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HK1203938B - 2h-indazoles as ep2 receptor antagonists - Google Patents

2h-indazoles as ep2 receptor antagonists Download PDF

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Publication number
HK1203938B
HK1203938B HK15104364.3A HK15104364A HK1203938B HK 1203938 B HK1203938 B HK 1203938B HK 15104364 A HK15104364 A HK 15104364A HK 1203938 B HK1203938 B HK 1203938B
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HK
Hong Kong
Prior art keywords
methyl
indazole
carboxamide
piperidin
methoxyethyl
Prior art date
Application number
HK15104364.3A
Other languages
Chinese (zh)
Other versions
HK1203938A1 (en
Inventor
N.布罗伊尔
A.门格尔
U.勒恩
A．罗特盖里
B.布赫曼
B．林登塔尔
A．特尔拉克
Original Assignee
拜耳知识产权有限责任公司
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Priority claimed from PCT/EP2012/073556 external-priority patent/WO2013079425A1/en
Publication of HK1203938A1 publication Critical patent/HK1203938A1/en
Publication of HK1203938B publication Critical patent/HK1203938B/en

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Description

As EP22H-indazoles as receptor antagonists
The present invention relates to a novel EP2Receptor antagonists, their preparation and their use as medicaments, as well as pharmaceutical formulations comprising the novel 2H-indazoles.
Prostaglandins have long been known to be key molecules in biological processes in female reproduction, such as the regulation of ovulation and fertilization. The effects on uterine contractions, implantation, decidua (e.g. placentation) and menstruation have also been described or become the subject of scientific research. Prostaglandins also play a role in pathological changes of the reproductive tract including menorrhagia, dysmenorrhea, endometriosis, fibroids (myomas) and cancer, and generally play a role in inflammation (e.g. crohn's disease), infection (e.g. bacterial infection) and neurodegenerative processes (e.g. alzheimer's disease, ALS), but also are known to function in immune defense, angiogenesis, pain, wound healing and interaction with the endocrine system (e.g. aromatase induction). To date, the mechanism by which prostaglandins affect such changes has not been fully elucidated. Recent findings suggest that prostaglandins, their receptors and their signal transduction pathways are involved in processes such as angiogenesis, apoptosis, proliferation and in inflammatory/anti-inflammatory processes.
The action of prostaglandins is mediated through their G-protein coupled receptors, which are located in the cell membrane. Of particular interest are prostaglandin E2(PGE2) Through interaction with a differently functioning receptor subtype (i.e. EP)1、EP2、EP3And EP4Receptors) to cause a wide variety of cellular effects. Prostaglandin E2The combined receptor subtype is particularly important for receptor-mediated effects involved in regulating fertility. Thus, it can be shown that reproductive function is in EP2Knockout mice (EP)2 -/-) In the case of no longer having a functional PGE2Receptor subtype EP2And these animals have smaller "piglets" (Matsumoto et al, 2001, Biology of reproduction64, 1557-1565). Again, these EP's can be shown2Knockout mice (Hizaki et al, 1999, Proc Natl Acad Sci U.S.A., Aug 31; 96(18):10501-10506) exhibit significantly reduced cumulus expansion and severe reproductive decline, which are believed to be causally linked to reduced reproductive processes such as ovulation and fertilization.
Thus, for the development of drugs for regulating female fertility, EP2Receptors are important targets. PGE24 of receptorThe existence of a subset opens up the possibility of targeted development of selectively active compounds. However, little has been known previously of any selective EP 2Receptors, since most known compounds are also associated with other PGEs2Receptor subtype binding, e.g. to EP4Receptor binding, or binding to other prostaglandin receptors such as the DP receptor.
EP2Receptor antagonists are described, for example, in applications US2005059742 and EP1467738(Jabbour, medical research Council). Methods for treating menorrhagia and dysmenorrhea are claimed, wherein EP may be used2And/or EP4An antagonist. AH6809 disclosed as EP2Or EP4Antagonists of the receptor, and no other specific antagonists and novel compounds are disclosed.
In application WO03/016254, the Ono Pharmaceutical claims the preparation of aryl carboxylic acids or aryl-or heterocycle-substituted saturated carboxylic acid derivatives, which are used in particular as PGE2A receptor antagonist. The disclosed compounds are claimed to treat a wide variety of diseases, also including allergic diseases, alzheimer's disease, pain, miscarriage, menstrual problems, menorrhagia and dysmenorrhea, endometriosis, bone disease, ischemia, and the like. However, the compounds are characterized by the presence of EP3Receptors have a particularly high affinity. In a further application (WO04/032964), newer compounds are described which are also characterized by a para-EP3Receptors have a particularly high affinity, but are also found as EP 2Use of antagonists for the treatment and prevention of allergic diseases.
In the applications WO03/053923 (substituted pyrrolidines) or WO03/035064 (substituted pyrazolidinones) by Applied Research Systems, Inc., compounds are claimed for the treatment of prostaglandin related diseases such as infertility, hypertension and osteoporosis. Said compounds with EP4And EP2Receptor subtype binding.
In application WO03/064391(Pfizer Products), [3- [ [ N- (4-tert-butylbenzyl) - (pyridin-3-ylsulfonyl) amino ] is described]Methyl radical]Metabolites of acetic acid, whichInhibition [ 2 ]3H]Prostaglandin E2With EP2Binding of the receptor. The use of these metabolites for the treatment of osteoporosis is disclosed.
In application US 2005124567, Tani et al claim 8-azaprostaglandin derivatives for the treatment of immune disorders, allergic disorders, premature labor, miscarriage and the like. The compounds with EP2And EP4Receptor binding.
EP is claimed for the first time in patent applications WO2007/057232, WO2007/071456, WO2008/028689, WO2008/028690 WO2008/028691, WO2008/0152099, WO2008/0152097, WO2008/0152094, WO2009/007421, WO2009/007422) and DE102009049662A1 from Bayer Schering Pharma AG 2A selective antagonist of the receptor.
In the applications of Summit Corporation PLC (WO2007/091107) and CM Sun et al (WO2008/070599), 2H-indazoles are disclosed, but not used to treat fertility disorders.
Applications WO2009/063365 and WO2008/139287 to Pfizer claim as EP2Azetidines as receptor antagonists and their use in the treatment of EP2Use of mediated conditions such as endometriosis and leiomyoma, WO2010/052625 being claimed as EP2Pyrrolidones of receptor antagonists and their use in the treatment of EP2-use of mediated conditions such as endometriosis and leiomyoma.
In a publication (British Journal of Pharmacology (2011),164,1847-2A selective antagonist of the receptor. These compounds are azetidines, which exhibit in vivo effects on the blood stream. The compounds exhibit high protein binding.
In a publication (239.ACS National Meeting of the Division of medical Chemistry, 21-25. March2010, San Francisco, USA; MEDI173) by P.M.Roveto et al, the novel thiazoles are described as EP2An antagonist.
Also in Ligard Pharmaceuticals Inc. (WO 2)010/008777) describe EP2A receptor antagonist. These compounds are bicyclic pyridine derivatives. The compounds are said to be useful in the treatment of pain, but also in the treatment of alzheimer's disease, multiple sclerosis and fertility disorders.
In order to regulate the processes that ultimately lead to ovulation and fertilization and thus help to inhibit fertility, other EP's with improved properties are needed2Antagonists of receptor activity in vivo.
It is therefore an object of the present invention to provide further EP's with improved properties2A receptor antagonist which is available in vivo and is therefore effective, and is stable.
This problem is solved by the compounds of the general formula I and their isomers, diastereomers, enantiomers and salts or cyclodextrin inclusion compounds for the preparation of medicaments,
wherein
R1: representation H, C1-C2Alkyl or C1-C2An alkoxy group;
R2: h or methyl;
with the proviso that two radicals R1Or R2One of them is H;
X：-(CH2)l-、-(CH2)k-O-、-CH2-S-、CH2-S(O)2-、-CH(CH3)-、-CH(CH3) -O-or-C (CH)3)2-O-；
k: 1 or 2;
l: 0. 1 or 2;
R4：H、C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
and in the presence of X: -CH2-or-CH (CH)3) -in the case of
R4: further represents a 4-6-membered heterocyclic group;
and in the presence of X: - (CH)2)l-or-CH (CH)3) -in the case of
R4: further represents CN;
or
X together with R4Together connected via a ring carbon to form a 4-6 membered heterocyclyl;
m: 1 or 2;
n: 1 or 2;
ar: 6-10-membered aryl or 5-10-membered heteroaryl,
R3: halogen, CN, SF5、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C4-C6Heterocyclyl radical, O-C1-C4Alkyl, O-C3-C6Cycloalkyl, O-C4-C6Heterocyclic radical, S-C 1-C4Alkyl, S (O)2-C1-C4Alkyl, Ar ', O-Ar', C (CH)3)2-CN or C (CH)3)2-OH；
Ar': optionally mono-or disubstituted 6-membered aryl or 5-6 membered heteroaryl;
wherein the substituent is selected from F, Cl, CN, C1-C4Alkyl, O-C1-C4Alkyl, C (CH)3)2-CN、C(CH3)2OH and C (O) NH2；
Which overcomes the known disadvantages and has improved properties such as good in vivo activity, good solubility and stability.
The compounds of the present invention have the same effect on EP2Antagonism of the receptor and is therefore particularly useful in female contraception.
C1-C2Alkyl or C1-C4Alkyl is understood to mean in each case a linear or branched alkyl radical, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
The alkyl group may be optionally mono-or poly-substituted with fluorine.
The hydrogen atom may optionally be replaced by deuterium.
C1-C2Alkoxy or C1-C4Alkoxy is understood to mean a straight-chain or branched radical of the formula alkyl-O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.
The alkoxy group may be optionally mono-or poly-substituted with fluorine.
C3-C6Cycloalkyl is understood to mean monocycloalkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The cycloalkyl group may be optionally mono-or poly-substituted with fluorine.
4-6-membered heterocyclyl is understood to mean one or more heteroatoms such as oxygen, sulphur and/or nitrogen which comprise an alternative carbon atom or a group such as-S (O) -or-SO2-a single ring of a hetero group. The linkage may be at any carbon atom or at a nitrogen atom.
For example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1, 4-diazepanyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1, 4-dioxanyl, and 2-oxooxazolidinyl may be mentioned.
The heterocyclyl group may be optionally mono-or polysubstituted by fluorine, hydroxy, methoxy or by oxo.
Halogen is to be understood as meaning in each case fluorine, chlorine, bromine or iodine.
C6-C10The aryl radicals contain in each case 6 to 10 carbon atoms and may be benzo-condensed. Mention may be made of phenyl and naphthyl.
Said C is6-C10-a meta aryl group may be optionally mono-substituted with fluorine, chlorine or methyl.
C5-C10Heteroaryl is understood to mean monocyclic or bicyclic ring systems which each contain 5 to 10 ring atoms and may contain one or more identical or different heteroatoms such as, for example, oxygen, sulfur or nitrogen instead of carbon atoms. The linkage may be at any carbon atom or at a nitrogen atom.
For example, thienyl, thiazolyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, phthalyl, thiophthalyl (thiophthalidyl), indolyl, isoindolyl, indazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, azocinyl (azocinyl), indolizinyl, purinyl, isoquinolyl, quinolyl, quinolizinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1, 7-naphthyridinyl or 1, 8-naphthyridinyl and pteridinyl may be mentioned.
Said C is5-C10-membered heteroaryl may be optionally mono-substituted by fluorine, chlorine or methyl.
Physiologically compatible salts of organic and inorganic acids are suitable if basic functional groups are included, such as, inter alia, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid and tartaric acid.
Preferred are compounds of formula I and isomers, diastereomers, enantiomers, and salts thereof or cyclodextrin inclusion complexes thereof, wherein
R1、R2: represents H or methyl;
with the proviso that two radicals R 1Or R2One of them is H;
X：-(CH2)l-or- (CH)2)k-O-；
k: 1 or 2;
l: 0. 1 or 2;
R4：C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
m、n：2；
and R is3Ar and Ar' have the aforementioned meanings.
Also preferred are compounds of formula I and isomers, diastereomers, enantiomers, and salts thereof, or cyclodextrin inclusion complexes thereof, wherein
R1、R2: represents H or methyl;
with the proviso that two radicals R1Or R2One of them is H;
X：-(CH2)l-or- (CH)2)k-O-；
k: 1 or 2;
l: 0. 1 or 2;
R4：C1-C4alkyl, -C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
m、n：1；
and R is3Ar and Ar' have the aforementioned meanings.
Also preferred are compounds of formula I and isomers, diastereomers, enantiomers, and salts thereof, or cyclodextrin inclusion complexes thereof, wherein
R1: represents a methyl group;
R2：H；
X：-(CH2)l-or- (CH)2)k-O-；
k：1；
l: 0 or 1;
R4：C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
m、n：2；
ar: a phenyl group;
and R is3And Ar' has the aforementioned meaning.
Also preferred are compounds of formula I and isomers, diastereomers, enantiomers, and salts thereof, or cyclodextrin inclusion complexes thereof, wherein
R1: represents a methyl group;
R2：H；
X：-(CH2)l-or- (CH)2)k-O-；
k：1；
l: 0 or 1;
R4：C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
m、n：1；
ar: a phenyl group;
and R is3And Ar' has the aforementioned meaning.
The following compounds of the invention are very particularly preferred:
1.2- { [1- (4-cyano-2-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
2- { [1- (4-tert-Butoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
3.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4-morpholinobenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
5.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
6.2- { [1- (2-fluoro-4-methanesulfonylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
7.2- { [1- (2-fluoro-4-methoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
2- { [1- (4-bromo-2-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
9.2- { [1- (2-fluoro-4-methylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
10.2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
13.2- ({1- [4- (4-chlorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (4-methylphenoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
15.2- ({1- [4- (4-tert-butylphenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -2- ({1- [4- (4-methoxyphenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4-phenoxybenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
19.2- { [1- (4-cyclopropylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
20.2- { [1- (4-methoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
21.2- { [1- (4-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
23.2- { [1- (2-methoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [ (trifluoromethyl) sulfonyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [3- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (3-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
27.2- { [1- (3-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
28.2- ({1- [4- (4-carbamoylphenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
29.2- ({1- [4- (cyclopentyloxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
30.2- ({1- [4- (difluoromethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
31.2- { [1- (4-cyanobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
32.2- ({1- [4- (1H-imidazol-1-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (oxazol-2-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (oxazol-5-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (isoxazol-5-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (1H-pyrazol-1-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (1H-1,2, 4-triazol-1-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
38.2- ({1- [4- (difluoromethoxy) -2-fluorobenzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
39.2- ({1- [ 2-fluoro-4- (pyrrolidin-1-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
40.2- ({1- [ (3,4' -difluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
41.2- ({1- [ (3-fluoro-4' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
42.2- ({1- [ (3-fluoro-4' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
43.2- [ (1- { [ 3-fluoro-3' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
44.2- [ (1- { [ 3-fluoro-2' - (trifluoromethoxy) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
45.2- ({1- [ (2' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
46.2- ({1- [ (2',4' -difluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
47.2- ({1- [ (2-fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [ (2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (4-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (4H-1,2, 4-triazol-4-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
51.2- { [1- (2-fluoro-4-morpholinobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
52.2- { [1- (4-bromobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
53.N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
54.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
56.4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
57.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
58.4-methyl-N- (2,2, 2-trifluoroethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
59.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
61.N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
63.N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
64.2- { [1- (4-cyclopropylbenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
65.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
67.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
68.4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
69.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
70.2- { [1- (4-cyclopropylbenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
71.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-Isopropoxyethyl) -4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
73.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-Isopropoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
75.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
76.2- { [1- (4-Cyclopropylbenzoyl) piperidin-4-yl ] methyl } -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
77.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
78.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
79.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
N- (2-tert-butoxyethyl) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
82.N- (2-tert-butoxyethyl) -2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-tert-butoxyethyl) -2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-tert-butoxyethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
85.2- { [1- (4-chlorobenzoyl) piperidin-4-yl]Methyl } -4-methyl-N- {2- [ ((s))2H3) Methoxy radical]-(2H4) Ethyl } -2H-indazole-5-carboxamide
86.2- ({1- [4- (4-fluorophenoxy) benzoyl]Piperidin-4-yl } methyl) -4-methyl-N- {2- [ (A)2H3) Methoxy radical](2H4) Ethyl } -2H-indazole-5-carboxamide
87.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
88.N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
89.N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
90.2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
91.2- { [1- (4-chloro-2-fluorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
92.2- ({1- [ 3-fluoro-4- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
93.2- ({1- [ 4-chloro-3- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
94.2- { [1- (4-cyclopropylbenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
95.N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
96.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
97.4-methyl-N- (2,2, 2-trifluoroethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
98.2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
99.4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
N- [2- (Cyclopropoxy) ethyl ] -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
N- [2- (cyclobutoxy) ethyl ] -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
102.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2- { [1- (4-methylbenzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
105.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
N- (2-tert-butoxyethyl) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
108.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
109.2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
110.2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
111.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
112.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
113.4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
114.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
115.2- ({1- [4- (4-chlorophenoxy) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
116.2- ({1- [4- (4-chlorophenoxy) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
118.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
119.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N-ethyl-4-methyl-2H-indazole-5-carboxamide
120.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
121.2- ({1- [4- (4-chlorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
122.4-methyl-2- ({1- [4- (methylphenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
123.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
4-methyl-2- { [1- (4-morpholinobenzoyl) piperidin-4-yl ] methyl } -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
125.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
126.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
127.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
128.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [6- (trifluoromethyl) pyridin-3-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
129.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [6- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
130.2- ({1- [4- (4-cyanophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
131.2- ({1- [4- (3-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
132.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [3- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
133.2- [ (1- {4- [ (5-cyanopyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
134.2- [ (1- {4- [ (5-chloropyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [5- (trifluoromethyl) pyridin-2-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
136.2- ({1- [4- (2, 4-Difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
137.2- ({1- [4- (3, 4-Difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
138.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- { [4' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
139.2- { [1- (4-bromobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
140.2- ({1- [4- (5-Chloropyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
141.2- ({1- [ (4 '-methoxy-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
142.4-methyl-2- ({1- [4- (6-methylpyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
143.2- ({1- [ (4 '-fluoro-2' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
144.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [6- (trifluoromethyl) pyridin-3-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
145.2- ({1- [4- (6-methoxypyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
146.2- ({1- [4- (6-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
147.4-methyl-2- ({1- [4- (5-methylpyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
148.2- ({1- [4- (5-Fluoropyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
149.2- ({1- [4- (5-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
150.4-methyl-2- ({1- [4- (2-methylpyrimidin-5-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
151.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [2- (trifluoromethyl) pyrimidin-5-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
152.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [6- (trifluoromethyl) pyridin-2-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
153.2- ({1- [4- (4-cyanophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
154.2- { [1- (4-bromo-3-methylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
155.2- { [1- (4-tert-butylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
156.2- ({1- [4- (1-hydroxy-1-methylethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
157.2- { [1- (4-cyclohexylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
158.2- ({1- [4- (1-cyano-1-methylethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
159.N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (pyrimidin-2-yloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (3-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (2-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [4- (trifluoromethyl) pyrimidin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [6- (trifluoromethyl) pyridin-3-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [6- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
166.2- ({1- [ (4' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (3,4,5, 6-tetrahydro-2H-pyran-4-yloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [3- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
169.2- [ (1- {4- [ (5-cyanopyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -N- (2-methoxy-2-ethyl) -4-methyl-2H-indazole-5-carboxamide
170.2- [ (1- {4- [ (5-Chloropyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -N- (2-methoxy-2-ethyl) -4-methyl-2H-indazole-5-carboxamide
171.2- ({1- [4- (2, 4-difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
172.2- ({1- [4- (3, 4-Difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- { [4' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
174.2- ({1- [4- (3-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
175.2- { [1- (2-fluoro-4-isopropoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
176.2- ({1- [ (3-fluoro-3 ',4' -dimethylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
177.2- ({1- [ (2', 3-difluoro-4' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
178.2- ({1- [4- (difluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
179.2- ({1- [4- (2-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
180.2- ({1- [ (4 '-cyano-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
181.2- ({1- [4- (5-Chloropyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [6- (trifluoromethyl) pyridin-2-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -2- ({1- [ (4 '-methoxy-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
184.2- ({1- [ (4 '-chloro-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
185.2- [ (1- { [4' - (1-cyano-1-methylethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -2- ({1- [4- (5-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [6- (trifluoromethyl) pyridin-3-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -2- ({1- [4- (6-methoxypyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
189.2- ({1- [ (4 '-fluoro-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (6-methylpyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
191N- (2-methoxyethyl) -2- ({1- [4- (6-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (2-methylpyrimidin-5-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
193.2- ({1- [ (4 '-fluoro-2' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
194.2- ({1- [ (4 '-chloro-2' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
195N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [2- (trifluoromethyl) pyrimidin-5-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
196.2- ({1- [ (4 '-chloro-2' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
197.2- ({1- [ (2 '-chloro-4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
198.2- ({1- [4- (5-chloropyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
199.2- ({1- [4- (5-fluoropyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [5- (trifluoromethyl) pyridin-3-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
201.2- [ (1- { [4' - (1-hydroxy-1-methylethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
202.2- ({1- [ (3',5' -difluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
203.2- ({1- [ (4 '-fluoro-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
204.2- ({1- [ (3',5' -difluoro-2-methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [ 3-methyl-4- (3-pyridyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [ 3-methyl-4- (4-pyridyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
N- (2-methoxyethyl) -4-methyl-2- ({1- [ (2-methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
The subject of the present invention is the use of the compounds of the invention for the preparation of a medicament comprising at least one compound of formula I.
The invention also relates to medicaments containing the compounds according to the invention and suitable formulation and carrier substances.
With known prostaglandin EP2These new EP's in comparison with antagonists2Antagonists are characterized by improved properties, such as better availability and stability.
The subject of the present invention is a medicament for birth control/contraception and a medicament for the treatment and prevention of diseases including infectious diseases, cancer, cardiovascular diseases, angiogenic diseases, uterine contractile disorders, pain, inflammatory diseases, neuroinflammatory diseases, neurodegenerative diseases, autoimmune diseases, immune-dependent diseases/therapies, renal diseases and ophthalmic diseases.
Infectious diseases are understood as meaning diseases which are induced by unicellular parasites, for example of the genus Klebsiella or Streptococcus. For infectious diseases, the drug may have an immunomodulatory effect in order to treat the disease either prophylactically (reducing the risk of infection, e.g. in bone marrow transplantation) or therapeutically. Cancer is understood to mean solid tumors and leukemias; viral infections such as cytomegalovirus infection, hepatitis b and c, and HIV disease; cardiovascular disease, ischemia-reperfusion disease, stenosis, arteriosclerosis, restenosis, arthritis, kawasaki syndrome, and aneurysm; angiogenic diseases such as endometriosis and fibroid myoma in the uterus; uterine contractility disorders, such as menstrual problems; pain, such as inflammatory hyperalgesia and arthritis, inflammatory diseases, such as inflammatory bowel disease; neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, alzheimer's disease, parkinson's disease, ALS, and stroke; immune-dependent diseases/therapies, such as transplantation where immunomodulation increases the success of the treatment; autoimmune diseases, such as the ophthalmological disease graves' disease, and also the renal disease polycystic kidney disease and glomerulonephritis.
The invention also relates to medicaments for the treatment and prophylaxis of the abovementioned diseases, which comprise at least one compound of the general formula I and which have suitable formulations and carrier substances.
For the use of the compounds of the invention as medicaments, these compounds are converted into the form of pharmaceutical preparations which, in addition to the active substance, comprise pharmaceutically acceptable, organic or inorganic inert carrier materials suitable for enteral or parenteral administration, for example water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. The pharmaceutical formulations may be in solid form (e.g. as tablets, coated tablets or capsules), semi-solid form (e.g. as ointments, creams, gels or suppositories) or liquid form (e.g. as solutions, suspensions or emulsions).
They optionally contain additives, which are intended, for example, to act as fillers, binders, disintegrants, lubricants, solvents, solution media, taste masking agents, colorants or emulsifiers. In the sense of the present invention, the types of additives are, for example, sugars (mono-, di-, tri-, oligo-and/or poly-sugars), fats, waxes, oils, hydrocarbons, anionic, nonionic, cationic, natural, synthetic or semisynthetic surfactants. In addition, they optionally contain additives such as preservatives, stabilizers, wetting agents or emulsifiers; salts for varying the osmotic pressure, or buffers.
These pharmaceutical preparations are also the subject of the present invention.
For inhalation, it is advantageous to prepare an aerosol solution or other suitable solid substance formulation for inhalation.
For oral use, tablets, coated tablets or capsules with talc and/or hydrocarbon carriers or binders (e.g. lactose, corn starch or potato starch) are particularly suitable. It can also be used in liquid form, for example in the form of a syrup, to which a sweetener is optionally added. Likewise, for the oral use of such compounds, inclusion complexes are also suitable, for example inclusion complexes with alpha-, beta-or gamma-cyclodextrins or other beta-hydroxypropyl cyclodextrins may be mentioned.
For parenteral administration, sterile injectable aqueous or oleaginous solutions are used. Injection solutions or suspensions are particularly suitable, especially aqueous solutions of the active compounds in polyethoxylated castor oil.
For vaginal administration, for example suppositories, tampons, gels, foams or intra-uterine pessaries are suitable and commonly used.
For intra-articular injection, a suitably prepared crystal suspension may be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot formulations can be used.
For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments for systemic and topical treatment.
For pulmonary administration of the novel compounds, these compounds can be used in aerosol and inhalation formulations.
For topical use in the eye, external auditory canal, middle ear, nostrils and paranasal sinuses, the novel compounds can be used in suitable pharmaceutical preparations in the form of drops, ointments and tinctures.
Formulations in the form of gels, ointments, fatty ointments, creams, pastes, powders, lotions (milk), and tinctures may be used for topical application. The dosage of the compounds of formula I in these preparations should be 0.01% to 20% in order to achieve sufficient pharmacological effect.
The dosage of the active substance may vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated and similar factors. Treatment may be effected by a single administration or by multiple administrations over a longer period of time. The daily dose is 0.5 to 1000mg, preferably 50 to 200mg, and the dose may be administered in a single dosage form for single administration, or divided into 2 or more daily doses.
As carrier system, use can be made of surface-active additives, for example salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or fractions thereof.
The formulations and statements mentioned above are also subject matter of the present invention.
Administration of the compounds of the present invention can be accomplished by any conventional means, including orally and parenterally (e.g., by subcutaneous or intramuscular injection), as well as by various inhalation techniques. Enteral, parenteral, vaginal, intrauterine and oral administration are also subjects of the present invention.
Compounds of the invention of the general formula I and EP2The receptors bind and have an antagonistic effect. This antagonism can be determined by antagonism assays (see example 1.2.1 of the biological examples).
Antagonists are understood to mean molecules which bind to their appropriate receptor and inhibit the initiation of a signaling pathway coupled to said receptor by a naturally occurring ligand. Typically, an antagonist competes with the receptor's naturally occurring ligand for binding to the receptor. However, other alterations to the receptor (e.g., noncompetitive spatial alteration of the receptor) are also possible with molecules that prevent activation of the signaling pathway coupled to the receptor by naturally occurring ligands.
More preferably, antagonists reversibly bind to their corresponding receptors.
EP as compared to any other EP receptor2Receptor antagonist pair EP2The receptors have a preferential affinity. In natural agonists (PGE) 2) Measuring antagonism in the presence of.
For the determination of selectivity, EP can be determined2Antagonists on human EP4The effects of the receptor (example 2.2.1) or the PGD receptor (example 3.2.1) (Table 1).
Furthermore, the substances according to the invention are compatible with EP's described in the closest prior art (DE 102009049662A 1)2The receptor antagonist is more stable in vivo than in vivo, and this results in a higher half-life (see table 3).
The subject of the invention is also the substances according to the invention as EP2Use of receptor antagonists for the treatment of diseases caused by EP2Use of a disease resulting from a disorder of the signal transduction chain of a receptor, such as pain and fertility disorders. The EP2Receptor antagonists are also suitable for birth control.
In the pre-ovulatory antral follicle, the oocyte is surrounded by cumulus cells, which form a compact cell crown around the oocyte. After the luteinizing hormone peak (LH-peak), a series of processes is initiated, which results in a significant morphological change of the cell corona of the cumulus cell. During this time, cumulus cells form an extracellular matrix, which leads to the so-called cumulus expansion (Vanderhyden et al, 1990, Dev biol., Aug; 140(2): 307-317). This cumulus expansion is an important component of the ovulation process and the subsequent possibility of fertilization.
Prostaglandin and prostaglandin E therein during cumulus expansion2Of decisive importance is the synthesis of which is induced by the LH surge. Prostaglandin EP2Knockout mice (Hizaki et al, 1999, Proc Natl Acad Sci U S A., Aug 31; 96(18):10501-6.) exhibited significantly reduced cumulus expansion and severe fertility decline, suggesting prostaglandin EP2The importance of the receptor to this process.
EP2The effect of antagonists on cumulus expansion can be measured in a cumulus expansion assay (see example 4.2).
The substances of the invention have an inhibitory effect in the cumulus expansion test and have an influence on the fertilization ability of the ovulated cumulus-oocyte complexes (see example 4.3 and table 4). The substances of the invention have a contraceptive effect in non-human primates (cynomolgus monkeys), where they lead to a significantly reduced conception rate without an effect on the cycle (cycle length and hormones) (see example 4.4 and table 5). This first indicates EP2Contraceptive effect of receptor antagonists in non-human primates. This effect is based on a non-hormonal mechanism, which illustrates the possibility of hormone-free contraception with the substances of the invention.
The subject of the invention is the use of the substances of the invention for birth control.
Despite EP2The receptor antagonist AH6809 inhibited cumulus expansion only by about 30% first at a concentration of 100-200. mu.M, but according to example 17, in the presence of the substances of the invention, an inhibition of cumulus expansion of about 70% was already able to be achieved at a concentration of 100-200 times lower (0.5. mu.M; IC)50: 3.4nM, seeTable 1). In these experiments, the test substances were compared with natural EP2Receptor agonist PGE2(0.3. mu.M) Competition.
By administering the substance of example 62 of patent application DE102009049662A1, it is likewise possible to achieve approximately 70% inhibition of cumulus expansion, for which, however, a concentration of 10. mu.M is required, which is 10-20 times lower than AH 6809. However, this is significantly higher than the concentration of 0.5 μ M of example 17 of the present invention (see table 2).
Inventive example 17 of this application is also characterized by a better terminal half-life. Although example 62 of patent application DE102009049662A1 had a t of 0.4 h1/2But for example 17 it was 2.5 hours (see table 3).
Thus, substance 17 of the present invention is significantly superior to such compounds known in the prior art.
The subject of the invention is the use of the substances of the invention for inhibiting cumulus expansion and thus ovulation and fertilization for contraception.
A particular form of contraception is emergency protection (also known as "next morning contraceptive pill"). This is understood to mean the administration of one or more substances intended to prevent possible pregnancy after unprotected sexual intercourse and in the event of possible failure of the protection method.
The subject of the invention is the use of the substances according to the invention for emergency protection.
The subject of the invention is also the substances according to the invention as EP2Use of receptor antagonists for prophylaxis and direct treatment of EP2Diseases in which the receptor is causally linked or by affecting EP2The use of the receptor for the treatment of a disease.
Prostaglandins play an important role in angiogenesis (Sales, Jabbour,2003, reproduction126, 559-567; Kuwano et al, 2004, FASEB j.18, 300-310; Kamiyama et al, 2006, oncogene25, 7019-7028; Chang et al, 2005, prostagladins & other Lipid Mediators76, 48-58).
Endometriosis is a chronic disease in which inflammatory, immunoregulatory and angiogenic processes are involved. Prostaglandins, particularly PGE, among other factors2And EP2Receptors are of particular importance (Banu et al, 2009, molecular Endocrinology 23: 1291-Bulun 1305; Bulun2009, N Engl J Med; 360, 268-279).
About 10% of women regularly experience severe bleeding during menstruation, which is induced by vascular changes in the endometrium. In addition, structural differences in blood vessels have been observed, such as incomplete formation of smooth muscle layers (Abberton et al, 1999, hum. reprod.14,1072-1079, Rogers et al, 2003, Microsc Res Tech.60(4), 412-. Since blood loss during menstruation is regulated in part by vasoconstriction, it is evident that defects in smooth muscle tissue substantially promote bleeding.
The subject of the present invention is the use of substances of the general formula I for the prevention and treatment of endometriosis.
Prostaglandins play an important role in uterine contractions, and too strong contractions lead to menstrual problems (Sales, Jabbour,2003, reproduction126, 559-567). Prostaglandins and in particular EP2And EP4Receptors have been implicated in severe menstrual bleeding (Smith et al, 2007(Human Reproduction, Vol.22, No. 5pp.1450-1456).
The subject of the present invention is the use of substances of the general formula I for the prevention and treatment of menstrual problems and severe menstrual bleeding and menstrual pain.
Fibroids (myomas) are benign tumors with high diffusion rates in the uterus. By PGE2The cAMP-mediated signaling pathway stimulates aromatase and, by other possible mechanisms, is associated with prostaglandin metabolism (Imir et al, 2007, JClin Endocrinol Metab92, 1979-1982).
The subject of the present invention is the use of substances of general formula I for the prevention and treatment of fibroids (myomas).
The increasing number of research results also confirm EP receptors, in particular EP2The importance of receptors in a variety of cancer types (e.g., breast, colon, lung, prostate, leukemia, and skin cancer) indicates EP 2Future possibilities for the use of modulators (antagonists or agonists) of receptors for the treatment and prevention (prophylactic and/or adjuvant) of Cancer (Fulton et al, 2006, Cancer Res; 66 (20): 9794-7; Castellone et al, 2005, Science Vol310, 1504-1510; Chang et al, 2005, Cancer Res; 65 (11): 4496-9); hull et al, 2004, Mol Cancer Ther; 3, (8) 1031-9; richards et al, 2003, J Clin Endocrinol Metab 88: 2810-2816; sinha et al, 2007, Cancer Res; 67(9): 4507-13; wang et al, 2004, sensiars in Oncology, Vol31, No1, Suppl 3: pp64-73), Yu et al, 2008; JPET was published as DOI 10.1124/jpeg.108.141275 on 26.6 months, Denizot et al, 2005, int.J. cancer: 115,499-501; fiancette et al, 2011, J oncol. 389021, Chun et al, 2011, Mol Carcinog.50(6): 439-48).
The subject of the invention is the use of substances of the general formula I for the treatment and prophylaxis of cancer diseases.
The activation of endothelial cells plays an important role in the pathological process of arteriosclerosis. Among them, oxidation products of low-density lipoprotein (LDL) are significant in the onset and development of arteriosclerotic diseases. Recent investigations have pointed out EP2Participation of the receptor (Li et al, 2006; Circ Res.98: 642-650).
The invention relates to the use of substances of the general formula I for the treatment and prophylaxis of arteriosclerosis.
Recent scientific publications indicate prostaglandins and EP in neurodegenerative, neuroinflammatory and ischemic diseases (Alzheimer's, Parkinson's, ALS and stroke)2Receptors are important components of pathological processes (Hoshino et al, 2007, J Biol chem.; 282 (45): 32676-88; Liang et al, 2005, The Journal of neuroscience; 25 (44): 10180-.
Multiple sclerosis is a chronic inflammation of the nervous system. Prostaglandins, especially PGE2And by EP2Receptor-mediated effects have a causal relationship with the pathological course of multiple sclerosis (Palumbo et al, 2011, Prostagladins, Leukotrienes and Essential Fatty Acids 85: 29-35; Palumbo et al, 2011, J.Neurochem.10.1111/j.1471-4159, Kihara et al, 2009, Proc Natl Acad Sci U.S.A.106, No. 51: 21807-21812).
The subject of the present invention is the use of substances of the general formula I for the treatment and prophylaxis of neurodegenerative, neuroinflammatory and ischemic diseases, such as Alzheimer's, Parkinson's, ALS and stroke, and for the treatment of multiple sclerosis.
Polycystic kidney disease is also associated with EP2Receptor association (Song et al, 2009, Human Molecular Genetics,18, No. 13: 2328-2343; Elberg et al, 2007, Am J Physiol Renal Physiol 293: F1622-F1632.).
The subject of the present invention is the use of substances of the general formula I for the treatment and prevention of polycystic kidney disease.
Reinold et al (J.Clin.invest.115,673-679(2005)) describe EP2PGE of subtype2The receptor acts as an important signaling element for inflammatory hyperalgesia. Mice no longer carrying this receptor (EP)2 -/-) Spinal inflammatory pain was not felt. There are indications that EP can be regulated by specificity2The receptor treats the increased sensitivity to pain of the inflammatory. In addition, EP2Receptors are associated with other types of pain (Zeilhofer,2007, Biochemical Pharmacology 73; 165- & 174), especially facial nerve pain (Patwardhan et al (J Dent Res87(3):262- & 266, 2008)).
The subject of the invention is the use of the substances of the invention for the treatment and prevention of pain of various origins, such as inflammatory hyperalgesia.
The latest scientific publications relate to EP2Use of an inhibitor for the prevention and/or treatment of a respiratory infection. Serezani et al (Am Respir Cell Mol Biol Vol37.pp562-570,2007) describes the passage of PGE 2Activating EP2The receptors impair the ability of respiratory macrophages to destroy bacteria. Bacterial infection leads to prostaglandins, particularly PGE2By which the endogenous defenses against the bacteria are weakened. As shown in this publication, EP's can be prepared by reacting EP' s2Receptors (and EP)4Receptor) to restore this ability to fight bacteria. Other relevant publications that set forth these relationships are: sadikot et al, 2007, eur.j.immunol.37: 1001 — 1009; aronoff et al, 2004, The Journal of immunology, 173: 559 and 565 and Medeeros et al, 2009, J Exp Med.206(1): 61-68.
The subject of the invention is the use of the substances according to the invention for the prophylaxis and treatment of infectious diseases of the lung.
Fibroblasts and in particular their function in the recovery of damaged tissue play a decisive role in chronic obstructive pulmonary disease. During this period, excess PGE2Inhibits the important repair function of fibroblasts (Togo et al, 2008, Am J Respir Crit Care Med, 178: 248-260).
The subject of the invention is the use of the substances according to the invention for the prophylaxis and treatment of chronic obstructive pulmonary disease.
Inflammatory diseases of the intestine (e.g. Crohn's disease) are also associated with prostaglandin EP2Receptor association (Sheibanie et al, 2007, The Journal of Immunology, 178: 8138-8147).
The subject of the present invention is the use of the substances of the invention for the prevention and treatment of inflammatory diseases of the intestine.
Complications often arise through infection during bone marrow transplantation, where PGE2Overproduction of (A) is associated with a reduced immune defense (Ballinger et al, 2006, The Journal of Immunology, 177: 5499-550 8).
The subject of the invention is the use of the substances according to the invention for prophylaxis and therapy in bone marrow transplantation.
Graves' disease is thyroidWherein the clinical manifestations may also include pathological changes of the eye (endocrine orbital disease; exophthalmos (exophthalmos)). During this time, infiltrating lymphocytes activate existing fibroblasts, which leads in particular to the accumulation of mucopolysaccharides. Possible consequences are impaired vision and even spread to blindness. Studies have shown that interleukin-6 is of decisive importance for the pathological mechanisms and that interleukin-6 is mediated by PGE2And EP2Receptor induction (Raychaudhuri et al 2010, PloS ONE, 5: e 15296; Wang et al 1995, J Clin Endocrinol Metab 80: 3553-3560).
The subject of the invention is the use of the substances according to the invention for the prevention and treatment of orbital disorders associated with Graves' disease or other pathological conditions of the eye.
Aneurysms are vasodilators with a risk of the blood vessels breaking down to bleeding, with serious and life-threatening effects in the case of cerebral hemorrhage, such as paralysis, loss or impairment of speech ability, cognitive limitations, and other neurological consequences. Even without rupture, cerebral aneurysms can induce severe neurological symptoms by pressure on nerve fibers. Cerebral aneurysms are found in about 1-5% of the population, with a higher incidence in women. Aneurysm rupture in peripheral blood vessels involves a high risk of thrombosis, myocardial infarction, pain, and a variety of other clinical manifestations. Pharmacological therapy mainly involves limiting risk factors such as hypertension.
Recent scientific studies can indicate EP2Receptors play an important role in the pathogenesis of cerebral aneurysms. In this connection, COX-2-PGE is cascaded2–EP2NF-. kappa.beta.to produce an inflammatory state which is causally associated with aneurysm formation (Aoki et al, 2011, British Journal of Pharmacology 163: 1237-1249; Aoki et al, 2007,116: 2830-2840).
The subject of the invention is the use of the substances according to the invention for the prevention and treatment of aneurysms.
Kawasaki syndrome is an acute generalized febrile disease that affects mainly up to 5 years of age The child below. Long-term injury can include changes in blood vessels, particularly coronary blood vessels (e.g., aneurysm formation) and diseases associated therewith, such as cardiac arrhythmia and myocardial infarction. The incidence varies regionally, so that for example, 100000 children under 5 years old are 185 in japan, and about 9 in 100000 children in germany. Prostaglandin E2Increased in the acute phase of the disease (Lee et al, 1988, Prostagladins Leukot essence Fatty Acids,31(2): 53-57). Recent research studies have shown that β 1 integrin is bound by PGE2Activated and via EP2Receptor-mediated, which is causally linked to vascular injury (Kajimoto et al, 2009, Inflamm. Res.58: 224-228).
The subject of the present invention is the use of the substances of the invention for the prevention and treatment of kawasaki syndrome, in particular for the prevention and avoidance of vascular damage.
Recent investigations have shown that EP2Receptors play an important role in arthritis, and among others, influence the pathogenesis of the disease through immune regulation mechanisms (Harizi et al, 2010, Immunology and Cell Biology, 1-8).
The subject of the invention is the use of the substances according to the invention for the prevention and treatment of arthritis.
EP2The natural ligand (agonist) of the receptor is PGE 2Its synthesis is mediated by the enzyme Cyclooxygenase (COX) enzyme (COX-1, COX-2). These enzymes are primarily involved in the clinical manifestations and their indications and onset via increased expression and activity. Thus, of all the mentioned possibilities of use, combinations of COX inhibitors (COX-2 and/or COX-1) are possible, the purpose of which is to
a) Achieving a higher and more effective pathological activity than using one substance type, and
b) lower doses of one or both substance types are achieved, which leads to a reduction in possible side effects and better tolerability.
Therefore, medicaments (combined preparations) comprising a combination of a compound of general formula (I) with a COX inhibitor for the treatment of diseases are also subject of the present invention. As COX inhibitors, mention may be made, for example, of non-selective COX inhibitors, such as aspirin, naproxen, indomethacin, ibuprofen, and the selective COX inhibitors meloxicam, ketoprofen, piroxicam, tenoxicam, nimesulide, mefenamic acid (mefanomic acid), ketorolac (ketoralac), celecoxib (4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide), parecoxib (N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] propionamide), rofecoxib (4- (4-methylsulfonylphenyl) -3-phenylfuran-2 (5H) -one), valdecoxib (4- [ 5-methyl-3-phenyl-4-isoxazolyl) propanamide) ) Benzenesulfonamide), NS-398 (N-methyl-2-cyclohexyloxy-4-nitrobenzenesulfonamide), lumiracoxib [2- (2 '-chloro-6' -fluorophenyl) amino-5-methylphenylacetic acid ], ceracoxib, and etoricoxib.
These combination preparations are useful for the treatment of the following diseases: infectious diseases, cancer, cardiovascular diseases, angiogenic diseases, uterine contractile disorders, pain, inflammatory diseases, neuroinflammatory diseases, neurodegenerative diseases, autoimmune diseases, immune-dependent diseases/therapies, renal diseases and ophthalmic diseases.
They can also be used for birth control.
Furthermore, the present invention relates to a process for the preparation of the compounds of the invention of the general formula I.
In this connection, for example, carboxylic acids of the formula VIII are reacted with amines of the formula XI by methods known to those skilled in the art to give the compounds of the invention of the formula I (scheme I).
This reaction occurs, for example, because the carboxylic acid of formula VIII is converted to a mixed anhydride with isobutyl chloroformate in the presence of a tertiary amine such as triethylamine, which is reacted with the appropriate alkali metal salt of the amine XI in an inert solvent or mixture of inert solvents such as tetrahydrofuran, N-dimethylformamide or dimethoxyethane at a temperature of-30 ℃ to +60 ℃ to give the target compound of formula I.
The carboxylic acid VIII may also be activated with a reagent such as 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-methylmethanemethylamine Hexafluorophosphate (HATU). For example, the reaction with HATU takes place in an inert solvent such as N, N-dimethylformamide or dimethylsulfoxide, in the presence of a suitable amine XI and a tertiary amine such as triethylamine or diisopropylamine, at a temperature of-30 ℃ to +60 ℃.
The carboxylic acids of formula VIII can also be converted to carboxylic acid chlorides with inorganic acid chlorides such as phosphorus pentachloride, phosphorus trichloride or thionyl chloride and then converted to the target compounds of formula I in pyridine or an inert solvent such as N, N-dimethylformamide in the presence of a suitable amine XI and a tertiary amine such as triethylamine at temperatures of-30 ℃ to +60 ℃.
The compounds of the invention of general formula I can also be obtained from bromoindazoles of general formula VI, catalyzed by palladium (0), by reaction with the appropriate amine XI and carbon monoxide (CO) or a carbon monoxide source such as molybdenum hexacarbonyl, under the conditions described below: in a suitable solvent or solvent mixture such as 1, 4-dioxane/water or tetrahydrofuran, with the addition of a base such as sodium carbonate or 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU) and a catalyst ligand mixture such as palladium (II) acetate or trans bis (acetoxy) bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II)/tri-tert-butylphosphino tetrafluoroborate, at a temperature of from 80 ℃ to 160 ℃ (optionally using microwave radiation of from 80 to 200 watts), and with carbon monoxide, at a CO pressure of from 5 to 15 bar (scheme 1).
It is also possible to use amines of the formula XV by reaction with carboxylic acids of the formula IX (Y ═ OH), chlorides (Y ═ Cl) or anhydrides (e.g. Y ═ O-C (O) -O-CH) 2(CH)3CH3) The compounds of the invention of general formula I are obtained in the manner described for the preparation of compound I from compounds VIII and XI (scheme 2).
Likewise, compounds of general formula I can be obtained from compounds of general formula XVI wherein LG' for example represents Br or I by reaction with compounds of formula XVIII (scheme 2).
Compounds of the formula XVIII are, for example, (hetero) arylboronic acids (R)3-Met ═ (hetero) Ar-B (OH)2) Or boronic acid pinacol ester (R)3-Met ═ Ar-BPin), which is converted into the biaryl compound of formula I by methods known to those skilled in the art, in a suitable solvent such as N, N-dimethylformamide, tetrahydrofuran, dimethoxyethane and optionally water, and with the addition of a base such as triethylamine, potassium carbonate, cesium carbonate and a mixture of catalyst ligands such as palladium (II) acetate/triphenylphosphine, bis (diphenylphosphino) ferrocene palladium (II) dichloride)/(1, 1' -bis (diphenylphosphino) ferrocene/cu (I) Cl), at a temperature of 20 ℃ to 120 ℃.
The compound of the formula XVIII may also be a (hetero) aryl alcohol (R)3-Met ═ ArO-H), which is converted into the biaryl ethers of formula I by methods known to those skilled in the art, in a suitable solvent such as N, N-dimethylformamide or dimethylsulfoxide, with the addition of a base such as potassium carbonate, cesium carbonate, catalyzed by copper (I) such as copper (I) bromide, at temperatures ranging from 60 ℃ to 120 ℃.
Carboxylic acids of the general formula VIII can be formed from the esters of the formula VII by ester saponification in a suitable solvent or solvent mixture such as methanol, ethanol or tetrahydrofuran, water, with addition of an aqueous solution of an alkali metal hydroxide such as sodium hydroxide or lithium hydroxide at temperatures of 20 ℃ to 60 ℃ (scheme 1).
In the same way, carboxylic acid XIII is obtained from ester XII (scheme 2, PG: e.g. Boc (tert-butoxycarbonyl)) and carboxylic acid XXI is obtained from ester XX (scheme 3, LG': e.g. Br or I).
Esters of formula VII can be obtained from bromoindazoles of formula VI by reaction with carbon monoxide or a carbon monoxide source such as molybdenum hexacarbonyl and methanol under palladium (0) catalysis under the conditions described below: in a suitable solvent such as dimethyl sulfoxide, N-dimethylformamide or tetrahydrofuran, and a base such as triethylamine or 1, 8-diazabicyclo (5.4.0) undec-7-ene and a catalyst ligand mixture such as palladium (II) acetate/bis-1, 3-diphenylphosphinopropane or trans bis (acetoxy) bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II)/tri-tert-butylphosphino tetrafluoroborate are added, at a temperature of from 20 ℃ to 140 ℃ (optionally using microwave irradiation at 80-200 watts), and, in the case of carbon monoxide, at a CO pressure of 5-15 bar (scheme 1).
The process is not limited to methyl esters, i.e. to the use of methanol, but can also be extended 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 way, ester XII (scheme 2, -PG: e.g. -Boc) can be obtained from bromide IV.
In analogy to the synthesis of compound I from compound XV (scheme 2), the amides of formula VII can also be obtained from amines of formula XIX by reaction with compounds of formula IX (scheme 3).
Similar to the described conversion of compound XVI to compound of formula I (scheme 2), compounds of general formula VII can also be obtained from compounds of formula XX as well as by reaction with compounds of formula XVIII (scheme 3).
As described for the conversion of amines XV into amides I (scheme 2), it is possible to react amines of the general formula V with carboxylic acids of the formula IX (Y ═ OH), chlorides (Y ═ Cl) or anhydrides (e.g. Y ═ O-c (O)) -O-CH2(CH)3CH3) Reaction to give the amide of formula VI (scheme 1).
In analogy to the reaction of an amine XV with a carboxylic acid or carboxylic acid derivative XVII (Y: e.g. OH, Cl or O-C (O) -O-CH)2(CH)3CH3(ii) a LG': e.g. Br or I), the amides of the general formula XVI can be obtained (scheme 2).
Analogously, it is possible to use amines XIX and carboxylic acids or carboxylic acid derivatives XVII (Y: for example OH, Cl or O-C (O) -O-CH 2(CH)3CH3(ii) a LG': for example Br or I) to obtain the amine XX (LG': example (b)Such as Br or I) (scheme 3).
Likewise, in this manner, carboxylic acids XIII (PG: e.g. Boc) can be converted into amides XIV with amines XI (scheme 2) and carboxylic acids XXI (LG': e.g. Br, I) can be converted into amides XVI with amines XI (scheme 3).
The secondary amines V can be obtained from the corresponding carbamates IV (PG: e.g. Boc) by methods known to the person skilled in the art (scheme 1).
Thus, for example, tert-butyl carbamate can be converted to amine V in an acidic medium in a suitable solvent or solvent mixture such as dichloromethane, dioxane or acetone/water using, for example, trifluoroacetic acid or hydrochloric acid. In an anhydrous medium, the amine V is formed as the corresponding salt.
Similarly, amines XV can be obtained from carbamate XIV (scheme 2), and amines XIX from carbamate XII (scheme 3).
The 2H-indazoles of formula IV and VI can be prepared in various ways.
For example, a 2H-indazole IV can be obtained from a 1H-indazole of formula II by alkylation with a compound of formula III (PG: e.g., Boc, LG: e.g., Br, I, O-Ts (tosyloxy) or O-Ms (mesyloxy)) under the conditions described below: in a suitable solvent such as N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, or THF, 1, 4-dioxane, a solvent such as potassium carbonate or cesium carbonate (optionally with tetrabutylammonium iodide), or sodium bis (trimethylsilyl) amide is added at a temperature of 25 ℃ to 100 ℃, or, in the case of sodium bis (trimethylsilyl) amide, at a temperature of 0 ℃ to 25 ℃ (scheme 1).
Similarly, 2H-indazoles of formula VI can be obtained from 1H-indazoles of formula II and compounds of formula X (LG: e.g., Br, I, O-Ts or O-Ms) (scheme 1).
2H-indazoles of general formula IV can also be obtained from o-nitrobenzaldehydes of general formula XXVII by reaction with the appropriate amine XXVIII (PG: e.g. Boc) under the conditions described below: in a suitable solvent such as 1, 4-dioxane, a reducing agent such as triethyl phosphite is added, optionally with potassium carbonate, cesium carbonate or powdered molecular sieves, at temperatures between 100 ℃ and 160 ℃ (scheme 4).
Similarly, 2H-indazoles of formula VI can be obtained from o-nitrobenzaldehyde XXVII by reaction with amine XXIX (scheme 4).
Similar to the described method for converting bromoindazole VI to compounds of general formula I (scheme 1), compounds of general formula XIV (PG: e.g., Boc) can also be obtained from bromoindazoles of general formula IV (PG: e.g., Boc) by reaction with a suitable amine XI and carbon monoxide or a carbon monoxide source such as, for example, molybdenum hexacarbonyl, under palladium (0) catalysis (scheme 2).
The o-nitrobenzaldehydes of the formula XXVII can be prepared from o-nitrotoluenes of the formula XXVI by methods known to the person skilled in the art in two reaction steps (scheme 4).
For this, the ortho-nitrotoluene XXVI is dissolved in a suitable solvent such as N, N-dimethylformamide and converted with N, N-dimethylformamide dimethyl acetal to the corresponding enamine at a temperature of 100-140 ℃ which is immediately reacted at a temperature of 0 ℃ to 20 ℃ in a suitable aqueous solvent mixture such as water/N, N-dimethylformamide and, optionally with the addition of solvents such as triethylamine, N-diisopropylethylamine, sodium bicarbonate or sodium carbonate, with the aid of a solvent such as NaIO4To the corresponding o-nitrobenzaldehyde.
Ortho-nitrotoluenes of formula XXVI can be prepared from ortho-toluidines of formula XXV by methods known to the person skilled in the art (scheme 4).
To this end, o-methylbenzylamine XXV is dissolved in a suitable solvent such as dichloromethane or chloroform, and the molecular sieve is milled with zirconium (IV) tert-butoxideAnd tert-butyl hydroperoxide and reacting at a temperature of 20-40 ℃.
The 1H-indazole of formula II can be released from the acetamide of formula XXIV by methods known to those skilled in the art (scheme 4).
For this purpose, for example, acetamide XXIV is reacted in a suitable solvent such as methanol or ethanol and with addition of 37% hydrochloric acid at a temperature of 40 to 80 ℃.
Analogously thereto, the aniline of formula XXV can be released from the acetanilide of formula XXIII (scheme 4).
The acetamides of the formula XXIV can be prepared from o-methylacetanilides of the formula XXIII by methods known to the person skilled in the art (scheme 4).
To this end, o-methylacetanilide XXIII is dissolved in a suitable solvent such as chloroform or toluene, treated with acetic anhydride, isoamyl nitrite or tert-butyl nitrite, and optionally treated with potassium acetate and 18-crown-6, and reacted at a temperature of 60 to 100 ℃.
The o-methylacetanilides XXIII (scheme 4) can be prepared from acetanilides of formula XXII by bromination by methods known to those skilled in the art.
For this purpose, acetanilide XXII, which can be obtained, for example, from the corresponding aniline by reaction with acetic anhydride in a suitable solvent (for example toluene) at temperatures of from 80 to 110 ℃, is reacted with bromine in glacial acetic acid at temperatures of from 10 to 25 ℃.
Compounds of the formula III in which LG represents-OTs or-OMs can be prepared from the corresponding alcohols by methods known to the person skilled in the art.
To this end, the alcohol is reacted with p-toluenesulfonyl chloride or methanesulfonyl chloride at a temperature of 0 ℃ to 40 ℃, in a suitable solvent such as dichloromethane, tetrahydrofuran or toluene and with the addition of a suitable base such as pyridine or triethylamine.
Compounds of formula X wherein LG represents-OTs or-OMs can be prepared from the corresponding amino alcohols XXX by methods known to those skilled in the art (scheme 4).
To this end, in a first step, in a suitable solvent such as dichloromethane, the reaction is carried out with a compound of formula Cl-C (O) -Ar-R3And a suitable base such as triethylamine is added to convert amino alcohol XXX to the corresponding amide XXXI at a temperature of from 0 ℃ to 25 ℃. Optionally, the corresponding ester formed as a by-product may be isolated or saponified to the corresponding alcohol XXXI under standard conditions, for example using a base such as potassium hydroxide in a suitable solvent mixture such as ethanol/water at a temperature of 20 ℃ to 40 ℃.
Analogously to the process described for the synthesis of compound III, the N-protected alcohol XXXI thus obtained can be converted into a compound of formula X, wherein LG: -OTs or-OMs. Can be prepared from the corresponding alcohol XXXI by methods known to those skilled in the art, by reaction with e.g. CBr4In the presence of PPh as an oxophilic (oxyphile) compound3In a suitable solvent such as chloroform at a temperature of from 20 ℃ to 40 ℃ to obtain a compound of formula X, wherein LG: -Br.
The compounds of the general formula XXIX can be prepared by methods known to those skilled in the art, for example from amines of the formula XXXII (scheme 4).
To this end, in a first step, the amine XXXII is converted into the corresponding amide XXXIII, analogously to the synthesis of compound I from compound XV.
The compound of formula xxxix can be obtained by cleaving tert-butoxycarbonyl group in the compound of formula XXXIII in analogy to the conversion of compound IV into compound V.
Preparation of the Compounds of the invention
The following examples illustrate the preparation of the compounds of the invention of general formula (I) without limiting the scope of the claimed compounds to these examples.
The compounds of the invention of general formula (I) may be prepared and characterized as described below.
LC-MS: waters Acquity HPLC/MS100-800 daltons; 20V (Micromass/Waters ZQ 4000); column: BEHC18(Waters), 2.1X 50mm, BEH1.7 μm; mobile phase: a: h2O/0.05％HCOOH,B：CH3CN/0.05% HCOOH. Gradient: 10-90% of B in 1.7min, keeping 90% of B for 0.2min, and 98-2% of B in 0.6 min; flow rate: 1.3ml/min, detection: UV 200-400 nm.
Chiral HPLC separation method a:
preparative chiral HPLC: the system comprises the following steps: dionex: pump P580, Gilson: liquid Handler215, Knauer: UV Detector K-2501 column: chiralpak AD-H5 μm 250X 20 mm; solvent: hexane/ethanol 50: 50; flow rate: 15 ml/min; sample introduction: 0.5 ml; and (3) detection: UV254 nm.
Analytical chiral HPLC: the system comprises the following steps: waters: alliance2695, DAD996, ESA: (ii) Corona; column: chiralpak AD-H5 μm 150X 4.6 mm; solvent: hexane/ethanol 50: 50; flow rate: 1.0 ml/min; temperature: 25 ℃; sample introduction: 5 mu l of the solution; and (3) detection: DAD254 nm.
Chiral HPLC separation method B:
preparative chiral HPLC: the system comprises the following steps: dionex: pump P580, Gilson: liquid Handler215, Knauer: UV detector K-2501; column: chiralpak IC5 μm 250X 30 mm; solvent: ethanol/methanol 50: 50; flow rate: 30 ml/min; sample introduction: 0.5 ml; and (3) detection: UV254 nm.
Analytical chiral HPLC: the system comprises the following steps: waters: alliance2695, DAD996, ESA: (ii) Corona; column: chiralpak IC5 μm 150X 4.6 mm; solvent: ethanol/methanol 50: 50; flow rate: 1.0 ml/min; temperature: 25 ℃; sample introduction: 5 mu l of the solution; and (3) detection: DAD254 nm.
Chiral HPLC separation method C:
preparative chiral HPLC: the system comprises the following steps: dionex: pump P580, Gilson: liquid Handler215, Knauer: UV detector K-2501; column: chiralpak AD-H5 μm 250X 20 mm; solvent: hexane/2-propanol 50: 50; flow rate: 15 ml/min; sample introduction: 0.25 ml; and (3) detection: UV254 nm.
Analytical chiral HPLC: the system comprises the following steps: waters: alliance2695, DAD996, ESA: (ii) Corona; column: chiralpak AD-H5 μm 150X 4.6 mm; solvent: hexane/2-propanol 50: 50; flow rate: 1.0 ml/min; temperature: 25 ℃; sample introduction: 5 mu l of the solution; and (3) detection: DAD254 nm.
Chiral HPLC separation method D:
preparative chiral HPLC: the system comprises the following steps: dionex: pump P580, Gilson: liquid Handler215, Knauer: UV detector K-2501; column: chiralpak IB5 mu m 250X 20 mm; solvent: hexane/ethanol 70: 30; flow rate: 20 ml/min; sample introduction: 0.1 ml; and (3) detection: UV210 nm.
Analytical chiral HPLC: the system comprises the following steps: waters: alliance2695, DAD996, ESA: (ii) Corona; column: chiralpak IB5 μm 150X 4.6 mm; solvent: hexane/ethanol 70: 30; flow rate: 1.0 ml/min; temperature: 25 ℃; sample introduction: 5 mu l of the solution; and (3) detection: DAD230 nm.
Chiral HPLC separation method E:
preparative chiral HPLC: the system comprises the following steps: dionex: pump P580, Gilson: liquid Handler215, Knauer: UV detector K-2501; column: chiralpak IC5 μm 250X 20 mm; solvent: ethanol/methanol 50: 50; flow rate: 15 ml/min; sample introduction: 0.3 ml; and (3) detection: UV230 nm.
Analytical chiral HPLC: the system comprises the following steps: waters: alliance2695, DAD996, ESA: (ii) Corona; column: chiralpak IC5 μm 150X 4.6 mm; solvent: ethanol/methanol 50: 50; flow rate: 1.0 ml/min; temperature: 25 ℃; sample introduction: 5 mu l of the solution; and (3) detection: DAD230 nm.
Abbreviations
Boc tert-butoxycarbonyl
CO 2
DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene
DCM dichloromethane
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
ESI; ES + electrospray ionization (in MS); positively charged ion tracing
hr(s) hours
HATU N- [ (dimethylamino) -1H-1,2, 3-triazolo [4,5-b ] pyridin-1-ylmethylene ] -N-methylmethanemethanemethanamine hexafluorophosphate N-oxide
HPLC high pressure high performance liquid chromatography
conc. concentrated
LC-MS liquid chromatography-mass spectrometry combination
M mol
min(s) min
MS Mass Spectrometry
N normal
NMR nuclear magnetic resonance spectrum
RtRetention time (in HPLC and LC)
RT Room temperature
tert
THF tetrahydrofuran
Example 1: 2- { [1- (4-cyano-2-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
To a solution of 33.7mg 4-cyano-2-fluorobenzoic acid in 1.0ml dimethyl sulfoxide were added 85.5mg HATU, 75mg of the amine prepared in example 1a and 0.071ml N, N-diisopropylethylamine and stirred at 25 ℃ for 1 hour. The mixture was concentrated in vacuo and the residue thus obtained was purified by HPLC. Obtaining: 43.3mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 material for the above-described title compound was prepared as follows.
Example 1 a: n- (2-methoxyethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
To 855.1mg of 1b were added 4.5ml of 4M dioxane hydrochloride solution and 1ml dioxane. An oily substance is formed, which is dissolved with vigorous stirring and mild warming. The mixture was stirred at about 30 ℃ for 1 hour. The reaction mixture was concentrated. Obtaining: 764.7mg of the title compound, which was reacted further without further purification.
1H-NMR(300MHz,DMSO-d6)：[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 1 b: 4- ({5- [ N- (2-methoxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
Mode A: 2820mg of 1c, 1556mg of 2-methoxyethylamine, 1823mg of molybdenum hexacarbonyl, 200.4mg of tri-tert-butylphosphine tetrafluoroborate and 647.5mg of trans-bis (acetoxy) -bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II) are placed in portions in three microwave tubes and suspended with 56ml of THF. Then, 3.1ml of DBU was added and the mixture was stirred for 20min at 125 ℃ in a 200 watt microwave. The reaction mixture was combined, filtered and diluted with some ethyl acetate, and the organic phase was washed twice with water and once with saturated sodium chloride solution. It was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP 4. Gradient: ethyl acetate/methanol 0-10%. Obtaining: 885.1mg of the title compound.
Mode B: 780mg of 1d and 1747mg of HATU were first dissolved in 10ml of DMSO. Next, 314mg of 2-methoxyethylamine and 1080mg of N, N-diisopropylethylamine were added. The mixture was stirred at RT for 1 hr. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP 4. Gradient: ethyl acetate/methanol 0-10%. Obtaining: 740mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 1 c: 4- [ (5-bromo-4-methyl-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
5g of 5-bromo-4-methyl-1H-indazole was dissolved in 110ml of DMF and treated with 11.5g of cesium carbonate and 7.9g N-Boc-4- (bromomethyl) piperidine. The mixture was stirred at 60 ℃ for 3hr and at RT overnight. The reaction mixture was then diluted with ethyl acetate and the organic phase was washed twice with water, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on biotage sp4 via a 65i-Si column. Gradient: hexane/ethyl acetate 0-100%. Obtaining: 3.53g of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 1 d: 2- { [1- (tert-butoxycarbonyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid
1080mg of 1e was dissolved in 8ml of methanol and treated with 10ml of water containing 1235mg of lithium hydroxide. An additional 2ml of THF was added as solubilizer. The mixture was stirred at RT for 24 hr. 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 over sodium sulfate, filtered and concentrated. Obtaining: 880mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 1 e: 2- { [1- (tert-Butoxycarbonyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid methyl ester
666mg of 1c, 156.8mg of methanol, 645.8mg of molybdenum hexacarbonyl, 47.3mg of tri-tert-butylphosphine tetrafluoroborate and 123.5mg of trans-bis (acetoxy) -bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II) are placed in a microwave tube and suspended in 15ml of THF. Then, 0.7ml DBU was added and the mixture was stirred for 20min at 125 ℃ in a 150 watt microwave. Next, it was concentrated, dissolved in ethyl acetate, and the organic phase was washed twice with water and once with saturated sodium chloride solution. It was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP 4. Gradient: hexane/ethyl acetate 0-100%. Obtaining: 363mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-tert-butoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, 35.9mg of the title compound were obtained from 75mg of the amine prepared in example 1a and 39.7mg of 4- (tert-butoxy) benzoic acid.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 75mg of the amine prepared in example 1a and 47.5mg of 4- (4-fluorophenoxy) benzoic acid 51.6mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-morpholinobenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 1a and 42.3mg 4-morpholinobenzoic acid 48.1mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 75mg of the amine prepared in example 1a and 44.2mg of 4- (4-fluorophenyl) benzoic acid 50.1mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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),7.272H),7.41(3H),7.67(4H),8.03-8.16(1H),8.48(1H)。
Example 6: 2- { [1- (2-fluoro-4-methanesulfonylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 75mg of the amine prepared in example 1a and 44.6mg 2-fluoro-4-methanesulfonylbenzoic acid 40.1mg of the title compound was obtained.
1H-NMR(300MHz,DMSO-d6)：[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-methoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 1a and 34.8mg 2-fluoro-4-methoxybenzoic acid 43.1mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 75mg of the amine prepared in example 1a and 44.7mg 4-bromo-2-fluorobenzoic acid 51.8mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-methylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 1a and 31.5mg 2-fluoro-4-methylbenzoic acid 38.3mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 75mg of the amine prepared in example 1a and 42.5mg 2-fluoro-4- (trifluoromethyl) benzoic acid 57.8mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Analogously to example 1, from 150mg of the amine prepared in example 1a and 101.5mg4- (pentafluoro-. lamda.) -6Sulfanyl) benzoic acid 135.1mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 analogously:
example 55: n- (2-methoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
150mg of the amine prepared in example 1a are initially dissolved in 1.5ml of pyridine. Then, 101mg4- (trifluoromethoxy) benzoyl chloride was added and the mixture was stirred at RT for 30 min. 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 bicarbonate solution (pH9) and once with saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP 4. Gradient: ethyl acetate/methanol 0-10%. Obtaining: 118.2mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 300mg of the amine prepared in example 1a and 157.4mg of 4-chlorobenzoyl chloride 183mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
First 60mg of the amine prepared in example 1a are dissolved at 0 ℃ in 2ml of DCM. Then, 0.034ml of triethylamine and 43.2mg of 4- [ (trifluoromethyl) sulfanyl ] benzoyl chloride were added, and the mixture was stirred at 0 ℃ for 2 hr. The reaction mixture was then diluted with DCM and washed with 1 molar hydrochloric acid, saturated sodium bicarbonate solution (pH9) and saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP 4. Gradient: DCM/methanol 0-10%. The product fractions were dissolved in ethyl acetate and extracted twice with saturated sodium bicarbonate solution. The organic phase was concentrated and the residue was purified again by HPLC. Obtaining: 26.5mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 58a and 37.0mg 2-fluoro-4- (trifluoromethyl) benzoic acid 34.6mg of the title compound are obtained.
1H-NMR (400MHz, methanol-d)4)：[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 material was prepared as follows:
example 58 a: 4-methyl-N- (2-morpholinoethyl) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
To 624.4mg58b were added 2.9ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. An oily substance is formed, which is dissolved with vigorous stirring and mild warming. The mixture was stirred at about 30 ℃ for 1 hour. The reaction mixture was concentrated. Obtaining: 980mg of the title compound, which was reacted further without further purification.
1H-NMR(300MHz,DMSO-d6)：[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 58 b: 4- ({ 4-methyl-5- [ N- (2-morpholinoethyl) carbamoyl ] -1H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
896mg of 1c, 857mg of 2-morpholinoethylamine, 579.3mg of molybdenum hexacarbonyl, 63.6mg of tri-tert-butylphosphine tetrafluoroborate and 205.8mg of trans-bis (acetoxy) -bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II) were placed in a microwave tube and suspended in 18ml of THF. Then, 1.0ml of DBU was added and the mixture was stirred for 20min at 125 ℃ in a 200 watt microwave. The reaction mixture was diluted with some ethyl acetate and filtered first through Celite (Celite). The filtrate was diluted with ethyl acetate and the organic phase was washed twice with water and once with saturated sodium chloride solution. Then, it was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP 4. Gradient: ethyl acetate/methanol 0-10%. Obtaining: 624.4mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-morpholinoethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 75mg of the amine prepared in example 58a and 43.9mg of 4- (trifluoromethoxy) benzoyl chloride 10.1mg of the title compound is obtained.
1H-NMR (400MHz, methanol-d)4)：[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-morpholinoethyl) -2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 58a and 44.1mg4- (pentafluoro-. lamda.) -6Sulfanyl) benzoic acid 14.0mg of the title compound are obtained.
1H-NMR (400MHz, chloroform-d): [ ppm of]＝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-morpholinoethyl) -2- ({1- [3- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 75mg of the amine prepared in example 58a and 43.9mg of 3- (trifluoromethoxy) benzoyl chloride 18.1mg of the title compound is obtained.
1H-NMR (400MHz, chloroform-d): [ ppm of]＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 75mg of the amine prepared in example 58a and 34.2mg 4-chlorobenzoyl chloride 14.9mg of the title compound are obtained.
1H-NMR (400MHz, methanol-d)4)：[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-morpholinoethyl) -2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 58a and 33.8mg of 4- (trifluoromethyl) benzoic acid 31.7mg of the title compound are obtained.
1H-NMR (400MHz, methanol-d)4)：[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-morpholinoethyl) -2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 58a and 44.1mg3- (pentafluoro-. lamda.) -6Sulfanyl) benzoic acid 24.7mg of the title compound are obtained.
1H-NMR (400MHz, methanol-d)4)：[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-morpholinoethyl) -2- ({1- [3- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 75mg of the amine prepared in example 58a and 33.8mg of 3- (trifluoromethyl) benzoic acid 14.0mg of the title compound are obtained.
1H-NMR (400MHz, methanol-d)4)：[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 analogously:
example 68: n- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl]-4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Similar to example 57, from 266.5mg of the amine prepared in example 68a and 150.3mg4- (pentakis) Fluorine-lambda6Sulfanyl) benzoyl chloride to yield 61.7mg of the title compound.
1H-NMR (300MHz, chloroform-d): [ ppm of]＝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 material was prepared as follows:
example 68 a: n- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
To 416.6mg68b was added 1.85ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. An oily substance is formed, which is dissolved with vigorous stirring and mild warming. The mixture was stirred at about 30 ℃ for 1 hour. The reaction mixture was concentrated. Obtaining: 439.2mg of the title compound, which was reacted further without further purification.
1H-NMR(400MHz,DMSO-d6)：[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 68 b: 4- [ (5- { N- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
220mg of 1c, 242.7mg of 2- (3, 3-difluoropyrrolidin-1-yl) ethylamine, 142.2mg of molybdenum hexacarbonyl, 15.6mg of tri-tert-butylphosphine tetrafluoroborate and 50.5mg of trans-bis (acetoxy) -bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II) were placed in a microwave tube and suspended in 4.4ml of THF. Then, 0.24ml DBU was added and the mixture was stirred for 20min at 125 ℃ in a 200 watt microwave. The reaction mixture was diluted with some ethyl acetate and filtered first through celite. The filtrate was diluted with ethyl acetate and the organic phase was washed twice with water and once with saturated sodium chloride solution. It was dried over sodium sulfate, filtered and concentrated. The residue (209.3mg) was chromatographed on Biotage SP 4. Gradient: DCM/methanol 0-10%. Obtaining: 53.4mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] -4-methyl-2H-indazole-5-carboxamide
Analogously to example 57, from 125.0mg of the amine prepared in example 68a and 54.5mg 4-chlorobenzoyl chloride 79.9mg of the title compound are obtained.
1H-NMR (300MHz, chloroform-d): [ ppm of]＝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) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 55, from 23.4mg of the amine prepared in example 68a and 14.0mg of 4- [ (trifluoromethyl) sulfanyl ] benzoyl chloride was obtained 15.2mg of the title compound.
1H-NMR (400MHz, chloroform-d): [ ppm of]＝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-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
Analogously to example 1, from 146.9mg of the amine prepared in example 71a and 93.3mg4- (pentafluoro-. lamda.) -6Sulfanyl) benzoic acid 124.8mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 material was prepared as follows:
example 71 a: 4-methyl-2- (4-piperidinylmethyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide hydrochloride
To 425.2mg71b was added 2.35ml4M dioxane hydrochloride and 0.5ml dioxane. An oily substance is formed, which is dissolved with vigorous stirring and mild warming. The mixture was stirred at about 30 ℃ for 1 hour. The reaction mixture was concentrated. Obtaining: 440.6mg of the title compound, which was further reacted without further purification.
1H-NMR(400MHz,DMSO-d6)：[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 71 b: 4- ({ 4-methyl-5- [ N- (2,2, 2-trifluoroethyl) carbamoyl ] -2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
2820mg of 1c, 2052mg of 2,2, 2-trifluoroethylamine, 1823.2mg of molybdenum hexacarbonyl, 200.4mg of tri-tert-butylphosphine tetrafluoroborate and 647.5mg of trans-bis (acetoxy) -bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II) are placed in a microwave tube and suspended in 56ml of THF. Then, 3.1ml of DBU was added and the mixture was stirred for 20min at 125 ℃ in a 200 watt microwave. The reaction mixture was diluted with some ethyl acetate and washed twice with water and once with saturated sodium chloride solution. It was dried over sodium sulfate, filtered and concentrated. The residue was chromatographed on Biotage SP 4. Gradient: hexane/ethyl acetate 0-100%. Obtaining: 475.2mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 146.9mg of the amine prepared in example 71a and 58.8mg 4-chlorobenzoic acid 97.8mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 146.9mg of the amine prepared in example 71a and 77.5mg of 4- (trifluoromethoxy) benzoic acid 105.4mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -6-methyl-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 79mg of the amine prepared in example 74a and 26mg of 4-chlorobenzoyl chloride 30mg of the title compound are obtained.
1NMR (400MHz, methanol-d)4)：[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 material was prepared as follows:
example 74 a: 6-methyl-N- (2-morpholinoethyl) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
768mg (1.58mmol) of tert-butyl carbamate 74b was dissolved in 4.0ml of 4M dioxane hydrochloric acid solution and stirred at room temperature under nitrogen. Another 0.8ml of 4M dioxane hydrochloric acid solution was added and the mixture was stirred at room temperature. The reaction solution was concentrated and yielded 760mg of the title compound, which was used in the next reaction without further purification.
1H-NMR(400MHz,DMSO-d6)：[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 74 b: 4- ({ 6-methyl-5- [ N- (2-morpholinoethyl) carbamoyl ] -2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
3.00g (7.35mmol) of 5-bromoindazole 74c and 2.87g (22.04mmol) of 2-morpholinoethylamine were dissolved in 134ml of dioxane and 1.94g (7.35mmol) of molybdenum hexacarbonyl, 167mg (1.47mmol) of palladium acetate, 213mg (0.74mmol) of tributylphosphonium tetrafluoroborate, 2.34g (22.0mmol) of sodium carbonate and 2 drops of water were added. The reaction mixture was heated to 125 ℃ under nitrogen and stirred at this temperature for 2.5 hr. For work-up, the suspension is filtered through celite, rewashed with dioxane, concentrated in vacuo and dried. The crude product was isolated by column chromatography. Obtaining: 518mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 74 c: 4- [ (5-bromo-6-methyl-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
10.0g (47.4mmol) of 5-bromo-4-methyl-1H-indazole and 21.0g (56.9mmol) of tert-butyl 4- [ (toluenesulfonyloxy) methyl ] piperidine-1-carboxylate were dissolved in 726ml of DMF. To this were added 21.0g (56.9mmol) of tetrabutylammonium iodide and 18.5g (56.9mmol) of cesium carbonate, and the reaction mixture was heated at 80 ℃ for 1.5hr under nitrogen. For work-up, it is treated with water and ethyl acetate, the organic phase is separated and the aqueous phase is extracted several times with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After purification by column chromatography, it gave the title compound in 5g yield.
1H-NMR (600MHz, chloroform-d): [ ppm of]＝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 analogously:
example 77: 6-methyl-N- (2-morpholinoethyl) -2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1, 23mg of the title compound are obtained from 79mg of the amine prepared in example 74a and 47mg of the acid.
1H-NMR (400MHz, methanol-d)4)：[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 analogously:
example 84: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 84a and 29mg 4-chlorobenzoic acid 38mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 84 a: n- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
To 781mg84b were added 3.7ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. The mixture was stirred at about 30 ℃ for 30 min. The reaction mixture was concentrated, dissolved in some toluene, and concentrated again. Obtaining: 751mg of the title compound, which was reacted further without further purification.
1H-NMR(400MHz,DMSO-d6)：[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 84 b: 4- [ (5- { N- [2- (cyclopropylmethoxy) ethyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
In analogy to 1B, mode B, 500mg of 1d was reacted with 203mg of amine. Obtaining: 781mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 analogously:
example 90: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 90a and 27mg 4-chlorobenzoic acid 40mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 90 a: 4-methyl-2- (4-piperidinylmethyl) -N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
To 610mg90b were added 3.0ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. The mixture was stirred at about 30 ℃ for 30 min. The reaction mixture was concentrated, dissolved in some toluene, and concentrated again. Obtaining: 619mg of the title compound, which was reacted further without further purification.
1H-NMR(400MHz,DMSO-d6)：[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 90 b: 4- [ (4-methyl-5- { N- [2- (2,2, 2-trifluoroethoxy) ethyl ] carbamoyl } -2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
In analogy to 1B, mode B, 500mg of 1d was reacted with 240mg of amine. Obtaining: 670mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 analogously:
example 96: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 96a and 30mg 4-chlorobenzoic acid, 36mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 material was prepared as follows:
example 96 a: n- (2-Isopropoxyethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
To 650mg of 96b were added 3.2ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. The mixture was stirred at about 30 ℃ for 30 min. The reaction mixture was concentrated, dissolved in some toluene, and concentrated again. Obtaining: 529mg of the title compound, which was reacted further without further purification.
1H-NMR(400MHz,DMSO-d6)：[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 96 b: 4- ({5- [ N- (2-Isopropoxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to 1B, manner B, 500mg of 1d were reacted with 138mg of amine. Obtaining: 650mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 analogously:
example 102: (+/-) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) propyl ] -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 100mg of the amine prepared in example 102a and 37mg 4-chlorobenzoic acid 41mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 102 a: (+/-) -N- [2- (cyclopropylmethoxy) propyl ] -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
To 632mg102b were added 2.9ml4M dioxane hydrochloride solution and 0.5ml dioxane. The mixture was stirred at about 30 ℃ for 30 min. The reaction mixture was concentrated, dissolved in some toluene, and concentrated again. Obtaining: 561mg of the title compound, which was further reacted without further purification.
1H-NMR(300MHz,DMSO-d6)：[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 102 b: (+/-) -4- [ (5- { N- [2- (cyclopropylmethoxy) propyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
In analogy to 1B, mode B, 500mg of 1d was reacted with 222mg of amine. Obtaining: 631mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 analogously:
example 107: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
Analogously to example 1, from 75mg of the amine prepared in example 107a and 28mg 4-chlorobenzoic acid, 26mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 material was prepared as follows:
example 107 a: 4-methyl-2- (4-piperidinylmethyl) -N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
To 648mg of 107b were added 3.0ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. The mixture was stirred at about 30 ℃ for 30 min. The reaction mixture was concentrated, dissolved in some toluene, and concentrated again. Obtaining: 766mg of the title compound, which was reacted further without further purification.
1H-NMR(300MHz,DMSO-d6)：[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 107 b: 4- [ (4-methyl-5- { N- [2- (trifluoromethoxy) ethyl ] carbamoyl } -2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
In analogy to 1B, manner B, 500mg of 1d were reacted with 293mg of amine. Obtaining: 748mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 analogously:
example 111: n- (2-tert-butoxyethyl) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 75mg of the amine prepared in example 111a and 28mg 4-chlorobenzoic acid 8mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 111 a: n- (2-tert-butoxyethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
To 743mg111b was added 3.5ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. The mixture was stirred at about 30 ℃ for 30 min. The reaction mixture was concentrated, dissolved in some toluene, and concentrated again. Obtaining: 677mg of the title compound in a mixture with N- (2-hydroxyethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide, which is further reacted without further purification.
Example 111 b: 4- ({5- [ N- (2-tert-butoxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to 1B, mode B, 500mg of 1d was reacted with 206mg of amine. Obtaining: 743mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 analogously:
example 115: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl]Methyl } -N- (2-, [ 2 ]2H3]Methoxy [ alpha ], [ beta ], [ alpha ], [ beta2H4]Ethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 54mg of the amine prepared in example 115a and 22mg 4-chlorobenzoic acid 1mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 material was prepared as follows:
example 115 a: 4-methyl-N- (2-, ")2H3]Methoxy [ alpha ], [ beta ], [ alpha ], [ beta2H4]Ethyl) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
To 131mg of 115b were added 0.7ml of 4M dioxane hydrochloride solution and 0.5ml dioxane. The mixture was stirred at about 30 ℃ for 30 min. The reaction mixture was concentrated, dissolved in some toluene, and concentrated again. Obtaining: 108mg of the title compound, which was further reacted without further purification.
1H-NMR(400MHz,DMSO-d6)：[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 115 b: 4- ({ 4-methyl-5- [ N- (2-, [ 2- ])2H3]Methoxy [ alpha ], [ beta ], [ alpha ], [ beta2H4]Ethyl) carbamoyl group]-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to 1B, mode B, 500mg of 1d was reacted with 110mg of the amine prepared in 115 c. Obtaining: 131mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 115 c: 2- [2H3]Methoxy [ alpha ], [ beta ], [ alpha ], [ beta2H4]Ethan-1-amines
110mg (0.51mmol) of 115d are initially placed in 2.2ml of toluene. After addition of 11mg palladium on charcoal (10%) and hydrogen at standard pressure, the mixture was stirred at room temperature for 50 min. The reaction mixture was filtered through celite and washed with toluene. The colorless filtrate was used in the subsequent reaction as a solution.
Example 115 d: n- (2-)2H3]Methoxy [ alpha ], [ beta ], [ alpha ], [ beta2H4]Ethyl) carbamic acid benzyl ester
1.32g (6.6mmol) of 115e) are dissolved in 23ml of acetonitrile. Then 2.3g (9.9mmol) of silver oxide and 1.64ml (3.8g,26mmol) of deuterated iodomethane were added. The reaction mixture was stirred at 40 ℃ for 1.5hr, at 72 ℃ for 7.5hr, and then at room temperature overnight. An additional 2.3g (9.9mmol) of silver oxide was added and the mixture was stirred at 72 ℃ for 1.5 hr. For work-up, the black solid was filtered off at the pump and the clear filtrate was concentrated. The residue was purified by column chromatography (hexane/ethyl acetate 0-10%). Obtaining: 1.13g of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝4.97(2H),7.31(5H)。
Example 115 e: n- (2-hydroxy-)2H4]Ethyl) carbamic acid benzyl ester
1.0g (15mmol) of deuterated aminoethanol are first dissolved in 29ml of dichloromethane. Then, 2.5ml (1.8g,18mmol) triethylamine was added and the reaction mixture was cooled to 0 ℃. At this temperature, 2.75ml (3.34g,19.6mmol) of benzyl chloroformate are immediately added dropwise with caution. After the addition was complete, the mixture was stirred for a further 1hr without an ice bath and warmed to RT in the process. The reaction mixture was diluted with some dichloromethane and washed once with 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% and ethyl acetate). Obtaining: 1.32g of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝4.54(1H),4.97(2H),7.12(1H),7.81(5H)。
The following compounds were prepared analogously:
example 117: 2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 55, 471mg of the title compound are obtained from 500mg of the compound prepared in example 117e) and 287mg 4-chlorobenzoyl chloride.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 117 a: 3- [ (5-bromo-4-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
To a solution of 21.1g 5-bromo-4-methyl-1H-indazole and 37.6g3- [ (tosyloxy) methyl ] azetidine-1-carboxylic acid tert-butyl ester in 100ml dioxane was added 150ml of a 1M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran at 25 ℃ and stirred at 90 ℃ for 6 hr. After cooling, the reaction mixture is treated with ethyl acetate and water, the organic phase is separated and the aqueous phase is extracted twice with 100ml portions of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration.
The residue thus obtained was purified by chromatography on a Flashmaster (hexane/ethyl acetate 1:0-0: 1). 15.0g of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 117 b: 2- { [1- (tert-Butoxycarbonyl) azetidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid methyl ester
To a solution of 8.16g of the bromide prepared in example 117a in 65.4ml of methanol at 25 ℃ were added 6.5g of 1, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride and 15g of potassium acetate, and the mixture was stirred in an autoclave at 10.15 bar CO and 120 ℃ for 24 hours. The reaction mixture was then cooled, filtered through celite at the pump, and the filtrate was concentrated in vacuo. The residue thus obtained was purified by chromatography on a Flashmaster (hexane/ethyl acetate 1:0-0: 1). 6.97g of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 117 c: 2- { [1- (tert-butoxycarbonyl) azetidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid
Analogously to example 1d, 5.2g of the title compound are obtained from 15.1g of the ester prepared in example 117 b.
1H-NMR(300MHz,DMSO-d6)：＝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 117 d: 3- ({5- [ N- (2-methoxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 2.5g of the acid prepared in example 117c and 0.54g 2-methoxyethylamine was obtained a crude product which was purified by using a Biotage unit (ethyl acetate: 0-30% methanol) to yield 2.69g of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 117 e: 2- (azetidin-3-ylmethyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, 2.59g of the title compound were obtained from 2.69g of the amide prepared in example 117d, which was reacted without further purification.
Example 118: n- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 55, from 55mg of the compound prepared in example 117e and 43mg of 4- [ (trifluoromethyl) sulfanyl ] benzoyl chloride 29mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 55mg of the compound prepared in example 117e and 40mg of 4- (trifluoromethoxy) benzoyl chloride 27mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 55mg of the compound prepared in example 117e and 41mg 2-fluoro-4- (trifluoromethyl) benzoyl chloride 17mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-fluorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 42mg of the compound prepared in example 117e and 26mg of 4-chloro-2-fluorobenzoyl chloride was obtained 19mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 42mg of the compound prepared in example 117e and 31mg 3-fluoro-4- (trifluoromethyl) benzoyl chloride was obtained 15mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 42mg of the compound prepared in example 117e and 33mg of 4-chloro-3- (trifluoromethyl) benzoyl chloride 6mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-cyclopropylbenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 163mg of the compound prepared in example 117e and 78mg 4-cyclopropylbenzoic acid 76mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
Analogously to example 1, from 1.20g of the compound prepared in example 117e and 850mg of 4- [4- (trifluoromethyl) phenoxy ] benzoic acid 478mg of the title compound is obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 43mg of the compound prepared in example 126a and 20mg of 4-chlorobenzoyl chloride 38mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 126 a: 2- (azetidin-3-ylmethyl) -N- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 50mg of the compound prepared in example 126b 43mg of the title compound were obtained, which was reacted without further purification.
Example 126 b: 3- [ (5- { N- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1b, from 70mg of the compound prepared in example 117a and 83mg2- (3, 3-difluoropyrrolidin-1-yl) ethylamine there was obtained 71mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：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-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 55, from 130mg of the compound prepared in example 127b and 61mg 4-chlorobenzoyl chloride 143mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 127 a: 3- { [ 4-methyl-5- (N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } carbamoyl) indazol-2-yl ] methyl } azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, 674mg of the title compound were obtained from 500mg of the compound prepared in example 117 c.
1H-NMR(300MHz,DMSO-d6)：＝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 127 b: 2- (azetidin-3-ylmethyl) -4-methyl-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 150mg of the compound prepared in example 127a 130mg of the title compound are obtained, which are reacted further without purification.
Example 128: 2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 50mg of the compound prepared in example 128b and 24mg of 4-chlorobenzoyl chloride was obtained 30mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 128 a: 3- ({ 4-methyl-5- [ N- (2-morpholinoethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1b, from 200mg of the compound prepared in example 117a and 205mg 2-morpholinoethylamine there was obtained 59mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 128 b: 2- (azetidin-3-ylmethyl) -4-methyl-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 59mg of the compound prepared in example 128a 63mg of the title compound are obtained, which is reacted further without purification.
Example 129: 2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 128mg of the compound prepared in example 129b and 68mg of 4-chlorobenzoyl chloride 127mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 129 a: 3- ({ 4-methyl-5- [ N- (2,2, 2-trifluoroethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, 1.02g of the title compound are obtained from 1.0g of the compound prepared in example 117c and 287mg2,2, 2-trifluoroethylamine.
1H-NMR(300MHz,DMSO-d6)：＝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 129 b: 2- (azetidin-3-ylmethyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 1.0g of the compound prepared in example 129a 852mg of the title compound were obtained, which were reacted further without purification.
Example 130: 4-methyl-N- (2,2, 2-trifluoroethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 128mg of the compound prepared in example 129b and 87mg of 4- (trifluoromethoxy) benzoyl chloride 113mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 128mg of the compound prepared in example 129b and 88mg 2-fluoro-4- (trifluoromethyl) benzoyl chloride 128mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
Similar to example 1, from 128mg of the compound prepared in example 129b and 96mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid 121mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 55, from 130mg of the compound prepared in example 127b and 78mg of 4- (trifluoromethoxy) benzoyl chloride 178mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 55, from 130mg of the compound prepared in example 127b and 79mg 2-fluoro-4- (trifluoromethyl) benzoyl chloride 128mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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)。
Examples135: 4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -N- {2- [ (trifluoromethyl) sulfanyl]Ethyl } -2H-indazole-5-carboxamide
Analogously to example 1, 130mg of the compound prepared in example 127b and 87mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid 84mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 161mg of the compound prepared in example 136b and 109mg4- (trifluoromethoxy) benzoyl chloride 172mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 136 a: 3- [ (5- { N- [2- (cyclopropoxy) ethyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 150mg of the compound prepared according to example 118c and 140mg 2-cyclopropoxyethylammonium tetrafluoroborate (which can be prepared according to examples 154a) and 154b), starting from cyclopropanol and bromoacetamide, and then cleaving Boc with trifluoroacetic acid analogously to example 1a), 189mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 136 b: 2- (azetidin-3-ylmethyl) -N- [ (2-cyclopropoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, 189mg of the compound prepared in example 136a gave 161mg of the title compound, which was reacted further without purification.
Example 137: n- [2- (cyclobutoxy) ethyl ] -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 254mg of the compound prepared in example 137b and 166mg4- (trifluoromethoxy) benzoyl chloride 207mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 137 a: 3- [ (5- { N- [2- (cyclobutoxy) ethyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 220mg of the compound prepared in example 117c and 143mg of 2- (cyclobutoxy) ethylammonium tetrafluoroborate (which can be prepared according to examples 154a) and 154b), starting from cyclobutanol and bromoacetamide, and then cleaving Boc with trifluoroacetic acid in analogy to example 1a), 297mg of the title compound is obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 137 b: 2- (azetidin-3-ylmethyl) -N- [ (2-cyclobutoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 297mg of the compound prepared in example 137a 254mg of the title compound were obtained, which was reacted further without purification.
Example 138: (+/-) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxypropyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 55, 237mg of the compound prepared in example 138b and 129mg of 4-chlorobenzoyl chloride gave 166mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 138 a: (+/-) -3- ({5- [ N- (2-methoxypropyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 323mg of the compound prepared in example 117c and 117mg 2-methoxypropylamine 331mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 138 b: (+/-) -2- (azetidin-3-ylmethyl) -N- (2-methoxypropyl) -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 280mg of the compound prepared in example 138a 247mg of the title compound are obtained, which are reacted further without purification.
Example 139: (R or S) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxypropyl) -4-methyl-2H-indazole-5-carboxamide
From 158mg of the racemate prepared in example 138, the racemate separation is carried out by preparative chiral HPLC (method a) to obtain 52mg of the title compound together with 48mg of the slower eluting enantiomer (example 140).
Analytical chiral HPLC: 14.5 min.
Example 140: (S or R) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxypropyl) -4-methyl-2H-indazole-5-carboxamide
From 158mg of the racemate prepared in example 138, the racemate separation is carried out by preparative chiral HPLC (method A) to yield 48mg of the title compound together with 52mg of the faster eluting enantiomer (example 139).
Analytical chiral HPLC: 17.1 min.
Example 141: (+/-) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 269mg of the compound prepared in example 141b and 136mg of 4-chlorobenzoyl chloride 177mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 141 a: (+/-) -3- ({5- [ N- (1, 4-dioxan-2-ylmethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 323mg of the compound prepared in example 117c and 110mg1, 4-dioxane-2-ylmethylamine was obtained 364mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 141 b: (+/-) -2- (azetidin-3-ylmethyl) -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 314mg of the compound prepared in example 141a 274mg of the title compound are obtained, which is reacted further without purification.
Example 142: (R or S) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2H-indazole-5-carboxamide
From 172mg of the racemate prepared in example 141, the racemate separation was carried out by preparative chiral HPLC (method B) to obtain 60mg of the title compound together with 60mg of the slower eluting enantiomer (example 143).
Analytical chiral HPLC: 5.84 min.
Example 143: (S or R) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2H-indazole-5-carboxamide
From 172mg of the racemate prepared in example 141, the racemate separation is carried out by preparative chiral HPLC (method B) to obtain 60mg of the title compound together with 60mg of the faster eluting enantiomer (example 142).
Analytical chiral HPLC: 6.28 min.
Example 144: (+/-) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide
Analogously to example 55, 255mg of the compound prepared in example 144b and 130mg of 4-chlorobenzoyl chloride gave 144mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 144 a: (+/-) -3- ({ 4-methyl-5- [ N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 323mg of the compound prepared in example 117c and 141mg3,4,5, 6-tetrahydro-2H-pyran-2-ylmethylamine hydrochloride 342mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 144 b: (+/-) -2- (azetidin-3-ylmethyl) -4-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 298mg of the compound prepared in example 144a 261mg of the title compound are obtained, which is reacted further without purification.
Example 145: (R or S) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide
From 140mg of the racemate prepared in example 144, the racemate separation is carried out by preparative chiral HPLC (method C) to yield 43mg of the title compound together with 35mg of the slower eluting enantiomer (example 146).
Analytical chiral HPLC: 4.38 min.
Example 146: (S or R) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide
From 140mg of the racemate prepared in example 144, the racemate separation is carried out by preparative chiral HPLC (method C) to yield 35mg of the title compound together with 43mg of the faster eluting enantiomer (example 145).
Analytical chiral HPLC: 4.88 min.
Example 147: (+/-) -2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxypropyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 42mg of the compound prepared in example 138b and 28mg4- (4-fluorophenoxy) benzoic acid, a material still contaminated after HPLC purification was obtained, which was further purified by additional preparative thick layer chromatography (using ethyl acetate/methanol as mobile phase in a ratio of 9: 1). In this way, the following results: 15mg of the title compound.
1H-NMR(300MHz,CDCl3)：＝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) benzoyl ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 43mg of the compound prepared in example 141b and 26mg of 4- (4-fluorophenoxy) benzoic acid 18mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 127mg of the compound prepared in example 149b and 65mg 4-chlorobenzoyl chloride 72mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 149 a: 3- [ (5- { N- [2- (cyclopropylmethoxy) ethyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 400mg of the compound prepared in example 117c and 133mg2- (cyclopropylmethoxy) ethylamine hydrochloride was obtained 448mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 149 b: 2- (azetidin-3-ylmethyl) -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 448mg of the compound prepared in example 149a 390mg of the title compound are obtained, which is reacted further without purification.
Example 150: n- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 102mg of the compound prepared in example 149b and 63mg of 4- (4-fluorophenoxy) benzoic acid 48mg of the title compound were obtained.
1H-NMR(300MHz,CDCl3)：＝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-methylbenzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1, from 127mg of the compound prepared in example 149b and 46mg 4-methylbenzoic acid 55mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
In analogy to example 55, from 234mg of the compound prepared in example 152b and 115mg 4-chlorobenzoyl chloride 122mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 152 a: 3- [ (4-methyl-5- { N- [2- (trifluoromethoxy) ethyl ] carbamoyl } -2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 250mg of the compound prepared in example 117c and 120mg of 2- (trifluoromethoxy) ethylamine hydrochloride, 272mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 152 b: 2- (azetidin-3-ylmethyl) -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 272mg of the compound prepared in example 152a 240mg of the title compound are obtained, which is reacted further without purification.
Example 153: n- (2-tert-butoxyethyl) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
Analogously to example 55), 12mg of the title compound are obtained from 160mg of the compound prepared in example 153b) and 81mg of 4-chlorobenzoyl chloride.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 153 a: 3- ({5- [ N- (2-tert-butoxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 250mg of the compound prepared in example 117c and 111mg of 2-tert-butoxyethylamine hydrochloride was obtained 284mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 153 b: 2- (azetidin-3-ylmethyl) -N- (2-tert-butoxyethyl) -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 284mg of the compound prepared in example 153a 240mg of the title compound are obtained, which is reacted further without purification.
Example 154: (+/-) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (cyclobutoxy) propyl ] -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 222mg of the compound prepared in example 154d and 109mg 4-chlorobenzoyl chloride 135mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 154 a: (+/-) -2- (cyclobutoxy) propylamine
To a suspension of 732mg sodium hydride in 15ml THF was added dropwise 2.0g cyclobutanol in 0.5ml THF and stirred for 30 minutes at 25 ℃. Then, the reaction mixture was cooled to 0 ℃ and 0.5ml of tetrahydrofuran containing 2.11g of (+/-) 2-bromopropylamine was added dropwise, followed by stirring at 25 ℃ for 18 hours. The reaction mixture was poured onto ice water and extracted once with 75ml dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. The crude product thus obtained was purified by column chromatography (on silica gel, using hexane/0-50% ethyl acetate). Obtaining: 0.79g of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 154 b: (+/-) -N- [2- (cyclobutoxy) propyl ] carbamic acid tert-butyl ester
To a suspension of 6.9g of lithium aluminum hydride in 250ml of THF at 0 ℃ 81ml of THF containing 6.5g of the amide prepared in example 154a are carefully added dropwise. Then, the mixture was first stirred at 0 ℃ for 30 minutes, and then heated under reflux for 5 hours. After cooling, the mixture was carefully treated with 20g of sodium sulfate decahydrate and 20g of potassium fluoride, immediately thereafter solid matter was removed by filtration. The filtrate was concentrated in vacuo. The residue thus obtained (5.8g) was dissolved in 174ml of dichloromethane without further purification and treated with 11.9g of di-tert-butyl dicarbonate. After stirring at 25 ℃ for 16 h, it is concentrated in vacuo and the residue thus obtained is purified by double column chromatography (on silica gel, using hexane/0-40% ethyl acetate).
Obtaining: 8.54g of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 154 c: (+/-) -3- [ (5- { N- [2- (cyclobutoxy) propyl ] carbamoyl } -4-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1a, 200mg of the compound prepared in example 154b) gave 2- (cyclobutoxy) propylamine as its hydrochloride salt, which was identical, without further purification, to 250mg of the compound prepared in example 117c, analogously to example 1, gave 259mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 154 d: (+/-) -2- (azetidin-3-ylmethyl) -N- [2- (cyclobutoxy) propyl ] -4-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 259mg of the compound prepared in example 154c 225mg of the title compound are obtained, which are reacted further without purification.
Example 155: (S or R) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (cyclobutoxy) propyl ] -4-methyl-2H-indazole-5-carboxamide
From 135mg of the racemate prepared in example 154, the racemate separation is carried out by preparative chiral HPLC (method A) to yield 41mg of the title compound together with 21mg of the slower eluting enantiomer (example 156).
Analytical chiral HPLC: 10.05 min.
Example 156: (R or S) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (cyclobutoxy) propyl ] -4-methyl-2H-indazole-5-carboxamide
From 135mg of the racemate prepared in example 154, the racemate separation is carried out by preparative chiral HPLC (method A) to yield 21mg of the title compound together with 41mg of the faster eluting enantiomer (example 155).
Analytical chiral 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, from 102mg of the compound prepared in example 149b and 58mg4' -fluorobiphenyl-4-carboxylic acid 54mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 108mg of the compound prepared in example 117e and 69mg4' -fluorobiphenyl-4-carboxylic acid 54mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 108mg of the compound prepared in example 117e and 74mg4- (4-fluorophenoxy) benzoic acid 28mg of the title compound were obtained.
1H-NMR(300MHz,CDCl3)：＝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) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 115mg of the compound prepared in example 129b and 74mg4- (4-fluorophenoxy) benzoic acid 47mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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
In analogy to example 1, from 115mg of the compound prepared in example 129b and 69mg4' -fluorobiphenyl-4-carboxylic acid 28mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
In analogy to example 55, from 252mg of the compound prepared in example 162a and 108mg 4-chlorobenzoyl chloride 197mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 162 a: 2- (azetidin-3-ylmethyl) -4-methyl-N- [2- (2,2, 2-trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, 583mg of the compound prepared in example 162b gave 505mg of the title compound, which was reacted further without purification.
Example 162 b: 3- [ (4-methyl-5- { N- [2- (2,2, 2-trifluoroethoxy) ethyl ] carbamoyl } -2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 500mg of the compound prepared in example 117c and 260mg of 2- (2,2, 2-trifluoroethoxy) ethylamine hydrochloride, 580mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1, from 252mg of the compound prepared in example 162a and 175mg of 4- [4- (trifluoromethyl) phenoxy ] benzoic acid 89mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
Analogously to example 1, 64mg of the title compound are obtained from 225mg of the compound prepared in example 129b and 149mg of 4- [4- (trifluoromethyl) phenoxy ] benzoic acid.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 225mg of the compound prepared in example 129b and 131mg4- (4-chlorophenoxy) benzoic acid 97mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 225mg of the compound prepared in example 117e and 140mg of 4- (4-chlorophenoxy) benzoic acid 99mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-indazol-2-yl) carbonyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 180mg of the compound prepared in example 129b and 82mg 5-fluoro-1-methyl-1H-indazole-2-carboxylic acid 48mg of the title compound were obtained.
1H-NMR(300MHz,CDCl3)：＝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-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 180mg of the compound prepared in example 129b and 87mg 5-methoxy-1-methyl-1H-indole-2-carboxylic acid 15mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 180mg of the compound prepared in example 129b and 87mg 6-methoxy-1-methyl-1H-indole-2-carboxylic acid 57mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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
In analogy to example 1, from 180mg of the compound prepared in example 117e and 87mg 5-fluoro-1-methyl-1H-indole-2-carboxylic acid 95mg of the title compound are obtained.
vNMR(300MHz,CDCl3)：＝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
In analogy to example 1, from 180mg of the compound prepared in example 117e and 95mg 5-chloro-1-methyl-1H-indole-2-carboxylic acid 90mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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 ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 180mg of the compound prepared in example 117e and 93mg 5-methoxy-1-methyl-1H-indole-2-carboxylic acid 86mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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 ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 180mg of the compound prepared in example 117e and 93mg 6-methoxy-1-methyl-1H-indole-2-carboxylic acid 97mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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 } benzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
Analogously to example 1, from 135mg of the compound prepared in example 117e and 96mg of 4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid 66mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-naphthoyl) azetidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 135mg of the compound prepared in example 117e and 69mg 7-methoxynaphthalene-2-carboxylic acid 72mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-naphthoyl) azetidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 135mg of the compound prepared in example 117e and 69mg 6-methoxynaphthalene-2-carboxylic acid 72mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 } benzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1, from 170mg of the compound prepared in example 129b and 113mg of 4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid 68mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 210mg of the compound prepared in example 178e and 119mg of 4-chlorobenzoyl chloride 154mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 178 a: 3- [ (5-bromo-6-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
To a solution of 6.18g of 5-bromo-6-methyl-1H-indazole and 15g of 3- [ (tosyloxy) methyl ] azetidine-1-carboxylic acid tert-butyl ester in 200ml of DMF at 25 deg.C were added 9.54g of cesium carbonate and 10.8g of tetrabutylammonium iodide, which was then heated at reflux for 1.5 hr. After cooling, the reaction mixture was treated with 1:1 hexane/diethyl ether and water, the phases were separated and the aqueous phase was extracted twice with 250ml portions of 1:1 hexane/diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration.
The residue thus obtained was purified by double column chromatography (on silica gel, using hexane/0-20% ethyl acetate). 2.88g of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 178 b: 2- { [1- (tert-Butoxycarbonyl) azetidin-3-yl ] methyl } -6-methyl-2H-indazole-5-carboxylic acid methyl ester
To a solution of 730mg of the bromide prepared in example 178a in 17.5ml of tetrahydrofuran were added 0.23ml of methanol, 145mg of trans-bis (acetoxy) -bis [ o- (di-o-tolylphosphino) benzyl ] dipalladium (II), 877mg of DBU and 760mg of molybdenum hexacarbonyl. The reaction mixture was then heated in a microwave (120 watts) at 125 ℃ for 20 minutes. Seven additional preparations were made in the same manner and all worked up together. For this purpose, they were concentrated in vacuo and the residue was dissolved in water and ethyl acetate. After phase separation, the aqueous phase is extracted three times with 75ml portions of ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo after filtration. The residue thus obtained was purified by double column chromatography (on silica gel, using hexane/0-30% ethyl acetate). Obtaining: 4.0g of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 178 c: 2- { [1- (tert-butoxycarbonyl) azetidin-3-yl ] methyl } -6-methyl-2H-indazole-5-carboxylic acid
Analogously to example 1d, 3.2g of the title compound are obtained from 4.0g of the ester prepared in example 178 b.
1H-NMR(300MHz,DMSO-d6)：＝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 178 d: 3- ({5- [ N- (2-methoxyethyl) carbamoyl ] -6-methyl-2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 500mg of the acid prepared in example 178c and 109mg 2-methoxyethylamine, 603mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 178 e: 2- (azetidin-3-ylmethyl) -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide hydrochloride
In analogy to example 1a, from 250mg of the amide prepared in example 178d 275mg of the title compound were obtained, which was reacted without further purification.
Example 179: 2- { [1- (3, 5-difluorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 77mg of the compound prepared in example 178e and 44mg3, 5-difluorobenzoyl chloride 51mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) sulfanyl ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
Analogously to example 55, from 43mg of the compound prepared in example 178e and 34mg of 4- [ (trifluoromethyl) sulfanyl ] benzoyl chloride, 30mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 294mg of the compound prepared in example 178e and 214mg4- (trifluoromethoxy) benzoyl chloride 221mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 43mg of the compound prepared in example 178e and 32mg 2-fluoro-4- (trifluoromethyl) benzoyl chloride 11mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-fluorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 70mg of the compound prepared in example 178e and 44mg 4-chloro-2-fluorobenzoyl chloride a material was obtained which remained contaminated after HPLC purification and which was further purified by additional preparative thick layer chromatography (using ethyl acetate/methanol as mobile phase in a ratio of 9: 1). This gave 12mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 70mg of the compound prepared in example 178e and 52mg 3-fluoro-4- (trifluoromethyl) benzoyl chloride 32mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 70mg of the compound prepared in example 178e and 55mg of 4-chloro-3- (trifluoromethyl) benzoyl chloride was obtained 30mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 70mg of the compound prepared in example 178e and 47mg of 4- (trifluoromethyl) benzoyl chloride 31mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -N- {2- [ (trifluoromethyl) sulfanyl]Ethyl } -2H-indazole-5-carboxamide
Analogously to example 1, 170mg of the compound prepared in example 187b and 103mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid 35mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 187 a: 3- { [ 6-methyl-5- (N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } carbamoyl) -2H-indazol-2-yl ] methyl } azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 800mg of the acid prepared in example 178c and 336mg of 2- [ (trifluoromethyl) sulfanyl ] ethylamine there was obtained 998mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 187 b: 2- (azetidin-3-ylmethyl) -6-methyl-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a), 402mg of the title compound are obtained from 395mg of the amide prepared in example 187a), which is reacted without further purification.
Example 188: 6-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
Analogously to example 1, 136mg of the compound prepared in example 188b and 93mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid 25mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 188 a: 3- ({ 6-methyl-5- [ N- (2,2, 2-trifluoroethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, 550mg of the title compound are obtained from 560mg of the acid prepared in example 178c and 160mg of 2,2, 2-trifluoroethylamine.
1H-NMR(300MHz,DMSO-d6)：＝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 188 b: 2- (azetidin-3-ylmethyl) -6-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 550mg of the amide prepared in example 188a 530mg of the title compound are obtained, which is reacted without further purification.
Example 189: 2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -6-methyl-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 55, from 170mg of the compound prepared in example 187b and 80mg of 4-chlorobenzoyl chloride 45mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -6-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 136mg of the compound prepared in example 188b and 72mg 4-chlorobenzoyl chloride 60mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -6-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 120mg of the compound prepared in example 191b and 61mg of 4-chlorobenzoyl chloride 49mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 191 a: (+/-) -3- ({ 6-methyl-5- [ N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 300mg of the acid prepared in example 178c and 105mg of 3,4,5, 6-tetrahydro-2H-pyran-2-ylmethylamine was obtained 140mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 191 b: (+/-) -2- (azetidin-3-ylmethyl) -6-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 140mg of the amide prepared in example 191a 132mg of the title compound were obtained, which was reacted without further purification.
Example 192: (+/-) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxypropyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 151mg of the compound prepared in example 192b and 82mg 4-chlorobenzoyl chloride 89mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 192 a: (+/-) -3- ({5- [ N- (2-methoxypropyl) carbamoyl ] -6-methyl-2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 300mg of the acid prepared in example 178c and 77mg of 2-methoxypropan-1-amine 358mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 192 b: (+/-) -2- (azetidin-3-ylmethyl) -N- (2-methoxypropyl) -6-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a), from 358mg of the amide prepared in example 192a) 319mg of the title compound are obtained, which are reacted without further purification.
Example 193: (+/-) -N- (2-methoxypropyl) -6-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 151mg of the compound prepared in example 192b and 106mg4- (trifluoromethoxy) benzoyl chloride 87mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 55, from 173mg of the compound prepared in example 187b and 105mg of 4- (trifluoromethoxy) benzoyl chloride 87mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 170mg of the compound prepared in example 188b and 116mg of 4- (trifluoromethoxy) benzoyl chloride 70mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
In analogy to example 55, from 179mg of the compound prepared in example 196b and 113mg4- (trifluoromethoxy) benzoyl chloride 22mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 196 a: 3- [ (6-methyl-5- { N- [2- (trifluoromethoxy) ethyl ] carbamoyl } -2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 300mg of the acid prepared in example 178c and 144mg of 2- (trifluoromethoxy) ethylamine hydrochloride, 417mg of the title compound was obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 196 b: 2- (azetidin-3-ylmethyl) -6-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 417mg of the amide prepared in example 196a 369mg of the title compound are obtained, which are reacted without further purification.
Example 197: 2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -6-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
In analogy to example 55, from 179mg of the compound prepared in example 196b and 88mg 4-chlorobenzoyl chloride 41mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 214mg of the compound prepared in example 198b and 109mg 4-chlorobenzoyl chloride 107mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 198 a: 3- [ (5- { N- [2- (cyclopropylmethoxy) ethyl ] carbamoyl } -6-methyl-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 245mg of the acid prepared in example 178c and 82mg2- (cyclopropylmethoxy) ethylamine hydrochloride, 247mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 198 b: 2- (azetidin-3-ylmethyl) -N- [2- (cyclopropylmethoxy) ethyl ] -6-methyl-2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 247mg of the amide prepared in example 198a 214mg of the title compound were obtained, which was reacted without further purification.
Example 199: 2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -6-methyl-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 1, from 173mg of the compound prepared in example 187b and 98mg of 4- (4-fluorophenoxy) benzoic acid 56mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-cyclopropylbenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 168mg of the compound prepared in example 178e and 80mg 4-cyclopropylbenzoic acid 86mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
Analogously to example 1, from 180mg of the compound prepared in example 188b and 95mg4- [4- (trifluoromethyl) phenoxy ] benzoic acid 71mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
Analogously to example 1, from 180mg of the compound prepared in example 178e and 102mg4- [4- (trifluoromethyl) phenoxy ] benzoic acid 108mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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
Analogously to example 1, from 180mg of the compound prepared in example 188b and 73mg4' -fluorobiphenyl-4-carboxylic acid 104mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 180mg of the compound prepared in example 178e and 78mg4' -fluorobiphenyl-4-carboxylic acid 73mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
Analogously to example 55, from 85mg of the compound prepared in example 205c and 45mg 4-chlorobenzoyl chloride, a material still contaminated after column chromatography was obtained, which was further purified by additional preparative thick layer chromatography (using dichloromethane/methanol as mobile phase at a ratio of 95: 5). Obtaining: 48mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 205 a: 4- [ (5-bromo-6-methyl-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1c, from 5.7g 5-bromo-6-methyl-1H-indazole and 15.0g4- [ (toluenesulfonyloxy) methyl ] piperidine-1-carboxylic acid tert-butyl ester was obtained 2.99g of the title compound.
1H-NMR(300MHz,CDCl3)：＝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 205 b: 4- ({5- [ N- (2-methoxyethyl) carbamoyl ] -6-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
Analogously to example 1b, from 600mg of the bromide prepared in example 205a and 331mg of 2-methoxyethylamine after four runs of chromatography and double purification, 3.56g of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 205 c: n- (2-methoxyethyl) -6-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 100mg of the amide prepared in example 205b 85mg of the title compound were obtained, which was reacted without further purification.
Example 206: 2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 85mg of the compound prepared in example 205c and 58mg 2-fluoro-4- (trifluoromethyl) benzoyl chloride a material was obtained which was still contaminated after column chromatography and which was further purified by additional preparative thick layer chromatography (using dichloromethane/methanol as mobile phase in a ratio of 95: 5). Obtaining: 40mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 85mg of the compound prepared in example 205c and 49mg of 4-chloro-2-fluorobenzoyl chloride 68mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 85mg of the compound prepared in example 205c and 58mg 3-fluoro-4- (trifluoromethyl) benzoyl chloride 70mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -6-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 85mg of the compound prepared in example 205c and 62mg 4-chloro-3- (trifluoromethyl) benzoyl chloride 92mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Similar to example 1, from 85mg of the compound prepared in example 205c and 58mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid to yield 126mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 85mg of the compound prepared in example 205c and 53mg of 4- (trifluoromethyl) benzoyl chloride 69mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-ethyl-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 91mg of the compound prepared in example 212i mg and 46mg 4-chlorobenzoyl chloride 61mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
Example 212 a: 4-bromo-3-ethyl-2-methylaniline
A suspension of 3g of 3-ethyl-2-methylaniline hydrochloride in 200ml of ethyl acetate is washed twice with 30ml parts of saturated sodium carbonate solution and twice with 20ml parts of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. This gave 2.69g of ethyl-2-methylaniline, which was reacted further without further purification.
A solution of 3.1g of N-bromosuccinimide in 14.5ml of DMF is added dropwise at 0 ℃ to a solution of 2.36g of the amine prepared above in 29ml of DMF and stirred for 30 minutes at 0 ℃. The reaction mixture was then diluted with 400ml of ethyl acetate and washed once with 30ml of 10% aqueous sodium carbonate solution and once with 30ml of water. After drying over sodium sulfate and filtration, it was concentrated in vacuo. The crude product thus obtained (3.86g) was used in the next step without further purification.
Example 212 b: n- (4-bromo-3-ethyl-2-methylphenyl) acetamide
To a solution of 3.86g of the bromide prepared in example 212a in 48ml of pyridine, 2.04ml of acetic anhydride are added dropwise at 0 ℃ and stirred for 20 hours at 25 ℃. The reaction mixture was concentrated in vacuo and the crude product thus obtained was purified by column chromatography (on silica gel, using hexane/0-100% ethyl acetate). In this manner, 3.73g of the title compound was obtained.
1H-NMR(300MHz,CDCl3)：＝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 a solution of 3.72g of the acetamide prepared in example 212b in 31.5ml of chloroform were added 4.1 ml of acetic anhydride and 2.85g of potassium acetate, followed by dropwise addition of 192mg of 18-crown-6 and 3.4g of isoamyl nitrite. The reaction mixture was heated at reflux for 20 hours and, after cooling, diluted with 200ml ethyl acetate. The organic phase is washed with 20ml of sodium carbonate solution and once with saturated sodium chloride solution. After drying over sodium sulfate and filtration, it is concentrated in vacuo and the crude product thus obtained is purified by column chromatography (on silica gel, using hexane/0-50% ethyl acetate). Yield: 3.78g of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝1.18(3H),2.68(3H),3.04(2H),7.73(1H),8.03(1H),8.64(1H)。
Example 212 d: 5-bromo-4-ethyl-1H-indazole
A mixture of 3.78g of the compound prepared in example 212c in 7.3ml of methanol and 2.63ml of 37% hydrochloric acid is heated under reflux for 2 hours. Then, it was diluted with 400ml of ethyl acetate. The organic phase is washed three times with 50ml portions of sodium bicarbonate solution and once with 50ml 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, using hexane/0-50% ethyl acetate). Yield: 2.97g of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝1.17(3H),2.98(2H),7.30(1H),7.41(1H),8.16(1H),13.17(1H)。
Example 212 e: 4- [ (5-bromo-4-ethyl-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
Analogously to example 1c, from 2.97g of the indazole prepared in example 212d and 7.3g4- [ (toluenesulfonyloxy) methyl ] piperidine-1-carboxylic acid tert-butyl ester 961mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 212 f: 2- { [1- (tert-Butoxycarbonyl) piperidin-4-yl ] methyl } -4-ethyl-2H-indazole-5-carboxylic acid methyl ester
Analogously to example 1e, 571mg of the title compound are obtained, after two runs, from 347mg of the bromide prepared in example 212e and 0.1ml of methanol.
1H-NMR(300MHz,DMSO-d6)：＝1.02-1.15(2H),1.17-1.24(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 212 g: 2- { [1- (tert-butoxycarbonyl) piperidin-4-yl ] methyl } -4-ethyl-2H-indazole-5-carboxylic acid
Analogously to example 1d, 427mg of the title compound were obtained from 371mg of the ester of example 212 f.
1H-NMR(300MHz,DMSO-d6)：＝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 212 h: 4- ({ 4-Ethyl-5- [ N- (2-methoxyethyl) carbamoyl ] -2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 427mg of the acid prepared in example 212g and 83mg 2-methoxyethylamine, 215mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 212 i: 4-Ethyl-N- (2-methoxyethyl) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 215mg of the amide prepared in example 212h 258mg of the title compound were obtained, which was reacted without further purification.
Example 213: 4-Ethyl-N- (2-methoxyethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 91mg of the compound prepared in example 212i and 59mg4- (trifluoromethoxy) benzoyl chloride 32mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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),4.31(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-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 68mg of the compound prepared in example 214c and 37mg 4-chlorobenzoyl chloride 691mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 214 a: 3- [ (5-bromo-4-methoxy-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
To a solution of 1.94g3- [ (tosyloxy) methyl ] azetidine-1-carboxylic acid tert-butyl ester in 15.5ml acetone was added 837mg lithium iodide and the reaction mixture was stirred at 35 ℃ for 16 h. After cooling, it is diluted with 200ml of ethyl acetate and the organic phase is washed twice with 30ml portions of water and once with 20ml of saturated sodium chloride solution. After drying over sodium sulfate and filtration, it was concentrated in vacuo. In this way, 1.6g3- (iodomethyl) azetidine-1-carboxylic acid tert-butyl ester was obtained, which was reacted further without purification.
To a solution of 620mg 5-bromo-7-methoxy-1H-indazole in 24ml DMF was added 1.11g potassium carbonate, and the mixture was stirred for 30 minutes at 25 ℃. Then, 1.25g of the iodide prepared above was added, and the reaction mixture was stirred at 60 ℃ for 3 hours. After cooling, it was diluted with 200ml1:1 tert-butyl methyl ether/hexane, washed once with 20ml portions of water and saturated sodium chloride solution, respectively, dried over sodium sulfate and concentrated in vacuo, and the crude product thus obtained was purified by column chromatography (on silica gel, using a hexane/ethyl acetate gradient). Obtaining: 263mg of the title compound.
1H-NMR(300MHz,CDCl3)：＝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 214 b: 3- ({ 4-methoxy-5- [ N- (2-methoxyethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1b, from 110mg and 252mg each of the compound prepared in example 214a and 63mg and 143mg each of 2-methoxyethylamine a total of 193mg of the title compound was obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 214 c: 2- (azetidin-3-ylmethyl) -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 50mg of the compound prepared in example 214b 42mg of the title compound are obtained, which is reacted further without purification.
Example 215: 4-methoxy-N- (2-methoxyethyl) -2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 55, from 42mg of the compound prepared in example 214c and 32mg of 4- [ (trifluoromethyl) sulfanyl ] benzoyl chloride was obtained 56mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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-bromobenzoyl) azetidin-3-yl ] methyl } -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 42mg of the compound prepared in example 214c and 29mg 4-bromobenzoyl chloride 48mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) pyrrolidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 106mg of the compound prepared in example 217e and 58mg 4-chlorobenzoyl chloride 50mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 217 a: (R) -3- [ (5-bromo-4-methyl-2H-indazol-2-yl) methyl ] pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of 9.0g of tert-butyl (R) -3- (hydroxymethyl) pyrrolidine-1-carboxylate in 100ml of pyridine at 0 ℃ under nitrogen was added 12.8g of p-toluenesulfonyl chloride and stirred at 25 ℃ for 3 hours. The reaction mixture was diluted with ethyl acetate and stirred with sodium bicarbonate for 30 minutes. Then, the phases were separated and the organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo after filtration. The residue thus obtained was purified by column chromatography (on silica gel, using hexane/0-100% ethyl acetate). Obtaining: 11.4g of (R) -3- [ (toluenesulfonyloxy) methyl ] pyrrolidine-1-carboxylic acid tert-butyl ester.
In analogy to example 1c, from 4.53g 5-bromo-4-methyl-1H-indazole and 11.4g tert-butyl (R) -3- [ (toluenesulfonyloxy) methyl ] pyrrolidine-1-carboxylate, prepared as above, by addition of 7.9g tetrabutylammonium iodide, 1.97g of the title compound was obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 217 b: 2- { [ (R) -1- (tert-Butoxycarbonyl) pyrrolidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid methyl ester
Analogously to example 1e, 820mg of the title compound were obtained after two runs from 563mg of the bromide prepared in example 217a and 0.17ml of methanol.
1H-NMR(300MHz,DMSO-d6)：＝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 217 c: 2- { [ (R) -1- (tert-Butoxycarbonyl) pyrrolidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid
Analogously to example 1d, from 620mg of the ester prepared in example 217b 701mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 217 d: (R) -3- ({5- [ N- (2-methoxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 350mg of the acid prepared in example 217c and 73mg 2-methoxyethylamine was obtained 376mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 217 e: n- (2-methoxyethyl) -4-methyl-2- [ (R) -pyrrolidin-3-ylmethyl ] -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 376mg of the amide prepared in example 217d 465mg of the title compound are obtained, which are reacted without further purification.
Example 218: n- (2-methoxyethyl) -4-methyl-2- ({ (R) -1- [4- (trifluoromethoxy) benzoyl ] pyrrolidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 106mg of the compound prepared in example 217e and 74mg4- (trifluoromethoxy) benzoyl chloride was obtained 61mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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-sulfanyl) benzoyl]Pyrrolidin-3-yl } methyl) -2H-indazole-5-carboxamide
Similar to example 1, from 106mg of the compound prepared in example 217e and 75mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid 29mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) pyrrolidin-3-yl ] methyl } -4-methyl-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 55, from 106mg of the compound prepared in example 220b and 48mg of 4-chlorobenzoyl chloride 29mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 220 a: (R) -3- { [ 4-methyl-5- (N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } carbamoyl) -2H-indazol-2-yl ] methyl } pyrrolidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 350mg of the acid prepared in example 217c and 141mg of 2- [ (trifluoromethyl) sulfanyl ] ethylamine there were obtained 245mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 220 b: 4-methyl-2- [ (R) -pyrrolidin-3-ylmethyl ] -N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 245mg of the amide prepared in example 220a 410mg of the title compound were obtained, which was reacted without further purification.
Example 221: 4-methyl-2- ({ (R) -1- [4- (trifluoromethoxy) benzoyl ] pyrrolidin-3-yl } methyl) -N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 55, from 106mg of the compound prepared in example 220b and 62mg4- (trifluoromethoxy) benzoyl chloride 49mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) pyrrolidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 55, from 134mg of the compound prepared in example 222a and 73mg 4-chlorobenzoyl chloride 67mg of the title compound were obtained.
1H-NMR(300MHz,CDCl3)：＝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 material was prepared as follows:
example 222 a: (S) -3- ({5- [ N- (2-methoxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
The title compound was prepared in an amount of 760mg in analogy to examples 217a to 217d, starting from (S) -3- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester.
1H-NMR(300MHz,DMSO-d6)：＝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 222 b: n- (2-methoxyethyl) -4-methyl-2- [ (S) -pyrrolidin-3-ylmethyl ] -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, 134mg of the title compound were obtained from 159mg of the amide prepared in example 222a, which was reacted without further purification.
Example 223: 2- ({ (S) -1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] pyrrolidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 230mg of the compound prepared in example 222b and 141mg4' -fluorobiphenyl-4-carboxylic acid 128mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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 ] benzoyl } pyrrolidin-3-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1, from 230mg of the compound prepared in example 222b and 184mg4- [4- (trifluoromethyl) phenoxy ] benzoic acid 102mg of the title compound are obtained.
1H-NMR(300MHz,CDCl3)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -4- (difluoromethoxy) -N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 55, from 106mg of the compound prepared in example 225h and 49mg 4-chlorobenzoyl chloride 90mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 225 a: n- [ 4-bromo-3- (difluoromethoxy) -2-methylphenyl ] acetamide
A solution of 5.1g N-bromosuccinimide in 24ml DMF was added dropwise to a solution of 5.0g 3-difluoromethoxy-2-methylaniline in 48ml DMF at 0 ℃ and stirred at 0 ℃ for 1 hour. The reaction mixture was then diluted with 400ml of hexane/ethyl acetate and washed once with 50ml of 10% aqueous sodium carbonate solution and three times with 50ml portions of water. After drying over sodium sulfate and filtration, it was concentrated in vacuo. The crude product thus obtained (6.68g) was used in the next step without further purification.
To a solution of 6.39g of bromide prepared as described above in 70ml of pyridine, 3.0ml of acetic anhydride was added dropwise at 0 ℃ and stirred for 20 hours at 25 ℃. The reaction mixture was concentrated in vacuo and the crude product thus obtained was purified by column chromatography (on silica gel, using hexane/0-100% ethyl acetate). The material was then recrystallized from hexane. In this manner, 6.39g of the title compound was obtained.
1H-NMR(300MHz,CDCl3)：＝2.22(3H),2.27(3H),6.51(1H),6.95(1H),7.46(1H),7.71(1H)。
Example 225 b: 1- [ 5-bromo-4- (difluoromethoxy) -1H-indazol-1-yl ] ethan-1-one
Analogously to example 212c, 5.32g of the title compound are obtained from 6.38g of the amide prepared in example 225 a.
1H-NMR(300MHz,DMSO-d6)：＝2.70(3H),7.34(1H),7.90(1H),8.16(1H),8.46(1H)。
Example 225 c: 5-bromo-4- (difluoromethoxy) -1H-indazole
In analogy to example 212d, from 5.32g of the indazole prepared in example 225b 4.12g of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝7.30(1H),7.44(1H),7.56(1H),8.06(1H),13.54(1H)。
Example 225 d: 4- { [ 5-bromo-4- (difluoromethoxy) -2H-indazol-2-yl ] methyl } piperidine-1-carboxylic acid tert-butyl ester
Analogously to example 212e, 4.1g of the indazole prepared in example 225c and 8.7g of 4- [ (toluenesulfonyloxy) methyl ] piperidine-1-carboxylic acid tert-butyl ester gave 2.06g of the title compound.
1H-NMR(300MHz,CDCl3)：＝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 225 e: 2- { [1- (tert-Butoxycarbonyl) piperidin-4-yl ] methyl } -4- (difluoromethoxy) -2H-indazole-5-carboxylic acid methyl ester
In analogy to example 1e, after three runs, 1.28g of the title compound are obtained from 683mg of the bromide prepared in example 225d and 0.18ml of methanol.
1H-NMR(300MHz,DMSO-d6)：＝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 225 f: 2- { [1- (tert-butoxycarbonyl) piperidin-4-yl ] methyl } -4- (difluoromethoxy) -2H-indazole-5-carboxylic acid
Analogously to example 1d, 1.05g of the title compound are obtained from 1.28g of the ester prepared in example 225 e.
1H-NMR(300MHz,DMSO-d6)：＝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 225 g: 4- ({4- (difluoromethoxy) -5- [ N- (2-methoxyethyl) carbamoyl ] -2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 520mg of the compound prepared in example 225f and 92mg 2-methoxyethylamine, 503mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 225 h: 4- (difluoromethoxy) -N- (2-methoxyethyl) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 122mg of the amide prepared in example 225g 106mg of the title compound are obtained, which are reacted without further purification.
Example 226: 4- (difluoromethoxy) -2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 106mg of the compound prepared in example 225h and 59mg4- (4-fluorophenoxy) benzoic acid 11mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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, from 106mg of the compound prepared in example 225h and 55mg4' -fluorobiphenyl-4-carboxylic acid 38mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-cyclopropylbenzoyl) piperidin-4-yl ] methyl } -4- (difluoromethoxy) -N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 106mg of the compound prepared in example 225h and 41mg 4-cyclopropylbenzoic acid 75mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4- (difluoromethoxy) -2H-indazole-5-carboxamide
In analogy to example 55, from 127mg of the compound prepared in example 229b and 53mg 4-chlorobenzoyl chloride 170mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 229 a: 4- { [5- { N- [2- (cyclopropylmethoxy) ethyl ] carbamoyl } -4- (difluoromethoxy) -2H-indazol-2-yl ] methyl } piperidine-1-carboxylic acid tert-butyl ester
Analogously to example 1, from 520mg of the compound prepared in example 225f and 185mg2- (cyclopropylmethoxy) ethylamine there was obtained 453mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 229 b: n- [ (2-Cyclopropylmethoxy) ethyl ] -4- (difluoromethoxy) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 145mg of the amide prepared in example 229a 127mg of the title compound were obtained, which was reacted without further purification.
Example 230: n- [2- (cyclopropylmethoxy) ethyl ] -4- (difluoromethoxy) -2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 127mg of the compound prepared in example 229b and 64mg4- (4-fluorophenoxy) benzoic acid 156mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 127mg of the compound prepared in example 229b and 60mg4' -fluorobiphenyl-4-carboxylic acid 164mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4- (2,2, 2-trifluoromethoxy) -2H-indazole-5-carboxamide
Analogously to example 55, from 109mg of the compound prepared in example 232h and 46mg of 4-chlorobenzoyl chloride 113mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 232 a: n- [ 4-bromo-2-methyl-3- (2,2, 2-trifluoroethoxy) phenyl ] acetamide
Analogously to example 225a, 6.13g of the title compound are obtained from 5.0g 2-methyl-3- (2,2, 2-trifluoroethoxy) aniline.
1H-NMR(300MHz,DMSO-d6)：＝2.07(3H),2.18(3H),4.55(2H),7.29(1H),7.45(1H),9.42(1H)。
Example 232 b: 1- [ 5-bromo-4- (2,2, 2-trifluoroethoxy) -1H-indazol-1-yl ] ethan-1-one
Analogously to example 212c, 5.08g of the title compound are obtained from 6.13g of the amide prepared in example 232 a.
1H-NMR(300MHz,DMSO-d6)：＝2.69(3H),5.14(2H),7.80(1H),7.99(1H),8.64(1H)。
Example 232 c: 5-bromo-4- (2,2, 2-trifluoroethoxy) -1H-indazole
Similar to example 212d, 3.57g of the title compound was obtained from 5.08g of the indazole prepared in example 232 b.
1H-NMR(300MHz,DMSO-d6)：＝5.05(2H),7.24(1H),7.45(1H),8.26(1H),13.38(1H)。
Example 232 d: 4- { [ 5-bromo-4- (2,2, 2-trifluoroethoxy) -2H-indazol-2-yl ] methyl } piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 212e, from 3.57g of the indazole prepared in example 232c and 6.7g of 4- [ (toluenesulfonyloxy) methyl ] piperidine-1-carboxylic acid tert-butyl ester was obtained 1.77g of the title compound.
1H-NMR(300MHz,CDCl3)：＝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 232 e: 2- { [1- (tert-Butoxycarbonyl) piperidin-4-yl ] methyl } -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxylic acid methyl ester
Analogously to example 1e, after three runs, 857mg of the title compound are obtained from 590mg of the bromide prepared in example 232d and 0.15ml of methanol.
1H-NMR(300MHz,DMSO-d6)：＝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 232 f: 2- { [1- (tert-Butoxycarbonyl) piperidin-4-yl ] methyl } -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxylic acid
Analogously to example 1d, 854mg of the ester prepared in example 232e gave 724mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 232 g: 4- ({5- [ N- (2-methoxyethyl) carbamoyl ] -4- (2,2, 2-trifluoroethoxy) -2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 360mg of the compound prepared in example 232f and 59mg 2-methoxyethylamine was obtained 386mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 232 h: n- (2-methoxyethyl) -2- (4-piperidinylmethyl) -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 109mg of the amide prepared in example 232g 113mg of the title compound were obtained, which was reacted without further purification.
Example 233: 2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxamide
In analogy to example 1, from 109mg of the compound prepared in example 232h and 56mg of 4- (4-fluorophenoxy) benzoic acid 51mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-methoxyethyl) -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxamide
Analogously to example 1, from 109mg of the compound prepared in example 232h and 52mg of 4- (4-fluorophenyl) benzoic acid 61mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxamide
In analogy to example 55, from 122mg of the compound prepared in example 235b and 48mg 4-chlorobenzoyl chloride 122mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 235 a: 4- { [5- { N- [2- (cyclopropylmethoxy) ethyl ] carbamoyl } -4- (2,2, 2-trifluoroethoxy) -2H-indazol-2-yl ] methyl } piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1, from 360mg of the compound prepared in example 232f and 119mg2- (cyclopropylmethoxy) ethylamine there was obtained 429mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 235 b: n- [2- (cyclopropylmethoxy) ethyl ] -2- (4-piperidinylmethyl) -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a, from 138mg of the amide prepared in example 235a 122mg of the title compound were obtained, which was reacted without further purification.
Example 236: n- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4- (2,2, 2-trifluoroethoxy) -2H-indazole-5-carboxamide
In analogy to example 1, from 122mg of the compound prepared in example 235b and 58mg of 4- (4-fluorophenoxy) benzoic acid 95mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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
In analogy to example 1, from 122mg of the compound prepared in example 235b and 54mg of 4- (4-fluorophenoxy) benzoic acid 98mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (3-methoxyazetidin-1-yl) ethyl ] -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 120mg of the compound prepared in example 238c and 40mg2- (3-methoxyazetidin-1-yl) ethylamine (prepared in analogy to WO 2006/104406) was obtained 33mg of the title compound.
1H-NMR(300MHz,CDCl3)：＝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 material was prepared as follows:
Example 238 a: 4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxylic acid methyl ester hydrochloride
Analogously to example 1a, 2.51g of the title compound were obtained from 3.0g of the ester prepared in example 1e, which were reacted without further purification.
Example 238 b: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid methyl ester
Analogously to example 55, from 2.5g of the compound prepared in example 238a and 1.5g 4-chlorobenzoyl chloride 3.27g of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 238 c: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxylic acid
Analogously to example 1d, 470mg of the title compound are obtained from 485mg of the ester prepared in example 238 b.
Example 239: (+/-) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 300mg of the compound prepared in example 238c and 92mg3,4,5, 6-tetrahydro-2H-pyran-2-ylmethylamine hydrochloride 188mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide
From 185mg of the racemate prepared in example 239, the racemate separation is carried out by preparative chiral HPLC (method B) to yield 51mg of the title compound together with 53mg of the slower eluting enantiomer (example 241).
Analytical chiral HPLC: 7.02 min.
Example 241: (S or R) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (3,4,5, 6-tetrahydro-2H-pyran-2-ylmethyl) -2H-indazole-5-carboxamide
From 185mg of the racemate prepared in example 239, the racemate separation is carried out by preparative chiral HPLC (method B) to obtain 53mg of the title compound together with 51mg of the faster eluting enantiomer (example 240).
Analytical chiral HPLC: 8.24 min.
Example 242: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N-ethyl-4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, from 300mg of the compound prepared in example 238c and 43mg of ethylamine (2M in THF) 85mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N-isobutyl-4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 300mg of the compound prepared in example 238c and 69mg of isobutylamine 92mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methanesulfonylethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 300mg of the compound prepared in example 238c and 151mg 2-methanesulfonylethylamine hydrochloride 132mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-Methanesulfonylethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1, from 137mg of the compound prepared in example 245b and 41mg 2-methanesulfonylethylamine hydrochloride 67mg of the title compound was obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 material was prepared as follows:
example 245 a: 4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxylic acid methyl ester
Analogously to example 1, from 3.76g of the compound prepared in example 238a and 3.28g4- [4- (trifluoromethyl) phenoxy ] benzoic acid 2.73g of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 245 b: 4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxylic acid
Analogously to example 1d, 1.1g of the title compound are obtained from 2.73g of the ester prepared in example 245 a.
Example 246: n- (2-cyanoethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
Analogously to example 1, 137mg of the compound prepared in example 245b and 18mg 3-aminopropionitrile obtain 144mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
Analogously to example 1, from 137mg of the compound prepared in example 245b and 24mg 2-aminoacetonitrile hydrochloride, 125mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1, from 254mg of the compound prepared in example 245b and 72mg of 3,4,5, 6-tetrahydro-2H-pyran-2-ylmethylamine was obtained 231mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1, from 254mg of the compound prepared in example 245b and 73mg1, 4-dioxane-2-ylmethylamine was obtained 280mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (cyclobutylmethyl) -4-methyl-2H-indazole-5-carboxamide
Similar to example 1, from 300mg of the compound prepared in example 238c and 115mg of cyclobutylmethylamine hydrochloride, 79mg of the title compound was obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2, 2-dimethylpropyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1, from 300mg of the compound prepared in example 238c and 83mg2, 2-dimethylpropan-1-amine 108mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-hydroxyethyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, from 370mg of the compound prepared in example 238c and 54mg 2-aminoethanol 84mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (3-hydroxypropyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1, from 370mg of the compound prepared in example 238c and 66mg 3-aminopropan-1-ol 95mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：＝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) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 100mg of the compound prepared in example 214c and 97mg of 4- (trifluoromethoxy) benzoic acid in DMF 90mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] azetidin-3-yl } methyl) -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 100mg of the compound prepared in example 214c and 98mg 2-fluoro-4- (trifluoromethyl) benzoic acid in DMF 40mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] azetidin-3-yl } methyl) -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 100mg of the compound prepared in example 214c and 106mg 4-chloro-3- (trifluoromethyl) benzoic acid in DMF 40mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-fluorobenzoyl) azetidin-3-yl ] methyl } -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1, from 100mg of the compound prepared in example 214c and 82mg 4-chloro-2-fluorobenzoic acid in DMF 20mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methoxy-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 66mg of the compound prepared in example 258d and 32 mg 2-morpholinoethylamine in DMF obtain 67mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 258 a: 2- { [1- (tert-Butoxycarbonyl) azetidin-3-yl ] methyl } -4-methoxy-2H-indazole-5-carboxylic acid methyl ester
Analogously to example 1e, from 750mg of the compound prepared in example 214a and 546mg of methanol 448mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 258 b: 2- (azetidin-3-ylmethyl) -4-methoxy-2H-indazole-5-carboxylic acid methyl ester
800mg of 258a are initially taken up in 40ml of acetone, treated with 40ml of half-concentrated hydrochloric acid, stirred until complete conversion and concentrated to dryness. Obtaining: 414mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 258 c: 2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methoxy-2H-indazole-5-carboxylic acid methyl ester
404mg of 258b were initially taken up in 30ml of DCM at 0 ℃ and treated with 0.21ml of 4-chlorobenzoyl chloride and 0.75ml of N-ethyldiisopropylamine and stirred at room temperature until complete conversion. For work-up, the reaction solution was treated with saturated sodium bicarbonate solution, extracted with DCM, and the combined organic phases were dried over sodium sulfate and concentrated to dryness. This yielded 608mg of the title compound, which was used in the next step without further purification.
Example 258 d: 2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methoxy-2H-indazole-5-carboxylic acid
550mg of 258c were initially taken in 20ml of ethanol, treated with 20ml of 2N sodium hydroxide and stirred until complete conversion. For work-up, the reaction solution is adjusted to pH 3 with 1N hydrochloric acid, extracted with ethyl acetate, and the combined organic phases are dried over sodium sulfate and concentrated to dryness. Obtained after purification by column chromatography (on silica gel, using a hexane/ethyl acetate gradient): 213mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-ethoxyethyl) -4-methoxy-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 66mg of the compound prepared in example 258d and 22mg 2-ethoxyethylamine in DMF obtain 30mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (3, 3-difluoropyrrolidin-1-yl) ethyl ] -4-methoxy-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 66mg of the compound prepared in example 258d and 37mg2- (3, 3-difluoropyrrolidin-1-yl) ethylamine in DMF 58mg of the title compound was obtained.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methoxy-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 261e and 46mg 2-morpholinoethylamine in DMF 77mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 261 a: 4- [ (5-bromo-4-methoxy-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1c, from 9.65g 5-bromo-4-methoxy-1H-indazole and 23.55g4- [ (toluenesulfonyloxy) methyl ] piperidine-1-carboxylic acid tert-butyl ester was obtained 5.57g of the title compound.
1H-NMR (400MHz, chloroform-d): [ ppm of]＝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 261 b: 2- { [1- (tert-Butoxycarbonyl) piperidin-4-yl ] methyl } -4-methoxy-2H-indazole-5-carboxylic acid methyl ester
Analogously to example 1e, from 2.4g of the compound prepared in example 261a and 1.63g of methanol 1.1g of the title compound are obtained.
Example 261 c: 4-methoxy-2- (4-piperidinylmethyl) -2H-indazole-5-carboxylic acid methyl ester
Analogously to example 258b, 1.1g of the title compound were obtained from 1.1g of the compound prepared in example 261b, which was reacted in the next step without purification.
Example 261 d: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methoxy-2H-indazole-5-carboxylic acid methyl ester
In analogy to example 258c, from 1.1g of the compound prepared in example 261c and 762mg 4-chlorobenzoyl chloride, 980mg of the title compound are obtained after purification by column chromatography (on silica gel using a hexane/ethyl acetate gradient).
1H-NMR(300MHz,DMSO-d6)：[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 261 e: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methoxy-2H-indazole-5-carboxylic acid
In analogy to example 258d, 547mg of the title compound were obtained from 980mg of the compound prepared in example 261 d.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 261e and 26mg 2-methoxyethylamine in DMF obtain 50mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methoxy-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 261e and 35mg2,2, 2-trifluoroethylamine in DMF obtain 68mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-ethoxyethyl) -4-methoxy-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 261e and 31mg 2-ethoxyethylamine in DMF 60mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methoxy-N- {2- [ (trifluoromethyl) sulfanyl ] ethyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 261e and 51mg2- [ (trifluoromethyl) sulfanyl ] ethylamine in DMF obtain 68mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 266B and 89mg of 4- (trifluoromethoxy) benzoic acid in DMF obtain 84mg of the title compound.
LC-MS：Rt＝1.16min,MS(ES+)：m/z＝435(M+H)+。
The starting material was prepared as follows:
example 266 a: 4- ({ 4-methoxy-5- [ N- (2-methoxyethyl) carbamoyl ] -2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
First 3g of compound 261a, 1.59g of 2-methoxyethylamine, 1.87g of molybdenum hexacarbonyl, 204mg of tri-tert-butylphosphine tetrafluoroborate and 316mg of palladium (II) acetate were suspended in 100ml of 1, 4-dioxane. Then 2.25g of sodium carbonate and a few drops of water are added and the mixture is stirred at 140 ℃ for 25min in a 150 watt microwave. The reaction mixture was concentrated and the residue was purified by column chromatography (on silica gel using a hexane/ethyl acetate/methanol gradient). Obtaining: 1.3g of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝0.99-1.22(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 266 b: 4-methoxy-N- (2-methoxyethyl) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
Analogously to example 258b, 1.48g of the title compound were obtained from 1.3g of the compound prepared in example 266a and used in the subsequent reaction without further purification.
Example 267: 2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 266B and 90mg 2-fluoro-4- (trifluoromethyl) benzoic acid in DMF obtain 20mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-Lambda)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Similar to example 1B, mode B, from 100mg of the compound prepared in example 266B and 107mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid in DMF to yield 39mg of the title compound.
LC-MS：Rt＝1.18min,MS(ES+)：m/z＝577(M+H)+。
Example 269: 4-methoxy-N- (2-methoxyethyl) -2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg of the compound prepared in example 266B and 96mg4- [ (trifluoromethyl) sulfanyl ] benzoic acid in DMF 25mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 266B and 97mg 4-chloro-3- (trifluoromethyl) benzoic acid in DMF obtain 27mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-fluorobenzoyl) piperidin-4-yl ] methyl } -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg of the compound prepared in example 266B and 75mg 4-chloro-2-fluorobenzoic acid in DMF 17mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 266B and 97mg 3-fluoro-4- (trifluoromethoxy) benzoic acid in DMF obtain 12mg of the title compound.
LC-MS：Rt＝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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg of the compound prepared in example 266B and 76mg 1-methyl-1H-indole-3-carboxylic acid in DMF obtain 19mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -4-ethoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 110mg of the compound prepared in example 274c and 72mg 4-chlorobenzoic acid in DMF 47mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 274 a: 4- [ (5-bromo-4-ethoxy-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 74c, from 484mg 5-bromo-4-ethoxy-1H-indazole and 1.11g4- [ (5-bromo-4-ethoxy-2H-indazol-2-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester was obtained 285mg of the title compound.
1H-NMR (400MHz, chloroform-d): [ ppm of]＝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 274 b: 4- ({ 4-ethoxy-5- [ N- (2-methoxyethyl) carbamoyl ] -2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 266a, from 285mg of the compound prepared in example 274a and 146mg 2-methoxyethylamine obtained 235mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 274 c: 4-ethoxy-N- (2-methoxyethyl) -2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
Analogously to example 258b, from 235mg of the compound prepared in example 274b 237mg of the title compound were obtained, which were reacted in the next step without further purification.
Example 275: 4-ethoxy-N- (2-methoxyethyl)) -2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl ]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
Similar to example 1B, mode B, from 110mg of the compound prepared in example 274c and 113mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid in DMF to yield 30mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) azetidin-3-yl ] methyl } -4-ethoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 50mg of the compound prepared in example 276c and 35mg 4-chlorobenzoic acid in DMF 25mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 276 a: 3- [ (5-bromo-4-ethoxy-2H-indazol-2-yl) methyl ] azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 74c, from 500mg 5-bromo-4-ethoxy-1H-indazole and 1.06g3- [ (toluenesulfonyloxy) methyl ] azetidine-1-carboxylic acid tert-butyl ester was obtained 204mg of the title compound.
1H-NMR (600MHz, chloroform-d): [ ppm of]＝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 276 b: 3- ({ 4-ethoxy-5- [ N- (2-methoxyethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 266a, from 191mg of the compound prepared in example 276a and 105mg 2-methoxyethylamine was obtained 121mg of the title compound, which was reacted without further purification in the next step.
Example 276 c: 2- (azetidin-3-ylmethyl) -4-ethoxy-N- (2-methoxyethyl) -2H-indazole-5-carboxamide
Similar to example 258b, from 121mg of the compound prepared in example 276b 93mg of the title compound were obtained, which were reacted in the next step without further purification.
Example 277: 4-ethoxy-N- (2-methoxyethyl) -2- ({1- [4- (pentafluoro-Lambda)6-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -2H-indazole-5-carboxamides
Similar to example 1B, mode B, from 50mg276c and 56mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid in DMF to yield 35mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) azetidin-3-yl ] methyl } -6-methyl-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg278B and 66mg 4-chlorobenzoic acid in DMF 23mg of the title compound was obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 278 a: 3- ({ 6-methyl-5- [ N- (2-morpholinoethyl) carbamoyl ] -2H-indazol-2-yl } methyl) azetidine-1-carboxylic acid tert-butyl ester
In analogy to example 1B, mode B, from 410mg178c and 232mg 2-morpholinoethylamine in DMF 418mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 278 b: 2- (azetidin-3-ylmethyl) -6-methyl-N- (2-morpholinoethyl) -2H-indazole-5-carboxamide
Analogously to example 258b, from 400mg of the compound prepared in example 278a 372mg of the title compound was obtained, which was reacted in the next step without further purification.
Example 279: 6-methyl-N- (2-morpholinoethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg278B and 86mg4- (trifluoromethoxy) benzoic acid in DMF was obtained 44mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-morpholinoethyl) -2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -2H-indazole-5-carboxamides
Similar to example 1B, mode B, from 100mg278B and 104mg4- (pentafluoro- λ)6Sulfanyl) benzoic acid in DMF to yield 37mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 150mg205c and 119mg 1-methyl-1H-indole-3-carboxylic acid in DMF obtain 4.2mg of the title compound.
LC-MS：Rt＝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 ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 175mg117e and 122mg 1-methyl-1H-indole-3-carboxylic acid in DMF obtain 35mg of the title compound.
LC-MS：Rt＝0.95min,MS(ES+)：m/z＝460(M+H)+。
Example 283: 2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
Analogously to example 1B, manner B, from 250mg71a and 246mg4- (4-fluorophenoxy) benzoic acid in DMF 267mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 105mg4- (4-chlorophenoxy) benzoic acid in DMF 55mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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- (methylphenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 97mg4- (4-methylphenoxy) benzoic acid in DMF 60mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 92mg4- (4-fluorophenyl) benzoic acid in DMF 39mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-morpholinobenzoyl) piperidin-4-yl ] methyl } -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 88mg 4-morpholinobenzoic acid in DMF 45mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 94mg4- [ (trifluoromethyl) sulfanyl ] benzoic acid in DMF 67mg of the title compound was obtained.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 74mg 1-methyl-1H-indole-3-carboxylic acid in DMF 43mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 74mg 1-methyl-1H-indole-2-carboxylic acid in DMF 51mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 150mg71a and 179mg4- [4- (trifluoromethyl) phenoxy ] benzoic acid in DMF 156mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 82mg 5-fluoro-1-methyl-1H-indole-2-carboxylic acid in DMF obtain 28mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 87mg 5-methoxy-1-methyl-1H-indole-2-carboxylic acid in DMF obtain 37mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 89mg 5-chloro-1-methyl-1H-indole-2-carboxylic acid in DMF obtain 43mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 87mg 6-methoxy-1-methyl-1H-indole-2-carboxylic acid in DMF obtain 36mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 68mg indole-2-carboxylic acid in DMF 43mg of the title compound is obtained.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 75mg 1-methyl-1H-benzimidazole-2-carboxylic acid in DMF obtain 26mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 87mg 2-phenylthiazole-5-carboxylic acid in DMF 53mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 69mg benzoxazole-2-carboxylic acid in DMF obtain 20mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 80mg 2-phenyloxazole-5-carboxylic acid in DMF was obtained 20mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 90mg4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid in DMF 23mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝1.13-1.35(2H),1.37-1.72(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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 57mg benzothiazole-2-carboxylic acid in DMF 35mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B), from 75mg71a and 90mg of the carboxylic acid prepared in example 303B) in DMF was obtained 42mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 303 a: 4- { [6- (trifluoromethyl) pyridin-3-yl ] oxy } benzonitrile
2.5g of 5-bromo-2- (trifluoromethyl) pyridine, 5.8g of 4-hydroxybenzonitrile, 10.8g of cesium carbonate and 1.87g of molybdenum hexacarbonyl in 100ml of 1, 4-dioxane were heated at reflux until complete conversion. The reaction mixture was diluted with water, extracted several times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (on silica gel, using a hexane/ethyl acetate gradient). Obtaining: 1.35g of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝7.35(2H),7.75-7.84(1H),7.89-8.03(3H),8.66(1H)。
Example 303 b: 4- { [6- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid
1.33g of the compound prepared in example 303a in 64ml of ethanol are treated with 32ml of 40% potassium hydroxide solution and heated under reflux until complete conversion. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. Obtaining: 1.32g of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 90mg4- { [6- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid in DMF 48mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 90mg71a and 73mg 3-phenyl-1, 2, 4-oxadiazole-5-carboxylic acid in DMF obtain 40mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 110mg71a and 101mg4- (4-cyanophenoxy) benzoic acid in DMF 59mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 89mg4- (3-fluorophenoxy) benzoic acid in DMF 40mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 119mg4- [3- (trifluoromethyl) phenoxy ] benzoic acid in DMF 47mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 73mg 5-phenyloxazole-2-carboxylic acid in DMF was obtained 10mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 119mg4- [3- (trifluoromethyl) phenoxy ] benzoic acid in DMF 47mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 96mg4- [ (5-chloropyridin-2-yl) oxy ] benzoic acid in DMF 72mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 103mg4- [5- (trifluoromethyl) pyridin-2-yl ] benzoic acid in DMF 83mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 96mg4- (2, 4-difluorophenoxy) benzoic acid in DMF 87mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 96mg4- (3, 4-difluorophenoxy) benzoic acid in DMF 48mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 102mg 4' - (trifluoromethyl) biphenyl-4-carboxylic acid in DMF 32mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝1.27(2H),1.37-1.71(2H),2.24-2.39(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-bromobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
6.96g of the title compound are obtained in analogy to example 1B, manner B, from 5.61g71a and 2.89g 4-bromobenzoic acid.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
80mg of the aryl bromide prepared in example 316 together with 32mg of (5-chloropyridin-2-yl) boronic acid are initially taken in 1ml of tetrahydrofuran, treated with 17.3mg of 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride and 0.17ml of 1M potassium carbonate solution and heated in a microwave at 120 ℃ for 10 minutes at 100 watts. After the new addition of 11mg of (5-chloropyridin-2-yl) boronic acid and 17.3mg of palladium (II) catalyst, the reaction mixture is heated again in a microwave at 120 ℃ for 10 minutes at 100W until complete conversion. The reaction mixture was concentrated. After HPLC purification, this gave 15mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝1.18-1.36(2H),1.37-1.75(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
In analogy to example 317, from 125mg316 and 53mg (4-methoxy-2-methylphenyl) boronic acid 50mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 44mg (6-methylpyridin-3-yl) boronic acid under reflux 37mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝1.15-1.35(2H),1.37-1.71(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
In analogy to example 317, from 125mg316 and 75g (4-fluoro-2-methoxyphenyl) boronic acid under reflux 60mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 84mg [6- (trifluoromethyl) pyridin-3-yl ] boronic acid under reflux was obtained 45mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝1.15-1.37(2H),1.37-1.71(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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 68mg (6-methoxypyridin-3-yl) boronic acid under reflux was obtained 54mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝1.13-1.35(2H),1.36-1.71(2H),2.20-2.40(1H),2.54(3H),2.73-3.16(2H),3.51-3.77(1H),3.90(3H),3.96-4.19(2H),4.37(3H),6.93(1H),7.20(1H),7.39-7.52(3H),7.73(2H),8.05(1H),8.47-8.63(2H),8.83(1H)。
Example 323: 2- ({1- [4- (6-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 49mg (6-methoxypyridin-2-yl) boronic acid under reflux were obtained 55mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 44mg (5-methylpyridin-2-yl) boronic acid under reflux was obtained 9mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 45mg (5-fluoropyridin-2-yl) boronic acid under reflux obtained 35mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 49mg (5-methoxypyridin-2-yl) boronic acid under reflux 94mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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, the following: 4-methyl-2- ({1- [4- (2-methylpyrimidin-5-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 102mg (2-methylpyrimidin-5-yl) boronic acid pinacol ester under reflux was obtained 46mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 89mg [2- (trifluoromethyl) pyrimidin-5-yl ] boronic acid under reflux obtained 34mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 317, from 125mg316 and 121mg [6- (trifluoromethyl) pyridin-2-yl ] boronic acid pinacol ester under reflux was obtained 70mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 213mg71a and 153mg4- (4-cyanophenoxy) benzoic acid in DMF 151mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 38mg71a and 36mg 1-methyl-1H-indole-3-carboxylic acid in DMF 26mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-methylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 807mg71a and 788mg 4-bromo-3-methylbenzoic acid in DMF 498mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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-tert-butylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 81mg 4-tert-butylbenzoic acid in DMF 50mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 82mg4- (1-hydroxy-1-methylethyl) benzoic acid in DMF 28mg of the title compound was obtained.
1H-NMR(400MHz,DMSO-d6)：[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-Cyclohexylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 93mg 4-cyclohexylbenzoic acid in DMF 75mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-naphthoyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
23mg of the title compound are obtained in analogy to example 1B, manner B) from 100mg71a) and 92mg 6-methoxynaphthalene-2-carboxylic acid in DMF.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 93mg 2-phenylthiazole-5-carboxylic acid in DMF 36mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 80mg 1-methyl-1H-benzimidazole-2-carboxylic acid in DMF 39mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 86mg 2-phenyloxazole-5-carboxylic acid in DMF was obtained 30mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 84mg benzoxazole-2-carboxylic acid in DMF 37mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 86mg4- (1-cyano-1-methylethyl) benzoic acid in DMF obtain 20mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝1.17-1.34(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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 98mg4- (2-pyrimidinyloxy) benzoic acid in DMF 37mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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- (3-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 75mg71a and 73mg4- (3-pyridyloxy) benzoic acid in DMF 7mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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-naphthoyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B), from 75mg71a and 69mg of the carboxylic acid prepared in example 344c) in DMF 28mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝1.21-1.35(2H),1.37-1.75(2H),2.23-2.39(1H),2.52(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),7.13-7.25(2H),7.29(1H),7.36-7.48(2H),7.77-7.93(3H),8.15(1H),8.52(1H)。
The starting material was prepared as follows:
example 344 a: 7-Methoxynaphthalene-2-yl-1, 1,2,2,3,3,4,4, 4-nonafluorobutyl-1-sulfonate
5.12g of 7-methoxy-2-naphthol were dissolved in 50ml of toluene and cooled to 0 ℃. 30.7ml of N, N-diisopropylethylamine and 17.6ml of nonafluorobutylsulfonyl chloride were successively added dropwise thereto, and then the reaction mixture was stirred at room temperature until complete conversion. The reaction mixture was poured into 600ml of saturated ammonium chloride solution, the brown oil which had precipitated was separated and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried and concentrated. The residue was purified by column chromatography (on silica gel, using a hexane/ethyl acetate gradient). Obtaining: 11.45g of the title compound.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝3.89(3H),7.28(1H),7.41(1H),7.52(1H),7.90-8.00(2H),8.05(1H)。
Example 344 b: 7-Methoxynaphthalene-2-carboxylic acid methyl ester
Analogously to example 1e, 2.34g of the title compound were obtained from 11.0g344a and 8.8ml methanol.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝3.89(3H),3.91(3H),7.31(1H),7.57(1H),7.82(1H),7.94(2H),8.54(1H)。
Example 344 c: 7-methoxynaphthalene-2-carboxylic acid
In analogy to example 258d, 1.27g of the title compound are obtained from 2.0g344 b.
1H-NMR(300MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 200mg71a and 232mg4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid in DMF 221mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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- (2-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 98mg4- (2-pyridyloxy) benzoic acid in DMF 29mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 97mg4- { [4- (trifluoromethyl) pyrimidin-2-yl ] oxy } benzoic acid in DMF 11mg of the title compound was obtained.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 61mg benzothiazole-2-carboxylic acid in DMF 28mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 96mg303B in DMF obtain 34mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 129mg4- { [6- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid in DMF 36mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 104mg 4' -methoxybiphenyl-4-carboxylic acid in DMF 15mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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
In analogy to example 1B, mode B, from 100mg71a and 78mg 3-phenyl-1, 2, 4-oxadiazole-5-carboxylic acid in DMF obtain 12mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 91mg4- (3,4,5, 6-tetrahydro-2H-pyran-4-yloxy) benzoic acid in DMF obtain 21mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 77mg 5-phenyloxazole-2-carboxylic acid in DMF was obtained 10mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 115mg4- [3- (trifluoromethyl) phenoxy ] benzoic acid in DMF 40mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 98mg4- [ (5-cyanopyridin-2-yl) oxy ] benzoic acid in DMF 15mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 102mg4- [ (5-chloropyridin-2-yl) oxy ] benzoic acid in DMF 40mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 102mg4- (2, 4-difluorophenoxy) benzoic acid in DMF 22mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 102mg4- (3, 4-difluorophenoxy) benzoic acid in DMF 23mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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 } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg71a and 109mg 4' - (trifluoromethyl) biphenyl-4-carboxylic acid in DMF 44mg of the title compound were obtained.
LC-MS：Rt＝1.28min,MS(ES+)：m/z＝579(M+H)+。
Example 361: 2- ({1- [4- (3-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 100mg71a and 95mg4- (3-fluorophenoxy) benzoic acid in DMF 43mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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-isopropoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 41mg 2-fluoro-4-isopropoxybenzoic acid 31mg of the title compound are obtained.
1H-NMR (300MHz, chloroform-d): [ ppm of]＝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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 50mg 3-fluoro-3 ',4' -dimethylbiphenyl-4-carboxylic acid 35mg of the title compound were obtained.
1H-NMR (300MHz, chloroform-d): [ ppm of]＝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
In analogy to example 1B, mode B, from 90mg71a and 65mg3,2 '-difluoro-4' -methoxybiphenyl-4-carboxylic acid 28mg of the title compound were obtained.
1H-NMR (300MHz, chloroform-d): [ ppm of]＝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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 75mg71a and 38mg4- (difluoromethoxy) benzoic acid 23mg of the title compound were obtained.
1H-NMR (300MHz, chloroform-d): [ ppm of]＝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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
120mg of compound 54, 26mg of o-fluorophenol, 152mg of cesium carbonate, 6.7mg of cuprous (I) bromide and 3.2mg of (2-pyridyl) acetone were suspended in 6ml of dimethyl sulfoxide, and stirred at 80 ℃ for 3 days. The reaction mixture was filtered, the filter cake was washed with water and ethyl acetate, and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by HPLC to obtain 12mg of the title compound.
1H-NMR (300MHz, chloroform-d): [ ppm of]＝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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 80mg54 and 38mg (2-methyl-4-cyanophenyl) boronic acid under reflux was obtained 40mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
200mg of the aryl bromide prepared in example 54 together with 187mg of (5-chloropyridin-2-yl) -2-boronic acid pinacol ester are initially taken up in 3ml of DMF, treated with 48mg of 1,1 '-bis (diphenylphosphino) ferrocene palladium (II) dichloride, 39mg of copper (I) chloride, 254mg of cesium carbonate and 22mg of 1, 1' -bis (diphenylphosphino) ferrocene and heated at 70 ℃ for about 1 day until no further reaction progress is observed. The reaction mixture was treated with water and saturated sodium bicarbonate solution, several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated. After HPLC purification, this gave 92mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝1.19-1.36(2H),1.37-1.72(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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 80mg [6- (trifluoromethyl) pyridin-2-yl ] boronic acid pinacol ester under reflux was obtained 33mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 48mg (4-methoxy-2-methylphenyl) boronic acid under reflux was obtained 52mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 50mg (4-chloro-2-methylphenyl) boronic acid under reflux was obtained 43mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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' - (1-cyano-1-methylethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 55mg [4- (1-cyano-1-methylethyl) phenyl ] boronic acid under reflux was obtained 67mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 368, from 200mg54 and 183mg (5-methylpyridin-2-yl) boronic acid pinacol ester under reflux was obtained 12mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 56mg [2- (trifluoromethyl) pyridin-5-yl ] boronic acid under reflux obtained 37mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 47mg (2-methoxypyridin-5-yl) boronic acid under reflux was obtained 50mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 300mg54 and 135mg (4-fluoro-2-methylphenyl) boronic acid under reflux was obtained 261mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 80mg54 and 32mg (2-methylpyridin-5-yl) boronic acid under reflux obtained 45mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[ppm]＝1.26(2H),1.37-1.71(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) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 45mg (6-methoxypyridin-2-yl) boronic acid under reflux was obtained 30mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 64mg (2-methylpyrimidin-5-yl) boronic acid pinacol ester under reflux was obtained 36mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 50mg (4-fluoro-2-methoxyphenyl) boronic acid under reflux obtained 47mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 54mg (4-fluoro-2-methoxyphenyl) boronic acid under reflux obtained 87mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 56mg [2- (trifluoromethyl) pyrimidin-5-yl ] boronic acid under reflux was obtained 14mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 317, from 100mg54 and 51mg (4-chloro-2-fluorophenyl) boronic acid under reflux obtained 51mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 317, from 100mg54 and 51mg (2-chloro-4-fluorophenyl) boronic acid under reflux obtained 26mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 46mg (5-chloropyridin-3-yl) boronic acid under reflux obtained 22mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 41mg (5-fluoropyridin-3-yl) boronic acid under reflux 57mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 56mg [5- (trifluoromethyl) pyridin-3-yl ] boronic acid under reflux was obtained 73mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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' - (1-hydroxy-1-methylethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 100mg54 and 77mg (4-hydroxy-tert-butylphenyl) boronic acid pinacol ester under reflux was obtained 46mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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
In analogy to example 317, from 100mg54 and 46mg (3, 5-difluorophenyl) boronic acid under reflux obtained 22mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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
In analogy to example 317, from 60mg332 and 19mg of (4-fluorophenyl) boronic acid under reflux obtained 25mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 317, from 60mg332 and 27mg (3, 5-difluorophenyl) boronic acid under reflux was obtained 30mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 60mg332 and 21mg pyridin-3-ylboronic acid under reflux obtained 19mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝1.20-1.33(2H),1.37-1.71(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) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
In analogy to example 317, from 60mg332 and 21mg pyridin-4-ylboronic acid under reflux obtained 19mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-indazole-5-carboxamide
In analogy to example 317, 57mg of the title compound are obtained from 60mg332 and 21mg of phenylboronic acid under reflux.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝1.19-1.34(2H),1.37-1.67(2H),2.25(4H),2.53(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-bromobenzoyl) piperidin-4-yl ] methyl } -N- (2-methanesulfonylethyl) -4-methyl-2H-indazole-5-carboxamide
Analogously to example 1B, mode B, from 1g395B and 797mg 4-bromobenzoic acid in DMF obtain 383mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 395 a: 4- ({5- [ N- (2-Methanesulfonylethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 266a, from 2.506g1c and 3.022g 2-methanesulfonylethylamine hydrochloride 1.26g of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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 395 b: n- (2-Methanesulfonylethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
In analogy to example 258b, from 1.26g of compound 395a was obtained 1.29g of the title compound which was reacted without further purification.
Example 396: n- (2-Methanesulfonylethyl) -4-methyl-2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 80mg395B and 90mg4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoic acid in DMF 30mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 80mg395B and 90mg303B in DMF obtain 30mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-methanesulfonylethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 80mg395B and 74mg2',4' -difluorobiphenyl-4-carboxylic acid in DMF 25mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (3-hydroxy-3-methylbutyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 160mg399B and 105mg 4-chlorobenzoic acid in DMF 37mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 399 a: 4- ({5- [ N- (3-hydroxy-3-methylbutyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1B, mode B, 150mg of 1d and 69mg of 4-amino-2-methylbutan-2-ol are reacted in DMF at 60 ℃. After phase separation and extraction, the combined organic phases are washed additionally with 0.1N hydrochloric acid and saturated sodium bicarbonate solution. This gave 132mg of the title compound, which was used in the next step without further purification.
Example 399 b: n- (3-hydroxy-3-methylbutyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
Similar to example 258b, 162mg of the title compound were obtained from 132mg399a and used in the next step without further purification.
Example 400: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-cyanoethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 177mg400B and 128mg 4-chlorobenzoic acid in DMF 55mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 400 a: 4- ({5- [ N- (2-cyanoethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1B, mode B, 150mg of 1d and 42mg of 3-aminopropionitrile in DMF at 60 ℃. After phase separation and extraction, the combined organic phases are washed additionally with 0.1N hydrochloric acid and saturated sodium bicarbonate solution. This gave 137mg of the title compound, which was used in the next step without further purification.
Example 400 b: n- (2-cyanoethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
In analogy to example 258b, from 137mg400a 177mg of the title compound were obtained and used in the next step without further purification.
Example 401: 2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (cyanomethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 90mg238c and 29mg aminoacetonitrile in DMF obtain 75mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (cyclopropylmethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B), from 90mg238c) and 19mg cyclopropylmethylamine in DMF obtain 44mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 137mg403B and 31mg (cyclobutylamino) methylamine hydrochloride 48mg of the title compound are obtained.
1H-NMR(400MHz,DMSO-d6)：[ppm]＝1.17-1.32(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 material was prepared as follows:
example 403 a: 4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxylic acid methyl ester
Analogously to example 1B, manner B, 2.73g of the title compound were obtained from 3.76g238a and 3.28g4- [4- (trifluoromethyl) phenoxy ] benzoic acid.
1H-NMR(400MHz,DMSO-d6)：[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 403 b: 4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxylic acid
Analogously to example 1d, 970mg of the title compound were obtained from 1.05g403a and used in the next step without further purification.
Example 404: n-isobutyl-4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg403B and 14mg isobutylamine 35mg of the title compound was obtained.
1H-NMR(300MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg403B and 16mg pivalic amine 36mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 100mg403B and 26mg cyclopropylmethylamine is obtained 33mg of the title compound.
1H-NMR(300MHz,DMSO-d6)：[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-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 140mg407a and 84mg4' -fluorobiphenyl-4-carboxylic acid 37mg of the title compound are obtained.
1H-NMR(300MHz,DMSO-d6)：[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 material was prepared as follows:
example 407 a: n- (2-cyanoethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
Similar to example 1a, 140mg of the title compound was obtained from 165mg400a and used in the next step without further purification.
Example 408: 2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methanesulfonylethyl) 4-methyl-2H-indazole-5-carboxamide
126mg of the title compound are obtained in analogy to manner B of example 1B) from 300mg408a) and 156mg4' -fluorobiphenyl-4-carboxylic acid.
LC-MS：Rt＝1.20min,MS(ES+)：m/z＝577(M+H)+。
The starting material was prepared as follows:
example 408 a: n- (2-Methanesulfonylethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
In analogy to example 1a, 300mg of the title compound was obtained from 346mg395a and used in the next step without further purification.
Example 409: 2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (3-hydroxypropyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B) from 124mg409B) and 73mg4' -fluorobiphenyl-4-carboxylic acid 20mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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 material was prepared as follows:
example 409 a: 4- ({5- [ N- (3-hydroxypropyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1B, mode B, from 150mg of 1d and 30mg of 3-aminopropan-1-ol 151mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 409 b: n- (3-hydroxypropyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide
Analogously to example 1a, 124mg of the title compound were obtained from 246mg409a and used in the next step without further purification.
Example 410: 2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-hydroxyethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 117mg410B and 72mg4' -fluorobiphenyl-4-carboxylic acid 36mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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 material was prepared as follows:
example 410 a: 4- ({5- [ N- (2-hydroxyethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1B, mode B) from 150mg of 1d) and 25mg of 2-aminoethan-1-ol gave 143mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 410 b: n- (3-hydroxypropyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
Analogously to example 1a), 117mg of the title compound were obtained from 138mg410a and used in the next step without further purification.
Example 411: (+/-) -N- (1, 4-dioxan-2-ylmethyl) -2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, manner B, from 226mg411B) and 119mg4' -fluorobiphenyl-4-carboxylic acid 62mg of the title compound were obtained.
1H-NMR(400MHz,DMSO-d6)：[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 material was prepared as follows:
example 411 a: (+/-) -4- ({5- [ N- (1, 4-dioxan-2-ylmethyl) carbamoyl ] -4-methyl-2H-indazol-2-yl } methyl) piperidine-1-carboxylic acid tert-butyl ester
In analogy to example 1B, mode B, from 250mg1d and 78mg (+/-) -1, 4-dioxane-2-ylmethylamine was obtained 267mg of the title compound.
1H-NMR(400MHz,DMSO-d6)：[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 411 b: (+/-) -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2- (4-piperidinylmethyl) -2H-indazole-5-carboxamide hydrochloride
Similar to example 1a, 226mg of the title compound were obtained from 261mg411a and used in the next step without further purification.
Example 412: (+/-) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (oxetan-2-ylmethyl) -2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 350mg238c) and 83mg (+/-) -oxetan-2-ylmethylamine 55mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2H-indazole-5-carboxamide
In analogy to example 1B, mode B, from 376mg238c and 111mg (+/-) -1, 4-dioxan-2-ylmethylamine hydrochloride 185mg of the title compound were obtained.
1H-NMR(300MHz,DMSO-d6)：[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-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2H-indazole-5-carboxamide
From 185mg of the racemate prepared in example 413, the racemate separation is carried out by preparative chiral HPLC (method D) to yield 51mg of the title compound together with 58mg of the slower eluting enantiomer (example 415).
Analytical chiral HPLC: 12.62 min.
Example 415: (S or R) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2H-indazole-5-carboxamide
From 185mg of the racemate prepared in example 413, the racemate separation is carried out by preparative chiral HPLC (method D) to yield 58mg of the title compound together with 51mg of the faster eluting enantiomer (example 414).
Analytical chiral 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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
From 231mg of the racemate prepared in example 248, the racemate separation is carried out by preparative chiral HPLC (method E) to yield 24mg of the title compound together with 24mg of the slower eluting enantiomer (example 417).
Analytical chiral 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 ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
From 231mg of the racemate prepared in example 248, the racemate separation is carried out by preparative chiral HPLC (method E) to yield 24mg of the title compound together with 24mg of the faster eluting enantiomer (example 416).
Analytical chiral HPLC: 8.98 min.
Example 418: (R or S) -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
From 280mg of the racemate prepared in example 249, the racemate separation was carried out by preparative chiral HPLC (method D (injection volume: 0.1 ml; detection: UV210nM)) to yield 65mg of the title compound together with 75mg of the slower-eluting enantiomer (example 419).
Analytical chiral HPLC: 13.66 min.
Example 419: (R or S) -N- (1, 4-dioxan-2-ylmethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
From 280mg of the racemate prepared in example 249, the racemate separation is carried out by preparative chiral HPLC (method D (injection volume: 0.1 ml; detection: UV210nM)) to yield 75mg of the title compound together with 65mg of the faster-eluting enantiomer (example 418).
Analytical chiral HPLC: 14.90 min.
Biological examples:
1. detection of human prostaglandin E 2 Antagonism of (subtype EP2) receptor signalling
1.1. Principle of detection
PGE2To human PGE2EP of receptor2Binding of the isoforms induces activation of membrane-localized adenylate cyclase and leads to the formation of cAMP. In the presence of the phosphodiesterase inhibitor IBMX, cAMP, which accumulates due to this stimulus and is released by cell lysis, is used in a competitive assay. In this assay, cAMP present in the lysate competes with fluorescently labeled cAMP (cAMP-d2) for binding to Eu cryptate-labeled anti-cAMP antibody.
In the absence of cellular cAMP, the maximum signal is produced due to the binding of this cAMP-d2 molecule to the antibody. After excitation of the cAMP-d2 molecule at 337nM, there is Fluorescence Resonance Energy Transfer (FRET) to the Eu cryptate molecule of the anti-cAMP antibody (labeled with it), followed by a persistent emission signal at 665nM (and at 620 nM). Both signals are measured in a suitable measuring instrument by a time delay, i.e. after the decay of the background fluorescence. From prostaglandins E2Any increase in low FRET signal (emission) due to application (change in pore ratio)665nmEmission620nm10000 forms) indicate antagonist effects.
1.2. Detection method
1.2.1. Antagonism assay (data per well of 384-well plate):
to a test plate with a solution of the added substance (0.05. mu.1; 100% DMSO, concentration range 0.8 nM-16.5. mu.M) was added 4. mu.l of cAMP-d 2/cell suspension (625000 cells/ml). After a 20min pre-incubation at Room Temperature (RT), 2. mu.l of 3xPGE2 solution (1.5nM in PBS-IBMX) was added and incubated in the presence of agonist at RT for an additional 60min (volume: about 6. mu.l). Next, the reaction was stopped by adding 2. mu.l of cell lysis buffer and incubated for another 20min at RT (volume: about 8. mu.l) before the actual measurement.
2. Detection of human prostaglandin E 2 Antagonism of (subtype EP4) receptor signalling
2.1. Principle of detection
PGE2To human PGE2EP of receptor4Binding of the isoforms induces activation of membrane-localized adenylate cyclase and leads to the formation of cAMP. In the presence of the phosphodiesterase inhibitor IBMX, cAMP, which accumulates due to this stimulus and is released by cell lysis, is used in a competitive assay. In this assay, cAMP present in the lysate competes with fluorescently labeled cAMP (cAMP-d2) for binding to Eu cryptate-labeled anti-cAMP antibody.
In the absence of cellular cAMP, the maximum signal is produced due to the binding of this cAMP-d2 molecule to the antibody. After excitation of the cAMP-d2 molecule at 337nM, there is Fluorescence Resonance Energy Transfer (FRET) to the Eu cryptate molecule of the anti-cAMP antibody (labeled with it), followed by a persistent emission signal at 665nM (and at 620 nM). Both signals are measured in a suitable measuring instrument by a time delay, i.e. after the decay of the background fluorescence. From prostaglandins E2Any increase in low FRET signal (emission as pore ratio change) resulting from application665nmEmission620nm10000 forms) indicate antagonist effects.
2.2. Detection method
2.2.1. Antagonism assay (data per well of 384-well plate):
to a test plate with a solution of the added substance (0.05. mu.l; 100% DMSO, concentration range 0.8 nM-16.5. mu.M) was added 4. mu.l of cAMP-d 2/cell suspension (312500 cells/ml). After a 20min pre-incubation at Room Temperature (RT), 2. mu.l of 3xPGE2 solution (0.3nM in PBS-IBMX) was added and incubated in the presence of agonist at RT for an additional 60min (volume: about 6. mu.l). Next, the reaction was stopped by adding 2. mu.l of cell lysis buffer and incubated for another 20min at RT (volume: about 8. mu.l) before the actual measurement.
3. Detection of antagonism to human prostaglandin D receptor signaling
3.1. Principle of detection
Prostaglandin D2Binding to the human PGD receptor induces activation of membrane-localized adenylate cyclase and leads to the formation of cAMP. In the presence of the phosphodiesterase inhibitor IBMX, cAMP, which accumulates due to this stimulus and is released by cell lysis, is used in a competitive assay. In this assay, cAMP present in the lysate competes with fluorescently labeled cAMP (cAMP-d2) for binding to Eu cryptate-labeled anti-cAMP antibody.
In the absence of cellular cAMP, the maximum signal is produced due to the binding of this cAMP-d2 molecule to the antibody. After excitation of the cAMP-d2 molecule at 337nM, there is Fluorescence Resonance Energy Transfer (FRET) to the Eu cryptate molecule of the anti-cAMP antibody (labeled with it), followed by a persistent emission signal at 665nM (and at 620 nM). Both signals are measured in a suitable measuring instrument by a time delay, i.e. after the decay of the background fluorescence. From prostaglandins E 2Any increase in low FRET signal (emission as pore ratio change) resulting from application665nmEmission620nm10000 forms) indicate antagonist effects.
3.2. Detection method
3.2.1. Antagonism assay (data per well of 384-well plate):
to a test plate with a solution of the added substance (0.05. mu.l; 100% DMSO, concentration 0.8 nM-16.5. mu.M) was added 4. mu.l of cAMP-d 2/cell suspension (625000 cells/ml). After a 20min pre-incubation at Room Temperature (RT), 2. mu.l of 3xPGD2 solution (6nM in PBS-IBMX) was added and incubated at RT for another 30min in the presence of agonist (volume: about 6. mu.l). Next, the reaction was stopped by adding 2. mu.l of cell lysis buffer and incubated for another 20min at RT (volume: about 8. mu.l) before the actual measurement.
4.PGE 2 EP of receptor 2 Subtype and Pre-ovulatory cumulus expansion
4.1. Background:
in the pre-ovulatory antral follicle, the oocyte is surrounded by cumulus cells, which form a compact cell cap around the oocyte. After the LH peak (luteinizing hormone), a series of processes are activated, which results in a significant morphological change of this cell cap of the cumulus cell. During this time, cumulus cells form extracellular matrix, which leads to the so-called cumulus expansion (Vanderhyden et al, Dev biol.1990Aug; 140 (2): 307-317). This cumulus expansion is an important component of the ovulation process and the subsequent possibility of fertilization.
Prostaglandin and prostaglandin E therein during cumulus expansion2Of decisive importance is the synthesis of which is induced by the LH surge. Prostaglandin EP2Knockout mice (Hizaki et al, 1999, Proc Natl Acad Sci U S A., Aug 31; 96(18):10501-6.) exhibited significantly reduced cumulus expansion and severe fertility decline, suggesting prostaglandin EP2The importance of the receptor to this process.
4.2. Cumulus expansion in vitro test
In immature female mice (strain: B6D2F1 from Charles River), folliculogenesis was induced by a single administration (intraperitoneally) of 10IU PMSG (pregnant horse serum gonadotropin; Sigma G-4877, Lot68H0909) at 14-18 days of age. At 47-50 hours post injection, ovaries were removed, and cumulus-oocyte complexes were removed. At this stage, the cumulus complex has not yet expanded.
With prostaglandin E 2 (PGE 2 ) (0.3. mu.M), vehicle control (ethanol) or test substance incubated the cumulus-oocyte complexes for 20-24 hours. Culture medium: alpha-MEN medium with 0.1mM IBMX, pyruvate (0.23mM), glutamate (2mM), penicillin/streptomycin 100IU/ml penicillin and 100. mu.g/ml streptomycin), HSA (8mg/ml) and fetal bovine serum (FBS, 10%). Then, cumulus expansion was established by four stages (according to Vanderhyden et al, Dev biol.1990 month 8; 140(2): 307-.
4.3 in vivo Effect on post-ovulatory in vitro fertilization
The substance may exert an effect on fertility by reducing the fertilization ability of the oocyte or cumulus-oocyte complex. To investigate such effects, the substance may be administered in vivo and subjected to in vitro fertilization after ovulation of the cumulus-oocyte complex occurs. In the absence of the test substance, the in vitro fertilization rate provides a conclusion about the in vivo effect of the test substance.
Immature female mice (strain: B6D2F1, Charles River, Suelzfeld, age: 19-25 days) were kept in indoor Macrolon cages with controlled lighting (12 hours dark: 12 hours light), fed a standard diet, and provided with free-access drinking water.
Mice were pretreated with PMSG (pregnant horse serum gonadotropin) (10 IU/animal, i.v.). After 48 hours, a stimulus triggering ovulation is generated in the animals by a single intravenous administration of 10 IU/animal (hCG, human chorionic gonadotropin). The test substances were dissolved in benzyl benzoate/castor oil (1+4v/v) and administered subcutaneously in a volume of 0.1ml 1 hour before hCG (n ═ 5 animals/group). Animals were sacrificed 14 hours after hCG administration. The expelled oocytes and cumulus-oocyte complexes are obtained from the ovarian cysts and/or oviducts and subjected to in vitro fertilization, wherein for fertilization 40000 sperm/0.5 ml sperm count is used for 1 hour. At 24 hours after incubation with sperm, the number of fertilized oocytes was determined and the percent fertilization rate was determined.
The results in Table 4 show that example 17 of the present invention has a dose-dependent effect on the fertilization ability of the expelled cumulus-oocyte complexes.
4.4 in vivo effects on fertility in non-human primates (cynomolgus monkeys):
to study the effect of substances on fertility, mating studies in monkeys were performed (Jensen et al, content 81(2010) 165-171). For this purpose, subjects were administered to female cynomolgus monkeys (macaca fascicularis) which were bred in groups, and then, these animals were mated with male animals. The mating was checked by daily sperm examination by vaginal smear. The pregnancy resulting therefrom is determined by hormone measurements and ultrasound examinations. By variation of serum estradiol concentration during the menstrual cycle, (rising before the mid-LH peak), the fertile phase within the menstrual cycle of an individual animal can be determined. Mating in this fertile period is called "timed mating" (mating in fertile period). In addition to the absolute number of pregnancies that occur, the effect on fertility can also be expressed as pregnancy/"timed mating".
To test EP2Effect of receptor antagonists on monkey fertility examples 17 and 56 of the present invention dissolved in 0.5ml castor oil were administered over 6 months. Example 17 (n-10 animals) was administered once daily at a dose of 10mg/kg, while example 56 (n-9 animals) was administered twice daily at a dose of 10 mg/kg. Vehicle alone (n-10 animals) was administered to the control group. During the first month of treatment, the male and female animals were not kept together. Thereafter, the female and male animals were kept together for 5 months, and pregnancy was monitored and the menstrual cycle was monitored.
Table 5 shows that both substances lead to a significant reduction in the number of pregnancies that occur. These data show for the first time EP2Strong contraceptive effect of receptor antagonists in primates. Further study results showed that these substances had no effect on hormone levels and cycle length.This confirms that these substances produce a contraceptive effect by a non-hormonal mechanism. After discontinuation of the treatment, some animals exhibited reversibility of fertility.
5. Determination of pharmacokinetic parameters after intravenous administration
5.1. Intravenous administration:
to this end, the substances are administered in dissolved form, using compatible solubilizers such as PEG400 and/or ethanol in tolerable amounts. The substance is administered in a dose of 0.1-1 mg/kg. Administration was carried out as a bolus injection in female rats. Here, at various points after the bolus, approximately 100-. Blood samples were treated with lithium heparin as an anticoagulant and stored refrigerated until further post-processing. After centrifugation of the sample at 3000rpm for 15min, 100 μ l aliquots were taken from the supernatant (plasma) and precipitated by addition of 400 μ l of cold acetonitrile or methanol (anhydrous). The precipitated samples were frozen at-20 ℃ overnight and then centrifuged again at 3000rpm for 15min, after which 150. mu.l of clear supernatant was taken for concentration determination. Analysis was performed using an Agilent1200HPLC system with LCMS/MS detection attached.
5.2 calculation of PK parameters
By PK calculation softwarePerforming a calculation of where t1/2Denotes the half-life (here: terminal t) within a defined interval1/2In hours).
Table 1: for the compound of the invention on hEP2Biological Activity of the receptor (measurement of IC by cAMP antagonism assay50) p-hDP&hEP4Selectivity (measurement of IC by cAMP antagonism assay)50) Examples of (2): x: 1-10, xx: 10-100, xxx>100：
Table 2: percent reduction in cumulus expansion upon stimulation with 0.3 μ M PGE2, control 1: example 62 of DE102009049662A1
Table 3: terminal half-life (t) after intravenous administration in female rats1/2) Control 1: example 62 of DE102009049662A1
Examples t1/2[hr]
Control 1 0.4
Example 17 2.5
Example 42 3.2
Example 117 2.0
Example 283 5.8
Table 4: reduction of in vitro fertilization rate following in vivo administration of a test substance:
table 5: reduction of pregnancy rates in non-human primates (cynomolgus monkeys)
Group of Animals/groups "timed mating" number Pregnancy % pregnancy/"timed mating"
Control 10 21 8 38
Example 17 10 25 3 6
Example 56 9 34 2 12
Detection of vaginal sperm during the fertile phase of the menstrual cycle

Claims (34)

1. A compound of the general formula (I) and isomers, diastereomers, enantiomers and salts thereof or cyclodextrin inclusion compounds thereof
Wherein
R1: representation H, C1-C2Alkyl or C1-C2An alkoxy group;
R2: h or methyl;
with the proviso that two radicals R1Or R2One of them is H;
X：-(CH2)l-、-(CH2)k-O-、-CH2-S-、CH2-S(O)2-、-CH(CH3)-、-CH(CH3) -O-or-C (CH)3)2-O-；
k: 1 or 2;
l: 0. 1 or 2;
R4：H、C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
and in the presence of X: -CH2-or-CH (CH)3) -in the case of
R4: further represents a 4-6-membered heterocyclic group;
and in the presence of X: - (CH)2)l-or-CH (CH)3) -in the case of
R4: further represents CN;
or
X together with R4Together connected via a ring carbon to form a 4-6 membered heterocyclyl;
m: 1 or 2;
n: 1 or 2;
ar: 6-10-membered aryl or 5-10-membered heteroaryl,
R3: halogen, CN, SF5、C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C4-C6Heterocyclyl radical, O-C1-C4Alkyl, O-C3-C6Cycloalkyl, O-C4-C6Heterocyclic radical, S-C1-C4Alkyl, S (O)2-C1-C4Alkyl, Ar ', O-Ar', C (CH)3)2-CN or C (CH)3)2-OH; and is
Ar': optionally mono-or disubstituted 6-membered aryl or 5-6 membered heteroaryl;
wherein the substituent is selected from F, Cl, CN, C1-C4Alkyl, O-C1-C4Alkyl, C (CH)3)2-CN、C(CH3)2OH and C (O) NH2。
2. A compound according to claim 1, and isomers, diastereomers, enantiomers, and salts thereof, or cyclodextrin inclusion compounds thereof, wherein
R1、R2: represents H or methyl;
With the proviso that two radicals R1Or R2One of them is H;
X：-(CH2)l-or- (CH)2)k-O-；
k: 1 or 2;
l: 0. 1 or 2;
R4：C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group; and is
m、n：2；
And R is3Ar and Ar' have the meanings given in claim 1.
3. A compound according to claim 1, and isomers, diastereomers, enantiomers, and salts thereof, or cyclodextrin inclusion compounds thereof, wherein
R1、R2: represents H or methyl;
with the proviso that two radicals R1Or R2One of them is H;
X：-(CH2)l-or- (CH)2)k-O-；
k: 1 or 2;
l: 0. 1 or 2;
R4：C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group; and is
m、n：1；
And R is3Ar and Ar' have the meanings given in claim 1.
4. A compound according to claim 1 or 2, and isomers, diastereomers, enantiomers, and salts thereof, or cyclodextrin inclusion compounds thereof, wherein
R1: represents a methyl group;
R2：H；
X：-(CH2)l-or- (CH)2)k-O-；
k：1；
l: 0 or 1;
R4：C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
m, n: 2; and is
Ar: a phenyl group;
and R is3And Ar' has the meaning of claim 1.
5. A compound according to claim 1 or 3, and isomers, diastereomers, enantiomers, and salts thereof, or cyclodextrin inclusion compounds thereof, wherein
R1: represents a methyl group;
R2：H；
X：-(CH2)l-or- (CH)2)k-O-；
k：1；
l: 0 or 1;
R4：C1-C4alkyl radical, C3-C4Cycloalkyl or CH2-C3-C4A cycloalkyl group;
m, n: 1; and is
Ar: a phenyl group;
and R is3And Ar' has the aforementioned meaning.
6. The compound of claim 1, selected from the group comprising:
1.2- { [1- (4-cyano-2-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
2- { [1- (4-tert-Butoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
3.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
4. N- (2-methoxyethyl) -4-methyl-2- { [1- (4-morpholinobenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
5.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
6.2- { [1- (2-fluoro-4-methanesulfonylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
7.2- { [1- (2-fluoro-4-methoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
2- { [1- (4-bromo-2-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
9.2- { [1- (2-fluoro-4-methylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
10.2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
11. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
12. N- (2-methoxyethyl) -4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
13.2- ({1- [4- (4-chlorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
14. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (4-methylphenoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
15.2- ({1- [4- (4-tert-butylphenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
16. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
17. N- (2-methoxyethyl) -2- ({1- [4- (4-methoxyphenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
18. N- (2-methoxyethyl) -4-methyl-2- { [1- (4-phenoxybenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
19.2- { [1- (4-cyclopropylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
20.2- { [1- (4-methoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
21.2- { [1- (4-fluorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
22. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
23.2- { [1- (2-methoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
24. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [ (trifluoromethyl) sulfonyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
25. N- (2-methoxyethyl) -4-methyl-2- ({1- [3- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
26. N- (2-methoxyethyl) -4-methyl-2- { [1- (3-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
27.2- { [1- (3-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
28.2- ({1- [4- (4-carbamoylphenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
29.2- ({1- [4- (cyclopentyloxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
30.2- ({1- [4- (difluoromethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
31.2- { [1- (4-cyanobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
32.2- ({1- [4- (1H-imidazol-1-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
33. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (oxazol-2-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
34. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (oxazol-5-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
35. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (isoxazol-5-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
36. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (1H-pyrazol-1-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
37. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (1H-1,2, 4-triazol-1-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
38.2- ({1- [4- (difluoromethoxy) -2-fluorobenzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
39.2- ({1- [ 2-fluoro-4- (pyrrolidin-1-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
40.2- ({1- [ (3,4' -difluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
41.2- ({1- [ (3-fluoro-4' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
42.2- ({1- [ (3-fluoro-4' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
43.2- [ (1- { [ 3-fluoro-3' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
44.2- [ (1- { [ 3-fluoro-2' - (trifluoromethoxy) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
45.2- ({1- [ (2' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
46.2- ({1- [ (2',4' -difluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
47.2- ({1- [ (2-fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
48. N- (2-methoxyethyl) -4-methyl-2- ({1- [ (2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
49. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (4-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
50. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (4H-1,2, 4-triazol-4-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
51.2- { [1- (2-fluoro-4-morpholinobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
52.2- { [1- (4-bromobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
53. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
54.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
55. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
56.4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
57.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
58.4-methyl-N- (2,2, 2-trifluoroethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
59.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
60. N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
61. N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
62. N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
63. N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
64.2- { [1- (4-cyclopropylbenzoyl) piperidin-4-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
65.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
67.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
68.4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
69.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
70.2- { [1- (4-cyclopropylbenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
71.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
72. N- (2-Isopropoxyethyl) -4-methyl-2- { [1- (4-methylbenzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
73.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
74. N- (2-Isopropoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
75.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
76.2- { [1- (4-Cyclopropylbenzoyl) piperidin-4-yl ] methyl } -N- (2-isopropoxyethyl) -4-methyl-2H-indazole-5-carboxamide
77.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
78.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
79.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
81. N- (2-tert-butoxyethyl) -2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
82. N- (2-tert-butoxyethyl) -2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
83. N- (2-tert-butoxyethyl) -2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
84. N- (2-tert-butoxyethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
85.2- { [1- (4-chlorobenzoyl) piperidine-4-radical]Methyl } -4-methyl-N- {2- [ ((s))2H3) Methoxy radical]-(2H4) Ethyl } -2H-indazole-5-carboxamide
86.2- ({1- [4- (4-fluorophenoxy) benzoyl]Piperidin-4-yl } methyl) -4-methyl-N- {2- [ (A)2H3) Methoxy radical](2H4) Ethyl } -2H-indazole-5-carboxamide
87.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
88. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
89. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
90.2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
91.2- { [1- (4-chloro-2-fluorobenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
92.2- ({1- [ 3-fluoro-4- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
93.2- ({1- [ 4-chloro-3- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
94.2- { [1- (4-cyclopropylbenzoyl) azetidin-3-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
95. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
96.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
97.4-methyl-N- (2,2, 2-trifluoroethyl) -2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
98.2- ({1- [ 2-fluoro-4- (trifluoromethyl) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
99.4-methyl-2- ({1- [4- (pentafluoro- λ)6-sulfanyl) benzoyl]Azetidin-3-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
100. N- [2- (Cyclopropoxy) ethyl ] -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
101. N- [2- (cyclobutoxy) ethyl ] -4-methyl-2- ({1- [4- (trifluoromethoxy) benzoyl ] azetidin-3-yl } methyl) -2H-indazole-5-carboxamide
102.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2H-indazole-5-carboxamide
103. N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
104. N- [2- (cyclopropylmethoxy) ethyl ] -4-methyl-2- { [1- (4-methylbenzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
105.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- [2- (trifluoromethoxy) ethyl ] -2H-indazole-5-carboxamide
106. N- (2-tert-butoxyethyl) -2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-2H-indazole-5-carboxamide
107. N- [2- (cyclopropylmethoxy) ethyl ] -2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] azetidin-3-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
108.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
109.2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
110.2- ({1- [4- (4-fluorophenoxy) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
111.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
112.2- { [1- (4-chlorobenzoyl) azetidin-3-yl ] methyl } -4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2H-indazole-5-carboxamide
113.4-methyl-N- [2- (2,2, 2-trifluoroethoxy) ethyl ] -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
114.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } azetidin-3-yl) methyl ] -2H-indazole-5-carboxamide
115.2- ({1- [4- (4-chlorophenoxy) benzoyl ] azetidin-3-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
116.2- ({1- [4- (4-chlorophenoxy) benzoyl ] azetidin-3-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
117. N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
118.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) azetidin-3-yl ] methyl } -2H-indazole-5-carboxamide
119.2- { [1- (4-chlorobenzoyl) piperidin-4-yl ] methyl } -N-ethyl-4-methyl-2H-indazole-5-carboxamide
120.2- ({1- [4- (4-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
121.2- ({1- [4- (4-chlorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
122.4-methyl-2- ({1- [4- (methylphenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
123.2- ({1- [ (4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
4-methyl-2- { [1- (4-morpholinobenzoyl) piperidin-4-yl ] methyl } -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
125.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [ (trifluoromethyl) sulfanyl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
126.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [4- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
127.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
128.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [6- (trifluoromethyl) pyridin-3-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
129.4-methyl-N- (2,2, 2-trifluoroethyl) -2- { [1- (4- { [6- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
130.2- ({1- [4- (4-cyanophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
131.2- ({1- [4- (3-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
132.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [3- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
133.2- [ (1- {4- [ (5-cyanopyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
134.2- [ (1- {4- [ (5-chloropyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [5- (trifluoromethyl) pyridin-2-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
136.2- ({1- [4- (2, 4-Difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
137.2- ({1- [4- (3, 4-Difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
138.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- { [4' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
139.2- { [1- (4-bromobenzoyl) piperidin-4-yl ] methyl } -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
140.2- ({1- [4- (5-Chloropyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
141.2- ({1- [ (4 '-methoxy-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
142.4-methyl-2- ({1- [4- (6-methylpyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
143.2- ({1- [ (4 '-fluoro-2' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
144.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [6- (trifluoromethyl) pyridin-3-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
145.2- ({1- [4- (6-methoxypyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
146.2- ({1- [4- (6-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
147.4-methyl-2- ({1- [4- (5-methylpyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
148.2- ({1- [4- (5-Fluoropyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
149.2- ({1- [4- (5-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
150.4-methyl-2- ({1- [4- (2-methylpyrimidin-5-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2,2, 2-trifluoroethyl) -2H-indazole-5-carboxamide
151.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [2- (trifluoromethyl) pyrimidin-5-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
152.4-methyl-N- (2,2, 2-trifluoroethyl) -2- [ (1- {4- [6- (trifluoromethyl) pyridin-2-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
153.2- ({1- [4- (4-cyanophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
154.2- { [1- (4-bromo-3-methylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
155.2- { [1- (4-tert-butylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
156.2- ({1- [4- (1-hydroxy-1-methylethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
157.2- { [1- (4-cyclohexylbenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
158.2- ({1- [4- (1-cyano-1-methylethyl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
159. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (pyrimidin-2-yloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
160. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (3-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
161. N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [5- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
162. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (2-pyridyloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
163. N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [4- (trifluoromethyl) pyrimidin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
164. N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [6- (trifluoromethyl) pyridin-3-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
165. N- (2-methoxyethyl) -4-methyl-2- { [1- (4- { [6- (trifluoromethyl) pyridin-2-yl ] oxy } benzoyl) piperidin-4-yl ] methyl } -2H-indazole-5-carboxamide
166.2- ({1- [ (4' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
167. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (3,4,5, 6-tetrahydro-2H-pyran-4-yloxy) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
168. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [3- (trifluoromethyl) phenoxy ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
169.2- [ (1- {4- [ (5-cyanopyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -N- (2-methoxy-2-ethyl) -4-methyl-2H-indazole-5-carboxamide
170.2- [ (1- {4- [ (5-Chloropyridin-2-yl) oxy ] benzoyl } piperidin-4-yl) methyl ] -N- (2-methoxy-2-ethyl) -4-methyl-2H-indazole-5-carboxamide
171.2- ({1- [4- (2, 4-difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
172.2- ({1- [4- (3, 4-Difluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
173. N- (2-methoxyethyl) -4-methyl-2- [ (1- { [4' - (trifluoromethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
174.2- ({1- [4- (3-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
175.2- { [1- (2-fluoro-4-isopropoxybenzoyl) piperidin-4-yl ] methyl } -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
176.2- ({1- [ (3-fluoro-3 ',4' -dimethylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
177.2- ({1- [ (2', 3-difluoro-4' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
178.2- ({1- [4- (difluoromethoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
179.2- ({1- [4- (2-fluorophenoxy) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
180.2- ({1- [ (4 '-cyano-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
181.2- ({1- [4- (5-Chloropyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
182. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [6- (trifluoromethyl) pyridin-2-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
183. N- (2-methoxyethyl) -2- ({1- [ (4 '-methoxy-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
184.2- ({1- [ (4 '-chloro-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
185.2- [ (1- { [4' - (1-cyano-1-methylethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
186. N- (2-methoxyethyl) -2- ({1- [4- (5-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
187. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [6- (trifluoromethyl) pyridin-3-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
188. N- (2-methoxyethyl) -2- ({1- [4- (6-methoxypyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
189.2- ({1- [ (4 '-fluoro-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
190. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (6-methylpyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
191. N- (2-methoxyethyl) -2- ({1- [4- (6-methoxypyridin-2-yl) benzoyl ] piperidin-4-yl } methyl) -4-methyl-2H-indazole-5-carboxamide
192. N- (2-methoxyethyl) -4-methyl-2- ({1- [4- (2-methylpyrimidin-5-yl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
193.2- ({1- [ (4 '-fluoro-2' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
194.2- ({1- [ (4 '-chloro-2' -methoxybiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
195. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [2- (trifluoromethyl) pyrimidin-5-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
196.2- ({1- [ (4 '-chloro-2' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
197.2- ({1- [ (2 '-chloro-4' -fluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
198.2- ({1- [4- (5-chloropyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
199.2- ({1- [4- (5-fluoropyridin-3-yl) benzoyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
200. N- (2-methoxyethyl) -4-methyl-2- [ (1- {4- [5- (trifluoromethyl) pyridin-3-yl ] benzoyl } piperidin-4-yl) methyl ] -2H-indazole-5-carboxamide
201.2- [ (1- { [4' - (1-hydroxy-1-methylethyl) biphenyl-4-yl ] carbonyl } piperidin-4-yl) methyl ] -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
202.2- ({1- [ (3',5' -difluorobiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
203.2- ({1- [ (4 '-fluoro-2' -methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
204.2- ({1- [ (3',5' -difluoro-2-methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -N- (2-methoxyethyl) -4-methyl-2H-indazole-5-carboxamide
205. N- (2-methoxyethyl) -4-methyl-2- ({1- [ 3-methyl-4- (3-pyridyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide
206. N- (2-methoxyethyl) -4-methyl-2- ({1- [ 3-methyl-4- (4-pyridyl) benzoyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide, and
207. n- (2-methoxyethyl) -4-methyl-2- ({1- [ (2-methylbiphenyl-4-yl) carbonyl ] piperidin-4-yl } methyl) -2H-indazole-5-carboxamide.
7. Pharmaceutical product comprising at least one compound according to any one of claims 1 to 6 and at least one pharmaceutically suitable carrier substance.
8. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for contraception/contraception.
9. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for contraception/contraception and for the treatment and prevention of a disease selected from the group consisting of: infectious diseases, cancer, cardiovascular diseases, angiogenic diseases, uterine contractile disorders, pain, inflammatory diseases, neuroinflammatory diseases, neurodegenerative diseases, autoimmune diseases, immune-dependent diseases/therapies, renal diseases and ophthalmic diseases.
10. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and treatment of endometriosis.
11. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis and treatment of menstrual disorders.
12. The use according to claim 11, wherein the menstrual disorder is severe and persistent bleeding, irregular bleeding and pain.
13. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and treatment of fibroids.
14. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis and treatment of cancer, wherein the cancer diseases are lung cancer, intestinal cancer, breast cancer, skin cancer, prostate cancer or esophageal cancer, and leukemia.
15. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis and treatment of arteriosclerosis.
16. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the prevention and treatment of neurodegenerative, neuroinflammatory and ischemic diseases, wherein the diseases are alzheimer's disease, parkinson's disease, ALS, stroke and multiple sclerosis.
17. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and treatment of polycystic kidney disease.
18. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the prevention and treatment of pain, wherein the pain is inflammatory hyperalgesia.
19. Use of a compound according to one of claims 1 to 6 for the preparation of a medicament for the prophylaxis and treatment of infectious diseases of the lung.
20. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the prophylaxis and treatment of chronic obstructive pulmonary disease.
21. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and treatment of inflammatory diseases of the intestine, wherein said inflammatory diseases of the intestine are crohn's disease and ulcerative colitis.
22. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for prophylaxis and treatment in bone marrow transplantation surgery.
23. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the prevention and treatment of a pathological ocular disease, wherein the pathological ocular disease is graves' disease.
24. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis and treatment of aneurysms.
25. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prevention and treatment of vascular injury and kawasaki syndrome.
26. Use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis and treatment of arthritis.
27. A medicament comprising a compound of general formula (I) in combination with a Cyclooxygenase (COX) inhibitor for the treatment of a disease, wherein the COX inhibitor is selected from the group consisting of: aspirin, naproxen, indomethacin, meloxicam, ibuprofen, ketoprofen, piroxicam, tenoxicam, nimesulide, mefenamic acid, ketorolac, celecoxib (4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide), parecoxib (N- [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl propionamide), rofecoxib (4- (4-methylsulfonylphenyl) -3-phenylfuran-2 (5H) -one), valdecoxib (4- [ 5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide), NS-398 (N-methyl-2-cyclohexyloxy-4-nitrobenzenesulfonesulfonamide) Amide), lumiracoxib [2- (2 '-chloro-6' -fluorophenyl) amino-5-methylphenylacetic acid ], ceracoxib, and etoricoxib.
28. The medicament of claim 27, wherein the disease is an infectious disease, cancer, cardiovascular disease, angiogenic disease, uterine contractile disorder, pain, inflammatory disease, neuroinflammatory disease, neurodegenerative disease, autoimmune disease, immune-dependent disease/therapy, renal disease, and ophthalmologic disease, and wherein the medicament is also used for treating pain and for the treatment of transplantation and for birth control.
29. Use of a compound of the general formula I according to one of claims 1 to 6 for the preparation of a pharmaceutical preparation for enteral, parenteral, vaginal, intrauterine and oral administration of a medicament according to any one of claims 8 to 26.
30. Process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that compounds of the general formula (VIII) are reacted
Wherein R is1、R2、R3Ar, m and n have the meanings given in claim 1,
with an amine of the general formula (XI),
wherein R is4And X has the meaning as claimed in claim 1.
31. Process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that compounds of the general formula (VI) are reacted
Wherein R is1、R2、R3Ar, m and n have the meanings given in claim 1,
with amines of the general formula (XI) and carbon monoxide or a carbon monoxide source under palladium (0) catalysis,
wherein R is4And X has the meaning as claimed in claim 1.
32. The method of claim 31, wherein the carbon monoxide source is molybdenum hexacarbonyl.
33. Process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that compounds of the general formula (XV)
Wherein R is1、R2、R4X, m, n have the meanings indicated in claim 1,
With compounds of the general formula (IX)
Wherein Y ═ OH, or Y ═ Cl, or Y ═ O-c (O) -O-CH2(CH3)CH3And is and
wherein R is3And Ar has the meaning as claimed in claim 1.
34. Process for the preparation of compounds of the general formula (I) according to claim 1, characterized in that compounds of the general formula (XVI) are reacted
Wherein R is1、R2、R4X, Ar, m and n have the meanings as claimed in claim 1, and wherein LG' represents Br or I,
with a boronic acid or boronic ester of the general formula (XVIII),
Met–R3(XVIII)
wherein R is3Have the meaning as claimed in claim 1.
HK15104364.3A 2011-11-28 2012-11-26 2h-indazoles as ep2 receptor antagonists HK1203938B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE102011087170.5 2011-11-28
DE102011087170 2011-11-28
DE102012206715 2012-04-24
DE102012206715.9 2012-04-24
PCT/EP2012/073556 WO2013079425A1 (en) 2011-11-28 2012-11-26 Novel 2h-indazoles as ep2 receptor antagonists

Publications (2)

Publication Number Publication Date
HK1203938A1 HK1203938A1 (en) 2015-11-06
HK1203938B true HK1203938B (en) 2017-09-01

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