (3H), 8.15 (1H), 8.52 (1H), 8.60-8.69 (2H).

Example 394: N-(2-Methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl )-2H-carbazole-5-carbamide

Similar to Example 317, from 60 mg 332 and 21 mg phenyl under reflux The acid gave 57 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.34 (2H), 1.37-1.67 (2H), 2.25 (4H), 53 (3H), 2.68-2.88 (1H), 2.92 -3.17(1H), 3.28(3H), 3.36-3.43(2H), 3.45(2H), 3.59-3.81(1H), 4.36(3H), 7.13-7.32(4H),7.33-7.50(6H), 8.15 (1H), 8.52 (1H).

Example 395: 2-{[1-(4-Bromobenzylidenyl)piperidin-4-yl]methyl}-N-(2-methylsulfonylethyl)-4-methyl-2H-indole Oxazol-5-carboxamide

Analogously to Example 1b, version B, 383 mg of the title compound was obtained from 797 mg of 4-bromobenzoic acid in 1 g 395b and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.32 (2H), 1.34-1.67 (2H), 2.21-2.38 (1H), 2.55 (3H), 2.68-2.87 (1H) , 3.05(4H), 3.39 (2H), 3.45-3.59(1H), 3.66(2H), 4.35(3H), 7.23(1H), 7.28-7.37(2H), 7.43(1H), 7.59-7.70(2H ), 8.34 (1H), 8.52 (1H).

The starting materials were prepared as follows:

Example 395a: 4-({5-[N-(2-Methanesulfonylethyl)amine-carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidine-1 -T-butyl formate

Similar to Example 266a, 1.26 g of the title compound was obtained from 2.506 g of 1c and 3.022 g of 2-methanesulfonylethylamine hydrochloride.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.02-1.17 (2H), 1.34-1.54 (11H), 2.08-2.24 (1H), 2.55 (3H), 2.73 (2H), 3.06 (3H), 3.34-3.47 (2H), 3.57-3.76 (2H), 3.91 (2H), 4.32 (2H), 7.23 (1H), 7.43 (1H), 8.33 (1H), 8.52 (1H).

Example 395b: N-(2-Methanesulfonylethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

Similar to Example 258b, 1.29 g of the title compound was obtained from 1.26 g of Compound 395a, which was carried out without further purification.

Example 396: N-(2-Methanesulfonylethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}- Benzyl hydrazino)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 30 mg of the title compound was obtained from 90 mg of 4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzoic acid in 80 mg of 395b and DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.19-1.35 (2H), 1.36-1.72 (2H), 2.22-2.41 (1H), 2.55 (3H), 3.06 (5H), 3.39 (2H), 3.49-3.89 (3H), 4.37 (3H), 7.20-7.32 (4H), 7.40-7.49 (3H), 8.25 (1H), 8.34 (1H), 8.53 (1H), 8.58 (1H).

Example 397: N-(2-Methanesulfonylethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}- Benzyl hydrazino)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 30 mg of the title compound was obtained from 80 mg of 303b and 90 mg of 303b from DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.24 (2H), 1.35-1.70 (2H), 2.22-2.40 (1H), 2.55 (3H), 3.06 (5H), 3.39 (2H) ), 3.55-3.75 (3H), 4.36 (3H), 7.20-7.28 (3H), 7.40-7.49 (3H), 7.65 (1H), 7.92 (1H), 8.34 (1H), 8.53 (1H), 8.60 ( 1H).

Example 398: 2-({1-[(2',4'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methylsulfonyl-B -4-methyl-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 25 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.35 (2H), 1.37- 1.70 (2H), 2.22-2.41 (1H), 2.55 (3H), 3.05 (5H), 3.38 (2H), 3.50-3.83 (3H), 4.37 (3H), 7.15-7.29 (2H), 7.31-7.52 (4H), 7.55-7.73 (3H), 8.34 (1H), 8.53 (1H).

Example 399: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(3-hydroxy-3-methylbutyl)-4-methyl-2H -carbazole-5-carboxamide

Analogously to Example 1b, version B, 37 mg of the title compound was obtained from &lt;RTI ID=0.0&gt;&gt;

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.14 (6H), 1.17-1.32 (2H), 1.33-1.71 (4H), 2.23 - 2.37 (1H), 2.51 (3H), 2.68 -2.87 (1H), 2.87-3.13 (1H), 3.31 (2H), 3.47-3.55 (1H), 4.34 (s, 4H), 7.17 (1H), 7.33-7.45 (3H), 7.50 (2H), 7.97 -8.09 (1H), 8.50 (1H).

The starting materials were prepared as follows:

Example 399a: 4-({5-[N-(3-Hydroxy-3-methylbutyl) aminemethanyl ]-4-methyl-2H-indazol-2-yl}methyl)piperidine- 1-butyl formate

Similar to Example 1b, version B, 69 mg of 1-amino-2-methylbutan-2-ol in 150 mg of 1d and DMF was reacted at 60 °C. After phase separation and extraction, the combined organic phases were additionally washed with 0.1 N hydrochloric acid and saturated sodium bicarbonate. This gave 132 mg of the title compound which was used in the next step without further purification.

Example 399b: N-(3-Hydroxy-3-methylbutyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

Similar to Example 258b, 162 mg of the title compound.

Example 400: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-cyanoethyl)-4-methyl-2H-indazole- 5-carbamamine

Similar to Example 1b, version B, 55 mg of the title compound was obtained from 177 mg of 400b and 128 mg of 4-chlorobenzoic acid in DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.23 (2H), 1.33-1.70 (2H), 2.20-2.38 (1H), 2.56 (3H), 2.78 (3H), 2.90-3.11 (1H), 3.47 (3H), 4.35 (3H), 7.22 (1H), 7.34-7.56 (5H), 8.44-8.57 (2H).

The starting materials were prepared as follows:

Example 400a: 4-({5-[N-(2-Cyanoethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}-methyl)-piperidin-1- Tert-butyl formate

Similar to Example 1b, version B, 150 mg of 1d and 42 mg of 3-aminopropionitrile in DMF were reacted at 60 °C. After phase separation and extraction, the combined organic phases were additionally washed with 0.1 N hydrochloric acid and saturated sodium bicarbonate. This gave 137 mg of the title compound which was used in the next step without further purification.

Example 400b: N-(2-Cyanoethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

Analogously to Example 258b, 177 mg of the title compound.

Example 401: 2-{[1-(4-Chlorobenzylidyl)piperidin-4-yl]methyl}-N-(cyanomethyl)-4-methyl-2H-indazole-5- Formamide

75 mg of the title compound was obtained from aminoacetonitrile in 90 mg of 238c and 29 mg of DMF.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.21-1.33 (23H), 1.34-1.69 (2H), 2.15-2.41 (1H), 2.57 (3H), 2.75-2.86 (1H) , 2.93-3.14(1H), 3.39-3.69(1H), 4.29(2H), 4.33-4.55(3H), 7.18-7.28(1H), 7.39(2H), 7.43-7.55(3H), 8.57(1H) , 8.77-8.90 (1H).

Example 402: 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(cyclopropylmethyl)-4-methyl-2H-indazole-5 -Procarbamide

Similar to Example 1b, version B, 44 mg of the title compound was obtained from 19 mg of cyclopropylmethylamine in 90 mg of 238c and DMF.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.23 (2H), 0.33-0.53 (2H), 0.94-1.11 (1H), 1.20-1.33 (2H), 1.34-1.68 (2H) , 2.21-2.41 (1H), 2.54 (3H), 2.69-2.85 (1H), 2.93-3.08 (1H), 3.13 (2H), 3.44-3.68 (1H), 4.35 (3H), 7.18 (1H), 7.33 -7.46(3H), 7.47-7.60(2H), 8.07- 8.30(1H), 8.51(1H).

Example 403: N-(Cyclobutylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}-piperidin-4-yl )methyl]-2H-carbazole-5-carboxamide

48 mg of the title compound were obtained from 137 mg of 403b and 31 mg of (cyclobutylamino)methylamine hydrochloride.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.7-1.32 (2H), 1.35- 1.64 (2H), 1.67-1.90 (4H), 1.93-2.08 (2H), 2.22-2.38 ( 1H), 2.51-2.52 (3H), 2.69-2.88 (1H), 2.90-3.13 (1H), 3.20-3.30 (2H), 3.51-3.83 (1H), 4.36 (3H), 7.09-7.27 (5H), 7.35-7.52 (3H), 7.76 (2H), 8.13 (1H), 8.51 (1H).

The starting materials were prepared as follows:

Example 403a: 4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl J-2H-carbazole -5-methyl formate

Similar to Example 1b, version B, 2.73 g of the title compound was obtained from 3.76 g of 238a and 3.28 g of 4-[4-(trifluoromethyl)phenoxy]benzoic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.19-1.35 (2H), 1.38-1.74 (2H), 2.17-2.41 (1H), 2.76 (3H), 2.78-3.14 (2H) , 3.44 - 3.76 (1H), 3.82 (3H), 4.37 (3H), 7.06-7.28 (4H), 7.38-7.50 (3H), 7.67 (1H), 7.76 (2H), 8.71 (1H).

Example 403b: 4-Methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)-methyl]-2H-indole Oxazol-5-formic acid

970 mg of the title compound was obtained from EtOAc EtOAc.

Example 404: N-Isobutyl-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl ]-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 35 mg of the title compound was obtained from 100 mg of 403b and 14 mg of isobutylamine.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.91 (6H), 1.24 (2H), 1.34-1.69 (2H), 1.82 (1H), 2.19-2.42 (1H), 2.52 (3H) ), 2.71-2.90 (1H), 3.06 (3H), 3.51-3.85 (1H), 4.36 (3H), 7.05-7.27 (5H), 7.37-7.52 (3H), 7.76 (2H), 8.16 (1H), 8.51 (1H).

Example 405: 4-Methyl-N-neopentyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl ]-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 36 mg of the title compound was obtained from 100 mg of 403b and 16 mg of pentylamine.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.92 (9H), 1.17-1.32 (2H), 1.34-1.69 (2H), 2.21-2.38 (1H), 2.52-2.57 (3H) , 2.70-2.88 (1H), 3.08 (3H), 3.53-3.85 (1H), 4.36 (3H), 7.04-7.28 (5H), 7.35-7.52 (3H), 7.76 (2H), 8.12 (1H), 8.51 (1H).

Example 406: N-(cyclopropylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzylidene]piperidin-4 -yl)methyl]-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 33 mg of the title compound was obtained from 100 mg of 403b and 26 mg of cyclopropylmethylamine.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 0.23 (2H), 0.35-0.54 (2H), 0.93-1.11 (1H), 1.23 (2H), 1.36-1.67 (2H), 2.18 -2.41 (1H), 2.54 (3H), 2.66-3.22 (4H), 3.47-3.85 (1H), 4.36 (3H), 7.03-7.29 (5H), 7.35-7.53 (3H), 7.76 (2H), 8.22 (1H), 8.52 (1H).

Example 407: N-(2-Cyanoethyl)-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}-methyl)-4-methyl -2-H-carbazole-5-carbamide

Analogously to Example 1b, version B, 37 mg of the title compound was obtained from 140 mg of 407a and 84 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.18-1.37 (2H), 1.37- 1.68 (2H), 2.22-2.41 (1H), 2.56 (3H), 2.78 (4H), 3.39 -3.53 (2H), 3.56-3.82 (1H), 4.37 (3H), 7.14-7.37 (3H), 7.39-7.53 (3H), 7.63-7.83 (4H), 8.36-8.60 (2H).

The starting materials were prepared as follows:

Example 407a: N-(2-Cyanoethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

140 mg of the title compound was obtained from 165 mg of EtOAc.

Example 408: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methylsulfonyl-ethyl)-4 -methyl-2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 126 mg of the title compound was obtained from 300 mg of 408a and 156 mg of 4'-fluorobiphenyl-4-carboxylic acid.

_{LC-MS: R t = 1.20min} , MS (ES +): m / z = 577 (M + H) +.

The starting materials were prepared as follows:

Example 408a: N-(2-Methanesulfonylethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

300 mg of the title compound was obtained from 346 mg of 395a, which was used in the next step.

Example 409: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(3-hydroxy-propyl)-4-methyl -2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 20 mg of the title compound was obtained from 124 mg of 409b and 73 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (2H), 1.38-1.59 (2H), 1.67 (2H), 2.23 - 2.42 (1H), 2.52-2.57 (3H), 2.69 -3.17(2H), 3.19-3.94(6H), 4.36(3H), 7.18(1H), 7.31(2H), 7.38-7.51(3H), 7.63-7.86(4H),8.08(1H),8.51(1H ).

The starting materials were prepared as follows:

Example 409a: 4-({5-[N-(3-hydroxypropyl)amine-carbamoyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidine-1-carboxylic acid Tributyl ester

Similar to Example 1b, version B, 151 mg of the title compound was obtained from 150 mg of 1d and 30 mg of 3-amino-propan-1-ol.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ [ppm] = 1.01-1.30 (3H), 1.32-1.49 (10H), 1.67 (2H), 2.08-2.27 (1H), 2.52 (3H), 2.57 -2.80 (2H), 3.29 (2H), 3.41-3.54 (2H), 3.81-4.00 (2H), 4.32 (2H), 4.48 (1H), 7.18 (1H), 7.42 (1H), 8.10 (1H), 8.50 (1H).

Example 409b: N-(3-hydroxypropyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide

The title compound was obtained from 246 mg of 409jjjjjjj

Example 410: 2-({1-[(4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-hydroxy-ethyl)-4-methyl -2H-carbazole-5-carboxamide

Similar to Example 1b, version B, 36 mg of the title compound was obtained from 117 mg of 410b and 72 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ [ppm] = 1.26 (2H), 1.39-1.74 (2H), 2.21-2.40 (1H), 2.53 (3H), 2.75-3.16 (2H), 3.20 -3.37(2H), 3.43-3.74(4H), 4.36(3H), 7.21(1H), 7.31(2H), 7.38-7.52(3H), 7.65-7.81(4H),8.03(1H),8.51(1H ).

The starting materials were prepared as follows:

Example 410a: 4-({5-[N-(2-hydroxyethyl)aminemethanyl]-4-methyl-2H-indazol-2-yl}-methyl)piperidine-1-carboxylic acid Tributyl ester

Similarly to Example 1b, version B, 143 mg of the title compound was obtained from 150 mg of 1d and 25 mg of 2-aminoethyl-1-ol.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.01-1.30 (3H), 1.32-1.51 (10H), 2.07-2.26 (1H), 2.52-2.55 (3H), 2.58-2.82 ( 2H), 3.30 (2H), 3.45-3.58 (2H), 3.83-3.98 (2H), 4.32 (2H), 4.69 (1H), 7.21 (1H), 7.41 (1H), 8.05 (1H), 8.50 (1H) ).

Example 410b: N-(3-Hydroxypropyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5-carboxamide hydrochloride

Analogously to Example 1a, 117 mg of the title compound.

Example 411: (+/-)-N-(1,4-dioxan-2-ylmethyl)-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]-piperidyl Pyridin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide

Similar to Example 1b, version B, 62 mg of the title compound was obtained from 226 mg of 411b and 119 mg of 4'-fluorobiphenyl-4-carboxylic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.19-1.34 (2H), 1.37-1.73 (2H), 2.23-2.42 (1H), 2.53 (3H), 2.69-2.90 (1H) , 2.90-3.14 (1H), 3.17-3.30 (3H), 3.47 (1H), 3.58 (1H), 3.59-3.70 (3H), 3.71-3.82 (2H), 4.37 (3H), 7.19 (1H), 7.31 (2H), 7.38-7.53 (3H), 7.66-7.81 (4H), 8.18 (1H), 8.52 (1H).

The starting materials were prepared as follows:

Example 411a: (+/-)-4-({5-[N-(1,4-dioxan-2-ylmethyl)aminemethanyl]-4-methyl-2H-indazole-2 -yl}methyl)piperidine-1-carboxylic acid tert-butyl ester

Analogously to Example 1b, version B, 267 mg of the title compound was obtained from 250 mg of 1d and 78 mg of (+/-)-1,4-dioxan-2-ylmethylamine.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.99-1.18 (2H), 1.38 (11H), 2.09-2.24 (1H), 2.53 (3H), 3.10-3.29 (4H), 3.41 -3.52 (1H), 3.53-3.70 (4H), 3.70-3.81 (2H), 3.84-3.98 (2H), 4.32 (2H), 7.18 (1H), 7.41 (1H), 8.12-8.24 (1H), 8.51 (1H).

Example 411b: (+/-)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-(4-piperidinylmethyl)-2H-indazole-5 -carbamidine hydrochloride

226 mg of the title compound was obtained from 261 mg of 411a.

Example 412: (+/-)-2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-(oxetane-2 -yl-methyl)-2H-indazole-5-carboxamide

55 mg of the title compound were obtained from 350 mg of 238c) and 83 mg of (+/-)-oxetane-2-ylmethylamine.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm] = 1.16-1.31 (2H), 1.33-1.69 (2H), 2.19-2.38 (2H), 2.53 (3H), 2.58-2.66 (1H) , 2.66-2.86 (1H), 2.90-3.14 (1H), 3.38-3.64 (3H), 4.35 (5H), 4.71-4.96 (1H), 7.19 (1H), 7.33-7.45 (3H), 7.47-7.55 ( 2H), 8.21-8.37 (1H), 8.51 (1H).

Example 413: (+/-)-2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(1,4-dioxan-2-ylmethyl) -4-methyl-2H-carbazole-5-carboxamide

Analogously to Example 1b, version B, 185 mg of the title compound was obtained from 376 mg of 238c and 111 mg of (+/-)-1,4-dioxan-2-ylmethylamine hydrochloride.

¹ H-NMR (300 MHz, DMSO-d ₆ ): δ [ppm]=1.19-1.32 (2H), 1.33-1.66 (2H), 2.20-2.40 (1H), 2.53 (3H), 2.71-2.86 (1H) , 2.90-3.11 (1H), 3.16-3.32 (3H), 3.40-3.59 (3H), 3.60-3.70 (2H), 3.71-3.83 (2H), 4.35 (3H), 7.18 (1H), 7.31-7.46 ( 3H), 7.46-7.60 (2H), 8.21 (1H), 8.51 (1H).

Example 414: (R or S)-2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(1,4-dioxan-2-yl- Methyl)-4-methyl-2H-indazole-5-carboxamide

51 mg of the title compound was obtained along with 58 mg of the slower enantiomer (by Example 415) by preparatively preparative-p- HPLC (Method D). ).

Analytical versus palm HPLC: 12.62 min.

Example 415: (S or R)-2-{[1-(4-Chlorobenzylidenyl)piperidin-4-yl]methyl}-N-(1,4-dioxan-2-yl- Methyl)-4-methyl-2H-indazole-5-carboxamide

58 mg of the title compound was obtained by dissolving the racemate in 413 mg from 185 mg by preparative-p-p. HPLC (Method D). The title compound was obtained with 51 mg of the faster-solving enantiomer (Example 414) ).

Analytical versus palm HPLC: 13.68 min.

Example 416: (R or S)-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2-[(1- {4-[ 4-(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

The title compound was obtained along with 24 mg of the slower enantiomer by 24 mg of the racemate prepared in Example 248 by means of preparative versus palm chromatography (Method E). ).

Analytical versus palm HPLC: 7.08 min.

Example 417: (S or R)-4-methyl-N-(3,4,5,6-tetrahydro-2H-pyran-2-ylmethyl)-2-[(1-{4-[ 4-(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

24 mg of the title compound was obtained along with 24 mg of the faster-dissolving enantiomer by means of preparative-type palmitic HPLC (Method E) racemic separation from 231 mg of the racemate prepared in Example 248 (Example 416) ).

Analytical versus palm HPLC: 8.98 min.

Example 418: (R or S)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)) -phenoxy]benzhydryl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

65 mg of the title compound were obtained by preparative racemic HPLC (Method D (injection volume: 0.1 ml; detection: UV 210 nM)). 75 mg of the slower enantiomer was dissolved (Example 419).

Analytical versus palm HPLC: 13.66 min.

Example 419: (R or S)-N-(1,4-dioxan-2-ylmethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)) -phenoxy]benzhydryl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide

75 mg of the title compound were obtained by preparative racemic HPLC (Method D (injection volume: 0.1 ml; detection: UV 210 nM)) from racemic separation from 280 mg of the racemate prepared in Example 249. 65 mg of the faster enantiomer was dissolved (Example 418).

Analytical versus palm HPLC: 14.90 min.

Biological example:

The following biological examples, which are described in Section 1.-5 and which are only used with the EP2 receptor antagonist, are included in the patent application PCT/EP2012/073556, which is hereby incorporated by reference.

1. Detection of human prostaglandin E ₂ Antagonism of receptor signal (subtype EP2) 1.1 Detection principle

PGE ₂ adenylate film of binding to human EP2 receptor subtype of PGE ₂ induced located cyclase activation and results in the formation of cAMP. In the presence of the phosphodiesterase inhibitor IBMX, cAMP released due to this stimulation and released by cell lysis is used in the competitive detection method. In this test, cAMP present in the lysate competes with fluorescently labeled cAMP (cAMP-d2) for binding to the Eu cryptate-labeled anti-cAMP antibody.

The maximum signal is produced in the absence of cellular cAMP, which can be attributed to the binding of the cAMP-d2 molecule to the antibody. After excitation of the cAMP-d2 molecule at 337 nm, there is fluorescence resonance energy transfer (FRET) of the Eu cryptate molecule to the anti-cAMP antibody (labeled with the Eu cryptate molecule), followed by 665 nm (and The permanent emission signal at 620 nM). In the case of a time delay, that is, after the background fluorescence decay, the two signals are measured in a suitable measuring instrument. Any increase in the low FRET signal caused by prostaglandin E ₂ administration (measured as pore ratio change = emission _{665 nm} / emission _{620 nm} * 10000) indicates the effect of the antagonist.

1.2. Detection method 1.2.1. Antagonistic test (data for each well of a 384-well plate):

4 μl of cAMP-d2/cell suspension (625,000 cells/ml) was added to the test disc of the added substance solution (0.05 μl; 100% DMSO, concentration in the range of 0.8 nM to 16.5 μM). After pre-incubation for 20 minutes at room temperature (RT), 2 μl of 3xPGE2 solution (1.5 nM in PBS-IBMX) was added and incubated for an additional 60 minutes (volume: about 6 μl) in the presence of an agonist at room temperature. Subsequently, the reaction was stopped by adding 2 μl of the lysis buffer and incubated for an additional 20 minutes at room temperature, followed by actual measurement (volume: about 8 μl).

2. Detection for human prostaglandin E ₂ Antagonism of receptor signal (subtype EP4) 2.1 Detection principle

PGE ₂ adenylate membrane of the human EP ₄ receptor subtypes induced PGE ₂ binding positioned cyclase activation and results in the formation of cAMP. In the presence of the phosphodiesterase inhibitor IBMX, cAMP released due to this stimulation and released by cell lysis is used in the competitive detection method. In this test, cAMP present in the lysate competes with fluorescently labeled cAMP (cAMP-d2) for binding to the Eu cryptate-labeled anti-cAMP antibody.

The maximum signal is produced in the absence of cellular cAMP, which can be attributed to the binding of the cAMP-d2 molecule to the antibody. After excitation of the cAMP-d2 molecule at 337 nm, there is fluorescence resonance energy transfer (FRET) of the Eu cryptate molecule to the anti-cAMP antibody (labeled with the Eu cryptate molecule), followed by 665 nm (and The permanent emission signal at 620 nM). In the case of a time delay, that is, after the background fluorescence decay, the two signals are measured in a suitable measuring instrument. Any increase in the low FRET signal caused by prostaglandin E ₂ administration (measured as pore ratio change = emission _{665 nm} / emission _{620 nm} * 10000) indicates the effect of the antagonist.

2.2. Detection method 2.2.1. Antagonistic test (data per well of 384-well plate):

To the test dish of the added substance solution (0.05 μl; 100% DMSO, concentration in the range of 0.8 nM to 16.5 μM), 4 μl of cAMP-d2/cell suspension (312500 cells/ml) was added. After pre-incubation for 20 minutes at room temperature (RT), 2 μl of 3xPGE2 solution (0.3 nM in PBS-IBMX) was added and incubated for an additional 60 minutes (volume: about 6 μl) in the presence of an agonist at room temperature. Subsequently, the reaction was stopped by adding 2 μl of the lysis buffer and incubated for an additional 20 minutes at room temperature, followed by actual measurement (volume: about 8 μl).

3. Detection of antagonism of human prostaglandin D receptor signaling 3.1 Detection principle

Prostaglandin D ₂ binding to human adenylate film of PGD receptor activation-induced located cyclase and results in the formation of cAMP. In the presence of the phosphodiesterase inhibitor IBMX, cAMP released due to this stimulation and released by cell lysis is used in the competitive detection method. In this test, cAMP present in the lysate competes with fluorescently labeled cAMP (cAMP-d2) for binding to the Eu cryptate-labeled anti-cAMP antibody.

The maximum signal is produced in the absence of cellular cAMP, which can be attributed to the binding of the cAMP-d2 molecule to the antibody. After excitation of the cAMP-d2 molecule at 337 nm, there is fluorescence resonance energy transfer (FRET) of the Eu cryptate molecule to the anti-cAMP antibody (labeled with the Eu cryptate molecule), followed by 665 nm (and The permanent emission signal at 620 nM). In the case of a time delay, that is, after the background fluorescence decay, the two signals are measured in a suitable measuring instrument. Any increase in the low FRET signal caused by prostaglandin E ₂ administration (measured as pore ratio change = emission _{665 nm} / emission _{620 nm} * 10000) indicates the effect of the antagonist.

3.2. Detection method 3.2.1. Antagonistic test (data for each well of a 384-well plate):

4 μl of cAMP-d2/cell suspension (625,000 cells/ml) was added to the test disc of the added substance solution (0.05 μl; 100% DMSO, concentration in the range of 0.8 nM to 16.5 μM). After pre-incubation for 20 minutes at room temperature (RT), 2 μl of 3xPGD2 solution (6 nM in PBS-IBMX) was added and incubated for an additional 30 minutes (volume: about 6 μl) in the presence of an agonist at room temperature. Subsequently, the reaction was stopped by adding 2 μl of the lysis buffer and incubated for an additional 20 minutes at room temperature, followed by actual measurement (volume: about 8 μl).

4. PGE ₂ Receptor EP2 subtype and pre-ovulation cumulus expansion 4.1. Background:

In sinusoidal follicles prior to ovulation, oocytes are surrounded by cumulus cells, which form a dense cell crown around the oocyte. After the LH peak (luteinizing hormone), a series of processes are activated which produce significant morphological changes in this cell crown of cumulus cells. During this time, cumulus cells form an extracellular matrix which leads to the so-called cumulus expansion (Vanderhyden et al. Dev Biol.; (1990); 140(2): 307-317). This cumulus extends to an important component of the ovulation process and the likelihood of subsequent fertilization.

Prostaglandins and prostaglandin E ₂ (the synthesis of which is induced by LH peaks) are of decisive importance during cumulus expansion. Prostaglandin EP2 knockout mice (Hizaki et al, 1999, Proc Natl Acad Sci USA; (1999) 96(18): 10501-10506) show significantly reduced cumulus spread and severe low fertility, which exhibits prostaglandins The importance of EP2-like receptors for this process.

4.2. In vitro cumulus extension test

In immature female mice (line: B6D2F1 from Charles River), a single dose (intraperitoneal) 10 IU of PMSG (pregnant horse serum gonadotropin; Sigma G-4877, batch) at 14-18 days of age 68H0909) Induction of follicle formation. The ovaries were removed 47-50 hours after injection and the cumulus-oocyte complex was removed. At this stage, the cumulus complex has not expanded.

The cumulus-oocyte complex is now incubated with prostaglandin E ₂ (PGE ₂ ) (0.3 μM), vehicle control (ethanol) or test substance for 20-24 hours. Medium: α-MEM medium with 0.1 mM IBMX, pyruvate (0.23 mM), glutamic acid (2 mM), penicillin/streptomycin 100 IU/ml penicillin and 100 μg/ml streptomycin), HSA (8 mg/ M) and fetal bovine serum (FBS, 10%). The cumulus expansion is then established by subdividing into 4 stages (following Vanderhyden et al. Dev Biol.; (1990); 140(2): 307-317).

4.3. In vivo effects of in vitro fertilization after ovulation:

The substance can exert an influence on fertility by reducing the fertilization of the oocyte or cumulus-oocyte complex. To investigate these effects, the substance can be administered in vivo and subjected to in vitro fertilization after ovulation of the cumulus-oocyte complex has occurred. The rate of in vitro fertilization (where the test substance no longer exists) allows conclusions to be drawn about the in vivo effects of the test substance.

Immature female mice (line: B6D2F1, Charles River, Suelzfeld, age: 19-25 days) were maintained in a Macrolon cage in a room with controlled illumination (12 hours dark: 12 hours light), fed on a standard diet Drinking water is provided at will.

Mice (10 IU/animal, intraperitoneal) were filled with PMSG (pregnant horse serum gonadotropin). After 48 hours, ovulation was triggered by a single intraperitoneal administration of 10 IU/animal (hCG, human chorionic gonadotropin) in the animals. The test substance was dissolved in benzyl benzoate/castor oil (1+4 v/v) and administered subcutaneously in an amount of 0.1 ml 1 hour before hCG (n=5 animals per group). Animals were sacrificed 14 hours after hCG administration. Ovulation oocytes and cumulus-oocyte complexes are obtained from the ovarian sac and/or fallopian tubes and subjected to in vitro fertilization, wherein For fertilization, 40,000 sperm/0.5 ml sperm were used for 1 hour. After 24 hours of incubation by sperm, the number of fertilized oocytes was determined and the percentage of fertilization was determined.

The results in Table 4 show that Example 17 of the present invention has a dose-dependent effect on the fertilization of ovulation cumulus-oocyte complexes.

4.4. In vivo effects on fertility of non-human primates (Crocodylus macaques):

In order to study the effects of substances on fertility, mating studies can be performed in monkeys (Jensen et al. Contraception 81; (2010) 82(2): 165-171). For this, test substances were administered to female cynomolgus monkeys (Macaca Fascicularis), which were kept in the group, and then the animals were mated with male animals. Mating is checked by sperm detection in a daily vaginal smear. Pregnancy from which it is produced is determined by hormone determination and ultrasonic testing. The fertile period within the circulation of an individual animal can be determined via a change in serum estradiol concentration during the cycle (rises before the mid-term LH peak). The mating during this pregnancy is described as "timed mating" (mating during the trimester). In addition to the absolute number of pregnancies, the effect on fertility can also be expressed as a pregnancies for each "timed mating".

To test the effect of the EP2 receptor antagonist on the fertility of monkeys, Examples 17 and 56 of the present invention were administered over 6 months and dissolved in 0.5 ml of castor oil. Example 17 was administered once daily at a dose of 10 mg/kg (n=10 animals) while Example 56 was administered twice daily at a dose of 10 mg/kg (n=9 animals). The vehicle was administered only to the control group (n=10 animals). In the first month of treatment, no male animals were placed with female animals. After that, female and male animals were kept together for 5 months under pregnancy detection and circulation monitoring.

Table 5 shows that both substances produced a significant reduction in the number of pregnancies that occurred. This data shows for the first time the strong contraceptive effect of EP2 receptor antagonists in primates. Other results of the study showed that the substance had no effect on hormone content and cycle length. This confirmed substance produces a contraceptive effect by a non-hormone mechanism. After interruption of treatment, some animals exhibited reversibility of fertility.

5. Determination of pharmacokinetic parameters after intravenous administration 5.1. Intravenous administration:

In this regard, the substance is administered in dissolved form, and a compatible solubilizing agent such as PEG400 and/or ethanol is used in an acceptable amount. The substance is administered at a dose of 0.1-1 mg/kg. Administration was achieved in a rapid injection form in female rats. Here, about 100-150 μl of blood sample is drawn from the jugular vein by means of a catheter at various times after the rapid injection. Blood samples were treated with lithium-heparin as an anticoagulant and stored frozen until further processing. After centrifuging the sample at 3000 rpm for 15 minutes, an aliquot of 100 μl was taken from the supernatant (plasma) and precipitated by adding 400 μl of cold acetonitrile or methanol (anhydrous). The precipitated samples were frozen overnight at -20 ° C, followed by centrifugation again at 3000 rpm for 15 minutes, followed by extraction of 150 μl of clear supernatant for concentration determination. Analysis was performed by an Agilent 1200 HPLC system with attached LCMS/MS detection.

5.2 Calculating PK parameters

Calculated by means of software WinNonLin ^® PK is calculated, where t _1/2 means at a specified time interval: the half-life of (here terminal t _1/2, h to the unit).

Table 4: Reduction of in vitro fertilization rate after administration of test substances in vivo:

6. Effects of single administration of EP2 receptor antagonists and COX inhibitors on fertility in rats, either alone or in combination

Rats are particularly suitable animal models for indicating the effect of a substance on fertility, as circulation can be readily observed by vaginal swabs and mating reliably leads to high numbers of progeny.

In the following experiments, female Han Wistar rats having a weight of 200-270 g were used. Animals were kept in Makrolon cages in a room with controlled lighting (12 hours dark; 12 hours light), fed on a standard diet and arbitrarily provided with water.

The EP2 receptor antagonist was dissolved in benzyl benzoate/castor oil (1+4 v/v), and the dose was administered subcutaneously in an amount of 1 ml/kg body weight. If necessary, the EP2 receptor antagonist is also administered orally in the same vehicle as the COX inhibitor (see below). Here, the oral administration was divided into three time points (12.30, 16.00 and 17.00 hours) (see Table 6.3).

The COX inhibitor was suspended in a carrier liquid (85 mg Myrj® 53 polyethylene glycol (50) stearate; CAS number 9004-99-3) in 100 ml 0.9% w/v NaCl solution) at 2 ml/ The amount of kg body weight was administered to the dose corresponding to the treatment group.

Two cycles were observed using a vaginal swab before starting the experiment. Only animals with a conventional 4-day cycle were used in the experiments. Animals were randomized into treatment groups.

The animals were treated once or in combination with the test substance in the pre-estrus phase (the peak of the LH in the circulation appeared on the night). On the night before the estrus, make the female and male Rats mate. Continuous mating was confirmed by detecting vaginal sperm in the vaginal swab the next morning. The effect on fertility was determined by the number of implant sites in the animals 9-15 days after mating. The group size is n=6 per group.

As can be seen from Tables 6.1-6.6, in these experiments, piroxicam, indomethacin and meloxicam, as well as various EP2 receptor antagonists, have a strong contraceptive effect. In particular, it should be noted that individual administration does not show an effect or only shows a weak effect, while the combination shows a significantly increased contraceptive efficacy.

Table 6.2: Single administration of the EP2 receptor antagonist E161, either alone or in combination: N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-( Trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide (Example 345) or piroxicam The effect of fertility in female rats.

Table 6.4: Single dose of EP2 receptor antagonist E16: N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4], alone or in combination -(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 17) or meloxicam on female rats The impact of fertility.

To sperm)

7. In vivo effects of in vitro fertilization after ovulation in mice

Substances can affect fertility by reducing the fertilization of oocytes or cumulus-oocyte complexes. To examine these effects, the substance can be administered in vivo and after ovulation of the cumulus-oocyte complex, which is subjected to in vitro fertilization. The in vitro fertilization rate in the absence of a test substance allows conclusions to be drawn about the in vivo effects of the test substance.

Immature female mice (line: B6D2F1, Charles River, Suelzfeld, age: 19-25 days) were kept in Makrolon cages in a room with controlled illumination (12 hours dark: 12 hours light), fed on a standard diet And provide water arbitrarily.

Mice (10 IU/animal, intraperitoneal) were filled with PMSG (pregnant horse serum gonadotropin). After 48 hours, ovulation-triggered stimulation (hCG, human chorionic gonadotropin) was produced in the animals by intraperitoneal administration of 10 IU/animal. The EP2 receptor antagonist was dissolved in benzyl benzoate/castor oil (1+4 v/v) and administered subcutaneously in an amount of 0.1 ml 1 hour before hCG (n=5 animals per group). The COX inhibitor was suspended in a carrier liquid (85 mg Myrj® 53 polyethylene glycol (50) stearate; CAS number 9004-99-3) in 100 ml 0.9% w/v NaCl solution) and before hCG The appropriate dose was orally administered in an amount of 2 ml/kg body weight for 1 hour. Animals were sacrificed 14 hours after administration of hCG. Ovulation oocytes and cumulus-oocyte complexes were obtained from the ovarian sac and/or fallopian tubes and subjected to in vitro fertilization for 1 hour with 40,000 sperm/0.5 ml sperm count for fertilization. After 24 hours of incubation by sperm, the number of oocytes fertilized by each animal and the number of 2-cell embryos were determined.

Table 7.1: The results in this table show the EP2 receptor antagonist of the present invention E126: 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4 -(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (Example 291) 2-cell embryo for each animal The number has a dose dependent effect.

Preparation Example 1 : Containing 60 mg of piroxicam and 600 mg of N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy) a combination tablet of benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide (E16)

In a fluidized bed granulator, 1667 g of E16, 167 g of piroxicam, 444 g of microcrystalline cellulose, and 125 g of croscarmellose sodium were first charged. This powder mixture was granulated using a granulated liquid consisting of 75 g of hydroxypropylmethylcellulose 5cP, 2.5 g of sodium lauryl sulfate, and 1800 g of water. The granules were dried in a fluid bed granulator and then sieved and then mixed with 20 g of magnesium stearate for 5 minutes. The powder mixture was then compressed on a rotary tablet machine into an oval tablet having a mass of 900 mg, a length of 18 mm and a width of 8 mm. The tablet was then coated with 55.6 g of ready-to-use film powder and 315 g of water dispersion. The ready-to-use film powder consisted of 50.56% hypromellose 5cP, 10.12% polyethylene glycol 3350, 10.12% talc, 23.20% titanium dioxide, and 6.00% yellow iron oxide.

Combination lozenges comprising other EP2 receptor antagonists of the invention and COX inhibitors can be similarly prepared. For alternative doses, the ratio can be adjusted appropriately.

Alternatively, it may be possible to administer an EP2 receptor antagonist and a COX inhibitor separately in two lozenges.

Claims (13)

A pharmaceutical composition for use in emergency contraception, the pharmaceutical composition comprising: (a) at least one EP2 receptor antagonist according to formula (I) Wherein R ¹ : means H, C ₁ -C ₂ alkyl or C ₁ -C ₂ alkoxy; R ² :H or methyl; the restriction is one of the two residues R ¹ or R ² Is equal to H; X: -(CH ₂ ) _l -, -(CH ₂ ) _k -O-, -CH ₂ -S-, CH ₂ -S(O) ₂ -, -CH(CH ₃ )-, - CH(CH ₃ )-O- or -C(CH ₃ ) ₂ -O-;k: 1 or 2; l: 0, 1 or 2; R ⁴ :H, C ₁ -C ₄ alkyl, C ₃ - C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ cycloalkyl; and in the case where X means that -1 is -(CH ₂ ) _l - or -CH(CH ₃ )- under 0 or 1, R ⁴ Further means 4 to 6 membered heterocyclic residue; and in the case where X means -(CH ₂ ) _l - or -CH(CH ₃ )-, R ⁴ : additionally means CN; m: 1 or 2 ;n: 1 or 2; Ar: 6 to 10 membered aryl or 5 to 10 membered heteroaryl residue, R ³ : halogen, CN, SF ₅ , C ₁ -C ₄ alkyl, C ₃ -C ₆ ring Alkyl, C ₄ -C ₆ heterocyclyl, OC ₁ -C ₄ alkyl, OC ₃ -C ₆ cycloalkyl, OC ₄ -C ₆ heterocyclyl, SC ₁ -C ₄ alkyl, S(O) ₂ -C ₁ -C ₄ alkyl, Ar', O-Ar', C(CH ₃ ) ₂ -CN or C(CH ₃ ) ₂ -OH; and Ar': optionally substituted or double substituted 6 membered aryl or 5 to 6 membered heteroaryl residue; wherein such substituents are selected from _{F, Cl, CN, C 1} -C 4 alkyl OC ₁ -C _{4 alkyl, C (CH 3) 2 -CN} , C (CH 3) 2 -OH and C (O) NH _2; and comprising (b) at least one compound selected from the following list of COX inhibitors: C1 Indomethacin; C2 diclofenac; C4 naproxen; C5 ibuprofen; C6 meloxicam; C7 piroxicam; C8 Nimesulide; C9 ketoprofen; C10 tenoxicam; C11 mefenamic acid; C12 ketorolac; C13 celecoxib (4-[5 -(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide); C14 parecoxib (N-[4-(5 -methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonylpropionamide; C15 rofecoxib (4-(4-methylsulfonylphenyl)-3 -Phenylfuran-2(5H)-one); C16 valdecoxib (4-[5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide); C17 etoricoxib ( Etoricoxib). The use of the pharmaceutical composition according to claim 1, wherein the EP2 receptor antagonist according to formula (I) is used, wherein R ¹ , R ² : means H or methyl; the restriction condition is the two residues R ^{One of 1} or R ² is equal to H; X: -(CH ₂ ) _l - or -(CH ₂ ) _k -O-; k: 1 or 2; l: 0, 1 or 2; R ⁴ : H, C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ cycloalkyl; m: 1 or 2; n: 1 or 2; Ar: 6 to 10 membered aryl or 5 to 10 membered heteroaryl residues, R ³ : halogen, CN, SF ₅ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₆ heterocyclic, OC ₁ -C _4- alkyl, OC ₃ -C ₆ cycloalkyl, OC ₄ -C ₆ heterocyclyl, SC ₁ -C ₄ alkyl, S(O) ₂ -C ₁ -C ₄ alkyl, Ar', O-Ar ', C(CH ₃ ) ₂ -CN or C(CH ₃ ) ₂ -OH; and Ar': a 6-membered aryl or a 5 to 6-membered heteroaryl residue which may be mono- or di-substituted as appropriate; The substituents are selected from the group consisting of F, Cl, CN, C ₁ -C ₄ alkyl, OC ₁ -C ₄ alkyl, C(CH ₃ ) ₂ -CN, C(CH ₃ ) ₂ -OH, and C(O) NH ₂ ; and its isomers, diastereomers, enantiomers and salts or cyclodextrin cage compounds. The use of the pharmaceutical composition according to claim 1 or 2, wherein the EP2 receptor antagonist according to formula (I) is used, wherein R ¹ :methyl; R ² :H; X:-(CH ₂ ) _l - or -(CH ₂ ) _k -O-;k:1;l:0 or 1; R ⁴ :C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ naphthenic a group; m, n: 1; and Ar: a phenyl residue; and isomers, diastereomers, enantiomers thereof and salts or cyclodextrin cage compounds, and R ³ and Ar' Has the meaning as described in claim 2. The use of the pharmaceutical composition according to claim 1 or 2, wherein the EP2 receptor antagonist according to formula (I) is used, wherein R ¹ : means methyl; R ² : H; X: -(CH ₂ ) _l -or-(CH ₂ ) _k -O-;k:1;l:0 or 1; R ⁴ :C ₁ -C ₄ alkyl, C ₃ -C ₄ cycloalkyl or CH ₂ -C ₃ -C ₄ a cycloalkyl group; m, n: 2; and Ar: a phenyl residue; and isomers, diastereomers, enantiomers thereof and salts or cyclodextrin cage compounds, and R ³ and Ar' has the meaning as described in claim 2. The use of the pharmaceutical composition of claim 3 or 4, wherein the EP2 receptor antagonist is selected from the group consisting of E1 2-{[1-(4-cyano-2-fluorobenzhydryl)piperidine 4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E2 2-{[1-(4-t-butoxy Benzomethylene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E3 2-({1 -[4-(4-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole- 5-Protonamine E4 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-(N-morpholinyl)benzylidene)piperidin-4-yl ]methyl}-2H-carbazole-5-carbamamine E5 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N- (2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E6 2-{[1-(2-fluoro-4-methylsulfonylbenzylidene) piperidine 4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E7 2-{[1-(2-fluoro-4- Methoxybenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E8 2-{ [1-(4-Bromo-2-fluorobenzhydryl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -carbamamine E9 2-{[1 -(2-fluoro-4-methylbenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5- Formamide E10 2-({1-[2-fluoro-4-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-formamide E11 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ ⁶ - Thio)benzimidyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E12 N-(2-methoxyethyl)-4-methyl-2-{ [1-(4-Methylbenzylidinyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E13 2-({1-[4-(4-chlorophenoxy) Benzomethylene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E14 N-(2 -Methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy)benzylidenyl]piperidin-4-yl}methyl)-2H-indole Oxazol-5-formamide E15 2-({1-[4-(4-t-butylphenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-formamide E16 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4 -(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E17 N-(2-methoxyethyl)- 2-({1-[4-(4-methoxyphenoxy)benzylidene] Pyridin-4-yl}methyl)-4-methyl-2H-indazole-5-carbamidamine E18 N-(2-methoxyethyl)-4-methyl-2-{[1-( 4-phenoxybenzhydryl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E19 2-{[1-(4-cyclopropylbenzylidene)per Pyridin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E20 2-{[1-(4-methoxy Benzyl hydrazino)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E21 2-{[1- (4-Fluorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E22 N- (2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-2H-carbazole -5-Protonamine E23 2-{[1-(2-Methoxybenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl 2-H-carbazole-5-carbamide E24 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)sulfonyl] Benzyl hydrazino}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E25 N-(2-methoxyethyl)-4-methyl-2-({1- [3-(Trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E26 N-(2-methoxyethyl)-4- Methyl-2-{[1-(3-methylbenzylidene) piperidine Pyridin-4-yl]methyl}-2H-indazole-5-formamide E27 2-{[1-(3-chlorobenzylidinyl)piperidin-4-yl]methyl}-N-( 2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E28 2-({1-[4-(4-Aminomethylphenoxy)benzhydryl] Piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E29 2-({1-[4-(ring Pentyloxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E30 2- ({1-[4-(Difluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-Protonamine E31 2-{[1-(4-Cyanobenzimidyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carbamide E32 2-({1-[4-(1H-imidazol-1-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2 -methoxyethyl)-4-methyl-2H-indazole-5-formamide E33 N-(2-methoxyethyl)-4-methyl-2-({1-[4- (oxazol-2-yl)benzimidyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E34 N-(2-methoxyethyl)-4-methyl Base-2-({1-[4-(oxazol-5-yl)benzylidenyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E35 N-(2 -methoxyethyl)-4-methyl-2-({1-[4-(isoxazole-5-yl)) Mercapto]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E36 N-(2-methoxyethyl)-4-methyl-2-({1-[ 4-(1H-pyrazol-1-yl)benzimidyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E37 N-(2-methoxyethyl) -4-methyl-2-({1-[4-(1H-1,2,4-triazol-1-yl)benzylidenyl]piperidin-4-yl}-methyl)-2H- Oxazol-5-formamide E38 2-({1-[4-(difluoromethoxy)-2-fluorobenzylidenyl]piperidin-4-yl}methyl)-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-formamide E39 2-({1-[2-fluoro-4-(pyrrolidin-1-yl)benzylidene]pipe Pyridin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E40 2-({1-[(3,4') -difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E41 2-({1-[(3-Fluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-formamide E42 2-({1-[(3-fluoro-4'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl} Methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide E43 2-[(1-{[3-fluoro-3'-(three Fluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl 2-H-carbazole-5-carbamide E44 2-[(1-{[3-fluoro-2'-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl )methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E45 2-({1-[(2'-fluorobiphenyl-4-) Carbonyl)piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E46 2-({1-[ (2',4'-Difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-Protonamine E47 2-({1-[(2-Fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-formamide E48 N-(2-methoxyethyl)-4-methyl-2-({1-[(2'-methylbiphenyl-4) -yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide E49 N-(2-methoxyethyl)-4-methyl-2-({1 -[4-(4-Pyridinyloxy)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E50 N-(2-methoxyethyl)- 4-methyl-2-({1-[4-(4H-1,2,4-triazol-4-yl)benzylidenyl]piperidin-4-yl}-methyl)-2H-indole Oxazol-5-formamide E51 2-({1-(2-fluoro-4-(morpholin-4-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E52 2-{[1-(4-bromobenzylidene)pipech 4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E53 N-(2-methoxyethyl)-4 -Methyl-2-({1-[4-(trifluoromethoxy)benzylidenyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide E54 2- {[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamidine Amine E55 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidene]piperidin-4-yl) Methyl]-2H-carbazole-5-formamide E56 4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidene]piperidin-4-yl }Methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carbamidamine E57 2-{[1-(4-chlorobenzhydryl)piperidine-4 -yl]methyl}-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E58 4-methyl-N-(2,2, 2-Trifluoroethyl)-2-({1-[4-(trifluoromethoxy)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E59 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H -carbazole-5-carbamide E60 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzimidyl)piperidine 4-yl]-methyl}-2H-indazole-5-formamide E61 N-[2-(cyclopropyl) Oxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl}-methyl)-4-methyl-2H-carbazole -5-Protonamine E62 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzylidene]pipe Pyridin-4-yl}methyl)-2H-indazole-5-carbamide E63 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluoro) Biphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E64 2-{[1-(4-cyclopropylbenzene) Mercapto)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide E65 2-{ [1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl] -2H-carbazole-5-carbamide E66 4-methyl-2-{[1-(4-methylbenzimidyl)piperidin-4-yl]methyl}-N-[2-( 2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-formamide E67 2-({1-[4-(4-fluorophenoxy)benzylidene] Piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide E68 4 -methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzylidene]piperidine-4 -yl}methyl)-2H-indazole-5-formamide E69 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl) ]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide E70 2-{[1-(4-cyclopropylbenzylidene)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoro-ethoxy Ethyl]-2H-carbazole-5-carbamide E71 2-{[1-(4-chlorobenzylidyl)piperidin-4-yl]methyl}-N-(2-isopropyl Oxyethyl)-4-methyl-2H-indazole-5-formamide E72 N-(2-isopropoxyethyl)-4-methyl-2-{[1-(4-A Benzomethylene)piperidin-4-yl]methyl}-2H-indazole-5-formamide E73 2-({1-[4-(4-fluorophenoxy)benzylidene] Piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide E74 N-(2-isopropoxy B 4-methyl-2-({1-[4-(trifluoromethyl)benzylidene]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide E75 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-isopropoxyethyl)-4-methyl -2H-carbazole-5-carbamide E76 2-{[1-(4-cyclopropylbenzylidene)piperidin-4-yl]methyl}-N-(2-isopropoxy B 4-methyl-2H-indazole-5-carbamidamine E77 2-{[1-(4-chlorobenzylidenyl)piperidin-4-yl]methyl}-4-methyl- N-[2-(Trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide E78 2 -({1-[4-(4-fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoro-methoxy) Ethyl]-2H-indazole-5-formamide E79 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl --N-[2-(trifluoro-methoxy)ethyl]-2H-indazole-5-formamide E80 4-methyl-N-[2-(trifluoromethoxy)ethyl] -2-[(1-{4-[4-(Trifluoromethyl)phenoxy]benzylidene}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E81 N-(2-Tertiyloxyethyl)-2-{[1-(4-chlorobenzylidyl)piperidin-4-yl]methyl}-4-methyl-2H-carbazole -5-formamide E82 N-(2-tert-butoxyethyl)-2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl} Methyl)-4-methyl-2H-indazole-5-carbamidamine E83 N-(2-tert-butoxyethyl)-2-({1-[(4'-fluorobiphenyl-4) -yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E84 N-(2-tert-butoxyethyl)-4-methyl -2-[(1-{4-[4-(Trifluoromethyl)phenoxy]benzylidene}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E85 2-{[1-(4-Chlorobenzylidene)piperidin-4-yl]methyl}-4-methyl-N-{2-[( ² H3)methoxy]-( ² H4 Ethyl}-2H-indazole-5-formamide E86 2-({1-[4-(4-fluorophenoxy) Benzyl hydrazino]piperidin-4-yl}methyl)-4-methyl-N-{2-[( ² H3)methoxy]( ² H 4 )ethyl}-2H-indazole-5 -Proline amine E87 2-{[1-(4-chlorobenzylidene)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carbamide E88 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzoic acid Mercapto}azetidin-3-yl)methyl]-2H-indazole-5-formamide E89 N-(2-methoxyethyl)-4-methyl-2-({1 -[4-(Trifluoromethoxy)benzylidene]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide E90 2-({1-[2- Fluoro-4-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-Protonamine E91 2-{[1-(4-Chloro-2-fluorobenzhydryl)azetidin-3-yl]methyl}-N-(2-methoxyethyl -4-methyl-2H-indazole-5-formamide E92 2-({1-[3-fluoro-4-(trifluoromethyl)benzylidene]azetidin-3- }}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E93 2-({1-[4-chloro-3-(trifluoro) Methyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E94 2-{[1-(4-cyclopropyl benzyl) Azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E95 N-(2-A Oxyethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}azetidin-3-yl)methyl -2H-carbazole-5-carbamamine E96 2-{[1-(4-chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-( 2,2,2-Trifluoroethyl)-2H-indazole-5-carbamidamine E97 4-methyl-N-(2,2,2-trifluoroethyl)-2-({1-[ 4-(Trifluoromethoxy)benzylidene]azetidin-3-yl}-methyl)-2H-indazole-5-carboxamide E98 2-({1-[2-Fluorine -4-(Trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H- Oxazole-5-formamide E99 4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]azetidin-3-yl}methyl )-N-(2,2,2-trifluoroethyl)-2H-indazole-5-formamide E100 N-[2-(cyclopropoxy)ethyl]-4-methyl-2- ({1-[4-(Trifluoromethoxy)benzylidenyl]azetidin-3-yl}methyl)-2H-indazole-5-carboxamide E101 N-[2-( Cyclobutoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3-yl}methyl)-2H -carbazole-5-carbamamine E102 2-{[1-(4-chloro Mercapto)azetidin-3-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide E103 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[4-(4-fluorophenoxy)benzylidene]azetidin-3-yl} -methyl)-4-methyl-2H-indazole-5-formamide E104 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-( 4-methylbenzhydryl)azetidin-3-yl]-methyl}-2H-indazole-5-formamide E105 2-{[1-(4-chlorobenzhydryl) Azetidin-3-yl]methyl}-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide E106 N-(2 -Tertibutoxyethyl)-2-{[1-(4-chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-2H-indazole-5 -Proline amine E107 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]azetidin-3 -yl}methyl)-4-methyl-2H-indazole-5-formamide E108 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]azetidine- 3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E109 2-({1-[4-(4-fluorobenzene) Oxy) benzhydryl)azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E110 2-({1-[4-( 4-fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-carbazole -5-Protonamine E111 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-N-( 2,2,2-trifluoroethyl)-2H-indazole-5-formamide E112 2-{[1-(4-chlorobenzylidene)azetidin-3-yl]methyl }-4-Methyl-N-[2-(2,2,2-trifluoroethoxy)-ethyl]-2H-indazole-5-carboxamide E113 4-methyl-N-[2 -(2,2,2-trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]-benzylidene}azetidine Alkyl-3-yl)methyl]-2H-indazole-5-formamide E114 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4- [4-(Trifluoromethyl)phenoxy]benzylidene}-azetidin-3-yl)methyl]-2H-indazole-5-carboxamide E115 2-({1- [4-(4-Chlorophenoxy)benzylidene]azetidin-3-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl) -2H-carbazole-5-carbamide E116 2-({1-[4-(4-chlorophenoxy)benzylidene]azetidin-3-yl}methyl)-N- (2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E117 N-(2-methoxyethyl)-4-methyl-2-{[1-( 4-{[5-(Trifluoromethyl)pyridin-2-yl]oxy}benzylidene)- Heterocyclobutane-3-yl]methyl}-2H-indazole-5-formamide E118 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1- (4-{[5-(Trifluoromethyl)pyridin-2-yl]oxy}-benzylidenyl)azetidin-3-yl]methyl}-2H-indazole-5-A Indoleamine E119 2-{[1-(4-chlorobenzylidyl)piperidin-4-yl]methyl}-N-ethyl-4-methyl-2H-indazole-5-carboxamide E120 2-({1-[4-(4-Fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl -2H-carbazole-5-formamide E121 2-({1-[4-(4-chlorophenoxy)benzylidene]piperidin-4-yl}methyl)-4-methyl --N-(2,2,2-trifluoroethyl)-2H-indazole-5-formamide E122 4-methyl-2-({1-[4-(4-methylphenoxy) Benzyl hydrazino]piperidin-4-yl}methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E123 2-({1-[ (4'-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole- 5-Protonamine E124 4-methyl-2-{[1-(4-(N-morpholinyl)benzylidene)piperidin-4-yl]methyl}-N-(2,2, 2-trifluoroethyl)-2H-indazole-5-formamide E125 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[( Trifluoromethyl)thio]benzimidyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E126 4 -methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}-piperidine- 4-yl)methyl]-2H-indazole-5-formamide E127 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[ 5-(Trifluoromethyl)pyridin-2-yl]oxy}-benzylidenyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E128 4-methyl- N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-benzylidene) piperazine Pyridin-4-yl]methyl}-2H-indazole-5-formamide E129 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4- {[6-(Trifluoromethyl)pyridin-2-yl]oxy}-benzylidenyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E130 2-( {1-[4-(4-Cyanophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoro-ethyl -2H-carbazole-5-formamide E131 2-({1-[4-(3-fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl -N-(2,2,2-trifluoro-ethyl)-2H-indazole-5-carbamidamine E132 4-methyl-N-(2,2,2-trifluoroethyl)-2- [(1-{4-[3-(Trifluoromethyl)phenoxy]benzylidenyl}-piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E133 2- [(1-{4-[(5-Cyanopyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-4-methyl-N- (2,2,2-trifluoroethyl)-2H-indazole-5-formamide E134 2-[(1-{4-[(5-chloropyridin-2-yl)oxy)benzhydrazide }}piperidin-4-yl)methyl]-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E135 4-methyl-N -(2,2,2-trifluoroethyl)-2-[(1-{4-[5-(trifluoromethyl)pyridin-2-yl]benzylidenyl}-piperidin-4-yl )methyl]-2H-indazole-5-formamide E136 2-({1-[4-(2,4-difluorophenoxy)benzylidene]piperidin-4-yl}methyl )-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-formamide E137 2-({1-[4-(3,4-difluorobenzene) Oxy) benzhydryl)piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E138 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]carbonyl}-piperidine- 4-yl)methyl]-2H-indazole-5-formamide E139 2-{[1-(4-bromobenzylidinyl)piperidin-4-yl]methyl}-4-methyl- N-(2,2,2-trifluoroethyl)-2H-indazole-5-formamide E140 2-({1-[4-(5-chloropyridin-2-yl)benzylidene] Piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E141 2-({1-[( 4'-Methoxy-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl -2H-carbazole-5-carbamide E142 4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzylidene]piperidin-4-yl} Methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-formamide E143 2-({1-[(4'-fluoro-2'-methoxy linkage) Benz-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E144 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoguanidinyl}- Piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E145 2-({1-[4-(6-methoxypyridin-3-yl)benzylidene]piperidine 4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E146 2-({1-[4-( 6-methoxypyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indole Oxazol-5-formamide E147 4-methyl-2-({1-[4-(5-methylpyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-N -(2,2,2-trifluoroethyl)-2H-indazole-5-carbamidamine E148 2-({1-[4-(5-fluoropyridin-2-yl)benzylidene]piperider Pyridin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E149 2-({1-[4- (5-methoxypyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl -2H-carbazole-5-formamide E150 4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzylidene]piperidin-4-yl }Methyl)-N-(2,2,2-trifluoroethyl)-2H-indazole-5-formamide E151 4-methyl-N-(2,2,2-trifluoroethyl) -2-[(1-{4-[2-(Trifluoromethyl)pyrimidin-5-yl]benzylidenyl}-piperidin-4-yl)methyl]-2H-indazole-5-A Indoleamine E152 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzamide }}-piperidin-4-yl)methyl]-2H-indazole-5-formamide E153 2-({1-[4-(4-cyanophenoxy)benzylidene]piperidine 4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E154 2-{[1-(4-bromo-3- Methyl benzhydryl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E155 2-{[ 1-(4-Teletonylbenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-A Indoleamine E156 2-({1-[4-(1-hydroxy-1-methylethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxy-B 4-methyl-2H-indazole-5-carbamamine E157 2-{[1-(4-cyclohexylbenzylidene)piperidin-4-yl]methyl}-N-(2 -methoxyethyl)-4-methyl-2H-indazole-5-formamide E158 2-({ 1-[4-(1-Cyano-1-methylethyl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carbamide E159 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyrimidin-2-yloxy))benzhydrazide Benzylpiperidin-4-yl}-methyl)-2H-indazole-5-formamide E160 N-(2-methoxyethyl)-4-methyl-2-({1-[4 -(pyridin-3-yloxy)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E161 N-(2-methoxyethyl)-4 -Methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidenyl)-piperidin-4-yl]methyl}-2H -carbazole-5-carbamide E162 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy)benzylidene] Piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E163 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[ 4-(Trifluoromethyl)pyrimidin-2-yl]oxy}-benzylidenyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E164 N-(2- Methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzylidene)-piperidine-4 -yl]methyl}-2H-carbazole-5-formamide E165 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(three Fluoromethyl)pyridin-2-yl]oxy}benzylidene)-piperidin-4- Methyl}-2H-indazole-5-formamide E166 2-({1-[(4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl) -N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E167 N-(2-methoxyethyl)-4-methyl-2-({ 1-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yloxy)benzylidenyl]-piperidin-4-yl}methyl)-2H-indazole- 5-Protonamine E168 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzylidene] Piperidin-4-yl)methyl]-2H-indazole-5-formamide E169 2-[(1-{4-[(5-Cyanopyridin-2-yl)oxy]benzylidene) }piperidin-4-yl)methyl]-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide E170 2-[(1-{4- [(5-Chloropyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-N-(2-methoxy-ethyl)-4-methyl-2H- Oxazole-5-formamide E171 2-({1-[4-(2,4-difluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-N- (2- Methoxyethyl)-4-methyl-2H-indazole-5-formamide E172 2-({1-[4-(3,4-difluorophenoxy)benzylidene]piperidine 4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E173 N-(2-methoxyethyl)-4 -methyl-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]carbonyl} -piperidin-4-yl)methyl]-2H-indazole-5-formamide E174 2-({1-[4-(3-fluorophenoxy)benzylidene]piperidin-4- }]methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E175 2-{[1-(2-fluoro-4-isopropoxy Benzomethylene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E176 2-({1 -[(3-fluoro-3',4'-dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4- Methyl-2H-indazole-5-formamide E177 2-({1-[(2',3-difluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4- }]methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E178 2-({1-[4-(difluoromethoxy)) Benzyl hydrazino]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E179 2-({1- [4-(2-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5 -Procarbamide E180 2-({1-[(4'-Cyano-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-formamide E181 2-({1-[4-(5-chloropyridin-2-yl)benzylidene]piperidine-4 -yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-carbazole- 5-Protonamine E182 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzamide }}-piperidin-4-yl)methyl]-2H-indazole-5-formamide E183 N-(2-methoxyethyl)-2-({1-[(4'-methoxy) -2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E184 2-({1-[ (4'-Chloro-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H- Oxazole-5-carbamamine E185 2-[(1-{[4'-(2-cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl] -N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E186 N-(2-methoxyethyl)-2-({1-[4- (5-methoxypyridin-2-yl)benzimidyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E187 N-(2-A Oxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzylidenyl}-piperidin-4-yl)methyl -2H-carbazole-5-carbamide E188 N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-3-yl)benzylidene) ]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-formamide E189 2-({1-[(4'-fluoro-2'-methylbiphenyl-4) -yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carbamide E190 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzene Mercapto]piperidin-4-yl}-methyl)-2H-indazole-5-formamide E191 N-(2-methoxyethyl)-2-({1-[4-(6 -Methoxypyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E192 N-(2-methoxy Ethyl)-4-methyl-2-({1-[4-(2-methylpyrimidin-5-yl)benzylidenyl]piperidin-4-yl}methyl)-2H-indazole- 5-Protonamine E193 2-({1-[(4'-Fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2- Methoxyethyl)-4-methyl-2H-indazole-5-formamide E194 2-({1-[(4'-chloro-2'-methoxybiphenyl-4-yl)carbonyl) ]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E195 N-(2-methoxyethyl -4-methyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzylidenyl}-piperidin-4-yl)methyl]-2H- Oxazole-5-formamide E196 2-({1-[(4'-Chloro-2'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2 -methoxy-ethyl)-4-methyl-2H-indazole-5-formamide E197 2-({1-[(2'-chloro-4'-fluorobiphenyl-4-yl)carbonyl) ]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H- Oxazol-5-formamide E198 2-({1-[4-(5-chloropyridin-3-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxy Ethylethyl)-4-methyl-2H-indazole-5-formamide E199 2-({1-[4-(5-fluoropyridin-3-yl)benzylidene]piperidin-4- }]methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E200 N-(2-methoxyethyl)-4-methyl -2-[(1-{4-[5-(Trifluoromethyl)pyridin-3-yl]benzylidene}-piperidin-4-yl)methyl]-2H-indazole-5-A Indoleamine E201 2-[(1-{[4'-(2-hydroxypropan-2-yl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-formamide E202 2-({1-[(3',5'-difluorobiphenyl-4-yl)carbonyl]piperidine- 4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-carboxamide E203 2-({1-[(4'-fluoro-) 2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy-ethyl)-4-methyl-2H-indazole-5-A Indole E204 2-({1-[(3',5'-Difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-formamide E205 N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl 4-(3-pyridyl)benzylidene]piperidin-4-yl}-methyl)-2H-indazole-5-A Amine E206 N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(4-pyridyl)benzylidene]piperidin-4-yl }-Methyl)-2H-carbazole-5-carbamide and E207 N-(2-methoxyethyl)-4-methyl-2-({1-[(2-methylbiphenyl)- 4-yl)carbonyl]piperidin-4-yl}-methyl)-2H-indazole-5-carboxamide. The use of the pharmaceutical composition of claim 5, wherein the EP2 receptor antagonist is selected from the group consisting of E2 2-{[1-(4-t-butoxybenzylidene)piperidin-4-yl ]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E3 2-({1-[4-(4-fluorophenoxy)) Benzyl hydrazino]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E5 2-({1- [(4'-Flutonbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5- Formamide E7 2-{[1-(2-Fluoro-4-methoxybenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4- Methyl-2H-indazole-5-formamide E8 2-{[1-(4-bromo-2-fluorobenzhydryl)piperidin-4-yl]methyl}-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-carbamidamine E9 2-{[1-(2-fluoro-4-methylbenzimidino)piperidin-4-yl]- }---(2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E10 2-({1-[2-fluoro-4-(trifluoromethyl)) Benzyl hydrazino]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E11 N-(2-A Oxyethyl)-4-methyl-2-({1-[4-(pentafluoro-λ ⁶ -thio)benzylidenyl]piperidin-4-yl}methyl)-2H-carbazole -5-甲醯E12 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-methylbenzylidenyl)piperidin-4-yl]methyl}-2H-carbazole- 5-Protonamine E13 2-({1-[4-(4-Chlorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-formamide E14 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(4-methylphenoxy) Benzo) benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-formamide E15 2-({1-[4-(4-t-butylphenoxy)benzene Mercapto]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E16 N-(2-methoxy Ethylethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)methyl]-2H- Oxazole-5-carbamamine E17 N-(2-methoxyethyl)-2-({1-[4-(4-methoxyphenoxy)benzylidene]piperidin-4- }}methyl)-4-methyl-2H-indazole-5-carbamidamine E18 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-phenoxy) Benzopyridinyl)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E19 2-{[1-(4-cyclopropylbenzylidene) piperidine-4- Methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E20 2-{[1-(4-methoxybenzimidyl) Piperidin-4-yl]methyl}-N-(2-methoxy B) )-4-methyl-2H-indazole-5-carbamamine E21 2-{[1-(4-fluorobenzhydryl)piperidin-4-yl]methyl}-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-formamide E22 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(three Fluoromethyl)benzimidyl]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E24 N-(2-methoxyethyl)-4-methyl-2- [(1-{4-[(Trifluoromethyl)sulfonyl]benzimidyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E25 N-(2- Methoxyethyl)-4-methyl-2-({1-[3-(trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5- Formamide E26 N-(2-methoxyethyl)-4-methyl-2-{[1-(3-methylbenzhydryl)piperidin-4-yl]methyl}-2H- Oxazole-5-carbamamine E27 2-{[1-(3-chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl 2-H-carbazole-5-carbamamine E29 2-({1-[4-(cyclopentyloxy)benzylidenyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-formamide E30 2-({1-[4-(difluoromethyl)benzylidene]piperidin-4-yl}A -N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E31 2-{[1-(4-cyanobenzoguanidino)piperidine- 4-yl]methyl}-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carbamide E36 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(1H-pyrazol-1-yl)benzene) Mercapto]piperidin-4-yl}methyl)-2H-indazole-5-formamide E38 2-({1-[4-(difluoromethoxy)-2-fluorobenzhydryl] Piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E39 2-({1-[2-Fluoro- 4-(pyrrolidin-1-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5- Formamide E40 2-({1-[(3,4'-Difluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-formamide E41 2-({1-[(3-fluoro-4'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl }Methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E42 2-({1-[(3-fluoro-4'-methyl) Biphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E43 2- [(1-{[3-Fluoro-3'-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl) 4-methyl-2H-indazole-5-carbamamine E44 2-[(1-{[3-fluoro-2'-(trifluoromethoxy)biphenyl-4-yl]carbonyl}piperidine 4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamidine Amine E45 2-({1-[(2'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carbamide E46 2-({1-[(2',4'-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N- (2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E47 2-({1-[(2-fluorobiphenyl-4-yl)carbonyl]piperidine-4 -yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E48 N-(2-methoxyethyl)-4-methyl 2-({1-[(2'-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E51 2-({ 1-[2-Fluoro-4-(morpholin-4-yl)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-carbamide E52 2-{[1-(4-bromobenzylidinyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4 -Methyl-2H-indazole-5-carbamidamine E53 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy)phenyl) Mercapto]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E54 2-{[1-(4-chlorobenzylidinyl)piperidin-4-yl]methyl} -N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E55 N-(2-methoxyethyl)-4-methyl-2-[( 1-{4-[(Trifluoromethyl)thio]benzimidyl}piperidin-4-yl)methyl]-2H-indole Oxazol-5-formamide E59 2-{[1-(4-chlorobenzylidenyl)piperidin-4-yl]methyl}-N-[2-(cyclopropylmethoxy)ethyl] -4-methyl-2H-indazole-5-formamide E60 N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methyl Benzyl hydrazino)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E61 N-[2-(cyclopropylmethoxy)ethyl]-2-({1- [4-(4-Fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E62 N-[2-(ring Propylmethoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethyl)benzylidenyl]piperidin-4-yl}methyl)-2H-carbazole -5-Protonamine E63 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4- }}methyl)-4-methyl-2H-indazole-5-carbamidamine E64 2-{[1-(4-cyclopropylbenzylidene)piperidin-4-yl]methyl}- N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide E65 2-{[1-(4-chlorobenzhydryl)piperidine 4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide E66 4-A Base-2-{[1-(4-methylbenzylidenyl)piperidin-4-yl]methyl}-N-[2-(2,2,2-trifluoroethoxy)ethyl] -2H-carbazole-5-carbamide E67 2-({1-[4-(4-fluorophenoxy)) Mercapto]piperidin-4-yl}methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-A Indoleamine E68 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2-({1-[4-(trifluoromethyl)benzylidene] Piperidin-4-yl}methyl)-2H-indazole-5-formamide E69 2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl} Methyl)-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide E70 2-{[1-(4 -cyclopropylbenzimidyl)piperidin-4-yl]methyl}-4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indole Oxazol-5-formamide E71 2-{[1-(4-chlorobenzylidene)piperidin-4-yl]methyl}-N-(2-isopropoxyethyl)-4-methyl 2-H-carbazole-5-carbamide E72 N-(2-isopropoxyethyl)-4-methyl-2-{[1-(4-methylbenzimidyl)piperidine- 4-yl]methyl}-2H-indazole-5-formamide E73 2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl}methyl -N-(2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide E74 N-(2-isopropoxyethyl)-4-methyl-2 -({1-[4-(Trifluoromethyl)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E75 2-({1-[(4) '-Fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-isopropoxy B 4-methyl-2H-indazole-5-carbamidamine E76 2-{[1-(4-cyclopropylbenzylidinyl)piperidin-4-yl]methyl}-N-( 2-isopropoxyethyl)-4-methyl-2H-indazole-5-carboxamide E77 2-{[1-(4-chlorobenzylidyl)piperidin-4-yl]methyl }-4-Methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-formamide E78 2-({1-[4-(4-fluorophenoxy) Benzomethylene]piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl]-2H-indazole-5-carboxamide E79 2 -({1-[(4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-4-methyl-N-[2-(trifluoromethoxy)ethyl ]-2H-carbazole-5-carbamide E80 4-methyl-N-[2-(trifluoromethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl) Phenyloxy]benzhydryl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E81 N-(2-tert-butoxyethyl)-2-{ [1-(4-Chlorobenzylidinyl)piperidin-4-yl]methyl}-4-methyl-2H-indazole-5-carbamidamine E82 N-(2-tert-butoxy B 2-({1-[4-(4-fluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamidine Amine E83 N-(2-Tertioxyethyl)-2-({1-[(4'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4- methyl-2H-carbazole-5-carbamide E84 N-(2-third butoxide Ethylethyl)-4-methyl-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)methyl]-2H- Oxazol-5-formamide E85 2-{[1-(4-chlorobenzylidinyl)piperidin-4-yl]methyl}-4-methyl-N-{2-[(2H3) A Oxy](2H4)ethyl}-2H-indazole-5-formamide E86 2-({1-[4-(4-fluorophenoxy)benzylidene]piperidin-4-yl} Methyl)-4-methyl-N-{2-[(2H3)methoxy](2H4)ethyl}-2H-indazole-5-carboxamide E87 2-{[1-(4-chloro Benzyl hydrazino)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E88 N-( 2-methoxyethyl)-4-methyl-2-[(1-{4-[(trifluoromethyl)thio]benzylidenyl}azetidin-3-yl)methyl -2H-carbazole-5-carbamide E89 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(trifluoromethoxy))benzylidene ]azetidin-3-yl}methyl)-2H-indazole-5-formamide E90 2-({1-[2-fluoro-4-(trifluoromethyl)benzylidene] Azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E91 2-{[1-(4 -Chloro-2-fluorobenzhydryl)azetidin-3-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-A Indoleamine E92 2-({1-[3-fluoro-4-(trifluoromethyl)benzene) Indenyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E93 2-({1 -[4-chloro-3-(trifluoromethyl)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl- 2H-carbazole-5-formamide E94 2-{[1-(4-cyclopropylbenzylidene)azetidin-3-yl]methyl}-N-(2-methoxy Ethyl)-4-methyl-2H-indazole-5-formamide E95 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[4-( Trifluoromethyl)phenoxy]benzhydryl}azetidin-3-yl)methyl]-2H-indazole-5-carboxamide E100 N-[2-(cyclopropoxy) Ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidin-3-yl}methyl)-2H-indazole-5 -Procarbamide E101 N-[2-(cyclobutoxy)ethyl]-4-methyl-2-({1-[4-(trifluoromethoxy)benzylidene]azetidine Alkyl-3-yl}methyl)-2H-indazole-5-formamide E102 2-{[1-(4-chlorobenzylidenyl)azetidin-3-yl]methyl}- N-[2-(cyclopropylmethoxy)ethyl]-4-methyl-2H-indazole-5-carboxamide E103 N-[2-(cyclopropylmethoxy)ethyl]- 2-({1-[4-(4-Fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamidine Amine E104 N-[ 2-(cyclopropylmethoxy)ethyl]-4-methyl-2-{[1-(4-methylbenzylidenyl)azetidin-3-yl]methyl}-2H -carbazole-5-formamide E105 2-{[1-(4-chlorobenzylidene)azetidin-3-yl]methyl}-4-methyl-N-[2-( Trifluoromethoxy)ethyl]-2H-indazole-5-formamide E107 N-[2-(cyclopropylmethoxy)ethyl]-2-({1-[(4'-fluoro) Biphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E108 2-({1-[(4'-) Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamidine Amine E109 2-({1-[4-(4-fluorophenoxy)benzylidene]azetidin-3-yl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazole-5-formamide E112 2-{[1-(4-chlorobenzylidenyl)azetidin-3-yl]methyl}-4-methyl- N-[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazole-5-carboxamide E113 4-methyl-N-[2-(2,2,2- Trifluoroethoxy)ethyl]-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidene}azetidin-3-yl)methyl] -2H-carbazole-5-carbamide E114 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)) Phenoxy]benzhydryl}azetidin-3-yl) Methyl]-2H-indazole-5-formamide E115 2-({1-[4-(4-chlorophenoxy)benzylidene]azetidin-3-yl}methyl) 4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-formamide E116 2-({1-[4-(4-chlorophenoxy)benzene Methiol]azetidin-3-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E117 N-(2 -Methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)azetidine Alkyl-3-yl]methyl}-2H-indazole-5-formamide E125 4-methyl-N-(2,2,2-trifluoroethyl)-2-[(1-{4- [(Trifluoromethyl)thio]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E126 4-methyl-N-(2,2,2 -trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)methyl]-2H-carbazole- 5-Protonamine E127 4-methyl-N-(2,2,2-trifluoroethyl)-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl ]oxy}benzhydryl)piperidin-4-yl]methyl}-2H-indazole-5-formamide E128 4-methyl-N-(2,2,2-trifluoroethyl) -2-{[1-(4-{[6-(Trifluoromethyl)pyridin-3-yl]oxy}benzylidene)piperidin-4-yl]methyl}-2H-carbazole- 5-Protonamine E131 2-({1-[4-(3-Fluorophenoxy)benzylidene] Pyridin-4-yl}methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E132 4-methyl-N-(2 ,2,2-trifluoroethyl)-2-[(1-{4-[3-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)methyl]-2H -carbazole-5-carbamide E137 2-({1-[4-(3,4-difluorophenoxy)benzylidenyl]piperidin-4-yl}methyl)-4-methyl -N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E138 4-methyl-N-(2,2,2-trifluoroethyl)-2-[ (1-{[4'-(Trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E141 2-({1 -[(4'-methoxy-2'-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-4-methyl-N-(2,2,2-tri Fluoroethyl)-2H-indazole-5-formamide E143 2-({1-[(4'-fluoro-2'-methoxybiphenyl-4-yl)carbonyl]piperidin-4-yl }Methyl)-4-methyl-N-(2,2,2-trifluoroethyl)-2H-indazole-5-carboxamide E153 2-({1-[4-(4-cyano) Phenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E154 2- {[1-(4-Bromo-3-methylbenzomethyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-carbazole -5-Protonamine E155 2-{[1-(4-Tertiary benzylbenzylidene)piperidin-4-yl]methyl}-N-(2- Oxyethyl)-4-methyl-2H-indazole-5-formamide E157 2-{[1-(4-cyclohexylbenzylidene)piperidin-4-yl]methyl}-N -(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E160 N-(2-methoxyethyl)-4-methyl-2-({1- [4-(Pyridin-3-yloxy)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E161 N-(2-methoxyethyl) 4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene)piperidin-4-yl]methyl}- 2H-carbazole-5-carbamide E162 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(pyridin-2-yloxy))benzylidene ]piperidin-4-yl}methyl)-2H-indazole-5-formamide E163 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{ [4-(Trifluoromethyl)pyrimidin-2-yl]oxy}benzylidene)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E164 N-(2- Methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoromethyl)pyridin-3-yl]oxy}benzylidene) piperidine-4- Methyl}-2H-carbazole-5-carbamide E165 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[6-(trifluoro) Methyl)pyridin-2-yl]oxy}benzylidene)piperidin-4-yl]methyl}-2H-indazole-5-carboxamide E166 2-({1-[(4'-) Methoxybiphenyl-4-yl)carbonyl]piperidine-4- }}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carbamidamine E168 N-(2-methoxyethyl)-4-methyl -2-[(1-{4-[3-(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E170 2-[(1-{4-[(5-chloropyridin-2-yl)oxy]benzylidenyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl) -4-methyl-2H-indazole-5-formamide E171 2-({1-[4-(2,4-difluorophenoxy)benzylidene]piperidin-4-yl}A -N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E172 2-({1-[4-(3,4-difluorophenoxy) Benzyl hydrazino]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E173 N-(2- Methoxyethyl)-4-methyl-2-[(1-{[4'-(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidin-4-yl)methyl]-2H -carbazole-5-carbamide E174 2-({1-[4-(3-fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxy Ethylethyl)-4-methyl-2H-indazole-5-carboxamide E175 2-{[1-(2-fluoro-4-isopropoxybenzylidene)piperidin-4-yl] Methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E176 2-({1-[(3-fluoro-3',4'- Dimethylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-A Oxyethyl)-4-methyl-2H-indazole-5-formamide E177 2-({1-[(2',3-difluoro-4'-methoxybiphenyl-4-yl) )carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E178 2-({1-[4 -(difluoromethoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamidine Amine E179 2-({1-[4-(2-fluorophenoxy)benzylidene]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl 2-H-carbazole-5-carbamide E180 2-({1-[(4'-cyano-2'-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl )-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E181 2-({1-[4-(5-chloropyridin-2-yl)benzene Mercapto]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E182 N-(2-methoxy Benzyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-2-yl]benzylidene}piperidin-4-yl)methyl]- 2H-carbazole-5-carbamide E183 N-(2-methoxyethyl)-2-({1-[(4'-methoxy-2'-methylbiphenyl-4-yl)) Carbonyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E184 2-({1-[(4'-chloro-2'-methylbiphenyl-) 4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl) 4-methyl-2H-indazole-5-carbamamine E185 2-[(1-{[4'-(2-cyanopropan-2-yl)biphenyl-4-yl]carbonyl}piperidine 4-yl)methyl]-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E186 N-(2-methoxyethyl)-2 -({1-[4-(5-methoxypyridin-2-yl)benzylidene]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamidine Amine E187 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[6-(trifluoromethyl)pyridin-3-yl]benzoguanidinyl}piperidine 4-yl)methyl]-2H-indazole-5-formamide E188 N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridine-3) -yl)benzimidyl]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-carboxamide E189 2-({1-[(4'-fluoro-2') -Methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E190 N-(2-methoxyethyl)-4-methyl-2-({1-[4-(6-methylpyridin-3-yl)benzylidene]piperidin-4-yl} Methyl)-2H-indazole-5-formamide E191 N-(2-methoxyethyl)-2-({1-[4-(6-methoxypyridin-2-yl)benzene) Mercapto]piperidin-4-yl}methyl)-4-methyl-2H-indazole-5-formamide E193 2-({1-[(4'-fluoro-2'-methoxy linkage) Benz-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxy B -4-methyl-2H-indazole-5-formamide E194 2-({1-[(4'-chloro-2'-methoxybiphenyl-4-yl)carbonyl]piperidine-4 -yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E195 N-(2-methoxyethyl)-4-methyl Benzyl-2-[(1-{4-[2-(trifluoromethyl)pyrimidin-5-yl]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-A Indoleamine E196 2-({1-[(4'-Chloro-2'-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl -4-methyl-2H-indazole-5-formamide E197 2-({1-[(2'-chloro-4'-fluorobiphenyl-4-yl)carbonyl)piperidin-4-yl }Methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E198 2-({1-[4-(5-chloropyridine-3- Benzomethane]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E199 2-({ 1-[4-(5-fluoropyridin-3-yl)benzylidenyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H- Oxazole-5-carbamide E200 N-(2-methoxyethyl)-4-methyl-2-[(1-{4-[5-(trifluoromethyl)pyridin-3-yl] Benzyl hydrazino}piperidin-4-yl)methyl]-2H-indazole-5-formamide E201 2-[(1-{[4'-(2-hydroxypropan-2-yl)biphenyl) 4-yl]carbonyl}piperidin-4-yl)methyl]-N-(2-methoxyethyl)-4-methyl -2H-carbazole-5-carbamide E202 2-({1-[(3',5'-difluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N- (2-methoxyethyl)-4-methyl-2H-indazole-5-formamide E203 2-({1-[(4'-fluoro-2-methylbiphenyl-4-yl)) Carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H-indazole-5-carboxamide E204 2-({1-[(3) ',5'-Difluoro-2-methylbiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-N-(2-methoxyethyl)-4-methyl-2H -carbazole-5-carbamide E205 N-(2-methoxyethyl)-4-methyl-2-({1-[3-methyl-4-(3-pyridyl)benzoquinone Benzylpiperidin-4-yl}methyl)-2H-indazole-5-carboxamide E206 N-(2-methoxyethyl)-4-methyl-2-({1-[3- Methyl-4-(4-pyridyl)benzylidene]piperidin-4-yl}methyl)-2H-indazole-5-carboxamide E207 N-(2-methoxyethyl)- 4-Methyl-2-({1-[(2-methylbiphenyl-4-yl)carbonyl)piperidin-4-yl}methyl)-2H-indazole-5-carboxamide. The use of the pharmaceutical composition of claim 6, wherein the EP2 receptor antagonist is selected from the list: E16 N-(2-methoxyethyl)-4-methyl-2-[(1-{4 -[4-(Trifluoromethyl)phenoxy]benzylidene}piperidin-4-yl)methyl]-2H-indazole-5-carboxamide E126 4-methyl-N-(2 ,2,2-trifluoroethyl)-2-[(1-{4-[4-(trifluoromethyl)phenoxy]benzylidenyl}piperidin-4-yl)methyl]-2H -carbazole-5-carboxamide E161 N-(2-methoxyethyl)-4-methyl-2-{[1-(4-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzylidene Piperidin-4-yl]methyl}-2H-indazole-5-carboxamide. The use of the pharmaceutical composition according to any one of claims 1 to 7, wherein the COX inhibitor is present in the following range: C1 indomethacin: 19-800 mg/day; C2 diclofenac: 37.5-800 mg/day ; C4 naproxen: 125-4000 mg / day; C5 ibuprofen: 200-4800 mg / day; C6 meloxicam: 2-60 mg / day; C7 piroxicam: 5-80 mg / day ; C8 Nimesulide: 25-800 mg / day; C9 ketoprofen: 25-1200 mg / day; C10 tenoxicam: 10-160 mg / day; C11 mefenamic acid: 125-2000 Mg/day; C12 ketorolac: 2.5-160 mg/day; C13 senepoxib: 25-800 mg/day; C14 parecoxib 12.5-200 mg/day; C15 rofecoxib: 6-200 Mg/day; C16 valdecoxib: 10-160 mg/day; C17 etodox: 15-360 mg/day. The use of the pharmaceutical composition according to any one of claims 1 to 8, wherein the COX inhibitor is C1 indomethacin; C2 diclofenac; C4 naproxen; C5 ibuprofen; C6 meloxicam; C7 piroxicam; C8 Nimesulide. The use of the pharmaceutical composition of claim 9, wherein the COX inhibitor is: C1 indomethacin; C2 diclofenac; C6 meloxicam; C7 piroxicam. The use of any one of claims 1 to 10, wherein the pharmaceutical composition is administered in a single administration dose for a period of up to 120 hours, preferably up to 72 hours after unprotected sexual intercourse. The use of the pharmaceutical composition according to any one of claims 1 to 10, which is in the form of a pharmaceutical preparation for oral, transpulmonary, nasal, transdermal or transdermal administration. The use of the pharmaceutical composition of claim 1, wherein in the case where X means that -1 is -(CH ₂ ) _l -, R ^{4 is} additionally a 4-6 membered heterocyclic group bonded through a ring carbon atom.