NZ624722B2 - Novel 2h-indazoles as ep2 receptor antagonists - Google Patents

Novel 2h-indazoles as ep2 receptor antagonists Download PDF

Info

Publication number
NZ624722B2
NZ624722B2 NZ624722A NZ62472212A NZ624722B2 NZ 624722 B2 NZ624722 B2 NZ 624722B2 NZ 624722 A NZ624722 A NZ 624722A NZ 62472212 A NZ62472212 A NZ 62472212A NZ 624722 B2 NZ624722 B2 NZ 624722B2
Authority
NZ
New Zealand
Prior art keywords
methyl
indazolcarboxamide
piperidinyl
jennyp
benzoyl
Prior art date
Application number
NZ624722A
Other versions
NZ624722A (en
Inventor
Nico Brauer
Bernd Buchmann
Bernhard Lindenthal
Anne Mengel
Ulrike Rohn
Andrea Rotgeri
Laak Antonius Ter
Original Assignee
Bayer Intellectual Property Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Intellectual Property Gmbh filed Critical Bayer Intellectual Property Gmbh
Priority claimed from PCT/EP2012/073556 external-priority patent/WO2013079425A1/en
Publication of NZ624722A publication Critical patent/NZ624722A/en
Publication of NZ624722B2 publication Critical patent/NZ624722B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present disclosure relates to novel 2H-indazoles of the general formula (I), methods for the preparation thereof and the use thereof for the production of pharmaceutical agents for the treatment of diseases and indications which are linked with the EP2- receptor. An example of the compound is 2-{[1-(4-cyano-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazol-S-carboxamide. {[1-(4-cyano-2-fluorobenzoyl)piperidin-4-yl]methyl}-N-(2-methoxyethyl)-4-methyl-2H-indazol-S-carboxamide.

Description

[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Novel 2H-indazoles as EPz Receptor Antagonists The present invention relates to novel EP2 or antagonists, the production thereof and the use thereof as drugs, and ceutical preparations which contain the new 2H—indazoles.
It has already long been known that prostaglandins are key molecules in the processes of female reproductive biology, such as for example the regulation of ovulation and fertilization. Effects on uterine contractions, tation, deciduation (e. g. placenta formation) and menstruation have also been described, or are the subject of scientific studies. Prostaglandins also play an important part in pathological changes in the reproductive tract, including menorrhagia, dysmenorrhoea, endometriosis, fibroids (myomas) and cancer, and in general in inflammatory (e.g. Crohn e), infections (e.g. bacterial infections) and neurodegenerative processes (e. g. Alzheimer, ALS), and functions in the immune defence, angiogenesis, pain, wound healing and interactions with the endocrine system (e.g. aromatase induction) are known. Hitherto, the mechanism through which prostaglandins effect the changes has not been tely elucidated. Recent findings indicate that prostaglandins, their receptors and their signal transduction paths are involved in processes such as angiogenesis, sis, proliferation and in inflammatory/anti- inflammatory processes.
The effects of the prostaglandins are mediated through their G protein coupled receptors, which are located in the cell membrane. Of particular interest is glandin E2 (PGEz), which effects a great variety of cellular actions by binding to functionally different receptor es, namely the EP1, EP2, EP3 and EP4 receptors. The or subtypes to which glandin E2 binds appear to be of particular importance for the receptor-mediated actions which are involved in the regulation of fertility. Thus it could be shown that the reproductive functions are impaired in EP2 knockout mice (EP2 '/'), e. g. in mice which no longer have a functional PGE2 receptor e EP2, and that these animals have a smaller “litter” (Matsumoto et al., 2001, Biology of Reproduction 64, 1557-1565). Likewise it could be shown that these EP2 knockout mice (Hizaki et al., 1999, Proc Natl Acad Sci U. S. A,. Aug 31; 96(18):10501-10506) display markedly decreased s ion and severe subfertility, which is to be regarded as being causally linked with decreased reproductive ses such as ovulation and fertilization.
Accordingly, the EP2 receptor is an important target for the pment of drugs for the regulation of female ity. The existence of the 4 subclasses of the PGE2 receptor opens up the possibility of targeted development of selectively active compounds. Previously, r, hardly any selective EP2 receptor antagonists were known, since most known compounds also [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp bind to the other PGE2 receptor subtypes, such as for example to the EP4 receptor or other prostaglandin receptors such as the DP receptor.
EP2 receptor antagonists are for example described in the application U82005059742 and EP1467738 ur, Medical Research Council). A method is claimed n an EP2 and/or an EP4 antagonist can be used for the treatment of menorrhagia and dysmenorrhoea. AH6809 is disclosed as an antagonist of the EP2 or EP4 or, and no other c antagonists and no new compounds are disclosed.
In the application WOO3/Ol6254, Ono Pharmaceutical claims the production of arylcarboxylic acids or saturated carboxylic acid derivatives which are aryl group or heterocycle—substituted inter alia as PGE2 receptor antagonists. The disclosed compounds are claimed for the treatment of a large number of diseases, also including allergic diseases, mer’s disease, pain, abortion, menstrual problems, menorrhagia and dysmenorrhoea, endometriosis, diseases of the bones, ischaemia etc. However, the compounds described are characterized by a particularly high affinity for the EP3 receptor. In a further application (WOO4/O32964), newer compounds are described which are also characterized by a particularly high affinity for the EP3 receptor, but also find use as EP2 antagonists, for the treatment and prophylaxis of allergic diseases.
In the applications from the company Applied Research s 53923 (substituted pyrrolidines) or WOO3/O35064 (substituted pyrazolidiones), compounds for the treatment of diseases which are associated with prostaglandins, such as for example infertility, hypertension and osteoporosis, are claimed. The compounds bind to the EP4 and the EP2 receptor subtypes.
In the application WOO3/O6439l (Pfizer Products), lites of [3-[[N—(4-tert-butylbenzyl)- (pyridinylsulphonyl)amino]methyl] acetic acid are described, which t the binding of [3H] prostaglandin E2 to the EP2 receptor. The use of these metabolites for the treatment of osteoporosis is disclosed.
In the ation 124577, Tani et al. claim rostaglandin derivatives for the treatment of immunological diseases, allergic diseases, premature labour, abortion, etc. The compounds bind to the EP2 and the EP4 receptor.
In the patent applications from Bayer ng Pharma AG (W02007/057232, W02007/07l456, W02008/028689, W02008/028690 W02008/02869l, W02008/0152099, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp W02008/0152097, W02008/0152094, W02009/007421, W02009/007422) and DE 10 2009 049 662 Al, ive antagonists of the EP2 ors are for the first time claimed.
In the applications from Summit ation PLC (W02007/091107) and CM Sun et al.
(W02008/070599) 2H—indazoles are disclosed, but not for the treatment of fertility disorders.
In the applications from Pfizer W02009/063365 and W02008/139287, ines and in W02010/052625 pyrrolidones as antagonists of the EP2 receptor, and the use thereof for the treatment of EPg-mediated conditions such as endometriosis and leiomyomata are claimed.
In a ation (British Journal of cology (2011), 164, 1847-1856), Forselles et al.
(Pfizer) describe selective antagonists of the EP2 receptors. The compounds are azetidines which display an in-vivo influence on the blood flow. The compounds display high n binding.
In a publication by PM. Roveto et al. (239. ACS National Meeting of the Division of Medicinal Chemistry, 21.-25. March 2010, San Francisco, USA; MEDI 173), novel thiazoles are described as EP2 antagonists.
EP2 receptor antagonists are also described in the application by Ligand Pharmaceuticals Inc. 0/008777). These compounds are bicyclic pyridine derivatives. The compounds are claimed for the treatment of pain, but also for the treatment of Alzheimer’s disease, multiple sclerosis and fertility disorders.
For the regulation of the processes which are ultimately responsible for ovulation and fertilization and which thus contribute to the inhibition of fertility, other in vivo active antagonists of the EP2 receptor with improved ties are needed.
Hence the purpose of the present invention was to provide other antagonists of the EP2 or with improved properties which are available in vivo, and thus effective, and stable.
This problem was solved through the compounds of the general formula I, [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp XH \N R4/V 0 R 1Wm(N Ar—R3 (I), wherein R1: means H, C1-C2 alkyl or C1-C2 alkyloxy; R2: H or methyl; subject to the proviso that one of the two residues R1 or R2 equals H; Xi -(CH2)1-; -(CH2)k-O-; -CH2-S-; CH2-S(O)2-; -CH(CH3)-; 3)-O- 01‘ -C(CH3)2-O-; k: l or 2; l: O, l or 2; R4: H, C1-C4 alkyl, C3-C4 cycloalkyl, or -C4 cycloalkyl; and in the case of X: -CH2- or -CH(CH3)- R4: additionally a 4membered heterocyclyl residue; and in the case of X: -(CH2)1- or -CH(CH3)- R4: additionally CN; X together With R4 form a 4membered heterocyclyl residue Via a ring carbon linkage; D lor2; [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp n: l or 2; Ar: a embered aryl or 5-lO-membered hetaryl residue, R3: halogen, CN, SFs, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C6 heterocyclyl, 4 alkyl, O-C3-C6 cycloalkyl, O-C4-C6 heterocyclyl, S-C1-C4 alkyl, C1-C4 alkyl, Ar', O-Al", C(CH3)2-CN 01‘ C(CH3)2-OH; Ar': an optionally singly or doubly substituted 6-membered aryl or 5membered heteroaryl residue; wherein the substituents are selected from F, Cl, CN, C1-C4 alkyl, 4 alkyl, C(CH3)2-CN, C(CH3)2-OH and C(O)NH2; and s, diastereomers, enantiomers and salts or cyclodextrin clathrates thereof, for the production of drugs Which overcome the known disadvantages and have improved properties such as good o activity, good solubility and stability.
The compounds according to the invention have an antagonistic action on the EP2 receptor and thus inter alia serve for female fertility control.
C1-C2 alkyl or C1-C4 alkyl should each be understood to mean a linear or ed alkyl residue, such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
The alkyl residues can optionally be singly or multiply substituted With fluorine.
The hydrogen atoms can optionally be replaced by deuterium.
C1-C2 alkoxy or C1-C4 alkoxy should be understood to mean a linear or branched residue of the formula alkyl-O-, such as for example methoxy, ethoxy, n—propoxy, isopropoxy, n—butoxy, sec- butoxy, isobutoxy or tert-butyloxy.
The alkoxy es can optionally be singly or multiply substituted With fluorine.
C3-C6 cycloalkyl should be understood to mean clic alkyl rings such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The cycloalkyl es can optionally be singly or multiply substituted With fluorine.
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 4membered heterocyclyl should be understood to mean monocyclic rings which instead of the carbon atoms contain one or more hetero atoms, such as oxygen, sulphur and/or nitrogen or a hetero group such as -S(O)- or -SOz-. The linking bond can be at any carbon atom or at a nitrogen atom.
For example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, l,4-diazepanyl, morpholinyl, thiomorpholinyl, yl, tetrahydrofuranyl, tetrahydropyranyl, l,4-dioxanyl and 2-oxo- oxazolidinyl may be mentioned.
The heterocyclyl residues can ally be singly or multiply substituted With fluorine, hydroxy, methoxy or with 0x0.
Halogen should in each case be understood to mean fluorine, chlorine, e or iodine.
The C6-C1o-membered aryl residue in each case comprises 6 - 10 carbon atoms and can be benzo-condensed. Phenyl and naphthyl may be mentioned The C6-C1o-membered aryl residue can optionally be singly substituted With fluorine, chlorine or a methyl group.
The C5-C1o heteroaryl residue should be understood to mean mono- or bicyclic ring systems Which each contain 5 - 10 ring atoms and Which instead of the carbon can contain one or more cal or different hetero atoms, such as oxygen, sulphur or nitrogen. The linking bond can be at any carbon atom or at a nitrogen atom.
For example, thienyl, thiazolyl, furyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, olyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, phthalidyl, thiophthalidyl, indolyl, isoindolyl, indazolyl, hiazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, azocinyl, indolizinyl, purinyl, isoquinolinyl, quinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl and pteridinyl may be ned.
The C5-C1o-membered heteroaryl residue can optionally be singly substituted by e, chlorine or a methyl group.
If a basic onal group is contained, the physiologically compatible salts of organic and inorganic acids, such as inter alia hydrochloric acid, sulphuric acid, oric acid, citric acid and tartaric acid, are suitable Dferred are compounds of the formula I, wherein [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp R1, R2: mean H or methyl; subject to the proviso that one of the two es R1 or R2 equals H; X: -(CH2)1- 01‘ -(CH2)k-O-; k: l or 2; l: O, l or 2; R4: C1-C4 alkyl, C3-C4 lkyl or CH2-C3-C4 cycloalkyl; m,n: 2; and isomers, diastereomers, enantiomers and salts or cyclodextrin clathrates thereof and R3, Ar and Ar' have the aforesaid meanings.
Also preferred are compounds of the formula I, n R1, R2: mean H or methyl; subject to the proviso that one of the two es R1 or R2 equals H; X: -(CH2)1— or -(CH2)k-O-; k: l or 2; l: O, l or 2; R4: C1-C4 alkyl, -C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; m, n: l; and isomers, diastereomers, enantiomers and salts or cyclodextrin clathrates thereof and R3, Ar Ar' have the aforesaid meanings.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Also preferred are nds of the formula I, wherein R1: means a methyl group; -(CH2)1- 01‘ -(CH2)k-O-; Oorl; C1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; m,n: Ar: a phenyl residue; and isomers, reomers, enantiomers and salts or cyclodextrin clathrates thereof and R3 and Ar' have the aforesaid meanings.
Additionally preferred are compounds of the formula I, Wherein R1: means a methyl group; -(CH2)1- 01‘ -(CH2)k-O-; Oorl; C1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Ar: a phenyl residue; and isomers, reomers, enantiomers and salts or cyclodextrin clathrates thereof and R3 and Ar' have the aforesaid meanings.
The following compounds according to the t invention are quite particularly preferred: 2- {[1-(4-cyanofluorobenzoyl)piperidinyl]methyl} -N-(2—methoxyethyl)methyl- 2H-indazol-5 -carboxamide 2- {[1 -(4-tert-butoxybenzoyl)piperidinyl]methyl} -N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 2-( { l - [4-(4-fluorophenoxy)benzoyl]piperidinyl} methyl)-N—(2-methoxyethyl) -2H-indazolcarboxamide N—(2-methoxyethyl)methyl {[1 -(4-morpholinobenzoyl)piperidin—4-yl]methyl} -2H- indazolcarboxamide 2-( { l - [(4'-fluorobiphenylyl)carbonyl]piperidinyl} methyl)-N—(2-methoxyethyl) methyl-2H-indazolcarboxamide 2- —fluoromesylbenzoyl)piperidin—4-yl]methyl} -N-(2—methoxyethyl)methyl- 2H-indazol-5 -carboxamide 2- {[1-(2-fluoromethoxybenzoyl)piperidin—4-yl]methyl}-N-(2—methoxyethyl) methyl-2H-indazolcarboxamide 2- {[1 -(4-bromofluorobenzoyl)piperidin—4-yl]methyl} -N-(2—methoxyethyl)methyl- 2H-indazol-5 -carboxamide 2- {[1 oromethylbenzoyl)piperidin—4-yl]methyl} -N-(2—methoxyethyl)methyl- 2H-indazol-5 -carboxamide . 2-( { l - [2-fluoro(trifluoromethyl)benzoyl]piperidin—4-yl} methyl)-N-(2-methoxyethyl) - 4-methyl-2H-indazolcarboxamide ll. N—(2-methoxyethyl)methyl( { l - [4-(pentafluoro-k6-sulphanyl)benzoyl]piperidin yl} methyl)-2H-indazolcarboxamide 12. N—(2-methoxyethyl)methyl {[1 -(4-methylbenzoyl)piperidinyl]methyl} -2H- indazolcarboxamide 13. 2-( { l - [4-(4-chlorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-methoxyethyl)-4 - methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 14. N—(2-meth0xyethyl)methyl( { 1 - [4-(4-methylphen0xy)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide . 2-( { 1 - [4-(4-tert-butylphen0xy)benzoyl]piperidin—4-y1}methyl)-N—(2-meth0xyethyl) methyl-ZH-indazol-S-carb0xamide 16. N—(2-meth0xyethyl)methyl [(1 - {4- [4-(trifluoromethyl)phen0xy]benzoyl}piperidin- 4-yl)methyl] -2H-indazolcarb0xamide 17. N—(2-meth0xyethyl)( { 1 - [4-(4-meth0xyphen0xy)benzoyl]piperidin—4-yl} methyl) methyl-ZH-indazol-S-carb0xamide 18. N—(2-meth0xyethyl)methyl {[1 -(4-phen0xybenzoyl)piperidinyl]methyl} -2H- indazol-S-carb0xamide 19. 2- {[1-(4-cyclopropylbenzoyl)piperidin—4-y1]methyl} meth0xyethyl)methyl-2H- indazol-S-carb0xamide . 2- { [1 -(4-meth0xybenzoyl)piperidin—4-yl]methyl} meth0xyethyl)methyl-2H- indazol-S-carb0xamide 21. 2- {[1-(4-fluorobenzoyl)piperidin—4-y1]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carboxamide 22. N—(2-meth0xyethyl)methyl( { 1 - ifluoromethyl)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide 23. 2- { [1 -(2-meth0xybenzoyl)piperidin—4-yl]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carb0xamide 24. N—(2-meth0xyethyl)methyl [( 1 - {4- [(trifluoromethyl)sulphonyl]benzoyl} piperidin- 4-yl)methyl] -2H-indazolcarb0xamide . N—(2-meth0xyethyl)methyl( { 1 - [3 -(trifluoromethyl)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide 26. N—(2-meth0xyethyl)methyl {[1 -(3 -methylbenzoyl)piperidinyl]methyl} -2H- indazol-S-carboxamide 27. 2- {[1 -(3 -ch10r0benzoyl)piperidin—4-y1]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carb0xamide 28. 2-( { 1 - [4-(4-carbamoylphenoxy)benzoyl]piperidin—4-y1}methyl)-N—(2-meth0xyethyl) methyl-ZH-indazol-S-carb0xamide 29. 2-( { 1 - [4-(cyc10pentyloxy)benzoyl]piperidin—4-y1}methyl)-N-(2-meth0xyethyl) -ZH-indazol-S-carb0xamide . 2-( { 1 - [4-(diflu0r0methyl)benzoyl]piperidinyl} methyl)-N—(2-meth0xyethyl)methyl- 2H-indazol-5 xamide 2- { [1 -(4-cyan0benzoyl)piperidin—4-yl]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 32. 2-( { l - [4-( l H-imidazol- l -yl)benzoyl]piperidin—4-yl}methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 33. \-(2-meth0xyethyl)methyl( { l - [4-(oxazolyl)benzoyl]piperidin—4-yl} methyl)- 2H-indazol-5 -carb0xamide 34. \-(2-meth0xyethyl)methyl( { l - [4-(oxazolyl)benzoyl]piperidin—4-yl} methyl)- 2H-indazol-5 -carb0xamide . \-(2-meth0xyethyl)methyl( { l - [4-(isoxazolyl)benzoyl]piperidin—4-yl} )- 2H-indazol-5 -carb0xamide 36. \-(2-meth0xyethyl)methyl( { l - [4-( l H-pyrazol- l -yl)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide 37. \-(2-meth0xyethyl)methyl( { l - [4-( l H- l ,2,4-triazol- l nzoyl]piperidin—4-yl} - )-2H-indazolcarb0xamide 38. 2-( { l - [4-(difluoromethoxy)flu0r0benzoyl]piperidin—4-yl} methyl)-N-(2-meth0xy— ethyl)methyl-2H-indazolcarb0xamide 39. 2-( { l - [2—flu0r0(pyrrolidin- l -yl)benzoyl]piperidin—4-yl} methyl)-N-(2-meth0xyethyl)- 4-methyl-2H-indazolcarb0xamide 40. 2-( { l - [(3 ,4'- difluorobiphenylyl)carbonyl]piperidinyl} methyl)-N-(2-meth0xyethyl)- 4-methyl-2H-indazolcarb0xamide 41. 2-( { l - [(3 -flu0r0-4'-meth0xybiphenylyl)carb0nyl]piperidin—4-yl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 42. 2-( { l - [(3 - flu0r0-4'-methylbiphenylyl)carbonyl]piperidinyl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 43. 2- [(l - { [3 -flu0r0-3 '-(trifluoromethyl)biphenylyl]carbonyl} piperidin—4-yl)methyl] -N- (2-meth0xyethyl)methyl-2H-indazol-S-carb0xamide 44. 2- [(l - { [3 -flu0r0-2'-(trifluoromethoxy)biphenylyl]carbonyl} piperidin—4-yl)methyl] -N- (2-meth0xyethyl)methyl-2H-indazol-S-carb0xamide 45. 2-( { l - [(2'-fluorobiphenylyl)carb0nyl]piperidinyl} )-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 46. 2-( { l - [(2',4'-difluorobiphenylyl)carb0nyl]piperidin—4-yl} methyl)-N-(2-meth0xy— ethyl)methyl-2H-indazolcarb0xamide 47. 2-( { l - [(2- fluorobiphenylyl)carbonyl]piperidin—4-yl } methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 48. eth0xyethyl)methyl( { l - ethylbiphenylyl)carb0nyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide eth0xyethyl)methyl( { l - [4-(4-pyridyloxy)benzoyl]piperidin—4-yl} methyl)- 2H-indazolcarb0xamide [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 50. N—(2-meth0xyethyl)methyl( { l - [4-(4H- l ,2,4-triazolyl)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide 51. 2- {[1-(2-flu0r0m0rpholin0benzoyl)piperidin—4-yl]methyl}-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 52. 2- {[1-(4-br0m0benzoyl)piperidinyl]methyl}-N-(2-meth0xyethyl)methyl-2H- indazol-S-carboxamide 53. N—(2-meth0xyethyl)methyl( { l - [4-(trifluoromethoxy)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide 54. 2- {[1-(4-chlor0benzoyl)piperidin—4-yl]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carb0xamide 55. N—(2-meth0xyethyl)methyl [( l - {4- [(trifluoromethyl)sulphanyl]benzoyl} piperidin— 4-yl)methyl] -2H-indazolcarb0xamide 56. 4-methyl( { l - ntafluoro-k6-sulphanyl)benzoyl]piperidin—4-yl} methyl)-N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 57. 2- {[1-(4-chlor0benzoyl)piperidin—4-yl]methyl} methyl-N—(2,2,2-triflu0r0ethyl)-2H- indazol-S-carboxamide 58. 4-methyl-N—(2,2,2-triflu0r0ethyl)( { l - [4-(trifluoromethoxy)benzoyl]piperidin yl} methyl)-2H-indazolcarb0xamide 59. 2- {[1-(4-chlor0benzoyl)piperidin—4-yl]methyl} -N- clopropylmethoxy)ethyl] methyl-2H-indazolecarb0xamide 60. N—[2-(cyclopropylmethoxy)ethyl] methyl {[1 -(4-methylbenzoyl)piperidinyl] - methyl} -2H-indazolcarb0xamide 61. N—[2-(cyclopropylmethoxy)ethyl] ( { l - [4-(4-flu0r0phen0xy)benzoyl]piperidin—4-yl} - methyl)methyl-2H-indazolcarb0xamide 62. N—[2-(cyclopropylmethoxy)ethyl] methyl( { l - [4-(trifluoromethyl)benzoyl]piperidin- 4-yl} methyl)-2H-indazolcarb0xamide 63. N—[2-(cyclopropylmethoxy)ethyl] ( { l - [(4'-fluorobiphenylyl)carb0nyl]piperidin yl} methyl)methyl-2H-indazolcarb0xamide 64. 2- {[1-(4-cyclopropylbenzoyl)piperidin—4-yl]methyl} -N- [2-(cyclopropylmethoxy)ethyl] - 4-methyl-2H-indazolcarb0xamide 65. 2- -chlor0benzoyl)piperidin—4-yl]methyl} methyl-N— 2,2-triflu0r0eth0xy)- ethyl] -2H-indazolcarb0xamide 66. 4-methyl {[1 -(4-methylbenzoyl)piperidin—4-yl]methyl} -N- [2-(2,2,2-triflu0r0eth0xy)- ethyl] dazolcarb0xamide 2-( { l - [4-(4-fluorophenoxy)benzoyl]piperidinyl} methyl)methyl-N— [2-(2,2,2- trifluoroethoxy)ethyl] -2H-indazolcarb0xamide ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 68. 4-methyl-N— [2-(2,2,2-triflu0r0eth0xy)ethyl] ( { l - [4-(trifluoromethyl)benzoyl] - piperidinyl} )-2H-indazolcarb0xamide 69. 2-( { l - [(4'-fluorobiphenylyl)carb0nyl]piperidinyl} methyl)methyl-N— [2-(2,2,2- trifluoroethoxy)ethyl] -2H-indazolcarb0xamide 70. 2- {[1-(4-cyclopropylbenzoyl)piperidin—4-yl]methyl} methyl-N— [2-(2,2,2-triflu0r0- ethoxy)ethyl] -2H-indazolcarb0xamide 71. 2- {[1-(4-chlor0benzoyl)piperidin—4-yl]methyl} -N-(2-isopr0p0xyethyl)methyl-2H- indazol-S-carb0xamide 72. N—(2-isopr0p0xyethyl)methyl {[1 -(4-methylbenzoyl)piperidinyl]methyl} -2H- indazol-S-carb0xamide 73. 2-( { l - [4-(4-fluorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-isopropoxyethyl) -2H-indazolcarb0xamide 74. N—(2-isopr0p0xyethyl)methyl( { l - [4-(trifluoromethyl)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide 75. 2-( { l - [(4'-fluorobiphenylyl)carb0nyl]piperidinyl} )-N—(2-isopr0p0xyethyl)- 4-methyl-2H-indazolcarb0xamide 76. 2- {[1-(4-cyclopropylbenzoyl)piperidin—4-yl]methyl} -N-(2-isopr0poxyethyl)methyl- 2H-indazol-5 -carb0xamide 77. 2- {[1-(4-chlor0benzoyl)piperidin—4-yl]methyl} hyl-N— [2-(triflu0r0meth0xy)ethyl] - 2H-indazol-5 -carb0xamide 78. 2-( { l - [4-(4-fluorophenoxy)benzoyl]piperidinyl} methyl)methyl-N— [2-(triflu0r0- methoxy)ethyl] -2H-indazolcarb0xamide 79. 2-( { l - uorobiphenylyl)carb0nyl]piperidinyl} methyl)methyl-N— [2- (trifluoromethoxy)ethyl] -2H-indazolcarb0xamide 80. 4-methyl-N— ifluoromethoxy)ethyl] [(1 - {4- [4-(trifluoromethyl)phen0xy] - benzoyl} piperidin—4-yl)methyl] -2H-indazolcarb0xamide 81. N—(2-tert-but0xyethyl) {[1-(4-chlor0benzoyl)piperidin—4-yl]methyl}methyl-2H- indazol-S-carb0xamide 82. N—(2-tert-but0xyethyl)( { l - [4-(4-flu0r0phen0xy)benzoyl]piperidinyl} methyl) methyl-2H-indazolcarb0xamide 83. N—(2-tert-but0xyethyl)( { l - [(4'-flu0r0biphenylyl)carbonyl]piperidin—4-yl} methyl) - 4-methyl-2H-indazolcarb0xamide 84. N—(2-tert-but0xyethyl)methyl [(1 - {4- [4-(trifluoromethyl)phen0xy]benzoyl} - piperidinyl)methyl] -2H-indazolcarb0xamide 2- {[1 -(4-chlor0benzoyl)piperidin—4-yl]methyl} methyl-N— {2- [(2H3)methyloxy] - (2H4)ethyl} -2H-indazol-5 -carb0xamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 86. 2-( { l - [4-(4-flu0r0phen0xy)benzoyl]piperidinyl} methyl)methyl-N— {2- [(2H3)methyloxy] (2H4)ethyl} -2H-indazolcarb0xamide 87. 2- {[1 -(4-chlor0benzoyl)azetidin-3 -yl]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carb0xamide 88. N—(2-meth0xyethyl)methyl [( l - {4- [(trifluoromethyl)sulphanyl]benzoyl} in-3 - yl)methyl] -2H-indazolcarboxamide 89. N—(2-meth0xyethyl)methyl( { l - ifluoromethoxy)benzoyl] azetidin-3 -yl} - methyl)-2H-indazolcarb0xamide 90. 2-( { l - [2-flu0r0(trifluoromethyl)benzoyl] azetidin-3 -yl} methyl)-N-(2-meth0xyethyl) - 4-methyl-2H-indazolcarb0xamide 91. 2- {[1 -(4-chlor0flu0r0benzoyl)azetidin—3 -yl]methyl} -N-(2-meth0xyethyl)methyl- 2H-indazol-5 -carb0xamide 92. 2-( { l - [3 -flu0r0(trifluoromethyl)benzoyl] azetidin-3 -yl} )-N—(2-meth0xyethyl)- 4-methyl-2H-indazolcarb0xamide 93. 2-( { l - [4-chlor0-3 -(trifluoromethyl)benzoyl] azetidin-3 -yl} methyl)-N—(2-meth0xyethyl)- 4-methyl-2H-indazolcarb0xamide 94. 2- {[1 -(4-cyclopr0pylbenzoyl)azetidin-3 -yl]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carb0xamide 95. N—(2-meth0xyethyl)methyl [( l - {4- [4-(trifluoromethyl)phen0xy]benzoyl} azetidin— 3 -yl)methyl] -2H-indazolcarb0xamide 96. 2- {[1-(4-chlor0benzoyl)azetidin-3 thyl} methyl-N—(2,2,2-triflu0r0ethyl)-2H- indazol-S-carb0xamide 97. 4-methyl-N—(2,2,2-triflu0r0ethyl)( { l - [4-(trifluoromethoxy)benzoyl] azetidin—3 -yl} - methyl)-2H-indazolcarb0xamide 98. 2-( { l - [2-flu0r0(trifluoromethyl)benzoyl] azetidin-3 -yl} methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 99. 4-methyl( { l - [4-(pentafluoro-k6-sulphanyl)benzoyl] azetidin—3 -yl} methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 100. N—[2-(cyclopr0pyloxy)ethyl] methyl( { l - ifluoromethoxy)benzoyl] azetidin—3 - yl} )-2H-indazolcarb0xamide 101. N—[2-(cyclobutyloxy)ethyl] methyl-2 -( { l - [4-(trifluoromethoxy)benzoyl] in—3 - yl} )-2H-indazolcarb0xamide 102. 2- {[1 -(4-chlor0benzoyl)azetidin-3 -yl]methyl} -N- [2-(cyclopropylmethoxy)ethyl] methyl-2H-indazolcarb0xamide N—[2-(cyclopropylmethoxy)ethyl] ( { l - [4-(4-flu0r0phen0xy)benzoyl] azetidin—3 -yl} - methyl)methyl-2H-indazolcarb0xamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 104. N—[2-(cyclopropylmethoxy)ethyl] methyl {[1 -(4-methylbenzoyl)azetidin—3 -yl] - methyl} -2H-indazolcarb0xamide 105. 2- {[1 -(4-chlor0benzoyl)azetidin-3 -yl]methyl} methyl-N— [2-(triflu0r0meth0xy)ethyl] - 2H-indazol-5 -carb0xamide 106. N—(2-tert-but0xyethyl) {[1-(4-chlor0benzoyl)azetidin-3 thyl} methyl-2H- indazol-S-carboxamide 107. N—[2-(cyclopropylmethoxy)ethyl] ( { l - [(4'-fluorobiphenylyl)carb0nyl] azetidin—3 - yl} methyl)methyl-2H-indazolcarb0xamide 108. 2-( { l - [(4'-flu0r0biphenylyl)carbonyl] azetidin—3 -yl } methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 109. 2-( { l - fluorophenoxy)benzoyl] azetidin—3 -yl}methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 110. 2-( { l - [4-(4-fluorophenoxy)benzoyl] azetidin—3 -yl } methyl)methyl-N—(2 ,2,2- trifluoroethyl)-2H-indazolcarb0xamide 111. 2-( { l - [(4'-fluorobiphenylyl)carb0nyl] azetidin—3 -yl}methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 112. 2- {[1 -(4-chlor0benzoyl)azetidin-3 -yl]methyl} methyl-N— [2-(2,2,2-triflu0r0eth0xy)- ethyl] dazolcarb0xamide 113. 4-methyl-N— [2-(2,2,2-triflu0r0eth0xy)ethyl] [(1 - {4- [4-(trifluoromethyl)phen0xy] - benzoyl} azetidin—3 -yl)methyl] -2H-indazolcarb0xamide 114. 4-methyl-N—(2,2,2-triflu0r0ethyl) [(1 - {4- [4-(trifluoromethyl)phen0xy]benzoyl} - azetidin—3 -yl)methyl] -2H-indazolcarb0xamide 115. 2-( { l - [4-(4-chlorophenoxy)benzoyl] azetidin—3 -yl}methyl)methyl-N—(2,2,2-triflu0r0- ethyl)-2H-indazolcarb0xamide 116. 2-( { l - [4-(4-chlor0phen0xy)benzoyl] azetidin—3 -yl } )-N-(2-meth0xyethyl)-4 - -2H-indazolcarb0xamide 117. N—(2-meth0xyethyl)methyl {[1 -(4- {[5-(trifluoromethyl)pyridinyl] oxy} benzoyl)- in—3 -yl]methyl} -2H-indazolcarb0xamide 118. 4-methyl-N—(2,2,2-triflu0r0ethyl) {[1-(4- {[5 -(trifluoromethyl)pyridin—2-yl] oxy} benzoyl)azetidin—3 -yl]methyl} -2H-indazol-5 -carb0xamide 119. 2- {[1 -(4-chlor0benzoyl)piperidin—4-yl]methyl} -N-ethylmethyl-2H-indazol-5 - carboxamide 120. 2-( { l - [4-(4-fluorophenoxy)benzoyl]piperidinyl} )methyl-N—(2,2,2-triflu0r0- ethyl)-2H-indazolcarb0xamide 2-( { l - [4-(4-chlor0phenoxy)benzoyl]piperidinyl} methyl)methyl-N—(2,2,2-triflu0r0- ethyl)-2H-indazolcarb0xamide ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 122. 4-methyl({1-[4-(4-methylphen0xy)benzoyl]piperidin—4-y1}methyl)-N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 123. 2-({1-[(4'-fluorobiphenylyl)carb0nyl]piperidinyl}methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 124. 4-methyl -m0rph01in0benzoyl)piperidinyl]methyl} -N-(2,2,2-triflu0roethyl)- 2H-indazol-5 -carb0xamide 125. 4-methyl-\ -(2,2,2-triflu0roethyl) [(1 - {4- [(trifluoromethyl)sulphanyl]benzoyl} - piperidinyl)methyl] -2H-indazolcarb0xamide 126. 4-methyl-\ -(2,2,2-triflu0roethyl) [(1 - {4- [4-(trifluoromethyl)phen0xy]benzoyl} - piperidinyl)methyl] -2H-indazolcarb0xamide 127. 4-methyl-\ -(2,2,2-triflu0roethyl) {[1 -(4- {[5 -(trifluoromethyl)pyridin—2-y1]oxy} - benzoyl)piperidin—4-yl]methyl} -2H-indazolcarb0xamide 128. 4-methyl-\ -(2,2,2-triflu0roethyl) {[1 -(4- {[6-(trifluoromethyl)pyridin—3 -y1] oxy} - benzoyl)piperidin—4-yl]methyl} -2H-indazolcarb0xamide 129. 4-methyl-\ -(2,2,2-triflu0roethyl) {[1 -(4- {[6-(trifluoromethyl)pyridin—2-y1]oxy} - benzoyl)piperidin—4-yl]methyl} -2H-indazolcarb0xamide 130. 2-({1-[4-(4-cyanophenoxy)benzoyl]piperidin—4-y1}methyl)methyl-N—(2,2,2-triflu0r0- ethyl)-2H-indazolcarb0xamide 131. 2-({1-[4-(3 -fluorophenoxy)benzoyl]piperidinyl} methyl)methyl-N—(2,2,2-triflu0r0- ethyl)-2H-indazolcarb0xamide 132. 4-methyl-N—(2,2,2-triflu0roethyl) [(1 - {4- [3 -(trifluoromethyl)phen0xy]benzoyl} - piperidinyl)methyl] -2H-indazolcarb0xamide 133. 2-[(1- {4- an0pyridin—2-yl)0xy]benzoyl}piperidinyl)methyl] methy1—N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 134. 2-[(1- {4- [(5-ch10r0pyridiny1)oxy]benzoyl} piperidin—4-yl)methyl] methy1—N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 135. 4-methyl-N—(2,2,2-triflu0roethyl) [(1 - {4- [5 -(trifluoromethyl)pyridin—2-y1]benzoyl} - piperidinyl)methyl] dazolcarb0xamide 136. 2-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 137. 2-({1-[4-(3 ,4-difluorophenoxy)benzoyl]piperidinyl} methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 138. 4-methyl-N—(2,2,2-triflu0roethyl) [(1 - {[4'-(trifluoromethyl)biphenyly1] carbonyl} - piperidinyl)methyl] dazolcarb0xamide 2- {[1-(4-br0m0benzoyl)piperidiny1]methyl}methyl-N—(2,2,2-triflu0roethyl)-2H- indazol-S-carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 140. 2-( { l - [4-(5-chlor0pyridin—2-yl)benzoyl]piperidin—4-yl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 141. 2-( { l - [(4'-meth0xy—2'-methylbiphenylyl)carb0nyl]piperidin—4-yl} methyl)methyl- N—(2,2,2-triflu0r0ethyl)-2H-indazolcarb0xamide 142. 4-methyl( { l - [4-(6-methylpyridin—3 -yl)benzoyl]piperidinyl} )-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 143. 2-( { l - [(4'-flu0r0-2'-meth0xybiphenylyl)carb0nyl]piperidin—4-yl}methyl)methyl-N- (2,2,2-triflu0r0ethyl)-2H-indazol-5 -carb0xamide 144. 4-methyl-N-(2,2,2-triflu0r0ethyl) [(1 - {4- [6-(triflu0r0methyl)pyridin—3 -yl]benzoyl} - piperidinyl)methyl] -2H-indazolcarb0xamide 145. 2-( { l - [4-(6-meth0xypyridin—3 -yl)benzoyl]piperidinyl} methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 146. 2-( { l - meth0xypyridin—2-yl)benzoyl]piperidinyl} methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 147. 4-methyl( { l - [4-(5-methylpyridin—2-yl)benzoyl]piperidinyl} methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 148. 2-( { l - [4-(5-fluoropyridin—Z-yl)benzoyl]piperidin—4-yl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 149. 2-( { l - [4-(5-meth0xypyridin—2-yl)benzoyl]piperidinyl} methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarb0xamide 150. 4-methyl( { l - [4-(2-methylpyrimidin—5 -yl)benzoyl]piperidin—4-yl} methyl)-N-(2,2,2- roethyl)-2H-indazolcarb0xamide 151. 4-methyl-N-(2,2,2-triflu0r0ethyl) [(1 - {4- ifluoromethyl)pyrimidin-5 -yl]benzoyl} - dinyl)methyl] -2H-indazolcarb0xamide 152. 4-methyl-N-(2,2,2-triflu0r0ethyl) [(1 - {4- [6-(trifluoromethyl)pyridin—2-yl]benzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide 153. 2-( { l - [4-(4-cyan0phen0xy)benzoyl]piperidin—4-yl } methyl)-N-(2-meth0xyethyl)-4 - methyl-2H-indazolcarb0xamide 154. 2- {[1 -(4-br0m0-3 lbenzoyl)piperidin—4-yl]methyl} -N-(2-meth0xyethyl)methyl- 2H-indazol-5 -carb0xamide 155. 2- {[1 -(4-tert-butylbenzoyl)piperidinyl]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carb0xamide 156. 2-( { l - [4-(1 -hydroxy-l -methylethyl)benzoyl]piperidin—4-yl} methyl)-N-(2-meth0xy— ethyl)methyl-2H-indazolcarb0xamide 2- {[1 -(4-cyclohexylbenzoyl)piperidin—4-yl]methyl} -N-(2-meth0xyethyl)methyl-2H- indazol-S-carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 158. 2-( { l - [4-(1 - l -methylethyl)benzoyl]piperidinyl} methyl)-N-(2-meth0xyethyl)- 4-methyl-2H-indazolcarb0xamide 159. \-(2-meth0xyethyl)methyl( { l - [4-(pyrimidin—2-yloxy)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarb0xamide 160. \-(2-meth0xyethyl)methyl( { l - [4-(3 -pyridyloxy)benzoyl]piperidin—4-yl} methyl)- 2H-indazol-5 -carb0xamide 161. \-(2-meth0xyethyl)methyl {[1 -(4- {[5-(trifluoromethyl)pyridinyl] oxy} benzoyl)- piperidinyl]methyl} -2H-indazolcarb0xamide 162. \-(2-meth0xyethyl)methyl( { l - [4-(2-pyridyloxy)benzoyl]piperidin—4-yl} methyl)- 2H-indazol-5 -carb0xamide 163. \-(2-meth0xyethyl)methyl {[1 -(4- {[4-(trifluoromethyl)pyrimidin—2-yl] oxy} - benzoyl)piperidin—4-yl]methyl} dazolcarb0xamide 164. eth0xyethyl)methyl {[1 -(4- {[6-(trifluoromethyl)pyridin-3 -yl] oxy} benzoyl)- piperidinyl]methyl} -2H-indazolcarb0xamide 165. \-(2-meth0xyethyl)methyl {[1 -(4- rifluoromethyl)pyridinyl] oxy} benzoyl)- piperidinyl]methyl} dazolcarb0xamide 166. 2-( { l - [(4'-meth0xybiphenylyl)carb0nyl]piperidin—4-yl} methyl)-N-(2-meth0xyethyl)- 4-methyl-2H-indazolcarb0xamide 167. N—(2-meth0xyethyl)methyl( { l - [4-(3 ,4,5,6-tetrahydr0-2H-pyran—4-yloxy)benzoyl] - dinyl} )-2H-indazolcarb0xamide 168. eth0xyethyl)methyl [( l - {4- [3 -(trifluoromethyl)phen0xy]benzoyl } piperidin- 4-yl)methyl] -2H-indazolcarb0xamide 169. 2- [(1 - {4- [(5-cyan0pyridin—2-yl)0xy]benzoyl}piperidinyl)methyl] -N-(2-meth0xy— ethyl)methyl-2H-indazolcarb0xamide 170. 2- [(1 - {4- [(5-chlor0pyridin—2-yl)oxy]benzoyl}piperidin—4-yl)methyl] -N-(2-meth0xy— ethyl)methyl-2H-indazolcarb0xamide 171. 2-( { l - [4-(2,4-difluorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 172. 2-( { l - [4-(3 ,4-difluorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 173. N—(2-meth0xyethyl)methyl [( l - {[4'-(trifluoromethyl)biphenylyl] carbonyl} - piperidinyl)methyl] -2H-indazolcarb0xamide 174. 2-( { l - [4-(3 -fluorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 2- {[1-(2-flu0r0is0pr0poxybenzoyl)piperidinyl]methyl}-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 176. 2-( { l - [(3 -flu0r0-3 ',4'-dimethylbiphenylyl)carb0nyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 177. 2-( { l - [(2',3 -diflu0r0-4'-meth0xybiphenylyl)carb0nyl]piperidin—4-yl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 178. 2-( { l - [4-(diflu0r0meth0xy)benzoyl]piperidinyl} methyl)-N-(2-meth0xyethyl)-4 - -2H-indazolcarb0xamide 179. 2-( { l - [4-(2-fluorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 180. 2-( { l - [(4'-cyan0-2'-methylbiphenylyl)carb0nyl]piperidinyl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 181. 2-( { l - [4-(5 -chlor0pyridin—2-yl)benzoyl]piperidin—4-yl } methyl)-N-(2-meth0xyethyl) methyl-2H-indazolcarb0xamide 182. eth0xyethyl)methyl [( l - {4- [6-(trifluoromethyl)pyridin—2-yl]benzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide 183. N—(2-meth0xyethyl)( { l - [(4'-meth0xy—2'-methylbiphenylyl)carbonyl]piperidin yl} methyl)methyl-2H-indazolcarb0xamide 184. 2-( { l - [(4'-chlor0-2'-methylbiphenylyl)carb0nyl]piperidin—4-yl} )-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 185. 2- [(1 - l -cyan0- l -methylethyl)biphenylyl]carbonyl}piperidin—4-yl)methyl] -N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 186. N—(2-meth0xyethyl)( { l - [4-(5-meth0xypyridin—2-yl)benzoyl]piperidin—4-yl} methyl)- 4-methyl-2H-indazolcarb0xamide 187. N—(2-meth0xyethyl)methyl [( l - {4- [6-(trifluoromethyl)pyridin—3 -yl]benzoyl} - piperidinyl)methyl] -2H-indazolcarb0xamide 188. N—(2-meth0xyethyl)( { l - [4-(6-meth0xypyridin—3 -yl)benzoyl]piperidin—4-yl} methyl)- 4-methyl-2H-indazolcarb0xamide 189. 2-( { l - [(4'-flu0r0-2'-methylbiphenylyl)carb0nyl]piperidin—4-yl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide 190. N—(2-meth0xyethyl)methyl( { l - [4-(6-methylpyridin—3 -yl)benzoyl]piperidin—4- yl} )-2H-indazolcarb0xamide 191. N—(2-meth0xyethyl)( { l - [4-(6-meth0xypyridin—2-yl)benzoyl]piperidin—4-yl} methyl)- 4-methyl-2H-indazolcarb0xamide 192. N—(2-meth0xyethyl)methyl( { l - [4-(2-methylpyrimidinyl)benzoyl]piperidin yl} methyl)-2H-indazolcarb0xamide 2-( { l - [(4'-flu0r0-2'-meth0xybiphenylyl)carb0nyl]piperidin—4-yl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarb0xamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 194. 2-( { l - [(4'-chloro-2'-methoxybiphenylyl)carbonyl]piperidin—4-yl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 195. ethoxyethyl)methyl [( l - {4- [2-(trifluoromethyl)pyrimidin—5-yl]benzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide 196. 2-( { l - [(4'-chloro-2'-fluorobiphenylyl)carbonyl]piperidinyl} methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 197. 2-( { l - [(2'-chloro-4'-fluorobiphenylyl)carbonyl]piperidinyl} methyl)-N-(2-methoxyethyl thyl-2H-indazolcarboxamide 198. 2-( { l - [4-(5-chloropyridin—3 -yl)benzoyl]piperidin—4-yl}methyl)-N—(2-methoxyethyl) methyl-2H-indazolcarboxamide 199. 2-( { l - [4-(5-fluoropyridin—3 -yl)benzoyl]piperidin—4-yl}methyl)-N—(2-methoxyethyl) methyl-2H-indazolcarboxamide 200. N—(2-methoxyethyl)methyl [( l - {4- [5-(trifluoromethyl)pyridin—3 nzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide 201. 2- [(1 - l -hydroxy- l -methylethyl)biphenylyl]carbonyl} piperidin—4-yl)methyl] -N- (2-methoxyethyl)methyl-2H-indazolcarboxamide 202. 2-( { l - [(3 ',5'-difluorobiphenylyl)carbonyl]piperidin—4-yl} methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 203. 2-( { l - [(4'-fluoromethylbiphenylyl)carbonyl]piperidinyl} methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide 204. 2-( { l - [(3 ',5'-difluoromethylbiphenylyl)carbonyl]piperidinyl} methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide 205. N—(2-methoxyethyl)methyl( { l - [3 -methyl(3 -pyridyl)benzoyl]piperidin—4-yl} - )-2H-indazolcarboxamide 206. N—(2-methoxyethyl)methyl( { l - [3 -methyl(4-pyridyl)benzoyl]piperidin—4-yl} - methyl)-2H-indazolcarboxamide 207. N—(2-methoxyethyl)methyl( { l - [(2-methylbiphenylyl)carbonyl]piperidin—4-yl} - methyl)-2H-indazolcarboxamide A subject of the t invention is the use of the compounds according to the invention for the production of drugs Which contain at least one of the compounds according to formula I.
Also a subject of the present invention are drugs which contain the compounds according to the ion, with suitable formulation and carrier substances.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Compared to known prostaglandin EP2 antagonists, the new EP2 nists are characterized by ed properties such as better availability and stability.
A subject of the present invention are drugs for fertility control/contraception and for the treatment and prophylaxis of diseases, which include infectious diseases, cancer, cardiovascular diseases, angiogenic diseases, uterine ction disorders, pain, inflammatory diseases, neuroinflammatory diseases, neurodegenerative diseases, autoimmune diseases, immuno- dependent diseases/therapies, nephrological es and ophthalmological diseases.
Infectious diseases should be understood to mean es caused by unicellular parasites (e. g.
Klebsiella or Streptococcus). With infectious diseases, the drugs can have an immunomodulatory action such that the diseases can be treated prophylactically (diminution of the infection risk, such as for e in bone marrow transplants) or therapeutically. Cancer should be understood to mean solid tumours and leukaemias; viral infections e. g. cytomegalus infections, hepatitis, hepatitis B and C and HIV diseases; vascular diseases ischaemic usion disease, stenoses, oscleroses, restenoses, arthritis, Kawasaki syndrome and aneurysms; angiogenic diseases e. g. endometriosis and fibrosis and flbroids in the uterus; uterine contraction disorders e. g. menstrual problems; pain, for example inflammatory lgesia and arthritis, inflammatory diseases, for example inflammatory intestinal diseases; neuroinflammatory and neuro-degenerative diseases e.g. multiple sclerosis, Alzheimer, Parkinson, ALS and stroke; immuno-dependent diseases/therapies e. g. transplants in which immunomodulation increases the therapeutic success; autoimmune diseases for e the ophthalmological disease Graves’ disease, and nephrological diseases polycystic kidney diseases and glomerulonephritis.
Also a subject of the present invention are drugs for treatment and prophylaxis of the diseases listed above which contain at least one compound according to the general formula I, and drugs with suitable formulation and carrier substances.
For the use of the compounds according to the invention as drugs, these are converted into the form of a pharmaceutical preparation which as well as the active substance contains pharmaceutical, organic or inorganic inert carrier materials le for enteral or parenteral administration, such as for example water, gelatine, gum Arabic, lactose, starch, magnesium te, talc, plant oils, polyalkylene glycols etc. The pharmaceutical preparations can be in solid form, for example as tablets, coated tablets or capsules, in semisolid form, for e as ointments, , gels or suppositories or in liquid form, for example as solutions, suspensions nemulsions.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp They optionally contain additives, which are for example intended to function as fillers, binders, disintegrants, lubricants, solvents, solution mediators, masking flavours, colorant, or emulsifiers.
Types of additive in the sense of the invention are for example saccharides (mono-, di-, tri-, , and/or polysaccharides), 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 alteration of the c pressure or buffers.
These pharmaceutical preparations are also a subject of the present invention.
For inhalation, l solutions, or else suitable solid substance preparations for inhalation, are advantageously prepared.
For oral use, tablets, coated tablets or capsules with talc and/or hydrocarbon rs or binders, such as for example lactose, maize or potato starch are particularly suitable. Use is also possible in liquid form, such as for example as syrup, to which a sweetener is optionally added. Likewise, for the oral use of such nds, clathrates are also le, for example the clathrates with alpha, beta or gamma cyclodextrin or else beta-hydroxypropyl cyclodextrin may be mentioned.
For parenteral administration, e, injectable, aqueous or oily solutions are used. Injection solutions or sions are particularly suitable, in particular aqueous solutions of the active compounds in polyethoxylated castor oil.
For vaginal application, for example suppositories, tampons, gels, foams or intrauterine pessaries are suitable and usual.
For rticular injection, suitably prepared crystal suspensions can be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
For rectal ation, the new compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of ) and ointments both for systemic and also for local therapy.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp For pulmonary ation of the new compounds, these can be used in the form of aerosols and inhalation formulations.
For local use on eyes, external auditory canal, middle ear, nostrils and paranasal sinuses, the new nds can be used as drops, ointments and tinctures in appropriate pharmaceutical preparations.
For topical ation, formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and res are le. The dosage of the compounds of the general formula I in these preparations should be 0.01% - 20% in order to e an adequate pharmacological action.
The dosage of the active nces can vary depending on the administration route, age and weight of the patient, nature and severity of the disease to be treated and similar factors. The treatment can be effected by single doses or by a large number of doses over a longer period.
The daily dose is 0.5 - 1000 mg, preferably 50 - 200 mg, and the dose can be given as a single dose for administration once or subdivided into 2 or more daily doses.
As carrier systems, surface-active additives such as salts of the bile acids or animal or plant phospholipids, but also mixtures thereof and liposomes or components thereof can also be used.
The formulations and presentations described above are also a subject of the present invention.
The administration of the compounds according to the invention can be effected by any conventional method, including oral and parenteral, e.g. by subcutaneous or uscular injections, and various inhalation techniques. The enteral, parenteral, vaginal, intrauterine and oral applications are also a subject of the present invention.
The compounds according to the invention of the general formula I bind to the EP2 receptor and have an nistic action. The antagonistic action can be determined by an antagonism test (see Example 1.2.1 of the biological examples).
Antagonists should be understood to mean les which bind to their appropriate ors and which inhibit the initiation of the signal transduction pathway(s) coupled with the receptor through the naturally occurring ligand(s). Normally, the antagonists compete with the naturally Durring ligand of the ors for the binding to the or. However, other modifications of ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp the receptor by les which prevent the signal transduction pathways coupled with the receptor from being activated by the naturally occurring ligand(s) are also possible (e.g. non- competitive, steric cations of the receptor).
More preferably, the antagonists bind reversibly to their corresponding receptors.
The EP2 receptor antagonist has a preferential y for the EP2 receptor compared to any other EP receptor. The antagonism is measured in the presence of the natural agonist (PGEz).
For the determination of the selectivity, the action of the EP2 nist on a human EP4 receptor le 2.2.1) or PGD receptor (Example 3.2.1) can be determined (Table 1).
Furthermore, the nces according to the invention are more stable in vivo than the EP2 receptor antagonists which are described in the closest state of the art (DE 10 2009 049 662 Al), and this results in higher half-lives (see Table 3).
Also a subject of the present invention is the use of the substances according to the invention as EP2 receptor antagonists for the treatment of diseases which are caused by disorders in the signal transduction chain in which the EP2 receptor is involved, such as for example pain and fertility disorders. The EP2 receptor antagonists are also suitable for fertility control.
In the pre-ovulatory antral follicle, the oocyte is surrounded by cumulus cells which form a dense cell crown around the oocyte. After the peak of the luteinizing hormone (LH peak), a series of processes is activated, which s in a marked logical change in this cell crown of cumulus cells. During this, the cumulus cells form an extracellular matrix, which leads to the so-called s expansion (Vanderhyden et al. 1990, Dev Biol., Aug;l40(2):307-3l7).
This cumulus expansion is an important component of the ovulatory process and the uent ility of fertilization.
During the cumulus expansion, prostaglandins and here prostaglandin E2, synthesis whereof is induced by the LH peak, are of decisive importance. Prostanoid EP2 knockout mice (Hizaki et al., 1999, Proc Natl Acad Sci U S A., Aug 31;96(l8):10501-6.) show a markedly decreased cumulus expansion and severe subfertility, which demonstrates the importance of the prostanoid EP2 receptors for this s.
The action of an EP2 antagonist on cumulus expansion can be ed in a cumulus expansion test (see Example 4.2).
The substances according to the invention have inhibitory effects in cumulus ion tests and Dinfluence on the fertilizability of ovulated cumulus-oocyte complexes (see Example 4.3 and [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Table 4). The substances according to the invention have a contraceptive effect in non-human primates (Cynomolgus), where they cause a markedly decreased pregnancy rate without haVing an influence on the cycle (length of the cycle and es) (see Example 4.4 and Table 5).
This for the first time shows a contraceptive effect of EP2 receptor antagonists in non-human primates. This effect is based on non-hormonal mechanisms, which demonstrates the possibility of hormone-free contraception with the substances according to the invention.
A subject of the present invention is the use of the substances according to the invention for fertility control.
While the EP2 receptor antagonist AH6809 f1rst suppresses the expansion of the cumulus, by only ca. 30%, at a concentration of 100 - 200 nM, in the presence of the substance according to the invention according to Example 17 a ca. 70% suppression of the cumulus expansion can already be attained at a 100-200 times lower concentration (0.5 uM; leo: 3.4 nM, see Table 1).
In these experiments, the test substances compete with the natural EP2 receptor agonist PGE2 (0.3 uM).
By stration of the substance of example 62 from the application DE 10 2009 049 662 A1, a ca. 70% suppression of the cumulus expansion can likewise be achieved, however for this a concentration of 10 uM is necessary, which represents a 10-20 times lower concentration in comparison to AH6809. r, this is markedly higher than the tration of 0.5 uM for Example 17 from the t invention (see Table 2).
Example 17 according to the invention from the present ion is also terized by a better al half-life. While example 62 from the ation DE 10 2009 049 662 A1 has a tug of 0.4 hours, for Example 17 this is 2.5 hours (see Table 3).
Accordingly substance 17 of the present invention is markedly superior to this compound known from the state of the art.
A t of the present invention is the use of the substances according to the invention for the inhibition of cumulus expansion and thereby of ovulation and ization for contraception.
A particular form of contraception is emergency protection (also known as g-after pill”).
This should be understood to mean the taking of one or more nces which is intended to prevent a possible pregnancy after ected sexual intercourse and in the event of a presumable failure of the protective method.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A subject of the t invention is the use of the substances according to the invention for emergency protection.
Also a subject of the present invention is the use of the substances according to the ion as EP2 receptor antagonists for the laxis and direct treatment of diseases Which are causally linked With the EP2 receptor or of diseases Which can be d by influencing the EP2 receptor.
Prostaglandins play an important part in angiogenesis (Sales, r, 2003, Reproduction 126, 559 — 567; Kuwano et al., 2004, FASEB J. 18, 300—310; Kamiyama et al., 2006, ne 25, 7019—7028; Chang et al., 2005, prostaglandins & other Lipid Mediators 76, 48—58). triosis is a chronic disease n atory, immunmodulatory and angiogenic processes are involved. Together With other factors, prostaglandins and here in particular the PGE2 and the EP2 receptor are of particular importance (Banu et al., 2009, Molecular Endocrinology 23: 1291—1305; Bulun 2009, N Engl J Med; 360, 268-279).
Circa 10% of women suffer regularly from severe bleeding during menstruation, caused by changes in the blood vessels of the endometrium. Additionally, structural differences in the blood vessels have been observed, such as for example the incomplete formation of the smooth muscle layer (Abberton et al., 1999, Hum. Reprod. 14, 1072-1079, Rogers et al. 2003, Microsc Res Tech. 60(4), 412-419). Since the blood loss during uation is partly regulated by the constriction of the blood vessels, it is obvious that the defects in the smooth musculature contribute substantially to the bleeding.
A subject of the present invention is the use of the substances of the general formula I for the prophylaxis and treatment of endometriosis.
Prostaglandins play an important part in uterine contraction, and excessively strong contractions are responsible for menstrual ms (Sales, Jabbour, 2003, Reproduction 126, 559 — 567).
Prostaglandins and here especially the EP2 and the EP4 receptor have been linked With severe menstrual bleeding (Smith et al., 2007 (Human Reproduction, Vol.22, No.5 pp. 1450—1456).
A subject of the present invention is the use of the nces of the general formula I for the prophylaxis and treatment of menstrual problems and severe menstrual bleeding and pains during menstruation.
Fibroids (myomas) are benign tumours in the uterus With a high dissemination rate. Via the Dnulation of aromatase by a AMP-mediated signal pathway, and by other possible ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp mechanisms, there is a link to the prostaglandin metabolism (Imir et al., 2007, J Clin Endocrinol Metab 92, 982).
A subject of the present invention is the use of the substances of the general formula I for the prophylaxis and treatment of fibroids (myomas).
An increasing number of research s also confirm the importance of the EP receptors, and in particular also of the EP2 receptor in a large number of cancer types (e. g. breast cancer, colon carcinoma, lung cancer, prostate cancer, leukaemia and skin cancer), Which points to future possibilities for the use of modulators (antagonists or ts) of the EP2 receptor for the therapy and tion ylactic and/or adjuvant) of cancer n et al., 2006, Cancer Res; 66(20): 9794-7; Castellone et al., 2005, Science Vol 310, 1504-1510; Chang et al., 2005, Cancer Res; 65(11): ); Hull et al., 2004, Mol Cancer Ther;3(8):1031—9; Richards et al., 2003, J Clin Endocrinol Metab 88: 816,; Sinha et al., 2007, Cancer Res; 67(9): 4507—13; Wang et al., 2004, Seminars in Oncology, Vol 31, No 1, Suppl 3: pp 64-73), Yu et al., 2008; JPET Published on June 26, as DOI:10.1124/jpet.108.141275, Denizot et al., 2005, Int. J. Cancer: 115, 499—501; Fiancette et al., 2011, J Oncol. pii: 389021, Chun et al., 2011, Mol og. 50(6):439-48).
A subject of the present invention is the use of the substances of the general formula I for the treatment and prevention of cancer diseases.
The activation of endothelial cells plays an important part in the pathogenic process of arteriosclerosis. Here oxidation products of low density lipoprotein (LDL) are significant in the onset and development of arteriosclerotic diseases. More recent researches indicate involvement of the EP2 receptor (Li et al., 2006; Circ Res. 98:642-650).
A subject of the present invention is the use of the substances of the general formula I for the treatment and prevention of arteriosclerosis.
More recent scientific publications show that in neurodegenerative, neuroinflammatory and ischaemic diseases imer, Parkinson, ALS and stroke), prostaglandins and the EP2 receptor are important ents of the pathological process (Hoshino et al., 2007, J Biol Chem.; 282(45): 88; Liang et al., 2005, The Journal of Neuroscience; 25(44): 10180 —10187; Jin et al., 2007, J Neuroinflammation. Jan 4;4:2.; Liang et al., 2008, Ann Neurol;64: 304—314; Dnino et al., 2008, Current Medicinal Chemistry, 1863-1869).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Multiple sclerosis is a chronic ation of the nervous system. Prostaglandins, especially PGEz, and effects mediated Via the EP2 receptor are causally linked With the pathological ses in multiple sclerosis (Palumbo et al., 2011, Prostaglandins, Leukotrienes and Essential Fatty Acids 85: 29—35; Palumbo et al., 2011, J. Neurochem. 1/j.1471-4159, Kihara et al., 2009, Proc Natl Acad Sci U. S. A, 106, No. 51: 21807—21812).
A t of the present invention is the use of the substances of the general formula I for the treatment and prevention of egenerative, neuroinflammatory and ischaemic diseases such as for example Alzheimer’s, son’s, ALS and stroke and for the treatment of multiple sclerosis.
Polycystic kidney diseases are also linked With the EP2 receptor (Song et al., 2009, Human Molecular Genetics, 18, No. 13: 2328—2343; Elberg et al., 2007, Am J l Renal Physiol 293: F1622—F1632.) A subject of the present invention is the use of the substances of the general formula I for the treatment and prevention of polycystic kidney es.
Reinold et al. (J. Clin. Invest. 115, 673-679 (2005)) describe PGE2 receptors of the EP2 subtype as the key signal elements in inflammatory hyperalgesia. Mice Which no longer carry this receptor ') feel no spinal atory pain. There are indications that an inflammatory, increased sensitiVity to pain can be treated by specifically modulating EP2 receptors.
Furthermore, the EP2 receptor is linked With other types of pain (Zeilhofer, 2007, Biochemical Pharmacology 73; 165— 174), inter alia in facial nerves (Patwardhan et a]. (J Dent Res 87(3):262-266, 2008)).
A subject of the present invention is the use of the nces according to the invention for the treatment and prevention of pain of various s such as for example inflammatory hyperalgesia.
Recent scientific publications refer to a use of EP2 inhibitors for the prevention and/or treatment of ions of the respiratory tract. Serezani et al. (Am Respir Cell Mol Biol Vol 37. pp 562- 570, 2007) states that the ability of macrophages of the respiratory tract to destroy bacteria is impaired Via the activation of the EP2 receptor by PGEg. Bacterial infections lead to increased production of prostaglandins, inter alia PGEz, Which Via this mechanism weakens the endogenous defence against bacteria. As shown in this publication, this ability to combat uteria can be restored by inactivation of the EP2 receptor (and of the EP4 receptor). Further [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp relevant publications which explain these connections are: Sadikot et al., 2007, Eur. J. Immunol.. 37: 1001—1009; Aronoff et al., 2004, The Journal of logy, 173: 559—565 and Medeiros et al., 2009, J Exp Med. 206(1):61-68.
A subject of the present invention is the use of the nces according to the invention for the prevention and treatment of infectious diseases of the lung.
Fibroblasts and here in particular their functions in the restoration of d tissue play a decisive part in c obstructive pulmonary disease. During this, an excess of PGE2 suppresses important repair functions of the f1broblasts (Togo et al., 2008, Am J Respir Crit Care Med, 178: 248—260).
A t of the present invention is the use of the substances according to the invention for prophylaxis and treatment in chronic obstructive pulmonary diseases.
Intestinal inflammatory es (e.g. Crohn’s disease) are also linked with the prostaglandin EP2 receptor (Sheibanie et al., 2007, The Journal of Immunology, 178: 8138—8147).
A subject of the present invention is the use of the substances according to the invention for the prevention and ent of intestinal inflammatory diseases.
During bone marrow transplantation, complications often occur through infections, wherein an overproduction of PGE2 is linked with decreased immune defence (Ballinger et al., 2006, The Journal of Immunology, 177: 508).
A subject of the present ion is the use of the substances according to the ion for prophylaxis and treatment in bone marrow transplantation.
Graves’ disease is an autoimmune disease of the thyroid, in which the clinical picture can also include pathological changes in the eye (endocrine orbitopathy; protrusion of the eyeballs (exophthalmus)). During this, invading lymphocytes activate fibroblasts that are present, which leads inter alia to an accumulation of mucopolysaccharides. Possible consequences are impairment of the vision even ing to blindness. Studies show that interleukin-6 is of decisive importance for the pathological mechanisms and that interleukin-6 is induced via PGE2 and the EP2 receptor (Raychaudhuri et al., 2010, PloS ONE, 5: e15296; Wang et al., 1995, J Clin niocrinol Metab 80: 3553-3560).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp A subject of the present invention is the use of the substances according to the invention for prophylaxis and treatment in orbitopathy in connection with Graves’ disease or other ogical diseases of the eye.
Aneurysms are vascular dilations with the risk of leading with ar ruptures to haemorrhages with grave and hreatening effects, e.g. paralysis, loss or impairment of , cognitive limitations and other neurological consequences in case of cerebral haemorrhages. Even t ruptures, cerebral aneurysms can cause severe neurological symptoms through the pressure on nerve fibres. Cerebral aneurysms are found in about 1 — 5% of the population, there being a higher incidence in women. Ruptures of aneurysms in the peripheral blood vessels involve a high risk of thromboses, cardiac infarctions, pain and a number of other clinical pictures.
Pharmacological therapies mainly comprise the tion of risk factors such as hypertension.
Recent ific studies were able to show that the EP2 receptor plays a ntial part in the pathogenesis of cerebral aneurysms. In this, via the cascade COX-2 — PGE2 — EPz- NF-K-B an inflammatory state is created which is causally involved in aneurysm ion (Aoki et al., 2011, h Journal of Pharmacology 163: 1237—1249; Aoki et al. 2007, 116:2830-2840).
A subject of the present invention is the use of the substances according to the invention for the prophylaxis and treatment of aneurysms.
Kawasaki syndrome is an acute, systemic feverish disease, by which children under 5 years are predominantly affected. erm damage can include changes in the blood vessels, in particular the coronary blood vessels (e.g. formation of aneurysms) and diseases connected therewith such as cardiac rhythm disorders and cardiac infarction. The incidence differs regionally, thus for example 185 out of 100000 children under 5 years in Japan and about 9 out of 100000 children in Germany. Prostaglandin E2 is elevated in the acute phase of the disease (Lee et al., 1988, Prostaglandins Leukot Essent Fatty Acids, 31(2):53-57). Through recent research s it could be shown that [3] integrin is ted by PGE2 and mediated via the EP2 receptor, which is causally linked with the vascular damage (Kajimoto et al., 2009, Inflamm.
Res. 58: 224—228).
A subject of the present invention is the use of the substances according to the invention for the prophylaxis and treatment of Kawasaki syndrome, in particular also for the prevention and fiidance of ar damage.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Recent ches show that the EP2 receptor has an important role in arthritis and here exerts an influence on the pathogenesis of this e via immunmodulatory mechanisms (Harizi et al., 2010, Immunology and Cell Biology, 1—8).
A t of the present invention is the use of the substances according to the invention for the prophylaxis and treatment of arthritis.
The natural ligand st) of the EP2 or is PGEg, the synthesis whereof is mediated via cyclooxygenases (COX) enzymes (COX-l, COX-2). These enzymes are mostly involved in the said clinical pictures and indications and the onset thereof via increased expression and activity.
Hence in all the use possibilities mentioned, a combination of a COX inhibitor (COX-2 and/or COX-l) is possible, with the aim of a) achieving a higher and more effective pharmacological activity than with one substance class and b) enabling a lower dosage of one of the two or of both substance classes, which leads to a reduction of possible side effects and better tolerance.
Hence drugs containing a compound of the general formula (I) in combination with a COX tor for the treatment of diseases (combination preparations) are also a subject of the present invention. As COX inhibitors, for example the non-selective COX inhibitors such as aspirin, naproxen, indomethacin, ibuprofen and the selective COX inhibitors meloxicam, ofen, piroxicam, cam, nimesulide, mefanemic acid, ketoralac, celecoxib (4-[5-(4-methylphenyl)- 3 uoromethyl)- l H-pyrazol- l -yl]benzenesulphonamide) parecoxib (N— [4-(5-methyl-3 - phenylisoxazolyl)phenyl]sulphonylpropionamide), rofecoxib (4-(4-mesylphenyl)phenyl- furan-2(5H)-one), valdecoxib (4-[5-methylphenylisoxazoyl)benzenesulphonamide), NS- 398 hylcyclohexanoxynitrobenzenesulphonamide), lumiracoxib [2-(2'-chloro-6'- fluoro-phenyl)-aminomethylbenzeneacetic acid], xib and etoricoxib may be mentioned.
These combination preparations can be used for the treatment of the following diseases: infectious diseases, cancer, cardiovascular diseases, angiogenic diseases, uterine contraction disorders, pain, inflammatory diseases, neuroinflammatory diseases, neurodegenerative es, autoimmune diseases, immunodependent diseases/therapies, nephrological diseases and ophthalmological diseases.
They can also be used for fertility control.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp In addition, the invention relates to a process for the tion of the compounds according to the invention of the general formula I.
For this, for example a carboxylic acid of the formula VIII is reacted with an amine of the general formula XI by methods known to those skilled in the art to give the compounds according to the ion of the general formula I (Scheme 1).
The reaction takes place in that for example a carboxylic acid of the formula VIII is converted with isobutyl chloroformate in the presence of a tertiary amine, for example triethylamine, into a mixed anhydride, which reacts with an alkali metal salt of the appropriate amine XI in an inert solvent or solvent mixture, for example tetrahydrofuran, N,N—dimethylformamide or dimethoxy- ethane at temperatures between -30°C and +60°C to give the target compounds of the formula I.
It is also possible to activate a carboxylic acid VIII with reagents such as for example dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)ethylcarbodiimide (EDCI), N—hydroxybenzotriazole (HOBT) or N—[(dimethylamino)-(3H-[l,2,3]triazolo[4,5-b]pyridin—3- methyliden]-N-methylmethanaminium hexafluorophosphate (HATU). For example the reaction with HATU takes place in an inert solvent, for example N,N—dimethylformamide or dimethyl sulphoxide in the presence of the riate amine XI and a ry amine, for example triethylamine or ropylamine, at temperatures between -30°C and +60°C.
It is also possible, to convert a carboxylic acid of the formula VIII into the corresponding carboxylic acid chloride with an inorganic acid chloride, for example phosphorus pentachloride, phosphorus trichloride or thionyl chloride and then into the target compounds of the general formula I in pyridine or an inert t, such as for example N,N—dimethylformamide, in the presence of the appropriate amine XI and a tertiary amine, for example triethylamine, at temperatures between -30°C and +60°C.
The compounds ing to the invention of the general formula I can also be obtained from bromoindazoles of the general formula VI under ium(0) catalysis by reaction with an appropriate amine XI and carbon monoxide (CO) or a carbon monoxide source, such as for e enum hexacarbonyl in a suitable solvent or solvent e, for example l,4-dioxan/water or tetrahydrofuran, addition of a base such as for e sodium carbonate or l,8-diazabicyclo(5.4.0)undecene (DBU) and a catalyst-ligand mixture, for example palladium(II) acetate or trans bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]-dipalladium(II) / tri-tert-butylphosphinotetrafluoroborate at atures between 80°C and 160°C (optionally with microwave irradiation between 80-200 watts), and in case of the use of carbon monoxide at a CO pressure of 5-15 bar (Scheme 1).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The compounds according to the invention of the general formula I can also be obtained from amines of the general formula XV by reaction with carboxylic acids (Y = OH), chlorides (Y = C1) or ides (e. g. Y = O-C(O)-O-CH2(CH)3CH3) of the formula IX in the manner described for the production of the nds I from the compounds VIII and XI (Scheme 2).
Likewise, the nds of the general a I can be ed from compounds of the general formula XVI, wherein LG' for example means Br or I, by on with compounds of the formula XVIII (Scheme 2).
Compounds of the formula XVIII are for example (Het)Arylboronic acids (R3-Met = (Het)Ar- B(OH)2) or boronic acid pinacol esters (R3-Met= (Het)Ar-BPin), which are ted to biaryl compounds of the formula I by methods known to those skilled in the art in a suitable solvent, for example N,N—dimethylformamide, tetrahydrofuran, dimethoxyethane and optionally water and addition of a base, for example triethylamine, potassium carbonate, m carbonate and a catalyst-ligand mixture, for example of ium(II) acetate / triphenylphosphine, bis(diphenylphosphino)ferrocenedichloropalladium (II) (/ 1,1’-bis(diphenylphosphino)ferrocene/ Cu(I)Cl) at temperatures between 20°C and 120°C.
Compounds of the formula XVIII can also be rylalcohols t = (Het)ArO-H), which are converted into biaryl ethers of the formula I by methods known to those skilled in the art in a suitable solvent, for example N,N—dimethylformamide or dimethyl sulphoxide with addition of a base, for example potassium carbonate, caesium carbonate under copper-(I) catalysis e.g. with copper(I) bromide at temperatures n 60°C and 120°C.
The carboxylic acids of the general formula VIII can for example be obtained from esters of the formula VII by ester saponif1cation in a suitable solvent or solvent mixture, for example methanol, ethanol or ydrofuran, water with addition of an aqueous solution of an alkali metal hydroxide, for example sodium hydroxide or m hydroxide at temperatures between °C and 60°C (Scheme 1).
In the same manner, the carboxylic acids XIII can be obtained from the esters XII (Scheme 2, PG: e. g. Boc (tert-butyloxycarbonyl) and the carboxylic acids XXI from the esters XX (Scheme 3, LG': e.g. Br or I).
The esters of the general formula VII can be obtained from bromoindazoles of the general formula VI under palladium(0) catalysis by reaction with carbon monoxide or a carbon monoxide source, such as for example molybdenum rbonyl, and methanol in a suitable solvent, for example dimethyl sulphoxide, N,N—dimethylformamide or tetrahydrofuran and Diition of a base, for example triethylamine or 1,8-diazabicyclo(5.4.0)undecene and a [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp catalyst-ligand mixture, for example of palladium(II) acetate / 3-diphenylphosphino- propane or trans bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) / tri-tert- butylphosphinotetrafluoroborate at temperatures between 20°C and 140°C (optionally with microwave irradiation between 80 - 200 watts), and in case of the use of carbon monoxide at a CO pressure of5 — 15 bar (Scheme 1).
This method is not restricted to methyl esters, i.e. to the use of methanol, but can also be ed to other esters. Thus for example by use of ethanol instead of methanol in this manner, the corresponding ethyl esters can be synthesized.
In the same manner, the esters XII can be obtained from the bromides IV e 2, -PG: e. g.
-Boc).
The amides of the general formula VII can also be obtained from the amines of the general formula XIX by reaction with compounds of the general formula IX (Scheme 3), analogously to the synthesis of the compounds I from the nds XV (Scheme 2).
The compounds of the general formula VII can also be obtained from compounds of the formula XX and reaction with nds of the formula XVIII (Scheme 3), analogously to the described conversion of the compounds XVI to the compounds of the formula I (Scheme 2).
The amides of the general formula VI can be obtained from amines of the l formula V by reaction with carboxylic acids (Y = OH), chlorides (Y = C1) or anhydrides (e. g. Y = O-C(O)-O- CH2(CH)3CH3) of the formula IX (Scheme 1), as described for the conversion of amines XV to amides I (Scheme 2).
The amides of the general formula XVI can be obtained in analogous manner from amines XV and carboxylic acids or ylic acid derivatives XVII (Y: e. g. OH, C1 or O-C(O)-O- CH2(CH)3CH3; LG': e. g. Br or I) (Scheme 2).
Analogously, amines XX (LG': e. g. Br or I) can be obtained from amines XIX and carboxylic acids or carboxylic acid derivatives XVII (Y: e. g. OH, C1 or O-C(O)-O-CH2(CH)3CH3; LG': e.g.
Br or I) (Scheme 3).
Likewise, carboxylic acids XIII (PG: e. g. Boc) can be converted with amines XI to amides XIV (Scheme 2) and carboxylic acids XXI (LG': e. g. Br, I) with amines XI to amides XVI e 3) in this manner.
The secondary amines V can be obtained from the corresponding carbamates IV (PG: e. g. Boc) bdmethods known to those d in the art (Scheme 1). ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Thus for example tert-butyl carbamates can be converted into the amines V in an acidic medium with the use of e.g. trifluoroacetic acid or hydrochloric acid in a suitable solvent or solvent mixture such as for example romethane, dioxan or acetone/water. In an anhydrous medium the amines V are formed as the corresponding salts.
Analogously, the amines XV can be obtained from the carbamates XIV (Scheme 2) and the amines XIX from the carbamates XII (Scheme 3).
The 2H—indazoles of the l formulae IV and VI can be produced in various ways.
For example, 2H—indazoles IV can be obtained from IH—indazoles of the general formula II by alkylation with compounds of the general formula III (PG: e.g. Boc, LG: e.g. Br, I, O-Ts (tosyloxy) or O-Ms (mesyloxy)) in a suitable solvent, for example N,N—dimethylformamide, N,N—dimethylacetamide, dimethyl sulphoxide or else THF, l,4-dioxan and addition of a base such as for example potassium carbonate or caesium carbonate (optionally with addition of tetrabutylammonium iodide) or else sodium bis(trimethylsilyl)amide, at temperatures between °C and 100°C or else in case of the use of sodium bis(trimethylsilyl)amide 0°C and 25°C (Scheme 1).
Analogously the 2H-indazoles of the general formula VI can be obtained from azoles of the general formula II and nds of the general formula X (LG: e.g. Br, I, O-Ts or O-Ms) (Scheme 1).
The 2H—indazoles of the general formula IV can also be ed from ortho-nitrobenzaldehydes of the general formula XXVII by reaction with an appropriate amine XXVIII (PG: e.g. Boc) in a suitable solvent, for example l,4-dioxan and addition of a ng agent such as for example triethyl phosphite, possibly with addition of potassium ate or caesium carbonate or powdered molecular sieve, at temperatures between 100°C and 160°C (Scheme 4).
Analogously, the 2H—indazoles of the general formula VI can be ed from ortho- nitrobenzaldehydes XXVII by reaction with amines XXIX (Scheme 4).
The compounds of the l formula XIV (PG: e. g. Boc) can also be obtained from bromo- indazoles of the general formula IV (PG: e.g. Boc) under palladium(0) catalysis by reaction with an appropriate amine XI and carbon monoxide or a carbon monoxide , such as for e molybdenum hexacarbonyl (Scheme 2), analogously to the described process for the conversion of the bromoindazoles VI to the compounds of the general formula I, (Scheme 1).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The ortho-nitrobenzaldehydes of the general formula XXVII can be produced from the ortho- oluenes of the general formula XXVI by methods known to those skilled in the art in two reaction steps (Scheme 4).
For this, an ortho-nitrotoluene XXVI is dissolved in a suitable solvent such as N,N—dimethyl- formamide and converted with methylformamide dimethyl acetal at temperatures of 100 — 140°C to the corresponding enamine, which is immediately oxidized at temperatures of 0°C — °C to the corresponding ortho-nitrobenzaldehyde with a suitable oxidizing agent such as for example NaIO4 in a suitable aqueous t e such as water/N,N—dimethylformamide and optionally with addition of a base such as for example triethylamine, N,N—diisopropyl- ethylamine, sodium hydrogen carbonate or sodium carbonate.
The ortho-nitrotoluenes of the general formula XXVI can be produced from the ortho- methylanilines of the general formula XXV by methods known to those d in the art (Scheme 4).
For this, an ortho-methylaniline XXV is dissolved in a suitable solvent such as dichloromethane or chloroform, treated with zirconium(IV) tert-butoxide, ground molecular sieve 3A and tert- butyl hydroperoxide and reacted at temperatures of 20-40°C.
The IH—indazoles of the general a II can be liberated from the acetamides of the general formula XXIV by methods known to those skilled in the art (Scheme 4).
For this, for example an acetamide XXIV is reacted in a suitable solvent such as methanol or ethanol and addition of 37% hloric acid at temperatures of 40 — 80°C.
Analogously thereto, the anilines of the formula XXV can be liberated from the acetanilides of the formula XXIII (Scheme 4).
The acetamides of the general formula XXIV can be produced from the ortho-methyl- acetanilides of the l formula XXIII by methods known to those skilled in the art e For this, the ortho-methyl-acetanilides XXIII are dissolved in a suitable t such as chloroform or toluene, treated with acetic anhydride, isopentyl or utyl nitrite, and optionally potassium acetate and 18-crown-6, and reacted at temperatures of 60 — 100°C.
The ortho-methyl-acetanilides XXIII can be produced from the acetanilides of the l formula XXII by bromination by methods known to those d in the art (Scheme 4).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp For this, the acetanilides XXII, which can for example be ed from the corresponding anilines by reaction with acetic anhydride in a suitable t (e. g. toluene) at temperatures of 80-110°C, is reacted with bromine in glacial acetic acid at temperatures of 10-25°C.
The nds of the general formula III wherein LG means -OTs or -OMs can be produced by methods known to those skilled in the art from the corresponding alcohols.
For this, the alcohols are reacted with p-toluenesulphonyl chloride or methanesulphonyl chloride at temperatures between 0°C and 40°C in a suitable solvent, e. g. dichloromethane or tetrahydrofuran or toluene and addition of a suitable base, e.g. pyridine or triethylamine.
The compounds of the general a X, wherein LG means -OTs or -OMs, can be produced from the corresponding amino alcohols XXX by methods known to those d in the art e 4).
For this, in a first step the amino alcohols XXX are ted to the corresponding amides XXXI in a suitable solvent, e.g. dichloromethane, with rboxylic acid chlorides of the formula Cl-C(O)-Ar-R3 and addition of a suitable base, e.g. triethylamine, at temperatures between 0°C and 25°C. Optionally, corresponding esters formed as by-products can be separated or else saponif1ed to the ponding alcohols XXXI under standard conditions, e. g. with use of a base, e. g. ium hydroxide, in a suitable solvent mixture, e. g. ethanol/water, at temperatures between 20°C and 40°C The N—protected alcohols XXXI thus obtained can be converted into the compounds of the formula X with LG: -OTs or -OMs analogously to the process described for the synthesis of the compounds III. Compounds of the formula X with LG: -Br can be obtained from the corresponding alcohols XXXI by methods known to those skilled in the art by reaction with a brominating agent such as for example CBr4 with addition of PPh3 as an oxophile in a suitable solvent, e. g. chloroform, at temperatures between 20°C and 40°C.
The compounds of the general a XXIX, can be produced by s known to those skilled in the art for example from the amines of the a XXXII (Scheme 4).
For this, in a first step, the amines XXXII are converted to the corresponding amides XXXIII analogously to the synthesis of the compounds I from the compounds XV.
The tert-butyloxycarbonyl group in compounds of the formula XXXIII is cleaved analogously to the conversion of the compounds IV to the compounds V, hence the compounds of the formula XXIX can be obtained.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Scheme 1 Ar—R3 0 (IX) HO N 1 m 1 )n o R ( m o R ( R1 m( N 3 3 (VIII) yAr-R (VII) yAr-R (VI) o _ X NH 4/ 2 2 R \/ /N /R4/X\/NH2"00..
(XI) H \N x (XI) 4 N \ o R1 m( (I) yAr-RS SchemeZ /N\ /N\ N N \ \ Br n 1 1 m( N) (IV) (XIII ) \ \ R4/XVNH2(XI) 1 m( N (XIV) \ Y Ar-LG' Ar_R3 \o (XVII) 0 (IX) N 3 — H N / Met R (N 4/XVN \ X N \ (XVIII) R 4/ V )n R ' )n O R1 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Scheme3 R2 Y 2 2 /N\N R Ar-R3 R /O \ N 0 (IX) __ O \ 0 H30 )n Hsc/ HsC/ 1 )n o m( bkPG 1 m 0 R ( NH 0 (XII) (XIX) JO>—Ar—LGY (XVII) Met—R3 H3/CO\';<;E/N ) ‘by‘ (XX) N>—Ar—LG' R2 l/MN R‘VXVNHZ H HO \ (XI) R4/XVN )n —> o R1 m( (XXI) Ar—LG' Scheme4 2 H 2 H CH 2 H R N\n/CH3 R NYCHS 3 R R2 y N\ N\ N O . O —* N / CH3 Br CH3 / Br 1 1 B r 1 R (XXII) R ) R ()II (XXIV) if}:I}2pc: ROOM R R (XXVI) (XXVII) my)” (XXVIII) m( N\ R2 (:X'XI/ELA R1 E)"() ('V) bkPG n m ( N ’Rs (XXX) rn( NH (XXXI) NZI/ArRR3 —> (X) rAr H C 0 CH 3 H C 3 O H C 3 COlN H N H:C 2 )n N Hwy _. m( N ’R3 H )n ”‘( 2fAr ( N 3 XXXIII ) ,R D (XXXII)MH rm (XXIX) The invention as claimed herein is described in the following Items 1 to 25: 1. Compounds of the general formula (I) R2 N H N X N R4 ( )n O R1 m( ) Ar R3 O wherein R1: means H, C 1-C2 alkyl or C1-C2 alkyloxy; R2: H or methyl; subject to the proviso that one of the two residues R1 or R2 equals H; X: -(CH2)l-, -(CH2)k-O-, -, CH2-S(O)2-, -CH(CH3)-, -CH(CH3)-O- or -C(CH3)2-O-; k: 1 or 2; l: 0, 1 or 2; R4: H, C 1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; and in the case of X: -CH2- or 3)- R4: additionally means a mbered heterocyclyl r esidue; and in the case of X: -(CH2)l- or -CH(CH3)- R4: additionally means CN; or 7850302_1 (GHMatters) P97018.NZ X together with R4 form a 4membered heterocyclyl residue via a ring carbon linkage; m: 1 or 2; n: 1 or 2; Ar: a 6membered aryl or 5membered hetaryl residue, R3: halogen, CN, SF 5, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C6 heterocyclyl, O-C1-C4 alkyl, O-C3-C6 cycloalkyl, O-C4-C6 heterocyclyl, S-C1-C4 alkyl, S(O)2-C1-C4 alkyl, Ar´, O-Ar´, C(CH3)2-CN or C(CH3)2-OH; and Ar´: an optionally singly or doubly substituted 6-membered aryl or 5membered aryl residue; wherein the substituents are selected from F, Cl, CN, C1-C4 alkyl, O-C1-C4 alkyl, C(CH 3)2-CN, C(CH3)2-OH and C(O)NH2; and diastereomers, enantiomers and salts or cyclodextrin clathrates f. 2. nds according to Item 1, n R1, R2: mean H or methyl; subject to the proviso that one of the two residues R1 or R2 equals H; X: -(CH2)l- or k-O-; k: 1 or 2; l: 0, 1 or 2; R4: C 1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; and m, n: 2; 7850302_1 (GHMatters) P97018.NZ and diastereomers, enantiomers and salts or cyclodextrin clathrates thereof and R3, Ar and Ar´ have the meanings stated in Item 1. 3. Compounds according to Item 1, wherein R1, R2: mean H or methyl; t to the proviso that one of the two residues R1 or R2 equals H; X: -(CH2)l- or -(CH2)k-O-; k: 1 or 2; l: 0, 1 or 2; R4: C 1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; and m, n: 1; and diastereomers, enantiomers and salts or cyclodextrin clathrates thereof and R3, Ar and Ar´ have the gs stated in Item 1. 4. Compounds according to Item 1 or 2, wherein R1: means methyl; R2: H; X: -(CH2)l- or -(CH2)k-O-; k: 1; l: 0 or 1; R4: C 1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; 7850302_1 ters) P97018.NZ m, n: 2; and Ar: a phenyl residue; and diastereomers, enantiomers and salts or extrin clathrates thereof and R3 and Ar´ have the gs stated in Item 1.
. Compounds according to Item 1 or 3, wherein R1: means a methyl group; R2: H; X: -(CH2)l- or -(CH2)k-O-; k: 1; l: 0 or 1; R4: C 1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; m, n: 1; and Ar: a phenyl residue; and diastereomers, enantiomers and salts or cyclodextrin clathrates thereof and R3 and Ar´ have the aforesaid meanings. 6. Compounds according to Item 4 or 5 selected from a group which contains the following compounds: 1. 2-{[1-(4-cyanofluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 2. (4-tert-butoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 3. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 4. N-(2-methoxyethyl)methyl{[1-(4-morpholinobenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 5. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 6. 2-{[1-(2-fluoromesylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 7. 2-{[1-(2-fluoromethoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 8. 2-{[1-(4-bromofluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 9. 2-{[1-(2-fluoromethylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 10. 2-({1-[2-fluoro(trifluoromethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 11. N-(2-methoxyethyl)methyl({1-[4-(pentafluoro-λ6-sulphanyl)benzoyl]piperidin yl}methyl)-2H-indazolcarboxamide 12. N-(2-methoxyethyl)methyl{[1-(4-methylbenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 13. 2-({1-[4-(4-chlorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) -2H-indazolcarboxamide 14. N-(2-methoxyethyl)methyl({1-[4-(4-methylphenoxy)benzoyl]piperidin hyl)-2H-indazolcarboxamide 15. 2-({1-[4-(4-tert-butylphenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 16. ethoxyethyl)methyl[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin yl)methyl]-2H-indazolcarboxamide 17. N-(2-methoxyethyl)({1-[4-(4-methoxyphenoxy)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 18. N-(2-methoxyethyl)methyl{[1-(4-phenoxybenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 19. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 20. 2-{[1-(4-methoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 21. 2-{[1-(4-fluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 22. N-(2-methoxyethyl)methyl({1-[4-(trifluoromethyl)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 23. 2-{[1-(2-methoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 24. N-(2-methoxyethyl)methyl[(1-{4-[(trifluoromethyl)sulphonyl]benzoyl}piperidin yl)methyl]-2H-indazolcarboxamide . N-(2-methoxyethyl)methyl({1-[3-(trifluoromethyl)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 26. N-(2-methoxyethyl)methyl{[1-(3-methylbenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 27. 2-{[1-(3-chlorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 28. 2-({1-[4-(4-carbamoylphenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 29. 2-({1-[4-(cyclopentyloxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide . 2-({1-[4-(difluoromethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 31. 2-{[1-(4-cyanobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H-indazol- -carboxamide 32. [4-(1H-imidazolyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 33. N-(2-methoxyethyl)methyl({1-[4-(oxazolyl)benzoyl]piperidinyl}methyl)-2H- indazolcarboxamide 34. N-(2-methoxyethyl)methyl({1-[4-(oxazolyl)benzoyl]piperidinyl}methyl)-2H- indazolcarboxamide . N-(2-methoxyethyl)methyl({1-[4-(isoxazolyl)benzoyl]piperidinyl}methyl)- azolcarboxamide 36. N-(2-methoxyethyl)methyl({1-[4-(1H-pyrazolyl)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 37. N-(2-methoxyethyl)methyl({1-[4-(1H-1,2,4-triazolyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 38. 2-({1-[4-(difluoromethoxy)fluorobenzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 39. 2-({1-[2-fluoro(pyrrolidinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 40. [(3,4'-difluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 41. 2-({1-[(3-fluoro-4'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 42. 2-({1-[(3-fluoro-4'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 43. 2-[(1-{[3-fluoro-3'-(trifluoromethyl)biphenylyl]carbonyl}piperidinyl)methyl]-N-(2- yethyl)methyl-2H-indazolcarboxamide 44. 2-[(1-{[3-fluoro-2'-(trifluoromethoxy)biphenylyl]carbonyl}piperidinyl)methyl]-N- hoxyethyl)methyl-2H-indazolcarboxamide 45. 2-({1-[(2'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 46. 2-({1-[(2',4'-difluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 47. 2-({1-[(2-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 48. N-(2-methoxyethyl)methyl({1-[(2'-methylbiphenylyl)carbonyl]piperidinyl}- methyl)-2H-indazolcarboxamide 49. N-(2-methoxyethyl)methyl({1-[4-(4-pyridyloxy)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 50. N-(2-methoxyethyl)methyl({1-[4-(4H-1,2,4-triazolyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 51. 2-{[1-(2-fluoromorpholinobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 52. 2-{[1-(4-bromobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 53. N-(2-methoxyethyl)methyl({1-[4-(trifluoromethoxy)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 54. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 55. N-(2-methoxyethyl)methyl[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin yl)methyl]-2H-indazolcarboxamide 56. 4-methyl({1-[4-(pentafluoro-λ6-sulphanyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 57. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-(2,2,2-trifluoroethyl)-2H- indazolcarboxamide 58. 4-methyl-N-(2,2,2-trifluoroethyl)({1-[4-(trifluoromethoxy)benzoyl]piperidin yl}methyl)-2H-indazolcarboxamide 59. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-[2-(cyclopropylmethoxy)ethyl] methyl-2H-indazolecarboxamide 60. N-[2-(cyclopropylmethoxy)ethyl]methyl{[1-(4-methylbenzoyl)piperidinyl]- methyl}-2H-indazolcarboxamide 61. N-[2-(cyclopropylmethoxy)ethyl]({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}- methyl)methyl-2H-indazolcarboxamide 62. N-[2-(cyclopropylmethoxy)ethyl]methyl({1-[4-(trifluoromethyl)benzoyl]piperidin- 4-yl}methyl)-2H-indazolcarboxamide 63. N-[2-(cyclopropylmethoxy)ethyl]({1-[(4'-fluorobiphenylyl)carbonyl]piperidin hyl)methyl-2H-indazolcarboxamide 64. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}-N-[2-(cyclopropylmethoxy)ethyl] methyl-2H-indazolcarboxamide 65. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-[2-(2,2,2-trifluoroethoxy)- ethyl]-2H-indazolcarboxamide 66. 4-methyl{[1-(4-methylbenzoyl)piperidinyl]methyl}-N-[2-(2,2,2-trifluoroethoxy)- ethyl]-2H-indazolcarboxamide 67. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-[2-(2,2,2- trifluoroethoxy)ethyl]-2H-indazolcarboxamide 68. 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]({1-[4-(trifluoromethyl)benzoyl]piperidin- 4-yl}methyl)-2H-indazolcarboxamide 69. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)methyl-N-[2-(2,2,2- trifluoroethoxy)ethyl]-2H-indazolcarboxamide 70. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}methyl-N-[2-(2,2,2-trifluoroethoxy )ethyl]-2H-indazolcarboxamide 71. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-(2-isopropoxyethyl)methyl-2H- indazolcarboxamide 72. N-(2-isopropoxyethyl)methyl{[1-(4-methylbenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 73. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-isopropoxyethyl) methyl-2H-indazolcarboxamide 74. N-(2-isopropoxyethyl)methyl({1-[4-(trifluoromethyl)benzoyl]piperidinyl}- )-2H-indazolcarboxamide 7850302_1 ters) P97018.NZ 75. [(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-isopropoxyethyl) methyl-2H-indazolcarboxamide 76. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}-N-(2-isopropoxyethyl)methyl- 2H-indazolcarboxamide 77. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-[2-(trifluoromethoxy)ethyl]- azolcarboxamide 78. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-[2-(trifluoromethoxy )ethyl]-2H-indazolcarboxamide 79. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)methyl-N-[2-(trifluoro- methoxy)ethyl]-2H-indazolcarboxamide 80. 4-methyl-N-[2-(trifluoromethoxy)ethyl][(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 81. N-(2-tert-butoxyethyl){[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-2H- indazolcarboxamide 82. N-(2-tert-butoxyethyl)({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 83. N-(2-tert-butoxyethyl)({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 84. N-(2-tert-butoxyethyl)methyl[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 85. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-{2-[( thyloxy]- thyl}-2H-indazolcarboxamide 86. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-{2- [( 2H3)methyloxy]( 2H4)ethyl}-2H-indazolcarboxamide 87. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}-N-(2-methoxyethyl)methyl-2H-indazol- -carboxamide 88. N-(2-methoxyethyl)methyl[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin yl)methyl]-2H-indazolcarboxamide 89. N-(2-methoxyethyl)methyl({1-[4-(trifluoromethoxy)benzoyl]azetidinyl}methyl)- 2H-indazolcarboxamide 90. 2-({1-[2-fluoro(trifluoromethyl)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 91. 2-{[1-(4-chlorofluorobenzoyl)azetidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 92. 2-({1-[3-fluoro(trifluoromethyl)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 93. 2-({1-[4-chloro(trifluoromethyl)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 94. 2-{[1-(4-cyclopropylbenzoyl)azetidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 95. N-(2-methoxyethyl)methyl[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin yl)methyl]-2H-indazolcarboxamide 96. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-N-(2,2,2-trifluoroethyl)-2H- indazolcarboxamide 97. 4-methyl-N-(2,2,2-trifluoroethyl)({1-[4-(trifluoromethoxy)benzoyl]azetidinyl}- methyl)-2H-indazolcarboxamide 98. 2-({1-[2-fluoro(trifluoromethyl)benzoyl]azetidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 99. 4-methyl({1-[4-(pentafluoro-λ6-sulphanyl)benzoyl]azetidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 100. N-[2-(cyclopropyloxy)ethyl]methyl({1-[4-(trifluoromethoxy)benzoyl]azetidin yl}methyl)-2H-indazolcarboxamide 101. N-[2-(cyclobutyloxy)ethyl]methyl({1-[4-(trifluoromethoxy)benzoyl]azetidin yl}methyl)-2H-indazolcarboxamide 102. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}-N-[2-(cyclopropylmethoxy)ethyl] methyl-2H-indazolcarboxamide 103. N-[2-(cyclopropylmethoxy)ethyl]({1-[4-(4-fluorophenoxy)benzoyl]azetidinyl}- methyl)methyl-2H-indazolcarboxamide 104. N-[2-(cyclopropylmethoxy)ethyl]methyl{[1-(4-methylbenzoyl)azetidinyl]- methyl}-2H-indazolcarboxamide 105. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-N-[2-(trifluoromethoxy)ethyl]- 2H-indazolcarboxamide 106. N-(2-tert-butoxyethyl){[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-2H- indazolcarboxamide 107. N-[2-(cyclopropylmethoxy)ethyl]({1-[(4'-fluorobiphenylyl)carbonyl]azetidin yl}methyl)methyl-2H-indazolcarboxamide 108. 2-({1-[(4'-fluorobiphenylyl)carbonyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 109. [4-(4-fluorophenoxy)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 110. 2-({1-[4-(4-fluorophenoxy)benzoyl]azetidinyl}methyl)methyl-N-(2,2,2- oroethyl)-2H-indazolcarboxamide 2_1 (GHMatters) P97018.NZ 111. 2-({1-[(4'-fluorobiphenylyl)carbonyl]azetidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 112. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-N-[2-(2,2,2-trifluoroethoxy)- ethyl]-2H-indazolcarboxamide 113. 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl][(1-{4-[4-(trifluoromethyl)phenoxy]- benzoyl}azetidinyl)methyl]-2H-indazolcarboxamide 114. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- azetidinyl)methyl]-2H-indazolcarboxamide 115. 2-({1-[4-(4-chlorophenoxy)benzoyl]azetidinyl}methyl)methyl-N-(2,2,2-trifluoro- ethyl)-2H-indazolcarboxamide 116. 2-({1-[4-(4-chlorophenoxy)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 117. N-(2-methoxyethyl)methyl{[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}benzoyl)- azetidinyl]methyl}-2H-indazolcarboxamide 118. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}- benzoyl)azetidinyl]methyl}-2H-indazolcarboxamide 119. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-ethylmethyl-2H-indazol carboxamide 120. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 121. 2-({1-[4-(4-chlorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 122. 4-methyl({1-[4-(4-methylphenoxy)benzoyl]piperidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 123. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)methyl-N-(2,2,2- oroethyl)-2H-indazolcarboxamide 124. 4-methyl{[1-(4-morpholinobenzoyl)piperidinyl]methyl}-N-(2,2,2-trifluoroethyl)- 2H-indazolcarboxamide 125. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 126. yl-N-(2,2,2-trifluoroethyl)[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 127. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}- l)piperidinyl]methyl}-2H-indazolcarboxamide 128. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}- benzoyl)piperidinyl]methyl}-2H-indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 129. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}- benzoyl)piperidinyl]methyl}-2H-indazolcarboxamide 130. 2-({1-[4-(4-cyanophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2-trifluoroethyl ndazolcarboxamide 131. 2-({1-[4-(3-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2-trifluoroethyl )-2H-indazolcarboxamide 132. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 133. 2-[(1-{4-[(5-cyanopyridinyl)oxy]benzoyl}piperidinyl)methyl]methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 134. 2-[(1-{4-[(5-chloropyridinyl)oxy]benzoyl}piperidinyl)methyl]methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 135. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[5-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 136. [4-(2,4-difluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 137. 2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 138. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{[4'-(trifluoromethyl)biphenylyl]carbonyl}- piperidinyl)methyl]-2H-indazolcarboxamide 139. 2-{[1-(4-bromobenzoyl)piperidinyl]methyl}methyl-N-(2,2,2-trifluoroethyl)-2H- indazolcarboxamide 140. [4-(5-chloropyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 141. 2-({1-[(4'-methoxy-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)methyl- N-(2,2,2-trifluoroethyl)-2H-indazolcarboxamide 142. 4-methyl({1-[4-(6-methylpyridinyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 143. 2-({1-[(4'-fluoro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)methyl-N- (2,2,2-trifluoroethyl)-2H-indazolcarboxamide 144. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 145. 2-({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 146. 2-({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 147. yl({1-[4-(5-methylpyridinyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 148. 2-({1-[4-(5-fluoropyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 149. 2-({1-[4-(5-methoxypyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 150. 4-methyl({1-[4-(2-methylpyrimidinyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 151. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[2-(trifluoromethyl)pyrimidinyl]benzoyl}- dinyl)methyl]-2H-indazolcarboxamide 152. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 153. 2-({1-[4-(4-cyanophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 154. 2-{[1-(4-bromomethylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 155. 2-{[1-(4-tert-butylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 156. 2-({1-[4-(1-hydroxymethylethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide 157. 2-{[1-(4-cyclohexylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 158. 2-({1-[4-(1-cyanomethylethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 159. N-(2-methoxyethyl)methyl({1-[4-(pyrimidinyloxy)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 160. N-(2-methoxyethyl)methyl({1-[4-(3-pyridyloxy)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 161. N-(2-methoxyethyl)methyl{[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}benzoyl)- piperidinyl]methyl}-2H-indazolcarboxamide 162. N-(2-methoxyethyl)methyl({1-[4-(2-pyridyloxy)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 163. N-(2-methoxyethyl)methyl{[1-(4-{[4-(trifluoromethyl)pyrimidinyl]oxy}- benzoyl)piperidinyl]methyl}-2H-indazolcarboxamide 164. N-(2-methoxyethyl)methyl{[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}benzoyl)- piperidinyl]methyl}-2H-indazolcarboxamide 7850302_1 ters) P97018.NZ 165. N-(2-methoxyethyl)methyl{[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}benzoyl)- piperidinyl]methyl}-2H-indazolcarboxamide 166. 2-({1-[(4'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 167. N-(2-methoxyethyl)methyl({1-[4-(3,4,5,6-tetrahydro-2H-pyranyloxy)benzoyl]- piperidinyl}methyl)-2H-indazolcarboxamide 168. N-(2-methoxyethyl)methyl[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}piperidin- ethyl]-2H-indazolcarboxamide 169. 2-[(1-{4-[(5-cyanopyridinyl)oxy]benzoyl}piperidinyl)methyl]-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide 170. 2-[(1-{4-[(5-chloropyridinyl)oxy]benzoyl}piperidinyl)methyl]-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 171. 2-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 172. 2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 173. N-(2-methoxyethyl)methyl[(1-{[4'-(trifluoromethyl)biphenylyl]carbonyl}- piperidinyl)methyl]-2H-indazolcarboxamide 174. 2-({1-[4-(3-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 175. 2-{[1-(2-fluoroisopropoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 176. 2-({1-[(3-fluoro-3',4'-dimethylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 177. 2-({1-[(2',3-difluoro-4'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 178. 2-({1-[4-(difluoromethoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 179. 2-({1-[4-(2-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 180. 2-({1-[(4'-cyano-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- yethyl)methyl-2H-indazolcarboxamide 181. 2-({1-[4-(5-chloropyridinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 182. ethoxyethyl)methyl[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 183. N-(2-methoxyethyl)({1-[(4'-methoxy-2'-methylbiphenylyl)carbonyl]piperidin yl}methyl)methyl-2H-indazolcarboxamide 184. 2-({1-[(4'-chloro-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- yethyl)methyl-2H-indazolcarboxamide 185. 2-[(1-{[4'-(1-cyanomethylethyl)biphenylyl]carbonyl}piperidinyl)methyl]-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 186. N-(2-methoxyethyl)({1-[4-(5-methoxypyridinyl)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 187. N-(2-methoxyethyl)methyl[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 188. N-(2-methoxyethyl)({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 189. 2-({1-[(4'-fluoro-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- yethyl)methyl-2H-indazolcarboxamide 190. N-(2-methoxyethyl)methyl({1-[4-(6-methylpyridinyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 191. N-(2-methoxyethyl)({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 192. N-(2-methoxyethyl)methyl({1-[4-(2-methylpyrimidinyl)benzoyl]piperidin yl}methyl)-2H-indazolcarboxamide 193. 2-({1-[(4'-fluoro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 194. 2-({1-[(4'-chloro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 195. N-(2-methoxyethyl)methyl[(1-{4-[2-(trifluoromethyl)pyrimidinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 196. 2-({1-[(4'-chloro-2'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl thyl-2H-indazolcarboxamide 197. 2-({1-[(2'-chloro-4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide 198. 2-({1-[4-(5-chloropyridinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 199. 2-({1-[4-(5-fluoropyridinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 200. N-(2-methoxyethyl)methyl[(1-{4-[5-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 7850302_1 (GHMatters) P97018.NZ 201. 2-[(1-{[4'-(1-hydroxymethylethyl)biphenylyl]carbonyl}piperidinyl)methyl]-N- (2-methoxyethyl)methyl-2H-indazolcarboxamide 202. 2-({1-[(3',5'-difluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 203. 2-({1-[(4'-fluoromethylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 204. 2-({1-[(3',5'-difluoromethylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 205. N-(2-methoxyethyl)methyl({1-[3-methyl(3-pyridyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 206. N-(2-methoxyethyl)methyl({1-[3-methyl(4-pyridyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide and 207. N-(2-methoxyethyl)methyl({1-[(2-methylbiphenylyl)carbonyl]piperidinyl}- methyl)-2H-indazolcarboxamide 7. Use of a compound according to any one of Items 1-6 for the production of a drug containing suitable formulation and carrier substances. 8. Use of a compound according to any one of Items 1-6 in the manufacture of a drug for use in the treatment of a medical condition. 9. Use of a compound according to any one of Items 1-6 in the cture of a drug for fertility control/contraception. 10. Use of a compound according to any one of Items 1-6 in the manufacture of a drug for the laxis and treatment of endometriosis. 11. Use of a compound according to any one of Items 1-6 in the manufacture of a drug for the prophylaxis and treatment of menstrual complaints, where the menstrual problems can be severe and persistent bleeding, lar bleeding and pains. 12. Use of a compound according to any one of Items 1-6 in the manufacture of a drug for the prophylaxis and treatment of fibroids (myomas). 13. Use of a nd according to any one of Items 1-6 in the cture of a drug for the prophylaxis and treatment of , where the cancer diseases can be lung, inal, breast, skin, prostate or oesophageal cancer and leukaemia. 7850302_1 (GHMatters) P97018.NZ 14. Use of a compound according to any one of Items 1-6 in the manufacture of a drug for the prophylaxis and treatment of arteriosclerosis.
. Use of a compound according to any one of Items 1-6 in the cture of a drug for the prophylaxis and treatment of - neurodegenerative, neuroinflammatory and ischaemic diseases, where the diseases can be Alzheimer’s disease, Parkinson’s disease, ALS, stroke and multiple sclerosis, - pain, where the pain can be inflammatory hyperalgesia, - infectious diseases of the lung, - chronic obstructive pulmonary diseases, - intestinal inflammatory diseases, where the intestinal inflammatory diseases can be Crohn’s disease and ulcerative colitis, - bone marrow transplantation operations, - aneurysms, - vascular damage and the Kawasaki me, or - arthritis. 16. Use of a compound according to any one of Items 1-6 in the manufacture of a drug for the prophylaxis and treatment of polycystic kidney diseases. 17. Use of a compound according to any one of Items 1-6 in the manufacture of a drug for the prophylaxis and treatment of pathological eye diseases, where the ogical eye diseases can be Graves’ disease. 18. Drug ning a nd according to any one of Items 1-6 in combination with a Cyclooxygenase (COX) inhibitor for the treatment of diseases, wherein the COX inhibitors can be selected from the following list: aspirin, naproxen, indomethacin, cam, ibuprofen, ketoprofen, piroxicam, tenoxicam, nimesulide, mefanemic acid, ketoralac, xib (4-methylphenyl)(trifluoromethyl)-1H-pyrazol yl]benzenesulphonamide), parecoxib (N-[4-(5-methylphenyl isoxazolyl)phenyl]sulphonylpropionamide), rofecoxib (4-(4-mesylphenyl) phenylfuran-(5H)-one), valdecoxib (4-[5-methylphenyl isoxazoyl)benzenesulphonamide), NS-398 (N-methylcyclohexanoxynitrobenzenesulphonamide ), lumiracoxib [2-(2'-chloro-6'-fluorophenyl)-aminomethylbenzene- acetic acid], ceracoxib and etoricoxib. 2_1 ters) P97018.NZ 19. Drug according to Item 18, where the es are infectious diseases, , cardiovascular diseases, angiogenic diseases, uterine contraction disorders, pain, inflammatory diseases, neuroinflammatory diseases, egenerative diseases, autoimmune diseases, immunodependent diseases/therapies, nephrological diseases and ophthalmological diseases and where the drugs can also be used for the treatment of pain and in transplantation and for fertility control.
. Use of a compound according to any one of Items 1-6, in the manufacture of a pharmaceutical preparation for enteral, parenteral, vaginal, intrauterine and oral administration. 21. Method for the preparation of the compounds of the general formula (I) according to Item 1, characterized in that a compound of the general formula (VIII) Formula (VIII) where R1, R2, R3, Ar, m and n have the meaning as stated in Item 1, is reacted with an amine of the general formula (XI), a (XI) where R4 and X have the meaning stated in Item 1. 22. Method for the preparation of the nds of the general formula (I) according to Item 1, characterized in that a compound of the l a (VI) Formula (VI) where R1, R2, R3, Ar, m and n have the meaning stated in Item 1, is reacted with an amine of the general formula (XI), Formula (XI) where R4 and X have the meaning stated in Item 1, and carbon monoxide or a carbon monoxide source, under palladium (0) sis. 8017637_1 (GHMatters) P97018.NZ 23. Method according to Item 22, wherein the carbon monoxide source is molybdenum hexacarbonyl. 24. Method for the preparation of the compounds of the general formula (I) according to Item 1, characterized in that a compound of the general formula (XV) Formula (XV) where R1, R2, R4, X, m, n have the meaning stated in Item 1, is reacted with a compound of the l formula (IX), Formula (IX) where R3 and Ar have the meaning stated in Item 1 and where either Y = OH ing in a carboxylic acid or Y = Cl resulting in a carboxylic acid chloride or Y = O-C(O)-O-CH2(CH 3)CH 3 resulting in an anhydride. 25. Method for the preparation of the compounds of the general formula (I) according to Item 1, characterized in that a nd of the general formula (XVI), Formula (XVI) where R1, R2, R4, X, Ar, m and n have the meaning stated in Item 1 and n LG´ means Br or I, is reacted with a boronic acid or a c acid ester of the general formula (XVIII), (Formular XVIII) where R3 means aryl or heteroaryl and Met means OH, boronic acids or – boronic acid pinacol esters. 8017637_1 (GHMatters) P97018.NZ ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Production of the compounds according to the invention The following examples rate the production of the compounds according to the invention of the general formula (1), Without ng the range of the claimed compounds to these examples.
The compounds according to the invention of the general formula (I) can be produced and characterized as described below.
LC-MS: Waters Acquity HPLC / MS 100-800 Daltons; 20 V (Micromass / Waters ZQ 4000); : BEHC 18 s), 2.] x 50 mm, BEH 1.7 um; Mobile phase: A: H20/0.05% HCOOH, B: CH3CN/0.05% HCOOH. Gradient: 10-90% B in 1.7 min, 90% B for 0.2 min, 98-2% B in 0.6 min; Flow rate: 1.3 ml / min, Detection: UV = 200 - 400 nm.
Chiral HPLC separation method A: Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: Liquid r 215, Knauer: UV or K-2501 Column: Chiralpak AD-H 5 um 250x20 mm; Solvent: hexane / ethanol 50:50; Flow rate: 15 ml/min; injection volume: 0.5 ml; Detection: UV 254 nm.
Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak AD-H 5 um l50x4.6 mm Solvent: hexane / ethanol 50:50; Flow rate: 1.0 ml/min; Temperature: 25°C; ion: 5 ul; Detection: DAD 254 nm.
Chiral HPLC separation method B: Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: Liquid Handler 215, : UV detector K-2501 Column: Chiralpak 1C 5 um 250x30 mm; Solvent: ethanol / methanol 50:50; Flow rate: 30 ml/min; ion volume: 0.5 ml; Detection: UV 254 nm.
Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak 1C 5 um l50x4.6 mm Solvent: l / methanol 50:50; Flow rate: 1.0 ml/min; Temperature: 25°C; injection: 5 ul; Detection: DAD 254 nm.
Chiral HPLC separation method C: Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 Column: pak AD-H 5 um 250x20 mm; Solvent: hexane / 2-pr0panol 50:50; Flow rate: 15 ml/min; injection volume: 0.25 ml; Detection: UV 254 nm.
Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak AD-H 5 um l50x4.6 mm Solvent: hexane / 2-pr0panol 50:50; Flow rate: 1.0 ml/min; Temperature: 25°C; injection: 5 ul; Detection: DAD 254 nm.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Chiral HPLC separation method D: ative chiral HPLC: System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 Column: pak 1B 5 um 250x20 mm; Solvent: hexane / ethanol 70:30; Flow rate: 20 ml/min; injection volume: 0.1 ml; Detection: UV 210 nm.
Analytical chiral HPLC: : Waters: ce 2695, DAD 996, ESA: ; Column: Chiralpak 1B 5 um 150x4.6 mm Solvent: hexane / ethanol 70:30; Flow rate: 1.0 ; Temperature: 25°C; injection: 5 ul; Detection: DAD 230 nm.
Chiral HPLC separation method E: Preparative chiral HPLC: System: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV detector K-2501 Column: Chiralpak 1C 5 um 250x20 mm; Solvent: ethanol / methanol 50:50; Flow rate: 15 ml/min; injection volume: 0.3 ml; Detection: UV 230 nm.
Analytical chiral HPLC: System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: Chiralpak 1C 5 um 150x4.6 mm Solvent: ethanol / ol 50:50; Flow rate: 1.0 ml/min; Temperature: 25°C; injection: 5 ul; Detection: DAD 230 nm Abbreviations Boc tert-butoxycarbonyl CO carbon monoxide DBU 1,8-diazabicyclo[5.4.0]undecene DCM dichloromethane DMF N,N—dimethylformamide DMSO dimethyl sulphoxide ESI; ES+ electrospray ionization (in MS); positive charged ion trace hr(s) hour(s) HATU N—[(dimethylamino)- 1H- 1 ,2,3 -triazolo[4,5-b]pyridin- l -ylmethylen] - N—methylmethanaminium hexafluorophosphate N—oxide HPLC high pressure, high performance liquid chromatography conc. concentrated LC-MS liquid tography-coupled mass spectroscopy M molar min(s) minute(s) MS mass spectroscopy N normal NMR nuclear resonance oscopy Rt retention time (in HPLC and LC) RT room temperature tert tertiary THF tetrahydrofuran [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 1 : 2- {[1-(4-cyanofluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 49799bJRH N 0 CH3 To a solution of 33.7 mg of 4-cyanofluorobenzoic acid in 1.0 ml yl sulphoxide were added 85.5 mg of HATU, 75 mg of the amine prepared in Example 1a and 0.071 ml of N,N— diisopropylethylamine and this was stirred for 1 hour at 25°C. The mixture was concentrated in vacuo and the residue thus obtained purified by HPLC. Yield: 43.3 mg of the title compound. 1H-NMR (400 MHz, DMSO-da): 8 [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 title compound was prepared as follows: Example 1a: N—(2-methoxyethyl)methyl(4-piperidylmethyl)-2H-indazolcarboxamide hydrochloride To 855.1 mg of 1b were added 4.5 ml of 4M hydrochloric acid in dioxan and 1 ml dioxan. An oily mass was formed, which dissolved on us stirring and gentle g. The mixture was d for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 764.7 mg of the title compound, which was further reacted without further purification. 1H-NMR (300 MHz, DMSO-da): 8 [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). e 1b: Tert-butyl 4-( {5- [N-(2-methoxyethyl)carbamoyl] methyl-2H-indazolyl} - methyl)piperidincarboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H N H3C\O/\/N \ b O CH Version A: 2820 mg of 1c, 1556 mg of 2-methoxyethylamine, 1823 mg of molybdenum hexa- carbonyl, 200.4 mg of rt-butylphosphine tetrafluoroborate and 647.5 mg of trans- bis(acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalladium(H) were placed in portions in three microwave tubes and suspended with 56 ml THF. Then 3.1 ml of DBU were added and the mixtures stirred for 20 mins at 125°C and 200 watts in the microwave. The reaction mixtures were combined, filtered and diluted with some ethyl acetate and the organic phase washed twice with water and once with saturated sodium chloride on. This was dried over sodium sulphate, filtered and concentrated. The residue was tographed on the Biotage SP4.
Gradient: ethyl acetate/methanol 0-10%. Yield: 885.1 mg of the title nd.
Version B: 780 mg of 1d and 1747 mg of HATU were first ved in 10 ml DMSO. Next, 314 mg of 2-methoxyethylamine and 1080 mg of N,N—diisopropylethylamine were added. The e was stirred for 1 hr at RT. 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 sulphate, filtered and trated. The residue was purified tographically on the Biotage SP4. Gradient: ethyl acetate/methanol 0-10%.
Yield: 740 mg of the title compound. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.01 - 1.13 (2H), 1.34 (9H), 1.36 - 1.43 (2H), 2.06 - 2.19 (1H), 2.49 (3H), 2.59 — 2.70 (2H), 3.29 (3H), 3.33 - 3.39 (2H), 3.40 - 3.45 (2H), 3.82 - 3.93 (2H), 4.28 (2H), 7.14 (1H), 7.38 (1H), 8.09 - 8.14 (1H), 8.46 (1H).
Example 1c: Tert-butyl 4-[(5-bromomethyl-2H-indazolyl)methyl]piperidin-l-carboxylate Br/Q/JRN\ H30 CH3 5 g of 5-bromomethyl-lH-indazole was dissolved in 110 ml DMF and treated with 11.5 g of caesium carbonate and 7.9 g of N—Boc(bromomethyl)piperidine. The mixture was stirred for 3 hrs at 60°C and overnight at RT. The reaction e was next diluted with ethyl acetate, and q organic phase was washed twice with water, dried over sodium sulphate, filtered and centrated. The residue was purified chromatographically on the Biotage SP4 via a 65i-Si [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp column. Gradient: hexane/ethyl acetate 0-100%. Yield: 3.53 g of the title compound. 1H-NMR (300 MHz, DMSO-ds): 8 [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} methyl-2H-indazol carboxylic acid H30 CH3 1080 mg of le were ved in 8 ml methanol and d with 1235 mg of lithium hydroxide in 10 ml water. A further 2 ml THF were added as solubilizer. The mixture was stirred for 24 hrs at RT. Next the 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% ric acid and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. Yield: 880 mg of the title compound. 1H-NMR (300 MHz, DMSO-ds): 8 [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 6: Methyl 2- {[1-(tert-butoxycarbonyl)piperidin—4-yl]methyl)} methyl-2H-indazol- 5-carboxylate H30 CH3 666 mg of 1c, 156.8 mg of ol, 645.8 mg of molybdenum hexacarbonyl, 47.3 mg of tri- tert-butylphosphine tetrafluoroborate and 123.5 mg of trans-bis(acetato)-bis[o-(di-o-tolylphosphino )benzyl]dipalladium(ll) were placed in a microwave tube and ded in 15 ml THF. Then 0.7 ml of DBU were added and the mixture was stirred for 20 mins at 125°C and 150 watts in the microwave. Next, it was concentrated, taken up in ethyl acetate and the organic phase washed twice with water and once with saturated sodium chloride solution. It was dried qtage SP4. Gradient: hexane/ethyl acetate 0-100%. Yield: 363 mg of the title compound.r sodium sulphate, filtered and concentrated. The residue was chromatographed on the [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-da): 5 [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). e 2: 2-( { 1 - [4-tert-(butoxy)benzoyl]piperidinyl} methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide H N \/N \ b 0 CH 0 CH3 Analogously to Example 1, 35.9 mg of the title compound was obtained from 75 mg of the amine prepared in e 1a and 39.7 mg of 4-(tert-butoxy)benzoic acid. 1H-NMR (300 MHz, DMSO-ds): 8 [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]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide H N \/N \ 0 CH3 0 : O C? Analogously to Example 1, 51.6 mg of the title compound was obtained from 75 mg of the amine prepared in Example 1a and 47.5 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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)methyl {[1 -(4-morpholinobenzoyl)piperidinyl]methyl} - 2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H C n \ 3 \O/\/ 0 CH3 Analogously to Example 1, 48.1 mg of the title compound was obtained from 75 mg of the amine prepared in Example 1a and 42.3 mg of holinobenzoic acid. 1H-NMR (300 MHz, a): 8 [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'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N—(2-methoxy- ethyl)methyl-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 F Analogously to Example 1, 50.1 mg of the title compound was obtained from 75 mg of the amine prepared in Example 1a and 44.2 mg of 4-(4-fluorophenyl)benzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [ppm]= 1.11 - 1.32 (2H), 1.32 - 1.64 (2H), 2.20 - 2.36 (1H), 2.49 (3H), 2.63 - 3.08 (2H), 3.24 (3H), 3.42 (4H), 3.50 - 3.73 (1H), 4.24 - 4.55 (3H), 7.10 - 7.20 (1H), 7.27 2H), 7.41 (3H), 7.67 (4H), 8.03 - 8.16 (1H), 8.48 (1H).
Example 6: 2- { [1 -(2-fluoromesylbenzoyl)piperidinyl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 \’S§O Analogously to Example 1, 40.1 mg of the title compound was obtained from 75 mg of the Dine prepared in Example 1a and 44.6 mg of 2-fluoromesylbenzoic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-da): 5 [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). e 7: 2- {[1 -(2-fluoromethoxybenzoyl)piperidinyl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 ously to Example 1, 43.1 mg of the title nd was ed from 75 mg of the amine prepared in Example 1a and 34.8 mg of 2-fluoromethoxybenzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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-bromofluorobenzoyl)piperidinyl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 Analogously to Example 1, 51.8 mg of the title compound was obtained from 75 mg of the amine prepared in Example 1a and 44.7 mg of 4-bromofluorobenzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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-fluoromethylbenzoyl)piperidinyl]methyl} -N-(2-methoxyethyl) Ethyl-ZH-indazol-S-carboxamide ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 38.3 mg of the title compound was obtained from 75 mg of the amine ed in Example la and 31.5 mg of 2-fluoromethylbenzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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 1 0: 2-( { l - [2-fluoro(trifluoromethyl)benzoyl]piperidinyl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide H N H30\O/\/N \ 0 CH3 ‘I'I Analogously to Example 1, 57.8 mg of the title compound was obtained from 75 mg of the amine prepared in Example la and 42.5 mg of o(trifluoromethyl)benzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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 1 1: N-(2-methoxyethyl)methyl( { l - [4-(pentafluoro-7t6-sulphanyl)benzoyl] piperidinyl} methyl)-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 Analogously to Example 1, 135.1 mg of the title compound was obtained from 150 mg of the ine prepared in Example la and 101.5 mg of 4-(pentafluoro-7t6-sulphanyl)benzoic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (300 MHz, DMSO-ds): 5 [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: 12 YQIN N-(2—methoxyethyl)- 1H—NMR (400 MHz DMSO-d6) \/N \ 4-methyl-2— {[1-(4- 8 [ppm]: 1.20 (2H), 1.42 (2H), methylbenzoyl)- 2.29 (4H), 2.49 (3H), 2.73 (1H), piperidinyl] - 2.93 (1H), 3.25 (3H), 3.37 (2H), methyl} -2H-indazol- 3.43 (2H), 3.57 (1H), 4.31 (2H), -carboxamide 4.40 (1H), 7.14 (1H), 7.21 (4H), 7.38 (1H), 8.09 (1H), 8.46 (1H).
N—(2—methoxyethyl)- 1H—NMR (300 MHz, DMSO-da): yl-2—( { l — [(3- 8 [ppm]: 1.25 (2H), 1.55 (2H), isoxazol-S- 2.34 (1H), 2.49 (3H), 2.83 (1H), yl)carbonyl]piperidin 3.15 (1H), 3.24 (3H), 3.40 (4H), yl} methyl)-2H- 3.87 (1H), 4.35 (3H), 7.15 (1H), indazol-S - 7.40 (1H), 7.46 (1H), 7.50 (3H), carboxamide 7.90 (2H), 8.13 (1H), 8.49 (1H). 2-({1-[4-(4-chloro- 1H—NMR (300 MHz, DMSO-da): phenoxy)benzoyl] - 5 [ppm]: 1.21 (2H), 1.45 (2H), piperidinyl} - 2.26 (1H), 2.49 (3H), 2.76 (1H), methyl)-N—(2 _ 2.94 (1H), 3.24 (3H), 3.40 (4H), methoxyethyl) 3.62 (1H), 4.33 (3H), 7.04 (4H), methyl-2H-indazol-5 - 7.15 (1H), 7.40 (5H), 8.12 (1H), carboxamide 8.47 (1H).
N—(2—methoxyethyl)- 1H—NMR (300 MHz, DMSO-da): 4-methyl-2—( { l - [4—(4_ 8 [ppm]: 1.20 (2H), 1.43 (2H), methylphenoxy) _ 2.26 (4H), 2.48 (3H), 2.76 (1H), benzoyl]piperidin—4_ 2.90 (1H), 3.24 (3H), 3.38 (4H), yl} methyl)-2H- 3.62 (1H), 4.32 (3H), 6.92 (4H), indazol-S - 7.71 (3H), 7.34 (3H), 8.12 (1H), carboxamide 8.47 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 6-—1UPAC“ameStructure 2-({l- [4-(4-tert- 1H—NMR (300 MHz DMSO-d6) H3\C \ 0 butylphenoxy)- 8 [ppm]—— 1.21 (2H), 1.25 (9H), benzoyl]piperidin—4_ 1.44 (2H), 2.26 (1H), 2.48 (3H), yl} methyl)-N—(2- 2.77 (1H), 2.291 (1H), 3.24 (3H), methoxyethyl) 3.39 (4H), 3.64 (1H), 4.32 (3H), -2H-indazol-5 - 6.95 (4H), 7.14 (1H), 7.36 (5H), carboxamide 8.12 (1H), 8.47 (1H).
N—(2-meth0xyethyl)- 1H—NMR (300 MHz, DMSO-d6): 4-methyl[(l - {4—[4_ 8 [ppm]: 1.22 (2H), 1.45 (2H), (trifluoromethyl)- 2.27 (1H), 2.49 (3H), 2.77 (1H), phenoxy]benzoyl} - 2.97 (1H), 3.24 (3H), 3.39 (4H), piperidinyl)- 3.61 (1H), 4.33 (3H), 7.15 (5H), ] -2H-indazol- 7.39 (3H), 7.73 (2H), 8.12 (1H), -carboxamide 8.48 (1H).
N—(2-meth0xyethyl)- 1H—NMR (300 MHz, DMSO-d6): 2-( { l -[4-(4-meth0xy— 8 [ppm]: 1.19 (2H), 1.44 (2H), y)benzoyl] - 2.25 (1H), 2.48 (3H), 2.86 (2H), piperidinyl} - 3.24 (3H), 3.40 (4H), 3.64 (1H), methyl)methy1_ 3.72 (3H), 4.32 (3H), 6.88 (2H), 2H-indazol-5 - 6.95 (2H), 7.02 (2H), 7.14 (1H), carboxamide 7.31 (2H), 7.38 (1H), 8.12 (1H), 8.47 (1H).
N—(2-meth0xyethyl)- 1H—NMR (300 MHz, DMSO-d6): 4-methyl {[1—(4_ 8 [ppm]: 1.21 (2H), 1.44 (2H), phenoxybenzoyl)- 2.26 (1H), 2.49 (3H), 2.77 (1H), piperidinyl] - 2.92 (1H), 3.24 (3H), 3.38 (4H), methyl} -2H-indazol- 3.64 (1H), 4.32 (3H), 6.97 (2H), -carboxamide 7.04 (2H), 7.16 (2H), 7.26 (5H), 8.12 (1H), 8.47 (1H). 2- {[1-(4-cyclopropyl- 1H—NMR (300 MHz, DMSO-d6): benzoyl)piperidin—4_ 8 [ppm]— 0.65 (2H), 0.93 (2H) yl]methyl} -N—(2_ 1.19 (2H), 1.43 (2H), 1.90 (1H), methoxyethyl)-4_ 2.25 (1H), 2.48 (3H), 2.73 (1H), methyl-2H-indazol 2.92 (1H), 3.24 (3H), 3.39 (4H), carboxamide 3.59 (1H), 4.32 (3H), 7.14 (5H), [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ——41414 14 4471114 2-{[1-(4-meth0xy- 1H—NMR (400 MHz, DMSO-da): benzoyl)piperidin—4- 8 [ppm]: 1.19 (2H), 1.44 (2H), yl]methyl}-N—(2- 2.26 (1H), 2.49 (3H), 2.82 (2H), methoxyethyl) 3.24 (3H), 3.36 (2H), 3.42 (2H), methyl-2H-indazol 3.50 (1H), 3.74 (3H), 4.31 (3H), amide 6.93 (2H), 7.14 (1H), 7.29 (2H), 7.38 (1H), 8.12 (1H), 8.47 (1H). 2-{[1-(4-flu0r0- 1H—NMR (400 MHz, DMSO-da): benzoyl)piperidin—4- 8 [ppm]: 1.20 (2H), 1.37 (1H), yl]methyl}-N—(2- 1.51 (1H), 2.27 (1H), 2.49 (3H), methoxyethyl) 2.72 (1H), 2.97 (1H), 3.24 (3H), methyl-2H-indazol 3.36 (2H), 3.42 (2H), 3.52 (1H), carboxamide 4.31 (2H), 4.40 (1H), 7.14 (1H), 7.23 (2H), 7.39 (3H), 8.12 (1H), 8.47 (1H).
N—(2-meth0xyethyl)- 1H-NMR (400 MHZ, DMSO-da): 4-methyl({1-[4- 8 [ppm]: 1.22 (2H), 1.34 (1H), (trifluoromethyl)- 1.56 (1H), 2.28 (1H), 2.49 (3H), benzoyl]piperidin—4- 2.75 (1H), 2.99 (1H), 3.24 (3H), yl}methyl)-2H- 3.35 (2H), 3.42 (3H), 4.32 (2H), indazol 4.44 (1H), 7.14 (1H), 7.38 (1H), carboxamide 7.55 (2H), 7.77 (2H), 8.12 (1H), 8.47 (1H). 2-{[1-(2-meth0xy- 1H—NMR (400 MHz, a): benzoyl)piperidin—4- 8 [ppm]: 1.11 (2H), 1.35 (1H), yl]methyl}-N—(2- 1.52 (1H), 2.23 (1H), 2.49 (3H), yethyl) 2.66 (1H), 2.87 (1H), 3.22 (1H), methyl-ZH-indazol-S- 3.24 (3H), 3.35 (2H), 3. 42 (2H), carboxamide 3.71 (3H), 4.29 (1H), 4.33 (1H), 4.45 (1H), 6. 94 (1H), 7.07 (3H), 7.33 (1H), 7.39 (1H), 8.12 (1H), 8.48 (1H).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -.—~.weN-(2-methoxyethyl)- 1H—NMR (400 MHz DMSO-d6) 4-methyl [(1- {4- 8 [ppm]1: 1.23 (2H), 1.36 (1H), [(trifluoromethyl)- 1.57 (1H), 2.29 (1H), 2.49 (3H), sulphonyl]benzoyl} - 2.77 (1H), 3.01 (1H), 3.24 (3H), piperidinyl)- 3.35 (3H), 3.42 (2H), 4.32 (2H), methyl]—2H-indazol- 4.44 (1H), 7.14 (1H), 7.38 (1H), -carboxamide 7.77 (2H), 8.15 (3H), 8.47 (1H). eth0xyethyl)- 1H—NMR (400 MHz, a): 4-methyl( { 1 — [3- 8 [ppm]: 1.24 (2H), 1.37 (1H), (trifluoromethyl)- 1.55 (1H), 2.28 (1H), 2.49 (3H), benzoyl]piperidin_4_ 2.75 (1H), 3.01 (1H), 3.24 (3H), yl} methyl)-2H- 3.36 (2H), 3.42 (3H), 4. 32 (2H), indazol-S- 4. 43 (1H), 7.14 (1H), 7.38 (1H), carboxamide 7.65 (3H), 7.78 (1H), 8.12 (1H), 8.47 (1H).
N—(2-meth0xyethyl)- 1H—NMR (400 MHz, a): 4-methyl {[1—(3_ 8 [ppm]: 1.20 (2H), 1.36 (1H), methylbenzoyl)- 1.52 (1H), 2.29 (4H), 2.49 (3H), piperidinyl] - 2.69 (1H), 2.95 (1H), 3.24 (3H), methyl} -2H-indazol- 3.36 (2H), 3.42 (2H), 3.53 (1H), -carboxamide 4.31 (2H), 4.41 (1H), 7.12 (3H), 7.21 (1H), 7.27 (1H), 7.38 (1H), 8.12 (1H), 8.47 (1H). 2- {[1-(3-ch10r0- 1H—NMR (400 MHz, DMSO-da): benzoyl)piperidin—4_ 8 [ppm]: 1.21 (2H), 1.36 (1H), yl]methyl} -N—(2_ 1.53 (1H), 2.27 (1H), 2.49 (3H), methoxyethyl)-4_ 2.72 (1H), 2.98 (1H), 3.24 (3H), methyl-ZH-indazol-S- 3.35 (2H), 3.42 (3H), 4.31 (2H), carboxamide 4.40 (1H), 7.14 (1H), 7.28 (1H), 7.43 (4H), 8.12 (1H), 8.47 (1H).
N—(2-meth0xyethyl)- 1H—NMR (400 MHz, DMSO-da): 4-methyl({1-[(1- 8 [ppm]: 1.25 (2H), 1.50 (2H), methyl- 1 H-indol-Z- 2.31 (1H), 2.49 (3H), 2.82 (1H), yl)carbonyl] - 3.05 (1H), 3.24 (3H), 3.36 (2H), piperidin 3.42 (2H), 3.69 (3H), 3.98 (1H), [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp yl}methyl)-2H- 4.34 (2H), 4.44 (1H), 6.57 (1H), indazol-S- 7.05 (1H), 7.15 (1H), 7.20 (1H), amide 7.39 (1H), 7.46 (1H), 7.56 (1H), 8.12 (1H), 8.49 (1H). 2-({1-[4-(4- 1H—NMR (400 MHz, DMSO-da): carbamoylphenoxy)_ 5 [ppm]: 1.22 (2H), 1.49 (2H), benzoyl]piperidin—4_ 2.31 (1H), 2.52 (3H), 2.82 (1H), yl} methyl)-N—(2- 2.98 (1H), 3.27 (3H), 3.39 (2H), methoxyethyl) 3.45 (2H), 3.65 (1H), 4.35 (2H), methyl-ZH-indazol-S- 4.43 (1H), 7.08 (4H), 7.17 (1H), carboxamide 7.29 (1H), 7.41 (3H), 7.91 (3H), 8.12 (1H), 8.50 (1H). 2-({1-[4-(cyc10- 1H—NMR (400 MHz, DMSO-da): pentyloxy)benzoyl] - 8 [ppm]: 1.23 (2H), 1.47 (2H), piperidinyl} - 1.57 (2H), 1.68 (4H), 1.90 (2H), methyl)-N—(2 - 2.28 (1H), 2.52 (3H), 2.86 (2H), methoxyethyl) 3.27 (3H), 3.39 (2H), 3.45 (2H), methyl-ZH-indazol-S - 3.85 (2H), 4.34 (2H), 4.83 (1H), carboxamide 6.91 (2H), 7.17 (1H), 7.28 (2H), 7.41 (1H), 8.12 (1H), 8.49 (1H). [4-(difluoro- 1H—NMR (400 MHz, DMSO-da): methyl)benzoyl]— 5 [ppm]: 1.24 (2H), 1.39 (1H), piperidinyl} - 1.57 (1H), 2.30 (1H), 2.52 (3H), methyl)-N—(2- 2.76 (1H), 3.01 (1H), 3.27 (3H), methoxyethyl) 3.39 (2H), 3.45 (3H), 4.35 (2H), methyl-ZH-indazol-S- 4.45 (1H), 7.18 (2H), 7.41 (1H), carboxamide 7.49 (2H), 7.62 (2H), 8.12 (1H), 8.49 (1H). 2- -cyan0- 1H—NMR (400 MHz, DMSO-da): benzoyl)piperidin—4_ 5 [ppm]: 1.24 (2H), 1.39 (1H), yl]methyl} -N—(2- 1.58 (1H), 2.30 (1H), 2.52 (3H), methoxyethyl) 2.77 (1H), 3.01 (1H), 3.27 (3H), methyl-ZH-indazol-S - 3.39 (3H), 3.45 (2H), 4.34 (2H), carboxamide 4.44 (1H), 7.17 (1H), 7.41 (1H), 7.54 (2H), 7.90 (2H), 8.12 (1H), [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ——<1H> 2-({1— [4-(1H- 1H—NMR (300 MHz DMSO-d6) imidazol-y1) 5 [ppm]1: 1.24 (2H), 1.39 (1H), benzoyl]piperidin-4_ 156 (1H), 2.29 (1H), 2.49 (3H), yl} methyl)-N—(2- 2.76 (1H), 3.04 (1H), 3.24 (3H), methoxyethyl)-4_ 3.37 (3H), 3.42 (3H), 4.33 (2H), methyl-ZH-indazol-S- 4.44 (1H), 7.15 (1H), 7.39 (1H), carboxamide 7.61 (2H), 7.84 (3H), 8.11 (1H), 8.26 (1H), 8.48 (1H).
N—(2-meth0xyethyl)- 1H—NMR (300 MHz, DMSO-da): 4-methyl( { 1 - [4- 5 [ppm]: 1.24 (2H), 1.37 (1H), (oxazol-Z-yl)- 1.54 (1H), 2.27 (1H), 2.49 (3H), l]piperidin—4_ 2.75 (1H), 3.00 (1H), 3.24 (3H), yl} methyl)-2H- 3.36 (2H), 3.42 (2H), 3.53 (1H), indazol-S- 4.32 (2H), 4.43 (1H), 7.14 (1H), carboxamide 7.38 (2H), 7.48 (2H), 8.00 (2H), 8.12 (1H), 8.23 (1H), 8.48 (1H).
N—(2-meth0xyethyl)- 1H—NMR (300 MHz, DMSO-da): 4-methyl( { 1 - [4- 5 [ppm]: 1.22 (2H), 1.38 (1H), (oxazol-S-yl)- 1.53 (1H), 2.28 (1H), 2.49 (3H), benzoyl]piperidin—4_ 2.74 (1H), 2.98 (1H), 3.24 (3H), yl} methyl)-2H- 3.36 (2H), 3.41 (2H), 3.55 (1H), indazol-S- 4.32 (2H), 4.41 (1H), 7.15 (1H), carboxamide 7.42 (3H), 7.74 (3H), 8.12 (1H), 8.47 (2H).
N—(2-meth0xyethyl)- 1H—NMR (300 MHz, a): 4-methyl( { 1 - [4- 5 [ppm]: 1.22 (2H), 1.36 (1H), (is -S-yl)- 1.55 (1H), 2.28 (1H), 2.49 (3H), benzoyl]piperidin—4_ 2.74 (1H), 2.99 (1H), 3.24 (3H), yl} methyl)-2H- 3.39 (5H), 4.31 (2H), 4.43 (1H), indazol-S- 4.74 (2H), 7.14 (1H), 7.38 (1H), carboxamide 7.50 (2H), 7.95 (2H), 8.12 (1H), 8.47 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -.—~.weN-(2-methoxyethyl)- 1H—NMR (300 MHz DMSO-d6) 4-methyl({l- [4- 5 [ppm]1: 1.22 (2H), 1.46 (2H), (lH-pyrazol- l -yl)- 2.28 (1H), 2.49 (3H), 2.76 (1H), benzoyl]piperidin 2.99 (1H), 3.24 (3H), 3.39 (4H), yl} methyl)-2H- 3.61 (1H), 4.32 (2H), 4.41 (1H), indazol-S - 6.54 (1H), 7.15 (1H), 7.39 (1H), carboxamide 7.46 (2H), 7.74 (1H), 7.87 (2H), 8.12 (1H), 8.50 (2H).
N—(2-meth0xyethyl)- 1H—NMR (300 MHz, DMSO-d6): 4-methyl( { l - [4- 5 [ppm]: 1.22 (2H), 1.39 (1H), (lH- l ,2,4-triazol- l - 1.53 (1H), 2.27 (1H), 2.49 (3H), y1)benzoy1]piperidin— 2.76 (1H), 3.00 (1H), 3.24 (3H), 4-yl} methyl)-2H- 3.39 (4H), 3.54 (1H), 4.32 (2H), indazol-S - 4.43 (1H), 7.15 (1H), 7.39 (1H), carboxamide 7.53 (2H), 7.90 (2H), 8.12 (1H), 8.24 (1H), 8.48 (1H), 9.32 (1H). 2-( { l iflu0r0- 1H—NMR (300 MHz, DMSO-d6): methoxy)flu0r0- 5 [ppm]: 1.16 (2H), 1.38 (1H), l]piperidin 1.55 (1H), 2.26 (1H), 2.48 (3H), yl} methyl)-N-(2- 2.73 (1H), 2.98 (1H), 3.24 (3H), methoxyethyl) 3.38 (5H), 4.31 (2H), 4.44 (1H), methyl-2H-indazol-5 - 7.12 (3H), 7.31 (1H), 7.40 (2H), carboxamide 8.12 (1H), 8.47 (1H). 2-( { l -[2-fluorO 1H—NMR (300 MHz, DMSO-d6): (pyrrolidin— l -yl)- 5 [ppm]: 1.14 (2H), 1.43 (2H), benzoyl]piperidin 1.90 (4H), 2.23 (1H), 2.48 (3H), yl} methyl)-N-(2- 2.68 (1H), 2.94 (1H), 3.19 (4H), methoxyethy1) 3.24 (3H), 3.36 (2H), 3.42 (3H), methyl-2H-indazol 4.31 (2H), 4.39 (1H), 6.29 (2H), carboxamide 7.10 (2H), 7.38 (1H), 8.12 (1H), 8.47 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -W:~we2-({1- [(34'-difluoro- 1H—NMR (300 MHz DMSO-d6) biphenylyl)- 5 [ppm]: 1 19 (2H) 1.39 (1H) carbonyl]piperidin—4- 1.57 (1H), 2.28 (1H), 2.49 (3H), yl} methyl)-N-(2- 2.76 (1H), 3.01 (1H), 3.24 (3H), yethyl) 3.38 (5H), 4.32 (2H), 4.47 (1H), methyl-2H-indazol 7.15 (1H), 7.28 (2H), 7.40 (2H), carboxamide 7.56 (2H), 7.76 (2H), 8.12 (1H), 8.48 (1H). 2-( { 1 -[(3-flu010-4'- 1H—NMR (300 MHz, DMSO-da): methoxybiphenyl 8 [ppm]: 1.19 (2H), 1.39 (1H), yl)carb0nyl]piperidin 1.57 (1H), 2.28 (1H), 2.49 (3H), yl} methyl)-N-(2 - 2.76 (1H), 3.01 (1H), 3.24 (3H), methoxyethyl) 3.38 (5H), 4.32 (2H), 4.47 (1H), -2H-indazol-5 7.15 (1H), 7.28 (2H), 7.40 (2H), carboxamide 7.56 (2H), 7.76 (2H), 8.12 (1H), 8.48 (1H). 2-( { 1 -[(3-flu010-4'- 1H—NMR (400 MHz, DMSO-da): methylbiphenyl 8 [ppm]: 1.19 (2H), 1.39 (1H), yl)carb0nyl]piperidin 1.57 (1H), 2.31 (4H), 2.49 (3H), yl} methyl)-N-(2 - 2.75 (1H), 3.01 (1H), 3.24 (3H), methoxyethyl) 3.36 (2H), 3.42 (3H), 4.32 (2H), methyl-2H-indazol-5 4.48 (1H), 7.14 (1H), 7.26 (2H), carboxamide 7.39 (2H), 7.56 (4H), 8.12 (1H), 8.48 (1H). 2-[(1- {[3-flu010-3'- 1H—NMR (400 MHz, DMSO-da): (trifluoromethyl)- 8 [ppm]: 1.20 (2H), 1.40 (1H), biphenylyl]— 1.57 (1H), 2.29 (1H), 2.49 (3H), carbonyl} -piperidin— 2.76 (1H), 3.03 (1H), 3.24 (3H), 4-yl)-methyl]—N—(2- 3.36 (2H), 3.41 (3H), 4.33 (2H), yethyl) 4.48 (1H), 7.15 (1H), 7.39 (1H), methyl-2H-indazol 7.45 (1H), 7.69 (4H), 8.03 (2H), carboxamide 8.12 (1H), 8.49 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -.—~.we2- [(1- {[3-fluoro-2'- 1H—NMR (300 MHz DMSO-d6) (trifluoromethoxy)- 8 [ppm]1: 1.20 (2H), 1.42 (1H), biphenylyl]— 1.57 (1H), 2.29 (1H), 2.49 (3H), carbonyl}piperidin—4- 2.76 (1H), 3.04 (1H), 3.24 (3H), yl)methyl] -N-(2- 3.36 (5H), 4.32 (2H), 4.48 (1H), methoxyethyl) 7.15 (1H), 7.44 (8H), 8.12 (1H), methyl-2H-indazol 8.49 (1H). carboxamide 2-({1-[(2'-fluoro- 1H—NMR (300 MHz, DMSO-da): biphenylyl)- 8 [ppm]: 1.23 (2H), 1.41 (1H), carbonyl]piperidin—4- 1.53 (1H), 2.29 (1H), 2.49 (3H), yl} methyl)-N-(2- 2.74 (1H), 3.01 (1H), 3.24 (3H), methoxyethyl) 3.36 (4H), 3.60 (1H), 4.33 (2H), methyl-2H-indazol 4.44 (1H), 7.15 (1H), 7.29 (2H), carboxamide 7.40 (4H), 7.55 (3H), 8.12 (1H), 8.48 (1H). 2-({1-[(2',4'-difluoro- 1H—NMR (300 MHz, DMSO-da): biphenylyl)- 8 [ppm]: 1.23 (2H), 1.39 (1H), carb0ny1]piperidin—4- 1.53 (1H), 2.28 (1H), 2.49 (3H), yl} )-N-(2- 2.75 (1H), 3.01 (1H), 3.24 (3H), methoxyethyl) 3.39 (4H), 3.60 (1H), 4.33 (2H), methyl-2H-indazol-5 - 4.43 (1H), 7.16 (2H), 7.40 (4H), carboxamide 7.56 (3H), 8.12 (1H), 8.48 (1H). [(2-fluoro- 1H—NMR (400 MHz, DMSO-da): biphenylyl)- 5 [ppm]: 1.24 (2H), 1.39 (1H), carb0ny1]piperidin—4- 1.56 (1H), 2.29 (1H), 2.49 (3H), yl} methyl)-N-(2- 2.74 (1H), 3.02 (1H), 3.25 (3H), methoxyethyl) 3.37 (2H), 3.42 (2H), 3.59 (1H), -2H-indazol 4.33 (2H), 4.43 (1H), 7.15 (1H), carboxamide 7.28 (2H), 7.40 (2H), 7.46 (2H), 7.54 (3H), 8.12 (1H), 8.48 (1H). ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -.—~.weN-(2-methoxyethyl)- 1H—NMR (400 MHz DMSO-d6) yl({1- [(2'- 8 [ppm]—— 1.24 (2H), 1.42 (1H), methylbiphenyl 1.55 (1H), 2.20 (3H), 2.29 (1H), yl)carb0nyl]piperidin .249 (3H), 2.75 (1H), 3.02 (1H), yl}methyl)-2H- 3.25 (3H), 3.37 (2H), 3.42 (2H), indazol-S- 3.64 (1H), 4.33 (2H), 4.42 (1H), carboxamide 7.21 (5H), 7.38 (5H), 8.12 (1H), 8.49 (1H). eth0xyethyl)- 1H—NMR (400 MHz, DMSO-da): 4-methyl({1-[4- 8 [ppm]: 1.24 (2H), 1.42 (1H), (pyridyloxy)benzoyl] 1.55 (1H), 2.29 (1H), 2.49 (3H), piperidinyl} - 2.76 (1H), 3.02 (1H), 3.25 (3H), methyl)-2H-indazol- 3.37 (2H), 3.43 (2H), 3.60 (1H), oxamide 4.33 (2H), 4.44 (1H), 7.15 (1H), 7.37 (3H), 7.48 (2H), 7.53 (2H), 8.12 (1H), 8.48 (1H), 8.75 (2H).
N—(2-meth0xyethyl)- 1H—NMR (400 MHz, DMSO-da): 4-methyl({1-[4- 8 [ppm]: 1.23 (2H), 1.38 (1H), (4H-1,2,4-triazol 1.54 (1H), 2.28 (1H), 2.49 (3H), yl)benzoyl]piperidin— 2.74 (1H), 3.02 (1H), 3.24 (3H), 4-yl} methyl)-2H- 3.36 (2H), 3.42 (2H), 3.53 (1H), indazol-S - 4.32 (2H), 4.42 (1H), 7.14 (1H), carboxamide 7.38 (1H), 7.55 (2H), 7.75 (2H), 8.14 (1H), 8.48 (1H), 9.15 (2H). 2- {[1-(2-fluorO 1H—NMR (600 MHz, DMSO-da): morpholinobenzoyl)- 8 [ppm]: 1.01 (1H), 1.21 (1H), piperidinyl] - 1.36 (1H), 1.48 (1H), 1.57 (1H), methyl} -N-(2- 2.08 (1H), 2.53 (3H), 2.96 (7H), methoxyethyl) 3.29 (3H), 3.41 (2H), 3.47 (2H), methyl-ZH-indazol-S - 3.67 (4H), 4.34 (2H), 4.50 (1H), carboxamide 6.86 (2H), 7.14 (2H), 7.41 (1H), 8.11 (1H), 8.47 (1H), 8.56 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp HYQIN 2 {[1(4bromo- 1H-NMR (300 MHz DMSO-d6) H30\ N \ CH3 benzoyl)piperidin—4- 8 [ppm]]=1.22 (2H), 1.36 (1H), yl]methyl}-N—(2- 1.52 (1H), 2.26 (1H), 2.49 (3H), methoxyethyl) 2.72 (1H), 2.97 (1H), 3.24 (3H), -2H-indazol 3.36 (2H), 3.42 (2H), 3.49 (1H), carboxamide 4.31 (2H), 4.40 (1H), 7.14 (1H), 7.29 (2H), 7.38 (1H), 7.60 (2H), 8.12 (1H), 8.47 (1H).
Example 55: N-(2-methoxyethyl)methyl({1-[4-(trifluoromethoxy)benzoyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 150 mg of the amine prepared in Example 1a were first dissolved in 1.5 ml pyridine. 101 mg of 4-(trifluoromethoxy)benzoyl chloride were then added and the mixture stirred for 30 min at RT.
The reaction mixture was then treated with some toluene and concentrated. The residue was taken up in ethyl acetate and washed twice with water, twice with ted sodium hydrogen carbonate solution (pH 9) and once with saturated sodium chloride solution. The organic phase was dried over sodium te, d and concentrated. The residue was purified chromato- graphically on the Biotage SP4. Gradient: ethyl acetate/methanol 0-10%. Yield: 118.2 mg of the title compound. 1H-NMR (300 MHz, DMSO-ds): 8 [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)piperidinyl]methyl} -N-(2-methoxyethyl)methyl-2H- indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 55, 183 mg of the title compound was obtained from 300 mg of the amine prepared in Example 1a and 157.4 mg of 4-chlorobenzoyl chloride. 1H-NMR (400 MHz, DMSO-da): 8 [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: ethoxyethyl)methyl [(1 - {4 - [(trifluoromethyl)sulphanyl]benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 60 mg of the amine prepared in Example 1a were first dissolved in 2 ml DCM at 0°C. 0.034 ml of triethylamine and 43.2 mg of 4-[(trifluoromethyl)sulphanyl]benzoyl chloride were then added and the mixture stirred for 2 hrs at 0°C. The reaction mixture was then diluted with DCM and washed with 1-molar hydrochloric acid, saturated sodium hydrogen carbonate solution (pH 9) and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, d and trated. The residue was purified chromatographically on the e SP4.
Gradient: DCM/Methanol 0-10%. The product fraction was taken up in ethyl acetate and extracted twice with saturated sodium hydrogen carbonate solution. The c phase was concentrated and the e again purified by HPLC. Yield: 26.5 mg of the title compound. 1H-NMR (400 MHz, DMSO-da): 8 [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(trifluoromethyl)benzoyl]piperidinyl}methyl)methyl-N—(2- rpholinoethyl)-2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to e 1, 34.6 mg of the title compound was obtained from 75 mg of the amine prepared in Example 58a and 37.0 mg of o(trifluoromethyl)benzoic acid. 1H-NMR (400 MHz, methanol-d4): 8 [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 58a: 4-methyl-N-(2-morpholinoethyl)(4-piperidylmethyl)-2H-indazolcarbox- amide hydrochloride H N (\N/VN \ b o\2 o CH H HCI To 624.4 mg of 58b were added 2.9 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan. An oily mass was formed, which dissolved on Vigorous ng and gentle warming. The mixture was stirred for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 980 mg of the title compound, which was further reacted without further purification. 1H-NMR (300 MHz, DMSO-ds): 8 [ppm]= 1.33 - 1.51 (2H), 1.58 - 1.64 (1H), 2.17 - 2.31 (1H), 2.55 (3H), 2.70 - 2.86 (2H), 3.02 - 3.31 (7H), 3.43 - 3.51 (2H), 3.61 - 3.71 (2H), 3.72 - 3.88 (3H), 3.89 - 3.99 (2H), 4.30 - 4.36 (2H), 7.29 (1H), 7.40 (1H), 8.46 - 8.52 (1H), 8.54 - 8.58 (1H), 8.69 - 8.85 (1H), 8.96 - 9.10 (1H).
Example 58b: Tert-butyl 4-( {4-methyl [N—(2-morpholinoethyl)carbamoyl] - l H-indazolyl} - methyl)piperidin- l xylate H N .0/\/N \ . 13 H30 g mg of 1c, 857 mg of holinoethylamine, 579.3 mg of molybdenum hexacarbonyl,.6 mg of tri-tert-butylphosphine tetrafluoroborate and 205.8 mg of trans-bis(acetato)-bis[o-(di- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp o-tolylphosphino)benzyl]dipalladium(ll) were placed in a microwave tube and suspended in 18 ml THF. 1.0 ml of DBU was then added and the mixture was stirred for 20 mins at 125°C and 200 watts in the microwave. The reaction mixture was diluted with some ethyl acetate and firstly filtered through Celite. The filtrate was diluted with ethyl acetate and the organic phase washed twice with water and once with ted sodium chloride solution. It was then dried over sodium sulphate, filtered and trated. The e was chromatographed on the Biotage SP4. Gradient: ethyl acetate/methanol 0-10%. Yield: 624.4 mg of the title compound. 1H-NMR (300 MHz, DMSO-da): 8 [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)({1-[4-(trifluoromethoxy)benzoyl] piperidinyl} methyl)-2H-indazolcarboxamide FNNNYCL/N\H N 0d 0 CH3 F?_F ously to Example 55, 10.1 mg of the title compound was obtained from 75 mg of the amine ed in Example 58a and 43.9 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (400 MHz, methanol-d4): 8 [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)( {1-[4-(pentafluoro-W—sulphanyl)benzoyl]- piperidinyl} methyl)-2H-indazolcarboxamide o 0 CH3 F ,S\F Analogously to Example 1, 14.0 mg of the title compound was obtained from 75 mg of the Dine prepared in Example 58a and 44.1 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid. ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, chloroform-d): 8 [ppm]= 1.16 - 1.32 (1H), 1.33 - 1.48 (1H), 1.50 - 1.63 (1H), 1.71 - 1.83 (1H), 1.84 - 2.08 (2H), 2.44 (1H), 2.55 (4H), 2.60 - 2.71 (5H), 2.72 - 2.85 (1H), 2.96 - 3.10 (1H), 3.60 (2H), 3.67 - 3.78 (4H), 4.33 (2H), 4.71 - 4.81 (1H), 6.45 (1H), 7.34 (1H), 7.47 (2H), 7.54 (1H), 7.79 (2H), 7.96 (1H).
Example 61: 4-methyl-N—(2-morpholinoethyl)( { 1 - [3 -(trifluoromethoxy)benzoyl]piperidin yl} methyl)-2H-indazolcarboxamide (\N/VHW‘/<;L/\N/N 0d 0 CH3 b 07F<F Analogously to Example 55, 18.1 mg of the title compound was ed from 75 mg of the amine prepared in Example 58a and 43.9 mg of 3-(trifluoromethoxy)benzoyl chloride. 1H-NMR (400 MHz, chloroform-d): 8 [ppm]= 1.18 - 1.46 (2H), 1.49 - 1.63 (1H), 1.66 - 1.82 (1H), 2.37 - 2.49 (1H), 2.62 (3H), 2.67 (3H), 2.70 - 2.78 (4H), 2.79 - 2.86 (2H), 2.93 - 3.09 (1H), 3.66 - 3.74 (2H), 3.83 (4H), 4.32 (2H), 4.66 - 4.82 (1H), 6.83 - 6.96 (1H), 7.23 - 7.29 (2H), 7.29 — 7.34 (1H), 7.39 (1H), 7.43 (1H), 7.54 (1H), 7.96 (1H).
Example 62: 2- { [1 -(4-chlorobenzoyl)piperidinyl]methyl} methyl-N—(2-morpholinoethyl)- 2H-indazol-5 -carboxamide H /N .0/\/N \ 70 Analogously to Example 55, 14.9 mg of the title compound was obtained from 75 mg of the amine prepared in Example 58a and 34.2 mg of 4-chlorobenzoyl chloride. 1H-NMR (400 MHz, methanol-d4): 8 [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)( { 1 - ifluoromethyl)benzoyl]piperidin amethyl)-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 31.7 mg of the title compound was ed from 75 mg of the amine prepared in Example 58a and 33.8 mg of fluoromethyl)benzoic acid. 1H-NMR (400 MHz, methanol-d4): 8 [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)( { l - [4-(pentafluoro-W—sulphanyl)benzoyl] - piperidinyl} methyl)-2H-indazolcarboxamide :8/N H N /\/N \ FIS\F_ Analogously to Example 1, 24.7 mg of the title compound was obtained from 75 mg of the amine prepared in Example 58a and 44.1 mg of 3-(pentafluoro-k6-sulphanyl)benzoic acid. 1H-NMR (400 MHz, methanol-d4): 8 [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)( { l - [3 -(trifluoromethyl)benzoyl]piperidin yl} methyl)-2H-indazolcarboxamide O/\/N:8\0 CH3 NbN Dalogously to e 1, 14.0 mg of the title compound was ed from 75 mg of the amine prepared in Example 58a and 33.8 mg of 3-(trifluoromethyl)benzoic acid. ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, methanol-d4): 8 [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: -—Nm2-({1-[(4'-fluoro- 1H-NMR (400 MHZ methanol- biphenylyl)- d4) 5 [ppm]: 1. 35 (2H) 1. 53 carbonyl]piperidin (1H), 1.66 (1H), 2.40 (1H), 2.66 yl} methyl)methyl- (3H), 2.85 (1H), 3.11 (1H), 3.24 orpholino- (2H), 3.42 (2H), 3.65 (2H), 3.76 ethyl)-2H-indazol (5H), 4.08 (2H), 4.40 (2H), 4.63 carboxamide (1H), 7.17 (2H), 7.38 (1H), 7.47 (3H), 7.65 (4H), 8.45 (1H). 2-({1-[4-(4-fluoro- 1H-NMR (400 MHZ, methanol- phenoxy)benzoyl] - d4) 5 [ppm]: 1. 33 (2H) 1. 68 piperidinyl} - (2H), 2.38 (1H), 2.66 (3H), 2.84 methyl)methyl-N— (1H), 3.11(1H), 3.25 (2H), 3.42 (2-morpholinoethyl)- (2H), 3.65 (2H), 3.76 (5H), 4.11 azol (2H), 4.38 (2H), 4.59 (1H), 6.98 carboxamide (2H), 7.04 (2H), 7.11 (2H), 7.38 (3H), 7.47 (1H), 8.44 (1H). e 68: N—[2-(3,3-difluoropyrrolidin—1-yl)ethyl]]—4-methyl({1-[4-(pentafluoro-7t6-sulphanyl )benzoyl]piperidinyl}methyl)-2H-indazolcarboxamide law?b FjSiF F F Analogously to Example 57, 61.7 mg of the title compound was obtained from 266.5 mg of the amine prepared in Example 68a and 150.3 mg of 4-(pentafluoro-7t6-sulphanyl)benzoyl chloride.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, chloroform-d): 8 [ppm]= 1.13 - 1.46 (2H), 1.48 - 1.65 (1H), 1.66 - 1.87 (1H), 2.26 - 2.50 (3H), 2.66 (3H), 2.71 - 3.23 (8H), 3.57 — 3.72 (3H), 4.25 - 4.42 (2H), 4.67 - 4.84 (1H), 6.40 - 6.61 (1H), 7.38 (1H), 7.47 (2H), 7.53 (1H), 7.79 (2H), 7.96 (1H).
The starting material was prepared as follows: Example 68a: N- [2-(3 ,3 -difluoropyrrolidin—1 -yl) ethyl] hyl(4-piperidylmethyl)-2H- indazolcarboxamide hydrochloride H N FAOqA/N OF \ To 416.6 mg of 68b were added 1.85 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan.
An oily mass was formed, which dissolved on Vigorous stirring and gentle warming. The mixture was d for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 439.2 mg of the title compound, which was further reacted without further purification. 1H-NMR (400 MHz, DMSO-ds): 8 [ppm]= 1.36 - 1.48 (2H), 1.54 - 1.63 (2H), 2.18 - 2.28 (1H), 2.40 — 2.45 (2H), 2.55 (3H), 2.72 - 2.83 (2H), 3.14 - 3.22 (2H), 3.38 - 3.44 (2H), 3.56 - 3.63 (2H), 3.65 - 3.95 (2H), 4.11 - 4.21 (2H), 7.32 (1H), 7.40 (1H), 8.43 - 8.48 (1H), 8.57 (1H), 8.68 - 8.82 (1H), 8.96 - 9.07 (1H).
Example 68b: Tert-butyl 4- [(5- {N— [2-(3 ,3 -difluoropyrrolidinyl)ethyl]carbamoyl}methyl- 2H-indazolyl)methyl] -piperidin- 1 xylate H N F N/\/N \ FAQ 0 CH3 >VCH3 H30 CH3 220 mg of 1c, 242.7 mg of 2-(3,3-difluoro-pyrrolidin—1-yl)ethylamine, 142.2 mg of molybdenum rbonyl, 15.6 mg of tri-tert-butylphosphine tetrafluoroborate and 50.5 mg of trans- bis(acetato)-bis-[o-(di-o-tolylphosphino)benzyl] dipalladium(11) were placed in a microwave tube and suspended in 4.4 ml THF. 0.24 ml of DBU were then added and the mixture stirred for mins at 125°C and 200 watts in the microwave. The on mixture was diluted with some ethyl acetate and firstly filtered through Celite. The filtrate was diluted with ethyl acetate and the organic phase washed twice with water and once with saturated sodium chloride on. It was dried over sodium te, filtered and concentrated. The e (209.3 mg) was chromato- Dphed on the Biotage SP4. Gradient: DCM/methanol 0-10%. Yield: 53.4 mg of the title compound.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-da): 5 [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)piperidinyl]methyl} -N- [2-(3 ,3 -difluoropyrrolidin— 1 - yl) ethyl] methyl-2H-indazolcarboxamide H N FACT/Vb! 0F \ ously to Example 57, 79.9 mg of the title compound was obtained from 125.0 mg of the amine prepared in Example 68a and 54.5 mg of 4-chlorobenzoyl de. 1H-NMR (300 MHz, chloroform-d): 8 [ppm]: 1.13 - 1.35 (2H), 1.46 - 1.84 (2H), 2.27 - 2.50 (3H), 2.66 (3H), 2.80 - 3.26 (8H), 3.59 - 3.83 (3H), 4.25 - 4.39 (2H), 4.62 - 4.85 (1H), 6.41 - 6.69 (1H), 7.30 - 7.40 (6H), 7.55 (1H), 7.96 (1H).
Example 70: 33-difluoropyrrolidin—1-yl)ethyl]methyl[(1-{4-[(trifluoromethyl) sulphanyl]benzoyl}piperidin—4-yl)methyl]2—H-indazolcarboxamide .21chb F?_F Analogously to Example 55, 15.2 mg of the title compound was obtained from 23.4 mg of the amine prepared in Example 68a and 14.0 mg of 4-[(trifluoromethyl)sulphanyl]benzoyl chloride. 1H-NMR (400 MHz, chloroform-d): 8 [ppm]: 1.23 — 1.26 (1H), 1.33 - 1.46 (1H), 1.48 - 1.61 (1H), 1.77 (1H), 2.20 — 2.35 (2H), 2.36 - 2.49 (1H), 2.64 (3H), 2.73 — 2.85 (5H), 2.90 — 3.10 (3H), 3.56 (2H), 3.63 — 3.76 (1H), 4.26 — 4.39 (2H), 4.70 — 4.82 (1H), 6.28 (1H), 7.33 (1H), 7.42 (2H), 7.53 (1H), 7.68 (2H), 7.96 (1H). e 71: 4-methyl( { 1 - [4-(pentafluorosulphanyl)benzoyl]piperidin—4-yl} methyl)-N- (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp F—S—F Analogously to Example 1, 124.8 mg of the title compound was obtained from 146.9 mg of the amine prepared in Example 71a and 93.3 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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 al was prepared as follows: Example 71a: 4-methyl(4-piperidylmethyl)-N-(2,2,2-trifluoroethyl)-2H-indazolcarbox- amide hydrochloride F J\ 5k) N N \ o CH HCI H To 425.2 mg of 71b were added 2.35 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan.
An oily mass was formed, which dissolved on us stirring and gentle warming. The mixture was stirred for 1 hr at ca. 30°C. The reaction mixture was concentrated. Yield: 440.6 mg of the title compound, which was further reacted t further purification. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.35 - 1.49 (2H), 1.53 - 1.62 (2H), 2.20 - 2.32 (1H), 2.51 (3H), 2.72 - 2.85 (2H), 3.14 - 3.23 (2H), 3.97 - 4.09 (2H), 4.34 (2H), 7.18 (1H), 7.43 (1H), 8.58 (1H), 8.64 - 8.77 (1H), 8.78 - 8.85 (1H), 8.93 - 9.08 (1H).
Example 71b: Tert-butyl 4-( {4-methyl-5 - [N—(2,2,2-trifluoroethyl)carbamoyl] -2H-indazolyl} - methyl)piperidin- l -carboxylate F J\ >k/H N N \ b O CH H30 CH3 2820 mg of 1c, 2052 mg of trifluoroethylamine, 1823.2 mg of molybdenum hexacarbonyl, D14 mg of tri-tert-butylphosphine tetrafluoroborate and 647.5 mg of trans-bis(acetato)-bis[o- (di-o-tolylphosphino)-benzyl]dipalladium(11) were placed in a ave tube and suspended in [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 56 ml THF. 3.1 ml of DBU were then added and the mixture was stirred for 20 mins at 125°C and 200 watts in the microwave. The reaction mixture was diluted with some ethyl e, washed twice with water and once with saturated sodium de on. It was dried over sodium sulphate, filtered and concentrated. The residue was chromatographed on the Biotage SP4. Gradient: hexane/ethyl acetate 0-100%. Yield: 475.2 mg of the title compound. 1H-NMR (300 MHz, DMSO-ds): 8 [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)piperidinyl]methyl} methyl-N—(2,2,2-trifluoroethyl)- 2H-indazolcarboxamide F J\ 5k)N \ 0 CH3 Analogously to Example 1, 97.8 mg of the title compound was obtained from 146.9 mg of the amine prepared in Example 71a and 58.8 mg of 4-chlorobenzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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)( { l - [4-(trifluoromethoxy)benzoyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide F J\ Bk) N N \ 0 CH3 F F Analogously to e 1, 105.4 mg of the title compound was obtained from 146.9 mg of the amine prepared in e 71a and 77.5 mg of 4-(trifluoromethoxy)benzoic acid. 1H-NMR (300 MHz, DMSO-ds): 8 [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 ml), 4.29 - 4.48 (3H), 7.17 (1H), 7.36 - 7.50 (5H), 8.52 (1H), 8.75 - 8.82 (1H). ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 74: 2- { [1 -(4-chlorobenzoyl)piperidinyl]methyl} methyl-N-(2-morpholinoethyl)- azolcarboxamide womb Analogously to Example 55, 30 mg of the title compound was obtained from 79 mg of the amine prepared in Example 74a and 26 mg of 4-chlorobenzoyl chloride. 1NMR (400 MHz methanol-d4): 8 [ppm]= 1. 31 (2H) 1.50 (1H) 1. 65 (1H) 235 (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 74a: 6-methyl-N—(2-morpholinoethyl)(4-piperidylmethyl)-2H-indazolcarbox- amide ©N~NH\101:<:L/Nc b 768 mg of (1.58 mmol) of tert-butyl carbamate 74b were dissolved in 4.0 ml 4M hydrochloric acid in dioxan and stirred under nitrogen at room ature. A further 0.8 ml 4M hydrochloric acid in dioxan were added and the mixture stirred at room temperature. The reaction solution was concentrated and d 760 mg of the title compound, which was used in the next on without further purification. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.34 - 1.50 (2H), 1.53 - 1.67 (2H), 2.21 - 2.30 (1H), 2.41 (3H), 2.74 - 2.89 (2H), 3.07 - 3.33 (8H), 3.62 - 3.71 (2H), 3.77 - 3.90 (2H), 3.90 - 4.03 (2H), 4.35 (2H), 7.39 (1H), 7.88 (1H), 8.44 (1H), 8.57 (1H), 8.62 - 8.79 (1H), 8.87 - 9.02 (1H), 11.17 (1H).
Example 74b: Tert-butyl 4-( {6-methyl [N—(2-morpholinoethyl)carbamoyl] -2H-indazolyl} - methyl)piperidincarboxylate [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp ed set by jennyp wap:‘0 H30 CH3 3.00 g (7.35 mmol) of 5-bromoindazole 74c and 2.87 g (22.04 mmol) of 2-morpholino- ethylamine were dissolved in 134 ml dioxan and 1.94 g (7.35 mmol) of molybdenum rbonyl, 167 mg (1.47 mmol) of palladium acetate, 213 mg (0.74 mmol) of tributylphosphonium tetrafluoroborate, 2.34 g (22.0 mmol) of sodium carbonate and 2 drops of water were added. The reaction mixture was heated to 125°C under nitrogen and stirred at this temperature for 2.5 hrs. For the work-up, the suspension was filtered over Celite, rewashed with dioxan, concentrated in vacuo and dried. The crude product was separated by column tography. Yield: 518 mg of the title compound. 1H-NMR (300 MHz, DMSO-ds): 8 [ppm]= 0.93 - 1.16 (2H), 1.26-1.37 (2H), 1.34 (9H), 1.99 - 2.17 (1H), 2.32 - 2.43 (10H), 2.54 - 2.72 (2H), 3.34 (1H), 3.48 - 3.59 (4H), 3.86 (2H), 4.26 (2H), 7.35 (1H), 7.63 (1H), 8.09 (1H), 8.32 (1H).
Example 74c: Tert-butyl 4-[(5-bromomethyl-2H-indazolyl)methyl]piperidincarboxylate H30 /N\ Br b H30 CH3 .0 g (47.4 mmol) of 5-bromomethyl-1H-indazole and 21.0 g (56.9 mmol) of tert-butyl 4-[(tosyloxy)methyl]piperidincarboxylate were dissolved in 726 ml DMF. To this were added 21.0 g (56.9 mmol) of tetrabutylammonium iodide and 18.5 g (56.9 mmol) of caesium carbonate and the reaction mixture was heated under nitrogen at 80°C for 1.5 hrs. For the work-up, it was treated with water and ethyl acetate, the organic phase ted and the aqueous phase extracted l times with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. After purification by column chromatography, this yielded the title compound in 5 g yield. 1H-NMR (600 MHz, chloroform-d): 8 [ppm]= 1.16 - 1.30 (2H), 1.45 (9H), 1.54 (2H), 2.22 - 2.33 (1H), 2.51 (3H), 2.67 (2H), 4.03 - 4.17 (2H), 4.27 - 4.32 (2H), 7.60 (1H), 7.81 (1H), 7.90 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The following nds were ed analogously: -—fl——6-methyl-N-(2- 1H-NMR (400 MHZ methanol- morpholinoethyl) d4): 8 [ppm]: 1. 32 (2H) 1. 51 -(trifluorometh- (1H), 1.65 (1H), 2.36 (1H), 2.47 oxy)benzoyl]piperidin- (3H), 2.60 (6H), 2.83 (1H), 3.10 4-yl}methyl)-2H— (1H), 3.52 (2H), 3.70 (5H), 4.35 indazolcarboxamide (2H), 4.61 (1H), 7.37 (3H), 7.49 (2H), 7.74 (1H), 8.24 (1H). 6-methyl-N—(2- 1H-NMR (400 MHZ, methanol- morpholinoethyl) d4): 8 [ppm]: 1. 32 (2H) 1.49 ({1-[3-(trifluorometh- (1H), 1.65 (1H), 2.36 (1H), 2.46 oxy)benzoy1]piperidin- (3H), 2.59 (6H), 2.83 (1H), 3.10 4-yl}methyl)-2H— (1H), 3.51 (2H), 3.69 (5H), 4.35 indazolcarboxamide (2H), 4.60 (1H), 7.33 (2H), 7.40 (2H), 7.54 (1H), 7.74 (1H), 8.24 (1H).
Example 77: 6-methyl-N—(2-morpholinoethyl)({1-[4-(pentafluoro-k6-sulphanyl)benzoyl] piperidinyl} )-2H-indazolcarboxamide NNWOJWOH30 /N\ Analogously to Example 1, 23 mg of the title compound was obtained from 79 mg of the amine prepared in Example 74a and 47 mg of the acid. 1H-NMR (400 MHz methanol-d4): 8 [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: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp -—.m2-({1- [4-(4-fluoro- 1H-NMR (400 MHZ, methanol- phenoxy)benZ0y1]- d4): 8 [ppm]: 1.31 (2H) 1.58 piperidinyl} - (2H), 2.35 (1H), 2.49 (3H), 2.40- methyl)methyl-N— 4.20 (15H), 4.35 (2H), 4.58 (1H), (2-m0rph01inoethyl)- 6.97 (2H), 7.04 (2H), 7.11 (2H), 2H-indaZ01-5 - 7.37 (2H), 7.43 (1H), 7.87 (1H), carboxamide 8.27 (1H). 6-methyl-N—(2- 1H-NMR (300 MHZ, methanol- linoethyl) d4): 8 [ppm]: 1. 34 (2H), 1.51 ({1- [4-(triflu0r0- (1H), 1.67 (1H), 2.38 (1H), 2.50 methyl)benZ0y1]- (3H), 2.85 (1H), 3.10 (1H), 3.25 piperidinyl} - (2H), 3.43 (2H), 3.64 (3H), 3.76 methyl)-2H-indaZ01-5 - (4H), 4.10 (2H), 4.38 (2H), 4.64 carboxamide (1H), 7.44 (1H), 7.57 (2H), 7.76 (2H), 7.89 (1H), 8.31 (1H). 2-({1-[2-flu0r0 1H-NMR (300 MHZ, methanol- (trifluoromethyl)benzo d4): 8 [ppm]: 1. 34 (2H), 1.54 y1]piperidinyl} - (1H), 1.68 (1H), 2.38 (1H), 2.50 methyl)methyl-N— (3H), 2.86 (1H), 3.12 (1H), 3.26 (2-m0rph01inoethyl)- (2H), 3.43 (3H), 3.66 (2H), 3.76 2H-indaZ01-5 - (4H), 4.11 (2H), 4.37 (2H), 4.67 carboxamide (1H), 7.44 (1H), 7.59 (3H), 7.89 (1H), 8.31(1H). 6-methyl-N—(2- 1H-NMR (300 MHZ, methanol- morpholinoethyl) d4) 5 [ppm]: 1. 35 (2H), 1. 53 ({1- [3 -(pentafluoro-W— (1H), 1.65 (1H), 2.38 (1H), 2.50 sulphanyl)benZ0y1]- (3H), 2.86 (1H), 3.14 (1H), 3.26 piperidinyl} - (2H), 3.43 (2H), 3.66 (3H), 3.76 methyl)-2H-indaZ01 (4H), 4.11 (2H), 4.37 (2H), 4.62 carboxamide (1H), 7.44 (1H), 7.63 (2H), 7.89 (3H), 8.30 (1H).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -*we6-methyl-N-(2-morph- 1H-NMR (300 MHZ methanol- olinoethyl)({1-[3- d4): 8 [ppm]: 1. 35 (2H) 1. 53 (trifluoromethyl)- (1H), 1.65 (1H), 2.38 (1H), 2.50 benzoyl]piperidin (3H), 2.85 (1H), 3.12 (1H), 3.26 yl}methyl)-2H- (2H), 3.43 (2H), 3.66 (3H), 3.76 indazolcarboxamide (4H), 4.11 (2H), 4.38 (2H), 4.63 (1H), 7.45 (1H), 7.66 (3H), 7.77 (1H), 7.90 (1H), 8.33 (1H). [(4'-fluoro- 1H-NMR (300 MHZ, methanol- biphenylyl)- d4): 5 [ppm]: 1. 35 (2H) 1. 53 carbony1]piperidin (1H), 1.65 (1H), 2.39 (1H), 2.50 hyl)methyl- (3H), 2.85 (1H), 3.12 (1H), 3.26 N—(2-morpholino- (2H), 3.42 (2H), 3.63 (3H), 3.74 ethyl)-2H-indazol (4H), 4.08 (2H), 4.37 (2H), 4.64 carboxamide (1H), 7.18 (2H), 7.46 (3H), 7.66 (4H), 7.88 (1H), 8.30 (1H).
Example 84: 2- {[1 -(4-chlorobenzoyl)piperidinyl]methyl} -N- [2-(cyclopropylmethoxy)ethyl] - 4-methyl-2H-indazolcarboxamide Analogously to Example 1, 38 mg of the title compound was obtained from 75 mg of the amine prepared in Example 84a and 29 mg of 4-chlorobenzoic acid. 1H-NMR (400 MHz DMSO-(15): 8 [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 84a: N-[2-(cyclopropylmethoxy)ethyl]methyl(4-piperidylmethyl)-2H-indazol carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H N /\/N \ b 0 CH To 781 mg of 84b were added 3.7 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan. The e was stirred for 30 mins at ca. 30°C. The reaction mixture was concentrated, taken up in some toluene and again concentrated. Yield: 751 mg of the title compound, which was further reacted t further purification. 1H-NMR (400 MHz DMSO-d6). 8 [ppm]— 0.14 (2H) 0.42 (2H) 0. 97 (1H) 1. 43 (2H) 1. 58 (2H), 2.26 (1H), 2.50 (3H), 2.65 (1H), 2.78(2H), 3.18 (2H), 3.22 (2H), 3.36 (2H), 3.49 (2H), 4.33 (2H), 7.16 (2H), 7.38 (1H), 8.11 (1H), 8.53 (1H), 8.80 (1H), 9.06 (1H).
Example 84b: Tert-butyl 4-[(5- {N-[2-(cyclopropylmethoxy)ethyl]carbamoyl} methyl-2H- indazolyl)methyl]piperidin-l -carboxylate Mfgix: HCCH3 500 mg of 1d was reacted with 203 mg of amine analogously to lb n B. Yield: 781 mg of the title compound. 1H-NMR (300 MHz, DMSO-d6): 8 [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: -—mm.
N- [2-(cyclopropyl- 1H-NMR (400 MHz, DMSO-d5): 8 V”o/\/N”g“1 0 ”'3 methoxy)ethyl]]—4- [ppm]— 0.14 (2H) 0.42 (2H), 0.97 methyl-Z-{U-(4- (1H), 1.19 (2H), 1.37 (1H), 1.50 methylbenzoyl)- (1H), 2.26 (1H), 2.29 (3H), 2.50 piperidinyl]— (3H), 2.72 (1H), 2.94 (1H), 3.23 }-2H-indazol (2H), 3.36 (2H), 3.48 (2H), 3.57 carboxamide (1H), 4.30 (2H), 4.39 (1H), 7.14 (1H), 7.21 (4H), 7.38 (1H), 8.12 (1H), 8.47 (1H).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ygL N[2(cyclopropyl- 1H—NMR (400 MHz DMSO-d6) 8 o/\/ methoxy)ethy1] ({1- = 0.14 (2H), 0.42 (2H), 0.97 [4-(4-fluorophenoxy)- (1H), 1.19 (2H), 1.45 (2H), 2.26 l]piperidin—4_ (1H), 2.50 (3H), 2.75 (1H), 2.96 yl} methyl)methy1_ (1H), 3.23 (2H), 3.36 (2H), 3.48 2H-indazol (2H), 3.62 (1H), 4.31 (2H), 4.39 carboxamide (1H), 6.95 (2H), 7.12 (3H), 7.23 (2H), 7.36 (3H), 8.12 (1H), 8.47 (1H). cyclopropyl- 1H—NMR (400 MHz, DMSO-da): 8 methoxy)ethyl] [ppm]: 0.14 (2H), 0.42 (2H), 0.96 methyl( { l - [4-(tri- (1H), 1.22 (2H), 1.36 (1H), 1.56 fluoromethyl)benzoyl] (1H), 2.28 (1H), 2.50 (3H), 2.74 piperidinyl} - (1H), 2.99 (1H), 3.23 (2H), 3.36 methyl)-2H-indazol-5 - (2H), 2.43 (1H), 3.48 (2H), 4.31 carboxamide (2H), 4.43 (1H), 7.15 (1H), 7.38 (1H), 7.55 (2H), 7.77 (2H), 8.12 (1H), 8.47 (1H).
N—[2-(cyclopropyl- 1H—NMR (400 MHz, DMSO-d6): 8 methoxy)ethyl] ( { l - [ppm]: 0.14 (2H), 0.42 (2H), 0.96 [(4'-fluorobiphenyl (1H), 1.23 (2H), 1.39 (1H), 1.55 yl)carb0nyl]piperidin— (1H), 2.28 (1H), 2.50 (3H), 2.74 4-yl} methyl) (1H), 3.01 (1H), 3.23 (2H), 3.36 methyl-2H-indazol-5 - (2H), 3.48 (2H), 3.61 (1H), 4.33 carboxamide (2H), 4.44 (1H), 7.15 (1H), 7.28 (2H), 7.40 (3H), 7.69 (4H), 8.12 (1H), 8.48 (1H). 2- {[1-(4-cyclopropyl- 1H—NMR (400 MHz, DMSO-da): 8 benzoyl)piperidin—4_ [ppm]: 0.17 (2H), 0.45 (2H), 0.69 yl]methyl} -N— [2- (2H), 0.97 (3H), 1.21 (2H), 1.47 (cyclopropylmethoxy) (2H), 1.93 (1H), 2.27 (1H), 2.52 ethyl]methyl-2H- (3H), 2.78 (1H), 2.93 (1H), 3.26 indazol-S-carboxamide (2H), 3.37 (2H), 3.51 (2H), 3.62 (1H), 4.34 (2H), 4.41 (1H), 7.10 (2H), 7.17 (1H), 7.22 (2H), 7.41 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -——(1H>’8‘11<1H>a8-49<1H>- Example 90: 2- { [l lorobenzoyl)piperidinyl]methyl} methyl-N—[2-(2,2,2-trifluoro- ethoxy)ethyl] dazolcarboxamide F H F\\/\O/\/N \ F 0 CH3 Analogously to Example 1, 40 mg of the title compound was obtained from 75 mg of the amine prepared in Example 90a and 27 mg of 4-chlorobenzoic acid. 1H-NMR (400 MHz, DMSO-ds): 8 [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 90a: 4-methyl(4-piperidylmethyl)-N—[2-(2,2,2-trifluoroethoxy)ethyl]-2H-indazol carboxamide F N F H WAC/V \ F 0 CH3 H To 610 mg of 90b were added 3.0 ml of 4M hydrochloric acid in dioxan and 0.5 ml . The mixture was stirred for 30 mins at ca. 30°C. The reaction mixture was concentrated, taken up in some toluene and again concentrated. Yield: 619 mg of the title compound, which was further reacted without further purification. 1H-NMR (400 MHz, DMSO-ds): 8 [ppm]= 1.42 (2H), 1.59 (2H), 2.26 (1H), 2.50 (3H), 2.64 (1H), 2.79 (2H), 3.20 (2H), 3.40 (2H), 3.70 (2H), 4.07 (2H), 4.33 (2H), 5.67(1H), 7.16 (1H), 7.39 (1H), 8.18 (1H), 8.53 (1H), 8.69 (1H), 8.94 (1H).
Example 90b: Tert-butyl 4- [(4-methyl {N— 2,2-trifluoroethoxy)ethyl]carbamoyl} -2H- indazolyl)methyl]piperidin- l -carboxylate YO o b r: X>= H30 CH3 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 500 mg of 1d was reacted with 240 mg of amine analogously to 1b version B. Yield: 670 mg of the title compound. 1H-NMR (400 MHz, DMSO-d5): 8 [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 ously: -,.—g.m4methyl2—{[1—(4- 1H—NMR (400 MHz 6): 8 methylbenzoyl)- [ppm]— 1. 19 (2H), 1.36 (1H), 1.49 piperidinyl]- (1H), 2.25 (1H), 2.29 (3H), 2.49 methyl} -N- [2- (3H), 2.71 (1H), 2.93 (1H), 3.40 (2,2,2-trifluoro- (2H), 3.56 (1H), 3.69 (2H), 4.07 ethoxy)ethyl]-2H- (2H), 4.31 (2H), 4.40 (1H), 7.15 indazol (1H), 7.21 (4H), 7.39 (1H), 8.19 carboxamide (1H), 8.48 (1H). 2-({1-[4-(4-fluoro- 1H-NMR (400 MHz, DMSO-d6): 8 phenoxy)benzoyl] - [ppm]: 1 , 144 (2H) 226 piperidinyl} - (1H), 2.49 (3H), 2.73 (1H), 2.95 methyl)methyl- (1H), 3.40 (2H), 3.60 (1H), 3.69 N—[2-(2,2,2-tri- (2H), 4.07 (2H), 4.31 (2H), 4.38 fluoroethoxy)ethyl] - (1H), 6.95 (2H), 7.12 (3H), 7.22 2H-indazol-5 - (2H), 7.37 (3H), 8.19 (1H), 8.48 carboxamide (1H). 4-methyl-N— [2- 1H-NMR (400 MHz, DMSO-d6): 8 (2,2,2-trifluoro- [ppm]: 122 (2H) 13,6(1H) 156 ethoxy)ethyl] ( { 1 - (1H), 2.28 (1H), 2.49 (3H), 2.74 [4-(trifluoro- (1H), 2.99 (1H), 3.40 (3H), 3.69 methyl)benzoyl] - (2H), 4.07 (2H), 4.32 (2H), 4.43 piperidinyl} - (1H), 7.15 (1H), 7.39 (1H), 7.55 methyl)-2H- (2H), 7.77 (2H), 8.19 (1H), 8.48 indazol-5 - (1H). carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp -..—».we2({1[(4'fluoro- 1H—NMR (300 MHz DMSO-d6): 8 biphenylyl)- [ppm]: 1. 23 (2H) 1.39 (1H) 1.52 carbonyl]piperidin— (1H), 2.28 (1H), 2.49 (3H), 2.75 ethyl) (1H), 3.00 (1H), 3.39 (2H), 3.60 methyl-N—[2-(2,2,2- (1H), 3.69 (2H), 4.07 (2H), 4.33 trifluoroethoxy)- (2H), 4.43 (1H), 7.15 (1H), 7.27 ethyl]-2H-indazol- (2H), 7.40 (3H), 7.68 (4H), 8.19 oxamide (1H), 8.49 (1H). 2-{[1-(4-cyclo- 1H—NMR (400 MHz, DMSO-ds): 8 propylbenzoyl)- [ppm]: 0.69 (2H), 0.96 (2H), 1.21 piperidinyl]— (2H), 1.47 (2H), 1.93 (1H), 2.28 methyl}methyl- (1H), 2.52 (3H), 2.77 (1H), 2.94 N—[2-(2,2,2-tri- (1H), 3.43 (2H), 3.61 (1H), 3.72 fluoroethoxy)ethyl]— (2H), 4.09 (2H), 4.34 (2H), 4.42 2H-indazol (1H), 7.10 (2H), 7.17 (1H), 7.22 carboxamide (2H), 7.41 (1H), 8.18 (1H).
Example 96: 2- {[1 -(4-chlorobenzoyl)piperidinyl]methyl} -N-(2-isopropoxyethyl)methyl- 2H-indazolcarboxamide Analogously to Example 1, 36 mg of the title compound was obtained from 75 mg of the amine prepared in Example 96a and 30 mg of 4-chlorobenzoic acid. 1H-NMR (300 MHz DMSO-(15): 8 [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 ng material was prepared as s: Example 96a: N-(2-isopropoxyethyl)methyl(4-piperidylmethyl)-2H-indazolcarbox- amide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp CH3 /N\ k N N o CH To 650 mg of 96b were added 3.2 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30°C. The on mixture was concentrated, taken up in some toluene and again concentrated. Yield: 529 mg of the title compound, which was further reacted without further purification. 1H-NMR (400 MHz DMSO-(15): 8 [ppm]— 1. 06 (3H) 1. 07 (3H) 1.42 (2H) 1.57 (2H) 2.25 (1H), 2.50 (3H), 2.65 (1H), 2.78 (2H), 3.19 (2H), 3.32 (2H), 3.45 (2H), 3.55 (1H), 4.32 (1H), 6.61 (1H), 7.15 (1H), 7.38 (1H), 8.11 (1H), 8.53 (1H), 8.78 (1H), 9.04 (1H).
Example 96b: Tert-butyl 4-( {5- [N—(2-isopropoxyethyl)carbamoyl] methyl-2H-indazolyl} - )piperidincarboxylate HCCH3 500 mg of 1d was reacted with 138 mg of amine analogously to lb version B. Yield: 650 mg of the title compound. 1H-NMR (400 MHz DMSO-(15): 8 [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: N-(2--1sopropoxy— 1H-NMR (300 MHz, 5): 8 ethyl)methyl [ppm]— 1. 07 (6H) 1. 19 (2H) 1 .45 {[1-(4-methyl- (2H), 2.29 (4H), 2.50 (3H), 2.75 benzoyl)piperidin—4- (1H), 2.92 (1H), 3.33 (2H), 3.45 yl]methyl}-2H- (2H), 3.55 (2H), 4.31 (2H), 4.40 indazol (1H), 7.14 (1H), 7.20 (4H), 7.38 carboxamide (1H), 8.05 (1H), 8.46 (1H). ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2({1[4(4—fluoro- 1H—NMR (300 MHz DMSO-d6): 8 phenoxy)benzoyl]— [ppm]: 1.07 (6H) 1.21 (2H) 1.45 piperidinyl} - (2H), 2.25 (1H), 2.49 (3H), 2.85 methyl)-N-(2 - (2H), 3.31 (2H), 3.45 (2H), 3.55 isopropoxyethyl) (2H), 4.31 (2H), 4.40 (1H), 6.95 methyl-ZH-indazol-S - (2H), 7.10 (3H), 7.22 (2H), 7.36 carboxamide (3H), 8.05 (1H), 8.46 (1H).
N—(2-isopropoxy- 1H—NMR (300 MHz, DMSO-da): 8 methyl [ppm]: 106 (6H) 122 (2H) 137 ({1- [4-(trifluoro- (1H), 1.56 (1H), 2.28 (1H), 2.50 methyl)benzoyl] - (3H), 2.75 (1H), 2.99 (1H), 3.33 piperidinyl} - (2H), 3.45 (3H), 3.55 (1H), 4.32 methyl)-2H-indazol- (2H), 4.43 (1H), 7.15 (1H), 7.38 -carboxamide (1H), 7.55 (2H), 7.77 (2H), 8.05 (1H), 8.46 (1H). 2-({1-[(4'-fluoro- 1H—NMR (300 MHz, DMSO-da): 8 biphenylyl)- [ppm]: 106 (6H) 123 (2H) 147 carb0ny1]piperidin—4- (2H), 2.28 (1H), 2.50 (3H), 2.76 yl} methyl)-N-(2- (1H), 2.98 (1H), 3.33 (2H), 3.45 isopropoxyethyl) (2H), 3.55 (2H), 4.33 (2H), 4.43 methyl-ZH-indazol-S - (1H), 7.15 (1H), 7.27 (2H), 7.39 carboxamide (3H), 7.68 (4H), 8.05 (1H), 8.47 (1H). 2- {[1-(4-cyc10propyl- 1H—NMR (300 MHz, DMSO-da): 8 benzoyl)piperidin—4_ [ppm]: 0.66 (2H), 0.94 (2H), 1.06 hyl} -N—(2_ (6H), 1.20 (2H), 1.44 (2H), 1.90 isopropoxyethyl) (1H), 2.24 (1H), 2.49 (3H), 2.82 methyl-ZH-indazol-S- (2H), 3.32 (2H), 3.45 (2H), 3.55 carboxamide (2H), 4.31 (2H), 4.39 (1H), 7.12 (5H), 7.38 (1H), 8.05 (1H), 8.46 (1H).
Example 1 02: (+/-) {[1-(4-chlorobenzoyl)piperidin—4-yl]methyl} -N- c10propylmeth0xy) Dpyl]methyl-2H-indazolcarb0xamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp N \ v/\0 0 CH3 b Analogously to Example 1, 41 mg of the title compound was obtained from 100 mg of the amine prepared in Example 102a and 37 mg of 4-chlorobenzoic acid. 1H-NMR (400 MHz, DMSO-da): 8 [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 102a: (+/-)-N—[2-(cyclopropylmethoxy)propyl]methyl(4-piperidylmethyl)-2H- indazolcarboxamide EVHH3 J\ V/\0 N \ 0 CH3 To 632 mg of 102b were added 2.9 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan. The e was stirred for 30 mins at ca. 30°C. The reaction mixture was trated, taken up in some toluene and again concentrated. Yield: 561 mg of the title compound, which was further reacted without further purification. 1H-NMR (300 MHz, DMSO-ds): 8 [ppm]= 0.13 (2H), 0.40 (2H), 0.94 (1H), 1.07 (3H), 1.44 (2H), 1.57 (2H), 2.26 (1H), 2.50 (3H), 2.77 (2H), 3.20 (6H), 3.57 (1H), 4.33 (2H), 6.33 (1H), 7.16 (1H), 7.39 (1H), 8.11 (1H), 8.53 (1H), 8.79 (1H), 9.06 (1H).
Example 102b: (+/-)-tert-butyl 4- [(5 - {N— [2-(cyclopropylmethoxy)propyl]carbamoyl} methyl- 2H-indazolyl)methyl]piperidin- l -carboxylate N \ v/\O 0 CH3 b H30 CH3 500 mg of 1d was reacted with 222 mg of amine analogously to lb n B. Yield: 631 mg of the title compound.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (300 MHz, s): 5 [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: 3V“ (+/)--N[2(cyclo- 1H—NMR (400 MHz DMSO-d6) W fenCH3 propylmethoxy)- 8 [ppm]—— 0.16 (2H), 0.43 (2H), pr0pyll({1-[4-(4- 0.97 (1H), 1.10 (3H), 1.22 (2H), fluorophenoxy)- 1.48 (2H), 2.29 (1H), 2.53 (3H), benzoyl]piperidin—4_ 2.81 (1H), 2.92 (1H), 3.23 (2H), yl} -methyl) 3.28 (2H), 3.60 (1H), 3.70 (1H), methyl-ZH-indazol-S- 4.34 (2H), 4.42 (1H), 6.98 (2H), carboxarnide 7.14 (3H), 7.25 (2H), 7.39 (3H), 8.09 (1H), 8.49 (1H).
(+/-)-N— [2-(cyclo- 1H—NMR (400 MHz, DMSO-da): propylmethoxy) - 8 [ppm]: 0.16 (2H), 0.43 (2H), propyl] methyl 0.97 (1H), 1.10 (3H), 1.24 (2H), -(trifluoro- 1.38 (1H), 1.59 (1H), 2.30 (1H), methyl)benzoyl] - 2.53 (3H), 2.78 (1H), 3.02 (1H), piperidinyl} - 3.23 (2H), 3.28 (2H), 3.45 (1H), methyl)-2H-indazol- 3.60 (1H), 4.34 (2H), 4.46 (1H), -carboxamide 7.17 (1H), 7.41 (1H), 7.57 (2H), 7.80 (2H), 8.09 (1H), 8.49 (1H).
(+/-)-N—[2-(cyclo- 1H—NMR (400 MHz, DMSO-da): propylmethoxy)- 8 [ppm]: 0.16 (2H), 0.42 (2H), l({1-[(4'- 0.97 (1H), 1.10 (3H), 1.26 (2H), fluorobiphenyl 1.45 (1H), 1.55 (1H), 2.32 (1H), yl)carbonyl] - 2.53 (3H), 2.7 9(1H), 3.03 (1H), piperidinyl} - 3.23 (2H), 3.27 (2H), 3.60 (2H), methyl)methyl- 4.36 (2H), 4.46 (1H), 7.17 (1H), azol 7.30 (2H), 7.42 (3H), 7.71 (4H), carboxarnide 8.09 (1H), 8.50 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp JVNY@ (+/)2 {[1(4— 1H-NMR (400 MHz, 6) VAC 1 CH3 5 cyclopropylbenzoyl) 8 [ppm]]= 0.16 (2H), 0.43 (2H), piperidiny1]- 0.69 (2H), 0.96 (3H), 1.10 (3H), methyl}-N—[2- 1.20 (2H), 1.47 (2H), 1.93 (1H), (cyclopropyl- 2.28 (1H), 2.53 (3H), 2.77 (1H), methoxy)propyl]—4- 2.93 (1H), 3.23 (2H), 3.28 (2H), methyl-2H-indazol 3.59 (2H), 4.34 (2H), 4.40 (1H), carboxamide 7.10 (2H), 7.17 (1H), 7.22 (2H), 7.41 (1H), 8.09 (1H), 8.49 (1H).
Example 107: 2- {[1-(4-chlorobenzoyl)piperidinyl]methyl} methyl-N—[2-(trifluoromethoxy) ethyl]]Hindazolcarboxamide 696% Analogously to Example 1, 26 mg of the title compound was obtained from 75 mg of the amine prepared in e 107a and 28 mg of 4-chlorobenzoic acid. 1H-NMR (300 MHz, DMSO-(15): 8 [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 s: Example 107a: 4-methyl(4-piperidylmethyl)-N—[2-(trifluoromethoxy)ethyl]-2H-indazol carboxamide F J\ )5 H \ O/\/ 0 CH3 H To 648 mg of 107b were added 3.0 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30°C. The reaction mixture was concentrated, taken up in some toluene and again concentrated. Yield: 766 mg of the title compound, which was further reacted t further purification.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 1H—NMR (300 MHz, DMSO-d6) 8 [ppm]= 143 (2H) 157 (2H) 224 (1H) 250 (3H) 278 (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 1 07b: Tert-butyl 4- [(4-methyl-5 - {N— [2-(trifluoromethoxy)ethyl]carbamoyl} -2H- indazolyl)methyl]piperidin-1 -carboxylate ”@613”: HOCH3 500 mg of 1d was reacted with 293 mg of amine analogously to 1b version B. Yield: 748 mg of the title compound. 1H—NMR (400 MHz, DMSO-d6) 8 [ppm]= 107 (2H) 134 (9H) 137 (2H) 212 (1H) 250 (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 ed analogously: 2-({1- fluoro- 1H—NMR (300 MHz, o/\/N phenoxy)benzoyl] - DMSO-ds): 8 [ppm]= 1.19 piperidinyl} methyl)- (2H), 1.46 (2H), 2.26 (1H), 4-methyl-N-[2-(tri- 2.49 (3H), 2.87 (2H), 3.51 fluoromethoxy)ethyl]- (3H), 4.17 (2H), 4.33 (3H), 2H-indazol 6.95 (2H), 7.16 (5H), 7.38 carboxamide (3H), 8.36 (1H), 8.49 (1H). 2-({1-[(4'-fluoro- 1H—NMR (300 MHz, biphenylyl)- DMSO-ds): 8 [ppm]= 1.23 carbonyl]piperidin (2H), 1.47 (2H), 2.28 (1H), yl} l)methyl- 2.50 (3H), 2.74 (1H), 2.99 N—[2-(trifluoro- (1H), 3.51 (2H), 3.61 (1H), methoxy)ethyl]-2H- 4.17 (2H), 4.34 (3H), 7.16 indazolcarboxamide (1H), 7.27 (2H), 7.40 (3H), 7.68 (4H), 8.37 (1H), 8.50 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4-methyl-N—[2- 1H-NMR (300 MHz, (trifluoromethoxy)ethyl] s): 8 [ppm]: 1.21 [(1-{4-[4-(trifluoro- (2H), 1.46 (2H), 2.27 (1H), methyl)phenoxy]- 2.50 (3H), 2.76 (1H), 2.98 benzoyl}piperidin—4-y1) (1H), 3.51 (2H), 3.61 (1H), methy1]-2H—indazol 4.17 (2H), 4.33 (2H), 4.43 carboxamide (1H), 7.14 (5H), 7.41 (3H), 7.73 (2H), 8.37 (1H), 8.49 (1H).
Example 1 1 1 : N—(2-tert-butoxyethyl) {[1 -(4-chlorobenzoyl)piperidinyl]methyl} methyl- 2H-indazolcarboxamide HC o/\/ Analogously to Example 1, 8 mg of the title compound was obtained from 75 mg of the amine prepared in Example 111a and 28 mg of 4-chlorobenzoic acid. 1H-NMR (400 MHz DMSO-(15): 8 [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 1 1 1 a: N—(2-tert-butoxyethyl)methyl(4-piperidylmethyl)-2H-indazolcarbox- amide C'bHXO/VNO JNb‘N To 743 mg of 1 1 1b were added 3.5 ml of 4M hydrochloric acid in dioxan and 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30°C. The reaction mixture was trated, taken up in some e and again concentrated. Yield: 677 mg of the title compound in a mixture with N- (2-hydroxyethyl)methyl(4-piperidylmethyl)-2H-indazolcarboxamide, which was further reacted without further purification.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 1 1 1b: Tert-butyl 4-( {5- [N—(2-tert-butoxyethyl)carbamoyl] hyl-2H-indazol yl} methyl)piperidincarboxylate HCCH3 500 mg of 1d was reacted with 206 mg of amine analogously to 1b version B. Yield: 743 mg of the title nd. 1H-NMR (300 MHz DMSO-d5): 8 [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: 0 “fl,“ N-(2-tert-butoxyethyl)- 1H-NMR (400 MHZ 5): ”CON ‘ 2-({1-[4-(4-fluoro- 5 [ppm]: 1 12 (9H) 1 20 (2H) phenoxy)benzoyl]— 1.44 (2H), 2.26 (1H), 2.50 (3H), piperidinyl}methyl)- 2.76 (1H), 2.93 (1H), 3.30 (2H), 4-methyl-2H-indazol 3.40 (2H), 3.57 (1H), 4.31 (2H), carboxamide 4.39 (1H), 6.95 (2H), 7.12 (3H), 7.23 (2H), 7.36 (3H), 8.04 (1H), 8.46 (1H).
N—(2-tert-butoxyethyl)- 1H-NMR (400 MHZ, DMSO-da): 2-({1-[(4'-fluoro- 5 [ppm]: 1. 11 (9H) 1.23 (2H) biphenylyl)- 1.40 (1H), 1.54 (1H), 2.29 (1H), carbonyl]piperidin—4- 2.50 (3H), 2.75 (1H), 3.00 (1H), yl}methyl)methyl- 3.29 (2H), 3.40 (2H), 3.65 (1H), 2H-indazol 4.32 (2H), 4.43 (1H), 7.15 (1H), carboxamide 7.28 (2H), 7.40 (3H), 7.69 (4H), 8.05 (1H), 8.47 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp N—(2-tert-butoxyethyl)- 1H-NMR (400 MHZ, DMSO-da): 4-methyl[(1-{4-[4- 8 [ppm]= 1.12 (9H), 1.21 (2H), (trifluoromethyl)- 1.40 (1H), 1.52 (1H), 2.27 (1H), y]benzoyl}- 2.50 (3H), 2.75 (1H), 2.99 (1H), piperidinyl)methyl]— 3.28 (2H), 3.40 (2H), 3.60 (1H), 2H-indazol 4.32 (2H), 4.40 (1H), 7.15 (5H), carboxamide 7.40 (3H), 7.73 (2H), 8.04 (1H), 8.47 (1H).
Example 1 1 5: 2- { [l -(4-chlorobenzoyl)piperidinyl]methyl} -N-(2- [2H3]methoxy[2H4] ethyl) methyl-2H-indazolcarboxamide DDD D J\ X H N \ D o D D 0 CH3 ously to Example 1, 1 mg of the title compound was obtained from 54 mg of the amine prepared in Example 115a and 22 mg of 4-chlorobenzoic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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 s: Example 1 1 5a: 4-methyl-N—(2- [2H3]methyloxy[2H4] ethyl)(4-piperidylmethyl)-2H-indazol-5 - carboxamide D DD D H /N\N D D 0 CH3 H To 131 mg of 115b were added 0.7 ml of 4M hloric acid in dioxan and 0.5 ml dioxan. The mixture was stirred for 30 mins at ca. 30°C. The reaction mixture was concentrated, taken up in some toluene and again trated. Yield: 108 mg of the title compound, which was further reacted without further purification. 1H-NMR (400 MHz, DMSO-ds): 8 [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), D7 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 1 1 5b: Tert-butyl 4-( {4-methyl [N—(2- [2H3]methyloxy[2H4] ethyl)carbamoyl] -2H- lyl} methyl)piperidin- l -carboxylate fli>§nY<fiN D D 0 CH3 b H09—CH3 1430 500 mg of 1d was reacted analogously to 1b version B with 110 mg of amine prepared in 115c.
Yield: 131 mg of the title compound. 1H-NMR (300 MHz, DMSO-ds): 5 [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). e 1 1 5c: 2- ethyloxy[2H4] ethan- l -amine D X:)$(NH2D D D DD 110 mg of (0.51 mmol) of 115d was first placed in 2.2 ml toluene. After on of 11 mg of palladium/charcoal (10%) and hydrogen under normal pressure, the mixture was d for 50 mins at room temperature. The reaction mixture was filtered through Celite and rewashed with toluene. The colourless filtrate was used as solution in the subsequent reaction.
Example 115d: Benzyl N—(2-[2H3]methyloxy[2H4]ethyl)carbamate D DD D DXofiNll/OH Q 1.32 g (6.6 mmol) of 115e) was dissolved in 23 ml acetonitrile. 2.3 g (9.9 mmol) of silver oxide and 1.64 ml (3.8 g, 26 mmol) of deuterated iodomethane were then added. The reaction mixture was stirred for 1.5 hrs at 40°C, 7.5 hrs at 72°C and then overnight at room temperature. A further 2.3 g (9.9 mmol) of silver oxide was added and the mixture stirred for 1.5 hrs at 72°C. For the work-up, the black solid was filtered off at the pump and the clear filtrate concentrated. The residue was purified by column chromatography (hexane/ethyl acetate . Yield: 1.13 g of the title nd. 1H—NMR (300 MHz, DMSO-da): 8 [ppm]: 4.97 (2H), 7.31 (5H).
Example 115e: Benzyl N—(2-hydroxy[2H4]ethyl)carbamate N O a. . 1 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1.0 g (15 mmol) of deuterated aminoethanol was first dissolved in 29 ml dichloromethane. Then 2.5 ml (1.8 g, l8mmol) of triethylamine was added and the reaction mixture cooled to 0°C. At this temperature 2.75 ml (3.34 g, 19.6 mmol) of benzyl chloroformate was now cautiously added se. After completion of the addition, the mixture was stirred for 1 hr more with no ice- bath and in the process warmed up to RT. The reaction mixture was diluted once with some dichloromethane and washed once with saturated sodium chloride on. The organic phase was dried over sodium sulphate, filtered and trated. The crude product was purified twice by column tography oromethane/methanol 0-10% and ethyl acetate). Yield: 1.32 g of the title compound. 1H—NMR (300 MHz, DMSO-da): 8 [ppm]= 4.54 (1H), 4.97 (2H), 7.12 (1H), 7.81 (5H).
The following compound was prepared analogously: I—D:m2({1[4(4fluoro- 1H—NMR (300 MHz, phenoxy)benzoyl]— DMSO-ds): 8 [ppm]= 1.19 piperidinyl}methyl)- <2H). 1.46 <2H). 2.25 (IH). 4-methyl-N—(2-[2H3]- 2.49 (3H), 2.85 (2H), 3.66 methyloxy[2H4]ethyl)- (1H), 4.31 (2H), 4.38 (1H), 2H-indazol 6.95 (2H), 7.16 (5H), 7.36 carboxamide (3H), 8.07 (1H), 8.46 (1H).
Example 1 1 7: 2- {[1-(4-chlorobenzoyl)azetidin-3 -yl]methyl} -N-(2-methoxyethyl)methyl-2H- lcarboxamide N C /N\ 4? H N H3C\O/\/N \ 0 CH3 ously to Example 55, 471 mg of the title compound was obtained from 500 mg of the compound prepared in Example ll7e) and 287 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). fie starting material was prepared as follows: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 1 1 7a: Tert-butyl 3 - [(5 -bromomethyl-2H-indazolyl)methyl] -azetidin—l - carboxylate >\_o N CH3 HSC CH3 J 4?\ To a solution of 21.1 g of 5-bromomethyl-lH-indazole and 37.6 g of tert-butyl[(tosyloxy)- methyl]azetidin—l-carboxylate in 100 ml dioxan were added 150 ml of a 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran at 25°C and this was stirred for 6 hrs at 90°C. After cooling, the reaction mixture was treated with ethyl acetate and water, the c phases separated and the aqueous phase extracted twice with 100 ml portions of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate, and concentrated in vacuo after ion.
The residue thus obtained was purified by chromatography on the Flashmaster (hexane/ethyl acetate 1:0-0:1). 15.0 g of the title compound was obtained. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 1 7b: Methyl 2- {[1-(tert-butoxycarbonyl)azetidin-3 -yl]methyl} methyl-2H-indazol- -carboxylate To a solution of 8.16 g of the bromide ed in Example 117a in 65.4 ml methanol, 6.5 g of 1,1 phenylphosphino)ferrocen-palladium(H) dichloride and 15 g of potassium acetate were added at 25°C and the mixture was stirred under CO at 10.15 bar and 120°C for 24 hours in an autoclave. The reaction mixture was then , filtered through Celite at the pump and the filtrate concentrated in vacuo. The residue thus obtained was purified by chromatography on the Flashmaster (hexane/ethyl acetate 1:0-0:1). 6.97g of the title compound was obtained. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 1 7c: 2- { [l -(tert-butoxycarbonyl)azetidin—3 -yl]methyl} hyl-2H-indazol aboxylic acid [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp HO \ O CH Analogously to Example 1d, 5.2 g of the title compound was obtained from 15.1 g of the ester ed in Example 1 17b. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 1 7d: Tert-butyl 3 -( {5- [N-(2-methoxyethyl)carbamoyl] methyl-2H-indazolyl} - methyl)azetidin— l xylate N>_O>VCH3 HSC CH3 J\ 4? H N H3C\O/\/N \ 0 CH3 Analogously to Example 1, from 2.5 g of the acid prepared in Example 117C and 0.54 g of 2-methoxyethylamine, a crude product was obtained which through purification with a Biotage unit (ethyl acetate : 0 to 30% methanol) yielded 2.69 g of the title compound. 1H-NMR (300 MHz, 6): 8 = 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 1 1 7e: 2-(azetidin—3 -ylmethyl)-N—(2-methoxyethyl)methyl-2H-indazolcarbox- amide hydrochloride H CIH /N\ 4? H N HSC\O/\/N \ 0 CH3 Analogously to Example la, from 2.69 g of the amide prepared in e 117d, 2.59 g of the title compound was obtained, which was reacted without further purification.
Example 1 18: N—(2-methoxyethyl)methyl [(1 - {4- [(trifluoromethyl)sulphanyl]benzoyl} azetidin—3 -yl)methyl] -2H-indazolcarboxamide O )l—F N : A. f H N HC\O/\/N \ D o [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ously to Example 55, 29 mg of the title compound was obtained from 55 mg of the compound prepared in Example ll7e and 43 mg of 4-[(trifluoromethyl)sulphanyl]benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 19: N—(2-methoxyethyl)methyl( { l - [4-(trifluoromethoxy)benzoyl] azetidin—3 - yl} methyl)-2H-indazolcarboxamide of C )l—F JR 4? H N HSC\O/\/N \ 0 CH3 Analogously to Example 55, 27 mg of the title compound was ed from 55 mg of the compound prepared in Example ll7e and 40 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .44 (3H), 7.70 (2H), 8.12 (1H), 8.54 (1H).
Example 120: 2-( { l - [2-fluoro(trifluoromethyl)benzoyl] azetidin—3 -yl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide o C F F H N H3C\O/\/N \ 0 CH3 Analogously to Example 55, 17 mg of the title nd was obtained from 55 mg of the compound prepared in Example ll7e and 41 mg of o(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-chlorofluorobenzoyl)azetidin-3 -yl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp J‘k y H N \/N \ 0 CH3 Analogously to Example 55, 19 mg of the title compound was obtained from 42 mg of the nd prepared in Example ll7e and 26 mg of 4-chlorofluorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-( { l - [3 -fluoro(trifluoromethyl)benzoyl] azetidin—3 -yl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 Analogously to Example 55, 15 mg of the title compound was obtained from 42 mg of the compound prepared in Example ll7e and 31 mg of 3-fluoro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-( { l - [4-chloro-3 -(trifluoromethyl)benzoyl] azetidin—3 -yl} )-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide /N\ P H N HSC\O/\/N \ 0 CH3 Analogously to Example 55, 6 mg of the title compound was obtained from 42 mg of the compound ed in Example ll7e and 33 mg of 4-chloro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 2.49 (3H), 3.21 (1H), 3.25 (3H), 3.31-3.46 (4H), 3.92 D1), 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).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 124: 2- {[1-(4-cyclopropylbenzoyl)azetidin-3 -yl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide of C ] /N\ 4? H N ch\O/\/N \ 0 CH3 Analogously to Example 1, 76 mg of the title compound was obtained from 163 mg of the compound prepared in e 117e and 78 mg of 4-cyclopropylbenzoic acid. 1H-NMR (300 MHZ, DMSO-d6): 8 = 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)methyl-2 - [(1 - {4- [4-(trifluoromethyl)phenoxy]benzoyl} azetidin—3 -yl)methyl] -2H-indazolcarboxamide C O N /N\ 4? H3C\O/\/N \ 0 CH3 Analogously to Example 1, 478 mg of the title nd was obtained from 1.20 g of the compound prepared in Example 117e and 850 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). e 126 : 2- {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} -N- [2-(3 ,3 -difluoropyrrolidin— l - yl) ethyl] methyl-2H-indazolcarboxamide Owe.
J. )3 H N F N/\/N \ F>C’ 0 CH3 Analogously to Example 55, 38 mg of the title compound was ed from 43 mg of the ”pound prepared in Example 126a and 20 mg of robenzoyl chloride.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 8 = 2.10—2.27 (3H), 2.49 (3H), 2.57 (2H), 2.72 (2H), 2.91 (2H), 3.17-3.36 (2H), 3.89 (1H), 4.08 (1H), 4.19 (1H), 4.36 (1H), 4.67 (2H), 7.14 (1H), 7.38 (1H), 7.48 (2H), 7.59 (2H), 8.05 (1H), 8.54 (1H).
Example 126a: 2-(azetidin—3-ylmethyl)-N—[2-(3,3-difluoropyrrolidin-l-yl)ethyl]—4-methyl-2H- l-S-carboxamide hloride N N F>O/\/F \ 0 CH3 ously to Example la, from 50 mg of the compound prepared in Example 126b, 43 mg of the title compound was obtained, which was reacted without further purification.
Example 126b: Tert-butyl 3 - [(5- {N— [2-(3 ,3 -difluoropyrrolidin- l -yl)ethyl]carbamoyl} methyl- 2H-indazolyl)methyl] azetidin—l -carboxylate Analogously to e lb, 71 mg of the title compound was obtained from 70 mg of the compound prepared in Example 117a and 83 mg of 2-(3,3-difluoropyrrolidin-l-yl)ethylamine. 1H-NMR (300 MHz, 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 (lH). e 127: 2- {[1-(4-chlorobenzoyl)azetidin—3-yl]methyl} methyl-N— {2-[(trifluoromethyl) sulphanyl] ethyl} -2H-indazolcarboxamide O800 F H ”NAP F>I\S/\/N \ 0 CH3 Analogously to e 55, 143 mg of the title compound was obtained from 130 mg of the compound prepared in Example 127b and 61 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 5 = 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), fi7 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The starting material was prepared as follows: Example 127a: Tert-butyl 3 - {[4-methyl(N- {2- [(trifluoromethyl)sulphanyl] ethyl} carbamoyl)- lyl]methyl} azetidin— 1 -carboxylate N>7}ng H c CH F J\ 4? 3 FF>|\S/\/NH N 0 CH3 Analogously to Example 1, 674 mg of the title compound was ed from 500 mg of the compound prepared in Example 117c. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.32 (9H), 2.52 (3H), 3.08 (1H), 3.17 (2H), 3.50 (2H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.19 (1H), 7.41 (1H), 8.38 (1H), 8.57 (1H).
Example 127b: 2-(azetidin—3-ylmethyl)methyl-N— {2-[(trifluoromethyl)sulphanyl]ethyl} -2H- indazolcarboxamide hloride Analogously to Example 1a, from 150 mg of the compound prepared in Example 127a, 130 mg of the title compound was obtained, which was further reacted without purification.
Example 128: 2- {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} methyl-N—(2-morpholinoethyl)- 2H-indazolcarboxamide O>—©—CI OWig?0 CH3 Analogously to e 55, 30 mg of the title nd was obtained from 50 mg of the compound prepared in Example 128b and 24 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, 6): 5 = 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: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp e 128a: Tert-butyl 3 -( {4-methyl [N—(2-morpholinoethyl)carbamoyl] -2H-indazol yl } methyl)azetidin—l -carboxylate N>7}ng 4?H30 CH3 FNNNYg/H AN 0d 0 CH3 Analogously to Example lb, 59 mg of the title compound was obtained from 200 mg of the compound prepared in Example 117a and 205 mg of 2-morpholinoethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.32 (9H), .44 (6H), 2.52 (3H), 3.08 (1H), 3.33 (2H), 3.54 (4H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.15 (1H), 7.39 (1H), 7.98 (1H), 8.55 (1H).
Example 128b: 2-(azetidin—3 -ylmethyl)methyl-N—(2-morpholinoethyl)-2H-indazole-5 - carboxamide hloride J“ P NNHYCPQ 0d 0 CH Analogously to Example la, from 59 mg of the nd prepared in Example 128a, 63 mg of the title compound was obtained, which was further reacted without purification.
Example 129: 2- {[1 -(4-chlorobenzoyl)azetidinyl]methyl} methyl-N—(2,2,2-trifluoroethyl)- 2H-indazolcarboxamide O800 F /N\ 4? 5K) N N \ 0 CH3 Analogously to Example 55, 127 mg of the title compound was obtained from 128 mg of the compound prepared in Example 12% and 68 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 2.50 (3H), 3.22 (1H), 3.90 (1H), .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 al was prepared as follows: Example 129a: Tert-butyl 3 -( {4-methyl-5 - [N—(2,2,2-trifluoroethyl)carbamoyl] -2H-indazol yl} methyl)azetidin— l -carboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp N>7}ng H C CH 3 3 F J\ 4? 5K) N N \ 0 CH3 ously to Example 1, 1.02 g of the title compound was obtained from 1.0 g of the compound ed in Example 1 17c and 287 mg of 2,2,2-trifluoroethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.32 (9H), 2.51 (3H), 3.09 (1H), 3.70 (2H), 3.86 (2H), 4.03 (2H), 4.62 (2H), 7.17 (1H), 7.43 (1H), 8.60 (1H), 8.79 (1H).
Example 129b: 2-(azetidin—3 -ylmethyl)methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 - carboxamide hydrochloride H CIH F A jg F>K/N N N \ 0 CH3 Analogously to Example la, from 1.0 g of the compound prepared in Example 129a, 852 mg of the title compound was obtained, which was further reacted t ation.
Example 130: 4-methyl-N—(2,2,2-trifluoroethyl)( { l - [4-(trifluoromethoxy)benzoyl] azetidin—3 - yl} methyl)-2H-indazolcarboxamide o :y.
F J\y 5K) N N \ 0 CH3 Analogously to Example 55, 113 mg of the title compound was obtained from 128 mg of the compound ed in Example 12% and 87 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 13 1: 2-( { l - [2-fluoro(trifluoromethyl)benzoyl] azetidin—3 -yl}methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide F J\ y :X/H N 0 CH3 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 55, 128 mg of the title compound was obtained from 128 mg of the compound ed in Example 12% and 88 mg of 2-fluoro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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( { l - ntafluoro-7t6-sulphanyl)benzoyl] azetidin-3 -yl} methyl)-N- (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide O F‘s/F F N F F F J\ 4? 5K) N N \ 0 CH3 Analogously to Example 1, 121 mg of the title compound was obtained from 128 mg of the nd prepared in e 12% and 96 mg of 4-(pentafluoro-7t6-sufanyl)benzoic acid. 1H-NMR (300 MHz, 6): 8 = 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( { l - [4-(trifluoromethoxy)benzoyl] azetidin-3 -yl} methyl)-N- {2- [(trifluoromethyl)sulphanyl] ethyl} -2H-indazolcarboxamide o >ZF F J‘Nfi F>|\S/\/NF H 0 CH3 Analogously to Example 55, 178 mg of the title compound was obtained from 130 mg of the compound prepared in Example 127b and 78 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHZ, DMSO-d6): 8 = 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-( { l - [2-fluoro(trifluoromethyl)benzoyl] in—3 -yl}methyl)methyl-N— {2- [(trifluoromethyl)sulphanyl] ethyl} -2H-indazolcarboxamide O :: F F dS/VNYEF/0F J‘k y F H N [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to e 55, 128 mg of the title compound was obtained from 130 mg of the compound prepared in Example 127b and 79 mg of o(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 2.51 (3H), 3.12-3.25 (3H), 3.50 (2H), 3.89-3.98 (2H), 4.06-4.16 (2H), 4.67 (2H), 7.19 (1H), 7.40 (1H), 7.64 (2H), 7.79 (1H), 8.39 (1H), 8.56 (1H).
Example 135: yl( { l - [4-(pentafluoro-k6-sulphanyl)benzoyl] azetidin-3 -yl} methyl)-N- {2- [(trifluoromethyl)sulphanyl] ethyl} -2H-indazolcarboxamide Analogously to Example 1, 84 mg of the title compound was obtained from 130 mg of the compound prepared in Example 127b and 87 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-(cyclopropyloxy)ethyl] hyl( { l - [4-(trifluoromethoxy)benzoyl] azetidin—3 thyl)-2H-indazolcarboxamide N>\\©\o)4FF F AO/\/“fig?“ 0 CH3 Analogously to Example 55, 172 mg of the title compound was ed from 161 mg of the compound prepared in Example l36b and 109 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 136a: Tert-butyl 3 - [(5- {N— [2-(cyclopropyloxy) ethyl] carbamoyl} methyl-2H- indazolyl)methyl] azetidin— l -carboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 189 mg of the title compound was obtained from 150 mg of the compound prepared in e 118C and 140 mg of 2-cyclopropoxy-ethylammonium trifluoroacetate (preparable ing to Example 154a) and 154b) starting from cyclopropanol and bromoacetamide followed by Boc cleavage with trifluoroacetic acid analogously to e 1a)). 1H-NMR (300 MHz, DMSO-d6): 8 = 0.36-0.48 (4H), 1.33 (9H), 2.49 (3H), 3.08 (1H), 3.25-3.39 (3H), 3.53 (2H), 3.70 (2H), 3.87 (2H), 4.61 (2H), 7.14 (1H), 7.38 (1H), 8.10 (1H), 8.54 (1H).
Example 136b: tidin—3-ylmethyl)-N—[(2-cyclopropyloxy)ethyl]methyl-2H-indazol carboxamide hydrochloride N CIH /N\ 4? A H N O/\/N \ 0 CH3 Analogously to Example la, from 189 mg of the compound prepared in Example 136a, 161 mg of the title compound was obtained, which was further reacted t purification.
Example 137: N—[2-(cyclobutyloxy)ethyl] methyl( { l - [4-(trifluoromethoxy)benzoyl] azetidin—3 -yl}methyl)-2H-indazolcarboxamide F F o : >LF O a H N O/\/N \ 0 CH3 Analogously to Example 55, 207 mg of the title compound was obtained from 254 mg of the compound prepared in Example l37b and 166 mg of fluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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: Dample 137a: Tert-butyl 3 - [(5- {N— [2-(cyclobutyloxy)ethyl]carbamoyl} hyl-2H-indazol- 2-yl)methyl] azetidin— l -carboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp nyoH3CCH3H WHYECEE‘l/N Analogously to Example 1, 297 mg of the title compound was obtained from 220 mg of the compound prepared in Example 117C and 143 mg of 2-(cyclobutyloxy)ethylammonium trifluoroacetate (preparable according to Example 154a) and 154b) starting from cyclobutanol and bromoacetamide followed by Boc cleavage with trifluoroacetic acid analogously to Example 1a)). 1H-NMR (300 MHZ, DMSO-d6): 8 = 1.33 (9H), 1.35-1.49 (1H), 1.59 (1H), 1.80 (2H), 2.11 (2H), 2.50 (3H), 3.08 (1H), .41 (4H), 3.69 (2H), 3.82-3.95 (3H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.10 (1H), 8.54 (1H).
Example 137b: tidinylmethyl)-N—[(2-(cyclobutyloxy)ethyl]methyl-2H-indazol amide hydrochloride N CH JR )3 H N /\/N \ 0 CH3 Analogously to Example la, from 297 mg of the compound prepared in Example 137a, 254 mg of the title compound was obtained, which was further reacted without ation.
Example 138: (+/-) {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} -N-(2-methoxypropyl) methyl-2H-indazolcarboxamide ..WW Analogously to Example 55, 166 mg of the title compound was obtained from 237 mg of the compound prepared in Example l38b and 129 mg of 4-chlorobenzoyl chloride. 1H—NMR (300 MHz, 6): 5 = 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: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Example 138a: (+/-)-tert-butyl 3 -( {5- [N—(2-methoxypropyl)carbamoyl] methyl-2H-indazol yl } methyl)azetidin—l xylate >\_o N >VCH3 H3C CH3 CH3 /N\ 4? 0 CH3 Analogously to Example 1, 331 mg of the title compound was obtained from 323 mg of the compound prepared in Example 1 17c and 117 mg of 2-methoxypropylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.08 (3H), 1.33 (9H), 2.50 (3H), 3.09 (1H), 3.16-3.31 (2H), 3.44 (1H), 3.69 (2H), 3.85 (2H), 4.61 (2H), 7.15 (1H), 7.39 (1H), 8.08 (1H), 8.54 (1H).
Example 138b: (+/-)(azetidin—3-ylmethyl)-N—(2-methoxypropyl)methyl-2H-indazol amide hydrochloride Analogously to Example la, from 280 mg of the compound prepared in Example 138a, 247 mg of the title compound was obtained, which was further reacted without purification.
Example 139: (R or S){[1-(4-chlorobenzoyl)azetidin—3-yl]methyl}-N-(2-methoxypropyl) methyl-2H-indazolcarboxamide H >_:| H >_I: CHJ "my EHJ any Hp r “F / hd “aU I: I: H1 '2' CH; From 158 mg of the racemate prepared in Example 138, 52 mg of the title compound er with 48 mg of the slower-eluting enantiomer (Example 140) were obtained by racemate tion by means of preparative chiral HPLC (Method A).
Analytical chiral HPLC: 14.5 min.
Example 140: (S or R){[1-(4-chlorobenzoyl)azetidin—3-yl]methyl}-N-(2-methoxypropyl) methyl-2H-indazolcarboxamide $$—{ ::—CI 033—: ::—C CH1 "I"? Inn-'1 My H hum/Q: “Fwd / d I: CHJ I: EHJ [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp From 158 mg of the racemate prepared in Example 138, 48 mg of the title compound together with 52 mg of the faster-eluting enantiomer (Example 139) were obtained by racemate separation by means of preparative chiral HPLC (Method A).
Analytical chiral HPLC: 17.1 min.
Example 141: (+/-) -chlorobenzoyl)azetidin—3 -yl]methyl} -N-(l ,4-dioxanylmethyl)- 4-methyl-2H-indazolcarboxamide o800 {01, Yifi}H N N \ 0 CH3 ously to Example 55, 177 mg of the title compound was obtained from 269 mg of the compound prepared in Example l4lb and 136 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 ed as follows: Example 141 a: (+/-)-tert-butyl 3 -( {5- [N—(l ,4-dioxan—2-ylmethyl)carbamoyl] methyl-2H- indazolyl } methyl)azetidin— l -carboxylate Analogously to Example 1, 364 mg of the title compound was obtained from 323 mg of the compound ed in e 117C and 110 mg of l,4-dioxan—2-ylmethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.33 (9H), 2.50 (3H), 3.09 (1H), 3.16-3.29 (3H), 3.40-3.77 (8H), 3.86 (2H), 4.61 (2H), 7.16 (1H), 7.39 (1H), 8.14 (1H), 8.55 (1H).
Example 141b: (+/-)(azetidin—3-ylmethyl)-N-(l,4-dioxan—2-ylmethyl)methyl-2H-indazol- -carboxamide hydrochloride O /N\ H N N \ ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Analogously to Example la, from 314 mg of the nd prepared in Example 141a, 274 mg of the title compound was obtained, which was further reacted without purification.
Example 142: (R or S) {[1-(4-chlorobenzoyl)azetidin—3-yl]methyl}-N-(l,4-dioxan—2-yl- methyl)methyl-2H-indazolcarboxamide 3% }Cl °H ya.
[Or/1gp0 )4. f A} .. £014.1YQJO 0 CH3 0 (:H3 From 172 mg of the racemate prepared in Example 141, 60 mg of the title compound together with 60 mg of the slower-eluting enantiomer (Example 143) were obtained by racemate separation by means of preparative chiral HPLC (Method B).
Analytical chiral HPLC: 5.84 min.
Example 143: (S or R){[1-(4-chlorobenzoyl)azetidin—3-yl]methyl}-N-(l,4-dioxan—2-ylmethyl )methyl-2H-indazolcarboxamide O O Cl : Cl N N U N P 0 N P ’ \ ’ \ H N N x C Li a O V 0 0 CH3 0 CH3 From 172 mg of the racemate prepared in Example 141, 60 mg of the title compound together with 60 mg of the faster-eluting enantiomer (Example 142) were obtained by te separation by means of preparative chiral HPLC (Method B).
Analytical chiral HPLC: 6.28 min.
Example 144: (+/-) {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} methyl-N-(3 -tetrahydro-2H-pyran —2-ylmethyl)-2H-indazolcarboxamide 0x00 H N N \ 0 CH3 Analogously to Example 55, 144 mg of the title nd was obtained from 255 mg of the compound prepared in Example l44b and 130 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 =1.10-1.23(1H),1.35-1.47(3H),1.61(1H),1.71-1.81(1H), D8 (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).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The starting material was prepared as follows: Example 144a: (+/-)-tert-butyl 3-( {4-methyl[N-(3,4,5,6-tetrahydro-2H-pyran—2-ylmethyl)- carbamoyl] dazolyl}methyl)azetidin— 1 -carboxylate N>2}ng HSC CH3 OVH J P\ N \ 0 CH3 Analogously to Example 1, 342 mg of the title compound was ed from 323 mg of the compound prepared in Example 117c and 141 mg of 3,4,5,6-tetrahydro-2H-pyran—2-ylmethyl- amine hloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .91 (3H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.06 (1H), 8.53 (1H).
Example 144b: (+/-)(azetidinylmethyl)methyl-N-(3,4,5,6-tetrahydro-2H-pyranyl- methyl)-2H-indazolecarboxamide hydrochloride H N N \ 0 CH3 Analogously to Example 1a, from 298 mg of the compound prepared in Example 144a, 261 mg of the title compound was obtained, which was further reacted without purification.
Example 145: (R or S) {[1-(4-chlorobenzoyl)azetidin—3-yl]methyl} methyl-N-(3,4,5,6- ydro-2H-pyran—2-ylmethyl)-2H-indazol-5 -carboxamide O O H >—C| H >—CI N N /N\ P fN\ P H N H N \ in.
O ""-/ or o 0 CH3 0 CH3 From 140 mg of the racemate prepared in Example 144, 43 mg of the title compound together with 35 mg of the slower-eluting enantiomer (Example 146) were obtained by racemate separation by means of preparative chiral HPLC d C).
Analytical chiral HPLC: 4.38 min.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 146: (S or R) -chlorobenzoyl)azetidin—3-yl]methyl} methyl-N—(3,4,5,6- tetrahydro-2H-pyran—2-ylmethyl)-2H-indazol-5 -carboxamide O O >—< >—CI >—< >—Cl N N N f N j) / \ / \ \_ ., "—. o or o "'-/ 0 CH3 0 CH3 From 140 mg of the racemate prepared in e 144, 35 mg of the title compound together with 43 mg of the faster-eluting enantiomer (Example 145) were obtained by racemate separation by means of preparative chiral HPLC (Method C).
Analytical chiral HPLC: 4.88 min.
Example 147: (+/-)( { l - [4-(4-fluorophenoxy)benzoyl] azetidin—3 -yl} methyl)-N-(2-methoxy- propyl)methyl-2H-indazolcarboxamide o C; C O N CH3 J\4P HC X/H \N 0 CH3 Analogously to Example 1, from 42 mg of the compound ed in Example l38b and 28 mg of 4-(4-fluorophenoxy)benzoic acid, a material still contaminated after HPLC purification was obtained, which was further purified by an additional preparative thick layer chromatography with ethyl acetate / methanol in the ratio 9:1 as mobile phase. Yield in this manner: 15 mg of the title compound. 1H-NMR (300 MHz, CDCl3): 8 = 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—(l ,4-dioxanylmethyl)( { l - [4-(4-fluorophenoxy)benzoyl] azetidin—3 - yl} methyl)methyl-2H-indazolcarboxamide [:LHYEFQ} D CH3 ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 18 mg of the title compound was obtained from 43 mg of the compound prepared in Example l4lb and 26 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). e 149: 2- {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} -N- [2-(cyclopropylmethoxy)ethyl] - 4-methyl-2H-indazolcarboxamide o>—©—CI . f H N 0 CH3 Analogously to e 55, 72 mg of the title compound was obtained from 127 mg of the compound prepared in Example 14% and 65 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.17 (2H), 0.45 (2H), 0.99 (1H), .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 149a: Tert-butyl 3 - [(5- {N— [2-(cyclopropylmethoxy)ethyl]carbamoyl} methyl-2H- indazolyl)methyl] azetidin— l xylate Analogously to Example 1, 448 mg of the title nd was obtained from 400 mg of the compound prepared in Example 117C and 133 mg of 2-(cyclopropylmethoxy)ethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.14 (2H), 0.42 (2H), 0.97 (1H), 1.33 (9H), 2.50 (3H), 3.09 (1H), 3.24 (2H), 3.36 (2H), 3.49 (2H), 3.69 (2H), 3.86 (2H), 4.61 (2H), 7.15 (1H), 7.38 (1H), 8.08 (1H), 8.54 (1H).
Example 149b: 2-(azetidin—3 -ylmethyl)-N- [2-(cyclopropylmethoxy)ethyl] methyl-2H- aazol-S-carboxamide hydrochloride ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H N v/\O/\/N \ 0 CH3 ously to Example la, from 448 mg of the compound prepared in Example 149a, 390 mg of the title compound was obtained, which was further reacted without purification.
Example 150: N—[2-(cyclopropylmethoxy)ethyl] ( { l - [4-(4-fluorophenoxy)benzoyl] azetidin—3 - yl} methyl)methyl-2H-indazolcarboxamide O d /N\ y H N 0 CH3 Analogously to Example 1, 48 mg of the title compound was obtained from 102 mg of the compound prepared in Example 14% and 63 mg of uorophenoxy)benzoic acid. 1H-NMR (300 MHz, CDCl3): 8 = 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 1 51 : N— [2-(cyclopropylmethoxy)ethyl] methyl -methylbenzoyl)azetidin—3 - yl]methyl} -2H-indazolcarboxamide H :>—CH3 J. )4 n N 0 CH3 Analogously to Example 1, 55 mg of the title compound was ed from 127 mg of the compound prepared in Example 14% and 46 mg of 4-methylbenzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)azetidinyl]methyl} methyl-N—[2-(trifluoromethoxy) ethyl]-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O>‘—Qa F H ”NAP F>|\O/\/N \ 0 CH3 ously to Example 55, 122 mg of the title compound was ed from 234 mg of the nd prepared in Example 152b and 115 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 5 = 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: e 1 52a: Tert-butyl 3 - [(4-methyl {N— [2-(trifluoromethoxy)ethyl]carbamoyl} -2H- indazolyl)methyl] azetidin— l -carboxylate Nyoga.
F J\}3HO OH X/VNH N F O 0 CH3 Analogously to Example 1, 272 mg of the title compound was obtained from 250 mg of the compound prepared in Example 117C and 120 mg of 2-(trifluoromethoxy)ethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 52b: 2-(azetidin—3 -ylmethyl)methyl-N— [2-(trifluoromethoxy)ethyl] -2H-indazol-5 - carboxamide hydrochloride FX /\/NH J\N F o 0 CH3 Analogously to Example la, from 272 mg of the compound ed in Example 152a, 240 mg of the title compound was obtained, which was further reacted without purification.
Example 1 53: N—(2-tert-butoxyethyl) {[1-(4-chlorobenzoyl)azetidin-3 -yl]methyl} methyl- 2H-indazolcarboxamide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp o>—©—CI H30 n4&1PN\ H30 o/\/ 0 CH3 Analogously to e 55) 12 mg of the title compound was obtained from 160 mg of the nd prepared in Example 153b) and 81 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 5 = 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: Tert-butyl 3 -( {5 - [N—(2-tert-butoxyethyl)carbamoyl] methyl-2H-indazolyl} - methyl)azetidin— l -carboxylate Analogously to Example 1, 284 mg of the title compound was obtained from 250 mg of the compound prepared in Example 1 17c and 111 mg of 2-tert-butoxyethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.11 (9H), 1.32 (9H), 2.50 (3H), 3.08 (1H), 3.27 (2H), 3.40 (2H), 3.69 (2H), 3.86 (2H), 4.60 (2H), 7.15 (1H), 7.38 (1H), 8.04 (1H), 8.54 (1H).
Example 153b: 2-(azetidin—3-ylmethyl)-N-(2-tert-butoxyethyl)methyl-2H-indazolcarbox- amide hydrochloride ch33 H AN H30 O/\/N 0 CH3 Analogously to Example la, from 284 mg of the nd prepared in Example 153a, 240 mg of the title nd was obtained, which was further reacted without purification.
Example 154: (+/-) {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} -N- [2-(cyclobutyloxy)propyl] - 4-methyl-2H-indazolcarboxamide ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 3x00 0 CH3 Analogously to Example 55, 135 mg of the title compound was ed from 222 mg of the compound prepared in Example 154d and 109 mg of robenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 154a: (+/-)(cyclobutyloxy)-propanamide a H3 NH2 To a suspension of 732 mg of sodium hydride in 15 ml THF, 2.0 g of utanol in 0.5 ml THF were added dropwise and stirred for 30 s at 25°C. The reaction mixture was then cooled to 0°C and 2.11 g of (+/-) 2-bromopropanamide in 0.5 ml tetrahydrofuran were added dropwise and then stirred for 18 hours at 25°C. The reaction mixture was poured onto ice-water and extracted once with 75 ml dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo after filtration.
The crude product thus obtained was purified by column chromatography on silica gel with hexane / 0-50% ethyl acetate. Yield: 0.79 g of the title compound. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.14 (3H), 1.38 (1H), 1.56 (1H), 1.83 (2H), 2.08 (2H), 3.62 (1H), 3.90 (1H), 7.07 (2H).
Example 154b: (+/-)-tert-butyl N-[2-(cyclobutyloxy)propyl]carbamate N 0 o \KCHSCH3 To a suspension of 6.9 g of lithium aluminium e in 250 ml THF, 6.5 g of the amide prepared in Example 154a in 81 ml THF were cautiously added dropwise at 0°C. The mixture was then first stirred for 30 minutes at 0°C and then heated for 5 hours under reflux. After cooling, the mixture was cautiously treated with 20 g of sodium sulphate decahydrate and 20 g of potassium fluoride and solid matter removed by filtration shortly afterwards. The filtrate was ncentrated in vacuo. The residue thus obtained (5.8 g) was dissolved t r purification in 174 ml dichloromethane and treated with 11.9 g of di-tert-butyl dicarbonate. After [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 16 hours’ stirring at 25°C, this was concentrated in vacuo and the residue thus obtained purified by two-fold column tography on silica gel with hexane / 0-40% ethyl acetate.
Yield: 8.54 g of the title compound. 1H-NMR (300 MHz, DMSO-d6): 5 = 0.94 (3H), 1.28-1.42 (10H), 1.53 (1H), 1.76 (2H), 2.07 (2H), 2.76 (1H), 2.90 (1H), 3.34 (1H), 3.92 (1H), 6.72 (1H).
Example 154C: (+/-)-tert-butyl 3-[(5- {N—[2-(cyclobutyloxy)propyl]carbamoyl} methyl-2H- indazolyl)methyl] azetidin— 1 -carboxylate Analogously to Example 1a, from 200 mg of the compound prepared in Example 154b), lobutyloxy)propylamine was obtained as the hloride, which without further purification together with 250 mg of the compound prepared in Example 117c analogously to Example 1, yielded 259 mg of the title compound. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 54d: (+/-)(azetidin—3 -ylmethyl)-N- [2-(cyclobutyloxy)propyl] methyl-2H- indazolcarboxamide hydrochloride CH3 A & jVH N N \ 0 CH3 Analogously to e 1a, from 259 mg of the compound ed in Example 154c, 225 mg of the title compound was obtained, which was further reacted without purification.
Example 1 55: (S or R) {[1-(4-chlorobenzoyl)azetidin—3 thyl} -N- [2-(cyclobutyloxy)- propyl] methyl-2H-indazolcarboxamide N N CH3 )1 P 9H3 J\ P a k1 N N \ a H \ O O/\/ 0 CH3 0 CH3 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp From 135 mg of the te prepared in Example 154, 41 mg of the title compound together with 21 mg of the slower-eluting enantiomer (Example 156) were obtained by racemate separation by means of preparative chiral HPLC d A).
Analytical chiral HPLC: 10.05 min.
Example 1 56 : (R or S) {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} -N- [2-(cyclobutyloxy)- propyl] methyl-2H-indazolcarboxamide o o N N & 3 CH3 H J‘KN‘P H ”NP \ a /'\/N \ o o 0 CH3 0 CH3 From 135 mg of the racemate prepared in Example 154, 21 mg of the title compound together with 41 mg of the faster-eluting enantiomer (Example 155) were obtained by te separation by means of preparative chiral HPLC (Method A).
Analytical chiral HPLC: 13.14 min.
Example 1 57: N— clopropylmethoxy)ethyl] ( { l - [(4'-fluorobiphenylyl)carbonyl] azetidin—3 -yl } methyl)methyl-2H-indazolcarboxamide VAMYEEE Analogously to Example 1, 54 mg of the title compound was obtained from 102 mg of the compound prepared in Example 14% and 58 mg of 4'-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, CDCl3): 8 = 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 1 58: 2-( { l - [(4'-fluorobiphenylyl)carbonyl] azetidin—3 -yl} )-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide H3C\o/\/HY<;L/NA )4 0 CH3 Dalogously to Example 1, 54 mg of the title compound was obtained from 108 mg of the compound prepared in Example ll7e and 69 mg of 4'-fluorobiphenylcarboxylic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 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-( { l - [4-(4-fluorophenoxy)benzoyl] azetidin-3 -yl} methyl)-N-(2-methoxyethyl) -2H-indazolcarboxamide of C O JR 4? H N \/N \ 0 CH3 Analogously to Example 1, 28 mg of the title compound was obtained from 108 mg of the compound prepared in Example ll7e and 74 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHZ, CDCl3): 8 = 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 1 60: 2-( { l - [4-(4-fluorophenoxy)benzoyl] azetidin—3 -yl}methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide O d F J\ y :S\/H N 0 CH3 Analogously to Example 1, 47 mg of the title compound was obtained from 115 mg of the compound prepared in Example 12% and 74 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHZ, CDCl3): 8 = 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). e 161: 2-( { l - [(4'-fluorobiphenylyl)carbonyl]azetidin—3-yl}methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide 546$” [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to e 1, 28 mg of the title compound was obtained from 115 mg of the compound prepared in Example 12% and 69 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). e 1 62: 2- {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} methyl-N- [2-(2,2,2-trifluoro- ethoxy)ethyl] -2H-indazolcarboxamide >—< :>—C| FAWNNYEKL/N\ 4?H N F 0 CH3 Analogously to Example 55, 197 mg of the title compound was obtained from 252 mg of the compound prepared in Example 162a and 108 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 5 = 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 ng material was ed as follows: e 1 62a: 2-(azetidin—3 -ylmethyl)methyl-N- [2-(2,2,2-trifluoroethoxy)ethyl] -2H- indazol-S-carboxamide hydrochloride FroF N \ /\/Hwy F 0 CH3 Analogously to Example la, from 583 mg of the compound prepared in Example 162b, 505 mg of the title compound was obtained, which was further reacted without purification.
Example 1 62b: Tert-butyl 3 - [(4-methyl {N- [2-(2,2,2-trifluoroethoxy)ethyl] carbamoyl} -2H- indazolyl)methyl] azetidin— l -carboxylate H30 CH3 0 CH3 ENNNYEKL5. fH N F 0 CH3 Analogously to Example 1, 580 mg of the title compound was obtained from 500 mg of the ”pound prepared in Example 117C and 260 mg of 2-(2,2,2-trifluoroethoxy)ethylamine hydrochloride.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 63: yl-N— 2,2-trifluoroethoxy)ethyl] [( l - {4- [4-(trifluoromethyl) phenoxy]benzoyl} azetidin—3 -yl)methyl] -2H-indazolcarboxamide F F C O N F H F>Fo/\/ \ F 0 CH3 Analogously to Example 1, 89 mg of the title compound was obtained from 252 mg of the compound prepared in Example 162a and 175 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 64: 4-methyl-N—(2,2,2-trifluoroethyl) [(1 - {4- [4-(trifluoromethyl)phenoxy] benzoyl} azetidin—3 -yl)methyl] -2H-indazolcarboxamide F F N C F J\ 4? 5k) N N \ 0 CH3 Analogously to Example 1, 64 mg of the title compound was obtained from 225 mg of the compound ed in e 12% and 149 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). e 1 65: 2-( { l - [4-(4-chlorophenoxy)benzoyl] azetidin—3 -yl}methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O 6 C O N F J\ 4? 5K) N N \ 0 CH3 Analogously to e 1, 97 mg of the title compound was obtained from 225 mg of the compound prepared in e 12% and 131 mg of 4-(4-chlorophenoxy)benzoic acid. 1H-NMR (300 MHZ, DMSO-d6): 8 = 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 1 66: 2-( { l - [4- (4-chlorophenoxy)benzoyl] azetidin—3 -yl} methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide of C O J‘k P H N \/N \ 0 CH3 Analogously to Example 1, 99 mg of the title compound was obtained from 225 mg of the compound prepared in Example ll7e and 140 mg of 4-(4-chlorophenoxy)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-( { l -[(5-fluoro-l-methyl-lH-indolyl)carbonyl]azetidin—3-yl}methyl) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 xamide 0%N F F J\4P HC :X/H \N 0 CH3 Analogously to e 1, 48 mg of the title compound was obtained from 180 mg of the compound prepared in Example 12% and 82 mg of 5-fluoro-l-methyl-lH-indolcarboxylic acid. 1H-NMR (300 MHZ, CDCl3): 8 = 2.66 (3H), 2.80 (3H), 3.36-3.51 (1H), 4.01 (3H), 4.04-4.63 D1), 4.70 (2H), 6.03 (1H), 6.68 (1H), 7.08 (1H), 7.22-7.36 (3H), 7.55 (1H), 8.05 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Example 1 68: 2-( { l - [(5 -methoxymethyl- 1 H-indolyl)carbonyl] azetidin—3 -yl} ) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide 0 O F A )1 5K) N N \ 0 CH3 Analogously to Example 1, 15 mg of the title compound was obtained from 180 mg of the compound prepared in Example 12% and 87 mg of 5-methoxy-l-methyl-lH-indolcarboxylic acid. 1H-NMR (300 MHz, CDCl3): 8 = 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 1 69: 2-( { l - [(6-methoxymethyl- 1 H-indolyl)carbonyl] azetidin—3 -yl} methyl) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide 0WI) F J\ 4? 5k) N N \ 0 CH3 Analogously to Example 1, 57 mg of the title compound was obtained from 180 mg of the compound prepared in Example 12% and 87 mg of oxy-l-methyl-lH-indolcarboxylic acid. 1H-NMR (300 MHz, CDCl3): 8 = 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 1 70: 2-( { l - [(5-fluoromethyl- 1 H-indolyl)carbonyl] in—3 -yl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide Analogously to Example 1, 95 mg of the title compound was obtained from 180 mg of the compound prepared in Example ll7e and 87 mg of 5-fluoro-l-methyl-lH-indolcarboxylic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp VNMR (300 MHz, CDC13): 8 = 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 1 71: 2-( { l - loromethyl- 1 H-indolyl)carbonyl] azetidin—3 -yl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide ously to Example 1, 90 mg of the title compound was obtained from 180 mg of the compound prepared in Example ll7e and 95 mg of 5-chloro-l-methyl-lH-indolcarboxylic acid. 1H-NMR (300 MHZ, CDCl3): 8 = 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), .38 (3H), 7.53 (1H), 7.58 (1H), 8.02 (1H).
E x a m p l e 1 72: N—(2-methoxyethyl)( { l - [(5-methoxymethyl- 1 lyl)carbonyl] azetidin—3 -yl} methyl)methyl-2H-indazolcarboxamide 0 O JR y H N HSC\O/\/N \ 0 CH3 Analogously to Example 1, 86 mg of the title compound was obtained from 180 mg of the compound prepared in Example ll7e and 93 mg of 5-methoxy-l-methyl-lH-indolcarboxylic acid. 1H-NMR (300 MHZ, CDCl3): 8 = 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).
E x a m p l e 1 73: N—(2-methoxyethyl)( { l - [(6-methoxymethyl- 1 H-indolyl)carbonyl] in—3 -yl} methyl)methyl-2H-indazolcarboxamide N 1“ O/CH3 . j; 3 H N O/\/N \ 0 CH3 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 97 mg of the title compound was obtained from 180 mg of the compound prepared in e ll7e and 93 mg of 6-methoxy-l-methyl-lH-indolcarboxylic acid. 1H-NMR (300 MHZ, CDCl3): 8 = 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).
Examp l e 1 74: N—(2-methoxyethyl)methyl {[1 -(4- {[5-(trifluoromethyl)pyridin—2-yl] oxy} benzoyl)azetidin-3 -yl]methyl} -2H-indazolcarboxamide C O N /N\ 4? H N H3C\O/\/N \ 0 CH3 ously to Example 1, 66 mg of the title compound was obtained from 135 mg of the compound prepared in e ll7e and 96 mg of (trifluoromethyl)pyridinyl]oxy}- benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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).
Ex am p l e 1 75: N—(2-methoxyethyl) {[1 -(7-methoxynaphthoyl)azetidin—3 -yl]methyl} methyl-2H-indazolcarboxamide N O /\ O H N —CH3 HSC\O/\/N \ 0 CH3 Analogously to Example 1, 72 mg of the title nd was obtained from 135 mg of the compound prepared in Example ll7e and 69 mg of 7-methoxy-naphthalencarboxylic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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).
Ex am p l e 1 76: N—(2-methoxyethyl) {[1 -(6-methoxynaphthoyl)azetidin—3 -yl]methyl} Ethyl-ZH-indazol-S-carboxamide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp N O /N\ P H N H3C\O/\/N \ 0 CH3 Analogously to Example 1, 72 mg of the title compound was obtained from 135 mg of the compound prepared in Example ll7e and 69 mg of 6-methoxynaphthalencarboxylic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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).
Ex am p l e 1 77: 4-methyl-N-(2,2,2-trifluoroethyl) {[1 -(4- {[5 -(trifluoromethyl)pyridinyl] oxy} benzoyl)azetidin—3 thyl} -2H-indazol-5 -carboxamide F.FX/N. 4.23 \ QK F FF 0 CH3 Analogously to Example 1, 68 mg of the title compound was obtained from 170 mg of the compound prepared in Example 12% and 113 mg of 4-{[5-(trifluoromethyl)pyridin yl]oxy}benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)methyl-2H- indazolcarboxamide 0W20 3 A jg H N HSC\O/\/N \ O Analogously to Example 55, 154 mg of the title compound was obtained from 210 mg of the nd prepared in Example l78e and 119 mg of 4-chlorobenzoyl chloride. 1H—NMR (300 MHz, DMSO-d6): 5 = 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).
De starting material was ed as follows: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Example 1 78 a: Tert-butyl 3 - [(5 -bromomethyl-2H-indazolyl)methyl] azetidin— 1 - carboxylate N CH3 H30 H30 CH3 J‘k 4? To a solution of 6.18 g of 5-bromomethyl-lH-indazole and 15 g of tert-butyl[(tosyl- oxy)methyl]azetidin—1-carboxylate in 200 ml DMF were added 9.54 g of caesium ate and .8 g of tetrabutylammonium iodide at 25°C, and this was then heated under reflux for 1.5 hrs.
After cooling, the reaction mixture was treated with 1:1 hexane / ether and water, the phases ted and the aqueous phase extracted twice with 250 ml portions of 1:1 hexane / ether. The combined organic phases were washed with saturated sodium de solution, dried over sodium sulphate, and concentrated in vacuo after filtration.
The residue thus obtained was purified by twofold column chromatography on silica gel with hexane / 0-20% ethyl acetate. 2.88 g of the title compound was obtained. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.32 (9H), 2.37 (3H), 3.05 (1H), 3.67 (2H), 3.85 (2H), 4.59 (2H), 7.56 (1H), 7.97 (1H), 8.33 (1H).
Example 178b: Methyl 2- ert-butoxycarbonyl)azetidin-3 -yl]methyl} methyl-2H-indazol- -carboxylate To a solution of 730 mg of the bromide prepared in Example 178a in 17.5 ml tetrahydrofuran were added 0.23 ml of methanol, 145 mg of trans-bis(acetato)-bis[o-(di-o-tolylphosphino)- benzyl]dipalladium(H), 877 mg of DBU and 760 mg of molybdenum hexacarbonyl This reaction mixture was then heated in the microwave (120 watts) for 20 s at 125°C. Seven further preparations were performed in the same manner and all worked up together. For this, they were concentrated in vacuo and the residue taken up in water and ethyl acetate. After phase separation, the aqueous phase was extracted three times with 75 ml ns of ethyl acetate and the combined organic phases washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo after filtration. The residue thus obtained was purified by twofold column tography on silica gel with hexane / 0-30% ethyl acetate. Yield: 4.0 g of a title compound.
[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 78c: 2- { [1 -(tert-butoxycarbonyl)azetidin—3 -yl]methyl} hyl-2H-indazol carboxylic acid Analogously to Example 1d, 3.2 g of the title compound was obtained from 4.0 g of the ester prepared in Example 178b. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1 78d: Tert-butyl 3 -( {5- methoxyethyl)carbamoyl] methyl-2H-indazolyl} - methyl)azetidin— 1 -carboxylate N>7}ng H30 H30 CH3 )1 4? H N \/N \ Analogously to Example 1, 603 mg of the title compound was obtained from 500 mg of the acid prepared in Example 178C and 109 mg of 2-methoxyethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 1786: 2-(azetidin—3-ylmethyl)-N—(2-methoxyethyl)methyl-2H-indazolcarbox- amide hydrochloride H CIH H N H3C\O/\/N \ Analogously to Example 1a, from 250 mg of the amide prepared in Example 178d, 275 mg of the title compound was obtained, which was reacted without further purification.
Example 179: 2- { [1 -(3 uorobenzoyl)azetidin—3 -yl]methyl} -N-(2-methoxyethyl)methyl- fi-indazol-S-carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp H30 J\ 4? H N HSC\O/\/N \ Analogously to Example 55, 51 mg of the title compound was obtained from 77 mg of the compound prepared in Example 178e and 44 mg of 3,5-difluorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)methyl [(1 - {4- [(trifluoromethyl)sulphanyl]benzoyl} azetidin—3 -yl)methyl] -2H-indazolcarboxamide o )l—F 3 S N H30 J‘K 4? H N HSC\O/\/N \ o Analogously to e 55, 30 mg of the title compound was obtained from 43 mg of the compound ed in Example l78e and 34 mg of 4-[(trifluoromethyl)sulphanyl]benzoyl 1H-NMR (300 MHz, DMSO-d6): 8 = 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)methyl( { l - [4-(trifluoromethoxy)benzoyl] azetidin—3 - yl} )-2H-indazolcarboxamide o )l—F C O N 3 A )4 H N H3C\O/\/N \ o Analogously to Example 55, 221 mg of the title compound was obtained from 294 mg of the compound prepared in Example l78e and 214 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), fii (1H), 8.42 (1H).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 182: 2—({1-[2-fluoro-4—(trifluoromethyl)benzoyl]azetidin—3 -yl} methyl)-N-(2-methoxy— ethyl)methyl-2H-indazolcarboxamide o C F F N F H30 A 4? H N HSC\O/\/N \ Analogously to Example 55, 11 mg of the title compound was obtained from 43 mg of the compound prepared in Example 178e and 32 mg of 2—fluoro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHZ, DMSO-d6): 8 = 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-chlorofluorobenzoyl)azetidin-3 -yl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide H30 /N\ 4? H N HSC\O/\/N \ Analogously to Example 55, from 70 mg of the compound prepared in Example 178e and 44 mg of 4-chlorofluorobenzoyl chloride, a material still contaminated after HPLC ation was obtained, which was further d by additional preparative thick layer chromatography with ethyl acetate / methanol in the ratio 9:1 as mobile phase. This d 12 mg of the title compound. 1H-NMR (300 MHz, DMSO-d6): 8 = 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} )-N-(2-methoxy— ethyl)methyl-2H-indazolcarboxamide N F H30 AP HSC\O/\/N \ o [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 55, 32 mg of the title compound was obtained from 70 mg of the compound prepared in e l78e and 52 mg of 3-fluoro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-( { l - [4-chloro-3 -(trifluoromethyl)benzoyl] azetidin—3 -yl} )-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide H30 /N\ 4? H N HSC\O/\/N \ o Analogously to Example 55, 30 mg of the title compound was obtained from 70 mg of the compound ed in Example l78e and 55 mg of 4-chloro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, 6): 8 = 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)methyl( { l - [4-(trifluoromethyl)benzoyl] azetidin-3 - yl} methyl)-2H-indazolcarboxamide H30 /N\ H N H3C\O/\/N \ O Analogously to Example 55, 31 mg of the title compound was obtained from 70 mg of the compound prepared in Example l78e and 47 mg of 4-(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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( { l - [4-(pentafluoro-k6-sulphanyl)benzoyl] azetidin-3 -yl} )-N- {2- [(trifluoromethyl)sulphanyl] ethyl} -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp N F F F A 4? :>|\S/\/“79(1) \ Analogously to Example 1, 35 mg of the title compound was obtained from 170 mg of the compound prepared in Example l87b and 103 mg of 4-(pentafluoro-7t6-sulphanyl)benzoic acid. 1H-NMR (300 MHZ, DMSO-d6): 8 = 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 187a: Tert-butyl 3 - thyl(N- {2- [(trifluoromethyl)sulphanyl] ethyl} carbamoyl)- 2H-indazolyl]methyl} azetidin— l -carboxylate >_O>VCH3 Amy H C OH H C 3 3 FXSNNF H Analogously to Example 1, 998 mg of the title compound was obtained from 800 mg of the acid prepared in Example l78c and 336 mg of 2-[(trifluoromethyl)sulphanyl]ethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.32 (9H), 2.36 (3H), 3.06 (1H), 3.13-3.21 (2H), 3.49 (2H), 3.67 (2H), 3.84 (2H), 4.59 (2H), 7.37 (1H), 7.70 (1H), 8.44 (1H), 8.47 (1H).
Example 187b: 2-(azetidin—3-ylmethyl)methyl-N— rifluoromethyl)sulphanyl] ethyl} -2H- indazol-S-carboxamide hydrochloride H CIH F H ”MAP F>|\S/\/N \ Analogously to Example la), from 395 mg of the amide prepared in Example 187a), 402 mg of the title compound was obtained, which was reacted without r purification.
Example 188: 6-methyl( { l - [4-(pentafluoro-k6-sulphanyl)benzoyl] in-3 -yl} )-N- (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide O>_©_F\SI:FI \ N F F F AN} [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 25 mg of the title nd was obtained from 136 mg of the compound prepared in Example l88b and 93 mg of tafluoro-7t6-sulphanyl)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 188a: Tert-butyl 3 -( {6-methyl-5 - [N—(2,2,2-trifluoroethyl)carbamoyl] dazol yl} methyl)azetidin— l -carboxylate >_O>VCH3 H C CH H30 3 F J‘k fl 3 N \ FBk) O Analogously to Example 1, 550 mg of the title compound was obtained from 560 mg of the acid prepared in Example 178C and 160 mg of 2,2,2-trifluoroethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). e 188b: 2-(azetidin—3-ylmethyl)methyl-N-(2,2,2-trifluoroethyl)-2H-indazol carboxamide hydrochloride H CIH F A jg 3K) N N \ Analogously to Example la, from 550 mg of the amide prepared in Example 188a, 530 mg of the title compound was obtained, which was reacted without further purification.
Example 189: 2- {[1-(4-chlorobenzoyl)azetidin—3-yl]methyl} methyl-N- {2-[(trifluoromethyl) nyl] ethyl} dazolcarboxamide Owool F>|\S/\/NF HH30 AN} Analogously to Example 55, 45 mg of the title compound was obtained from 170 mg of the compound prepared in Example 187b and 80 mg of 4-chlorobenzoyl chloride.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, 6): 5 = 2.39 (3H), .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)azetidinyl]methyl} methyl-N-(2,2,2—trifluoroethyl)- 2H-indazolcarboxamide O800' F J\ 4? 5K) N N \ ously to Example 55, 60 mg of the title compound was obtained from 136 mg of the compound prepared in Example l88b and 72 mg of 4-chlorobenzoyl de. 1H-NMR (300 MHz, DMSO-d6): 8 = 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: (+/-) {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} methyl-N-(3 ,4,5,6- tetrahydro-2H-pyran—2-ylmethyl)-2H-indazol-5 -carboxamide O800' (13w?H N N \ O Analogously to Example 55, 49 mg of the title compound was obtained from 120 mg of the compound prepared in Example l9lb and 61 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.08-1.23 (1H), 1.36-1.49 (3H), 1.62 (1H), 1.72—1.80 (1H), 2.34 (3H), 310343 (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 ed as follows: Example 191 a: (+/-)-tert-butyl 3 -( {6-methyl [N-(3 ,4,5,6-tetrahydro-2H-pyran—2-ylmethyl)- carbamoyl] -2H-indazolyl} methyl)azetidin— l -carboxylate HO OH 3 A} >VCH3 3 3 H N N \ Dalogously to e 1, 140 mg of the title compound was obtained from 300 mg of the acid prepared in Example 178C and 105 mg of 3,4,5,6-tetrahydro-2H-pyran—2-ylmethylamine.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 1.07—1.24 (1H), 1.27—1.49 (12H), 1.62 (1H), 1.76 (1H), 2.33 (3H), 3.06 (1H), 3.20 (2H), 3.29-3.45 (2H), 3.67 (2H), 3.78-3.90 (3H), 4.59 (2H), 7.35 (1H), 7.63 (1H), 8.16 (1H), 8.40 (1H).
Example 191b: (+/-)(azetidinylmethyl)methyl-N-(3,4,5,6-tetrahydro-2H-pyran—2- ylmethyl)-2H-indazolcarboxamide hydrochloride H CIH H30 /N\ E H N Analogously to Example 1a, from 140 mg of the amide prepared in Example 191a, 132 mg of the title compound was obtained, which was reacted without further purification.
Example 192: (+/-) {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} methoxypropyl) methyl-2H-indazolcarboxamide O400' HSC\Oj\/NH@eP\N Analogously to Example 55, 89 mg of the title compound was ed from 151 mg of the compound prepared in Example 192b and 82 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 ed as follows: e 192a: (+/-)-tert-butyl 3 -( {5- [N-(2-methoxypropyl)carbamoyl] hyl-2H-indazol yl} )azetidin— 1 -carboxylate >70>VCHS H C OH H C 3 3 H N H30\O N \ Analogously to Example 1, 358 mg of the title compound was obtained from 300 mg of the acid prepared in Example 178c and 77 mg of 2-methoxypropan—1-amine. g1), 3.43 (1H), 3.67 (2H), 3.84 (2H), 4.59 (2H), 7.35 (1H), 7.64 (1H), 8.18 (1H), 8.40 (1H).1 NMR (300 MHz, DMSO-d6): 8 = 1.08 (3H), 1.32 (9H), 2.34 (3H), 3.06 (1H), 3.13-3.31 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 192b: (+/-)(azetidin—3-ylmethyl)-N-(2-methoxypropyl)methyl-2H-indazol carboxamide hydrochloride H CIH CH3 /N\ 4? H N HSC\O N \ Analogously to Example 1a), from 358 mg of the amide prepared in Example 192a), 319 mg of the title compound was obtained, which was reacted without further purification.
Example 193: (+/-)-N-(2-methoxypropyl)methyl({1-[4-(trifluoromethoxy)benzoyl]- azetidin—3 -yl}methyl)-2H-indazolcarboxamide F F O C >LF CH3 /N\ y O Analogously to Example 55, 87 mg of the title compound was obtained from 151 mg of the compound prepared in Example 192b and 106 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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({1-[4-(trifluoromethoxy)benzoyl]azetidin-3 -yl} methyl)-N- {2- uoromethyl)sulphanyl] ethyl} -2H-indazolcarboxamide F F 0%» >LFO :XSNHmECL“H30F J‘k fl Analogously to Example 55, 87 mg of the title compound was ed from 173 mg of the compound prepared in e 187b and 105 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .74 (3H), 8.44 (1H), 8.46 (1H). amethyl)-2H-indazolcarboxamideample 195: 6-methyl-N-(2,2,2-trifluoroethyl)({1-[4-(trifluoromethoxy)benzoyl]azetidin—3- [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O V C F F J\ y 3K) N N \ Analogously to Example 55, 70 mg of the title compound was obtained from 170 mg of the compound prepared in e l88b and 116 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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( { l - [4-(trifluoromethoxy)benzoyl] azetidin-3 -yl} methyl)-N- [2- (trifluoromethoxy)ethyl] -2H-indazolcarboxamide F F 05 0 >LF F J‘k fl :>ko/\/H N Analogously to Example 55, 22 mg of the title nd was obtained from 179 mg of the compound prepared in Example l96b and 113 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, 6): 8 = 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 ed as follows: Example 196a: Tert-butyl 3 - [(6-methyl {N— [2-(trifluoromethoxy)ethyl]carbamoyl} -2H- lyl)methyl] azetidin— l -carboxylate N>7}ng HO OH HO 3 3 F H3 AN} >|\/\/N \ F O O Analogously to Example 1, 417 mg of the title compound was obtained from 300 mg of the acid prepared in Example 178C and 144 mg of 2-(trifluoromethoxy)ethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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).
Dample 196b: 2-(azetidin—3-ylmethyl)methyl-N—[2-(trifluoromethoxy)ethyl]-2H-indazol carboxamide hydrochloride [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp H CIH N \ Analogously to Example la, from 417 mg of the amide prepared in Example 196a, 369 mg of the title compound was obtained, which was reacted without further purification.
Example 197: 2- {[1 -(4-chlorobenzoyl)azetidinyl]methyl} methyl-N—[2-(trifluoromethoxy) ethyl]-2H-indazolcarboxamide 0x00 F AN} FXO/VHF \ Analogously to Example 55, 41 mg of the title compound was obtained from 179 mg of the compound prepared in e 196b and 88 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 5 = 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-indazolcarboxamide o>—©—CI foNHILHSC J‘k y H N Analogously to Example 55, 107 mg of the title compound was obtained from 214 mg of the compound prepared in Example l98b and 109 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 5 = 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 198a: Tert-butyl 3 - [(5- {N— [2-(cyclopropylmethoxy)ethyl]carbamoyl} hyl-2H- indazolyl)methyl] azetidin— l -carboxylate [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 3C nyoH30CHH v/\O/\/NH:!D;<:::\N Analogously to Example 1, 247 mg of the title compound was obtained from 245 mg of the acid prepared in Example 178C and 82 mg of 2-(cyclopropylmethoxy)ethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). e 198b: 2-(azetidin—3 -ylmethyl)-N- [2-(cyclopropylmethoxy)ethyl] methyl-2H- indazol-S-carboxamide hydrochloride if“; CIH Analogously to Example la, from 247 mg of the amide prepared in Example 198a, 214 mg of the title compound was obtained, which was d without further purification.
Example 199: 2-( { l - [4-(4-fluorophenoxy)benzoyl] azetidin—3 -yl} )methyl-N— {2- [(trifluoromethyl)sulphanyl] ethyl} -2H-indazolcarboxamide :iSNNWIIfljji—Q Analogously to Example 1, 56 mg of the title compound was obtained from 173 mg of the compound prepared in Example 187b and 98 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHZ, DMSO-d6): 8 = 2.38 (3H), .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) methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp HSC\O/\/N Analogously to Example 1, 86 mg of the title nd was obtained from 168 mg of the compound prepared in Example 178e and 80 mg of 4-cyclopropylbenzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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) [(1 - {4- [4-(trifluoromethyl)phenoxy] benzoyl} in—3 -yl)methyl] -2H-indazolcarboxamide F F C O N F J\} 5K) N N \ O Analogously to Example 1, 71 mg of the title compound was obtained from 180 mg of the compound prepared in e 188b and 95 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). e 202: N—(2-methoxyethyl)methyl [(1 - {4- [4-(trifluoromethyl)phenoxy]benzoyl} - azetidin—3 thyl] -2H-indazolcarboxamide F F O C5 N : O HSC\O/\/Nj‘:<:g/H30 J‘ 4? H N Analogously to Example 1, 108 mg of the title compound was obtained from 180 mg of the compound prepared in Example 178e and 102 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H—NMR (300 MHz, DMSO-d6): 5 = 2.34 (3H), .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-( { l - [(4'-fluorobiphenylyl)carbonyl] azetidin—3 -yl} methyl)methyl-N- (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide Rim} Analogously to Example 1, 104 mg of the title compound was obtained from 180 mg of the compound prepared in e l88b and 73 mg of robiphenylcarboxylic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-( { l - [(4'-fluorobiphenylyl)carbonyl] azetidin—3 -yl} methyl)-N-(2-methoxy— ethyl)methyl-2H-indazolcarboxamide H30\O/\/NW‘:<:L/HSC J\ 4? H N O Analogously to Example 1, 73 mg of the title nd was obtained from 180 mg of the compound prepared in Example l78e and 78 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)methyl- azolcarboxamide Owool H N HSC\O/\/N \ Analogously to Example 55, from 85 mg of the compound prepared in Example 205c and 45 mg of 4-chlorobenzoyl chloride, a material still contaminated after column tography was ained which was further purified by additional preparative thick layer chromatography with [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp dichloromethane / methanol in the ratio 95:5 as mobile phase. Yield: 48 mg of the title compound. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 205a: Tert-butyl 4- omomethyl-2H-indazolyl)methyl]piperidin- l - carboxylate N >VCH3 H30 CH3 ously to Example 1c, 2.99 g of the title compound was obtained from 5.7 g of 5-bromo methyl-lH-indazole and 15.0 g of tert-butyl[(tosyloxy)methyl]piperidin-l -carboxylate. 1H-NMR (300 MHz, : 8 = 1.14-1.30 (2H), 1.44 (9H), 1.53 (2H), 2.24 (1H), 2.50 (3H), 2.66 (2H), 4.11 (2H), 4.23 (2H), 7.55 (1H), 7.77 (1H), 7.87 (1H).
Example 205b: utyl 4-( {5- [N-(2-methoxyethyl)carbamoyl] methyl-2H-indazolyl} - methyl)piperidin- l -carboxylate >\._O N >VCH3 3 CH3 3 /N\ H30\O/\/N \ Analogously to Example 1b, 3.56 g of the title compound was obtained from 600 mg of the bromide prepared in Example 205a and 331 mg of 2-methoxyethylamine after four runs and twofold purification by chromatography. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.96-1.15 (2H), 1.29-1.42 (10H), 2.03-2.18 (1H), 2.34 (3H), 2.51-2.73 (3H), 3.25 (3H), 3.31-3.45 (4H), 3.86 (2H), 4.26 (2H), 7.35 (1H), 7.63 (1H), 8.21 (1H), 8.32 (1H).
Example 205C: ethoxyethyl)methyl(4-piperidylmethyl)-2H-indazolcarboxamide hydrochloride [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp H30 J\ H N H3C\O/\/N \ Analogously to Example la, from 100 mg of the amide ed in Example 205b, 85 mg of the title compound was obtained, which was reacted without further purification.
Example 206 : 2-( { l - [2-fluoro(trifluoromethyl)benzoyl]piperidin—4-yl} )-N-(2- methoxy-ethyl)methyl-2H-indazolcarboxamide H30 J\ H N \/N \ Analogously to Example 55, from 85 mg of the compound prepared in e 205c and 58 mg of 2-fluoro(trifluoromethyl)benzoyl chloride, a material still inated after column chromatography was obtained which was further purified by additional preparative thick layer chromatography with dichloromethane / methanol in the ratio 95:5 as mobile phase. Yield: 40 mg of the title compound. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-chlorofluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide HSC /N\p H N H3C\O/\/N \ Analogously to Example 55, 68 mg of the title nd was obtained from 85 mg of the compound prepared in Example 205c and 49 mg of 4-chlorofluorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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).
Dample 208: 2-( { l - [3 -fluoro(trifluoromethyl)benzoyl]piperidin—4-yl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp o F N F H30 J‘kp H N HSC\O/\/N \ Analogously to Example 55, 70 mg of the title compound was obtained from 85 mg of the compound prepared in Example 205c and 58 mg of 3-fluoro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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-( { l - [4-chloro-3 -(trifluoromethyl)benzoyl]piperidin—4-yl}methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide H30 /N\p H N HSC\O/\/N \ Analogously to Example 55, 92 mg of the title compound was obtained from 85 mg of the compound prepared in Example 205c and 62 mg of 4-chloro(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .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 21 0: ethoxyethyl)methyl( { l - [4-(pentafluoro-W—sulphanyl)benzoyl] - piperidinyl} )-2H-indazolcarboxamide F, ‘1: H30 J‘kp H N H30\O/\/N \ Analogously to Example 1, 126 mg of the title compound was obtained from 85 mg of the compound ed in Example 205c and 58 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 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 21 1: N—(2-methoxyethyl)methyl( { l - [4-(trifluoromethyl)benzoyl]piperidinyl} - methyl)-2H-indazolcarboxamide O C E F H \N HSC\O/\/N ously to Example 55, 69 mg of the title compound was obtained from 85 mg of the compound prepared in Example 205c and 53 mg of 4-(trifluoromethyl)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .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} ethyl-N-(2-methoxyethyl)-2H- indazolcarboxamide H N H3C\O/\/N \ Analogously to Example 55, 61 mg of the title compound was obtained from 91 mg of the compound prepared in Example 212i and 46 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 ng material was prepared as follows: e 212a: 4-bromoethylmethylaniline Br/EEECH3NH2 Dsuspension of 3 g of 3-ethylmethylaniline hydrochloride in 200 ml ethyl acetate was washed twice with 30 ml portions of saturated sodium carbonate solution and twice with 20 ml [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp portions of saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo after filtration. This yielded 2.69 g of ethylmethylaniline, which was further reacted without purification.
To a solution of 2.36 g of the amine prepared above in 29 ml DMF, a solution of 3.1 g of N—bromosuccinimide in 14.5 ml DMF was added dropwise at 0°C and stirred for 30 minutes at 0°C. Then the reaction e was diluted with 400 ml ethyl acetate and washed once with ml of a 10% aqueous sodium carbonate solution and once with 30 ml water. After drying over sodium sulphate and filtration, this was concentrated in vacuo. The crude t thus obtained (3.86 g) was used in the next step without purification.
Example 212b: N—(4-bromoethylmethylphenyl)acetamide N\n/CH3 Br CH3 To a solution of 3.86 g of the bromide ed in Example 212a in 48 ml pyridine, 2.04 ml of acetic anhydride was added dropwise at 0°C and stirred for 20 hours at 25°C. The reaction mixture was concentrated in vacuo and the crude product thus ed was purified by column chromatography on silica gel with hexane / 0-100% ethyl e. In this manner, 3.73 g of the title compound was obtained. 1H-NMR (300 MHz, CDCl3): 8 = 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-bromoethyl-1H-indazolyl)ethan—1-one 3 Br To a solution of 3.72 g of the acetamide prepared in Example 212b in 31.5 ml chloroform were added 4.1 ml of acetic anhydride and 2.85 g of potassium acetate, and 192 mg of wn-6 and 3.4 g of isopentyl nitrite were then added dropwise. The reaction mixture was heated for hours under reflux and after cooling diluted with 200 ml ethyl e. The organic phase was washed with 20 ml sodium carbonate solution and once with saturated sodium chloride solution.
After drying over sodium sulphate and filtration, this was concentrated in vacuo and the crude product thus obtained purified by column chromatography on silica gel with hexane / 0-50% ethyl acetate. Yield: 3.78 g of the title nd.
DNMR (300 MHZ, DMSO-d6): 8 = 1.18 (3H), 2.68 (3H), 3.04 (2H), 7.73 (1H), 8.03 (1H), 8.64 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 212d: oethyl- l H-indazole A mixture of 3.78 g of the compound prepared in Example 212c in 7.3 ml methanol and 26.3 ml of 37% hydrochloric acid was heated under reflux for 2 hours. This was then diluted with 400 ml ethyl acetate. The organic phase was washed three times with 50 ml portions of sodium hydrogen carbonate solution and once with 50 ml ted sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The crude product thus obtained was purified by column chromatography on silica gel with hexane / 0-50% ethyl e. Yield: 2.97 g of the title compound. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.17 (3H), 2.98 (2H), 7.30 (1H), 7.41 (1H), 8.16 (1H), 13.17 (1H).
Example 2126: Tert-butyl 4-[(5-bromoethyl-2H-indazolyl)methyl]piperidin- l -carboxylate Analogously to Example 1c, 961 mg of the title compound was obtained from 2.97 g of the le prepared in Example 212d and 7.3 g of utyl[(tosyloxy)methyl]piperidin-l- carboxylate. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.01-1.13 (2H), 1.16 (3H), 1.34 (9H), 1.41 (2H), 2.12 (1H), 2.63 (2H), 2.90 (2H), 3.87 (2H), 4.27 (2H), 7.27 (1H), 7.35 (1H), 8.49 (1H).
Example 212f: Methyl 2-{[1-(tert-butoxycarbonyl)piperidin—4-yl]methyl} ethyl-2H-indazol- -carboxylate ously to Example 1e, after two runs 571 mg of the title compound was obtained from 347 mg of the bromide prepared in Example 212e and 0.1 ml of methanol.
[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 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 212g: 2- { [l -(tert-butoxycarbonyl)piperidin—4-yl]methyl} ethyl-2H-indazol ylic acid HO \ Analogously to Example 1d, 427 mg of the title compound was obtained from 371 mg of the ester in Example 212f. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.00-1.15 (2H), 1.20 (3H), 1.34 (9H), 1.42 (2H), 2.14 (1H), 2.64 (2H), 3.19 (2H), 3.88 (2H), 4.29 (2H), 7.39 (1H), 7.61 (1H), 8.63 (1H), 12.33 (1H).
Example 212h: Tert-butyl 4-( {4-ethyl[N—(2-methoxyethyl)carbamoyl]-2H-indazolyl} - methyl)piperidin- l -carboxylate HSC\O/\/N \ Analogously to Example 1, 215 mg of the title compound was obtained from 427 mg of the acid prepared in e 212g and 83 mg of 2-methoxy-ethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.98-1.14 (2H), 1.19 (3H), 1.30-1.47 (11H), 2.13 (1H), 2.65 (2H), 2.90 (2H), 3.24 (3H), 3.32-3.45 (4H), 3.87 (2H), 4.28 (2H), 7.10 (1H), 7.38 (1H), 8.12 (1H), 8.50 (1H).
Example 212i: 4-ethyl-N-(2-methoxyethyl)(4-piperidylmethyl)-2H-indazolcarboxamide hydrochloride H N HSC\O/\/N \ Analogously to Example la, from 215 mg of the amide prepared in Example 212h, 258 mg of the title compound was obtained, which was reacted without further purification.
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 213: 4-Ethyl-N—(2-methoxyethyl)( { l - [4-(trifluoromethoxy)benzoyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide x026 H N H3C\O/\/N \ Analogously to Example 55, 32 mg of the title compound was obtained from 91 mg of the compound prepared in e 212i and 59 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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} methoxy-N—(2-methoxyethyl)- azolcarboxamide w. )1 H N HSC\O/\/N \ o 0 ‘CH3 Analogously to Example 55, 691 mg of the title nd was obtained from 68 mg of the compound prepared in Example 214c and 37 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 al was prepared as follows: Example 214a: Tert-butyl 3 - [(5-bromomethoxy-2H-indazolyl)methyl] azetidin— l - carboxylate >_O>VCH3 H30 CH3 J‘k fl \CH3 To a solution of 1.94 g of tert-butyl syloxy)methyl]azetidin—l-carboxylate in 15.5 ml Dtone were added 837 mg of lithium iodide and the reaction mixture was stirred for 16 hours at °C. After cooling, it was diluted with 200 ml ethyl acetate and the organic phase washed twice [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp with 30 ml portions of water and once with 20 ml saturated sodium chloride solution. After drying over sodium sulphate and filtration, this was concentrated in vacuo. In this manner, 1.6 g of tert-butyl(iodomethyl)azetidin—1-carboxylate were obtained, which was r reacted without purification.
To a solution of 620 mg of 5-bromomethoxy-1H-indazole in 24 ml DMF were added 1.11 g of potassium carbonate and the mixture stirred at 25°C for 30 minutes. Then 1.25 g of the iodide prepared above was added and the reaction mixture stirred for 3 hours at 60°C. After cooling, it was diluted with 200 ml 1:1 tert-butyl methyl ether/hexane, washed once each with 20 ml ns of water and saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo and the crude product thus ed purified by column chromatography on silica gel with a hexane / ethyl acetate gradient. Yield: 263 mg of the title compound. 1H-NMR (300 MHz, : 8 = 1.43 (9H), 3.23 (1H), 3.78 (2H), 4.07 (2H), 4.10 (3H), 4.59 (2H), 7.28 (1H), 7.36 (1H), 8.03 (1H).
Example 214b: Tert-butyl 3 -( {4-methoxy—5 - [N—(2-methoxyethyl)carbamoyl] -2H-indazol yl} methyl)azetidin— 1 -carboxylate H3C\O/\/N \ Analogously to Example 1b, a total of 193 mg of the title compound was obtained from 110 and 252 mg respectively of the compound prepared in Example 214a and 63 and 143 mg respectively of 2-methoxyethylamine. 1H-NMR (300 MHz, 6): 8 = 1.32 (9H), 3.10 (1H), 3.27 (3H), 3.38-3.48 (4H), 3.72 (2H), 3.82-3.94 (2H), 4.17 (3H), 4.60 (2H), 7.21 (1H), 7.63 (1H), 8.18 (1H), 8.87 (1H).
Example 214c: 2-(azetidin—3 hyl)methoxy-N—(2-methoxyethyl)-2H-indazol-5 - carboxamide hydrochloride /N\ P H N HSC\O/\/N \ o 0 \CH3 ously to Example 1a, from 50 mg of the nd prepared in Example 214b, 42 mg of the title compound was obtained, which was further reacted t purification. 3 0 Dample 21 5: 4-methoxy-N—(2-methoxyethyl) [(1 - {4- [(trifluoromethyl)sulphanyl]benzoyl} azetidin—3 -yl)methyl] -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp F F O C >LF S H N Hscxo/VN \ O 0 \CH3 Analogously to Example 55, 56 mg of the title nd was obtained from 42 mg of the nd prepared in Example 214C and 32 mg of 4-[(trifluoromethyl)sulphany]benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 21 6: 2- {[1 -(4-bromobenzoyl)azetidin-3 -yl]methyl} methoxy-N-(2-methoxyethyl) - 2H-indazolcarboxamide >—< >—Br JR 4? H N HSC\O/\/N \ o 0 \CH3 Analogously to Example 55, 48 mg of the title compound was obtained from 42 mg of the compound prepared in Example 214C and 29 mg of 4-bromobenzoyl de. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 21 7: 2- {[(R)- l -(4-chlorobenzoyl)pyrrolidin-3 -yl]methyl} -N-(2-methoxyethyl) -2H-indazolcarboxamide H N H HSC‘o/\/N \ ‘25 0 CH3 0*CL.
Analogously to e 55, 50 mg of the title compound was obtained from 106 mg of the compound prepared in Example 2l7e and 58 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .43 (1H), 7.45 (2H), fie (2H), 8.09-8.16 (1H), 8.47 / 8.55 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The ng material was prepared as follows: Example 21 7a: (R)-tert-butyl-3 -[(5-bromomethyl-2H-indazolyl)methyl]pyrrolidine carboxylate N H H30 CH3CH3 To a solution of 9.0 g of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidin—1-carboxylate in 100 ml pyridine was added 12.8 g of p-toluenesulphonyl de at 0°C under nitrogen and stirred for 3 hours at 25°C. The reaction mixture was diluted with ethyl acetate and stirred for minutes with sodium en carbonate. The phases were then separated and the organic phase washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo after filtration. The residue thus obtained was purified by column chromatography on silica gel with hexane / 0-100% ethyl acetate. Yield: 11.4 g of rt-butyl[(tosyloxy)methyl]pyrrolidin—1-carboxylate.
Analogously to Example 1c, 1.97 g of the title compound was obtained from 4.53 g of 5-bromo- 4-methyl-1H-indazole and 11.4 g of the (R)-tert-butyl[(tosyloxy)methyl]pyrrolidin carboxylate prepared above with addition of 7.9 g of tetrabutylammonium iodide. 1H-NMR (300 MHz, 6): 8 = 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 21 7b: Methyl 2- 1-(tert-butoxycarbonyl)pyrrolidin—3 -yl]methyl} methyl-2H- indazolcarboxylate Analogously to Example 1e, after two runs 820 mg of the title compound was obtained from 563 mg of the bromide prepared in Example 217a and 0.17 ml of methanol. 1H-NMR (300 MHz, DMSO-d6): 8 = 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). ample 217c: 2- {[(R)-1 -(tert-butoxycarbonyl)pyrrolidin—3 -yl]methyl} methyl-2H-indazolboxylic acid [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 3 CH3 Analogously to Example 1d, 701 mg of the title compound was obtained from 620 mg of the ester prepared in Example 217b. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 21 7d: (R)-tert-butyl 3 -( {5- [N-(2-methoxyethyl)carbamoyl] methyl-2H-indazol yl} methyl)pyrrolidin- l -carboxylate Analogously to Example 1, 376 mg of the title compound was obtained from 350 mg of the acid prepared in Example 217C and 73 mg of 2-methoxyethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.35 (9H), 1.57 (1H), 1.80 (1H), 2.50 (3H), 2.73-2.86 (1H), 3.01 (1H), 3.11-3.22 (1H), 3.25 (3H), 3.26-3.39 (3H), 3.39-3.46 (2H), 4.42 (2H), 7.15 (1H), 7.39 (1H), 8.13 (1H), 8.52 (1H).
Example 217e: ethoxyethyl)methyl[(R)-pyrrolidin—3-ylmethyl]-2H-indazol carboxamide hydrochloride H N H \/N \ E 0 CH3 Analogously to Example la, from 376 mg of the amide ed in e 217d, 465 mg of the title compound was ed, which was reacted without further purification.
Example 218: N—(2-methoxyethyl)methyl( {(R)- l - [4-(trifluoromethoxy)benzoyl] - pyrrolidin-3 -yl} methyl)-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H N H H30\O/\/N \ ‘25 O CH 3 N OAg J<FF O F Analogously to Example 55, 61 mg of the title nd was obtained from 106 mg of the compound ed in Example 217e and 74 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .16 (1H), 8.47 / 8.55 (1H).
Example 219: ethoxyethyl)methyl( {(3R) [4-(pentafluoro-7t6-sulphanyl)benzoyl] - pyrrolidin-3 -yl} methyl)-2H-indazolcarboxamide H N H HSC\O/\/N \ ‘6 0 CH3 PI? Analogously to Example 1, 29 mg of the title compound was obtained from 106 mg of the compound prepared in Example 217e and 75 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .44 (1H), 7.68 (2H), 7.90-7.97 (2H), 8.10—8.17 (1H), 8.46 / 8.55 (1H). e 220: 2- {[(R)- l -(4-chlorobenzoyl)pyrrolidin—3 -yl]methyl} methyl-N— {2- [(trifluoro- methyl)sulphanyl] ethyl} -2H-indazolcarboxamide F J\ PX H N H F S/\/ O CH 3 ‘6 O*Q.
Analogously to Example 55, 29 mg of the title compound was obtained from 106 mg of the compound prepared in Example 220b and 48 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .53 (5H), 8.35-8.42 (1H), 8.49/ 8.58 (1H). 1 Ee starting material was prepared as follows: ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Example 220a: (R)-tert-butyl 3 - { [4-methyl-5 -(N- {2- [(trifluoromethyl)sulphanyl] ethyl} - carbamoyl)-2H-indazolyl]methyl} pyrrolidin— 1 -carboxylate F>|\ H N‘25H F s/\/ 0 CH 3 N HO OH 3 3 Analogously to Example 1, 245 mg of the title compound was obtained from 350 mg of the acid prepared in Example 217c and 141 mg of 2-[(trifluoromethyl)sulphanyl]ethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.35 (9H), 1.52-1.64 (1H), 1.81 (1H), 2.52 (3H), 2.71-2.96 (2H), 2.97-3.05 (12H), 3.18 (2H), 3.23-3.28 (1H), 3.51 (2H), 4.42 (2H), 7.19 (1H), 7.42 (1H), 8.39 (1H), 8.54 (1H).
Example 220b: 4-methyl[(R)-pyrrolidin—3-ylmethyl]-N- rifluoromethyl)sulphanyl]- ethyl} -2H-indazolcarboxamide hydrochloride Analogously to Example 1a, from 245 mg of the amide prepared in e 220a, 410 mg of the title compound was obtained, which was reacted without further purification.
Example 221: 4-methyl({(R)[4-(trifluoromethoxy)benzoyl]pyrrolidin—3 -yl} methyl)-N- {2- [(trifluoromethyl)sulphanyl] ethyl} -2H-indazolcarboxamide F J\N F>l\S/\/NF H H \ ‘6 0 CH3 OAQ F OJ<FF Analogously to Example 55, 49 mg of the title compound was obtained from 106 mg of the compound prepared in Example 220b and 62 mg of 4-(trifluoromethoxy)benzoyl chloride. 1H-NMR (300 MHz, 6): 8 = 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), .43 (1H), 8.49 / 8.58 (1H).
Example 222: 2- {[(S)(4-chlorobenzoyl)pyrrolidin-3 -yl]methyl} -N-(2-methoxyethyl) nthyl-ZH-indazol-S-carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp H N \ ‘21S‘H HSC‘o/\/N 0 CH3 ously to Example 55, 67 mg of the title compound was obtained from 134 mg of the compound prepared in Example 222a and 73 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, : 8 = 1.72-1.86 (1H), 1.99-2.20 (1H), 2.64 (3H), 2.93-3.13 (1H), .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 s: e 222a: (S)-tert-butyl 3 -( {5- [N-(2-methoxyethyl)carbamoyl] methyl-2H-indazol yl} methyl)pyrrolidin- l -carboxylate H N ’H HmN/V \ 3'1 0 CH3 N C x Jim 0 0 CH3 Analogously to Example 217a to 217d, this title compound was prepared in a quantity of 760 mg starting from (S)-tert-butyl-3 -(hydroxymethyl)pyrrolidin— l -carboxylate. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.35 (9H), 1.52-1.64 (1H), 1.77-1.87 (1H), .82 (1H), 2.50 (3H), 2.74-2.86 (1H), 3.02 (1H), 3.12-3.20 (1H), 3.25 (3H), 3.31 (1H), 3.36 (2H), 3.43 (2H), 4.42 (2H), 7.16 (1H), 7.39 (1H), 8.10 (1H), 8.51 (1H).
Example 222b: N-(2-methoxyethyl)methyl[(S)-pyrrolidin—3-ylmethyl]-2H-indazol carboxamide hydrochloride H N ~H H30\o/\/N \ ‘23 0 CH3 H CIH Analogously to Example la, from 159 mg of the amide prepared in Example 222a, 134 mg of the title compound was obtained, which was reacted without further purification.
Example 223: 2 -( {(S)- l - [(4'- fluorobiphenylyl)carbonyl]pyrrolidin—3 -yl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp HC “ \ ‘H 3 \O/\/ 0 CH3 fik’j Analogously to e 1, 128 mg of the title compound was obtained from 230 mg of the compound prepared in Example 222b and 141 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, CDCl3): 8 = 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), .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)methyl {[(S)- l - {4- [4-(trifluoromethyl)phenoxy] benzoyl}pyrrolidin-3 -yl]methyl} -2H-indazolcarboxamide H ~H H3C\o/\/N \ ‘23 0 CH3 N F OAQ /©)<FF O Analogously to Example 1, 102 mg of the title compound was obtained from 230 mg of the compound prepared in Example 222b and 184 mg of trifluoromethyl)phenoxy]benzoic acid. 1H-NMR (300 MHz, CDCl3): 8 = .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)piperidinyl]methyl} (difluoromethoxy)-N—(2- methoxyethyl)-2H-indazolcarboxamide O O F F Analogously to e 55, 90 mg of the title compound was obtained from 106 mg of the compound prepared in Example 225h and 49 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.14-1.58 (4H), 2.19-2.34 (1H), 2.67-2.81 (1H), 2.97 (1H), $33.53 (9H), 4.37 (2H), 7.13 (1H), 7.31—7.39 (3H), 7.47 (2H), 7.54 (1H), 8.21 (1H), 8.50).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The starting material was prepared as follows: Example 225a: N— [4-bromo-3 -(difluoromethoxy)methylphenyl] ide HTCH3 Br CH? To a solution of 5.0 g of oromethoxy—2-methylaniline in 48 ml DMF, a on of 5.1 g of N—bromosuccinimide in 24 ml DMF was added dropwise at 0°C and stirred for 1 hour at 0°C.
Then the reaction mixture was diluted with 400 ml hexane / ethyl acetate, and washed once with 50 ml of a 10% aqueous sodium carbonate solution and three times with 50 ml portions of water.
After drying over sodium te and filtration, this was concentrated in vacuo. The crude product thus obtained (6.68 g) was used in the next step without purification.
To a solution of 6.39 g of the bromide prepared above in 70 ml pyridine, 3.0 ml of acetic anhydride were added se at 0°C and stirred for 20 hours at 25°C. The reaction mixture was concentrated in vacuo and the crude product thus obtained purified by column chromato- graphy on silica gel with hexane / 0-100% ethyl acetate. The substance was then recrystallized from hexane. In this manner, 6.39 g of the title compound was obtained. 1H-NMR (300 MHz, CDCl3): 8 = 2.22 (3H), 2.27 (3H), 6.51 (1H), 6.95 (1H), 7.46 (1H), 7.71 (1H).
Example 225b: l- [5-bromo(difluoromethoxy)- l zol-l -yl] ethanone >,CH3 Analogously to Example 212C, 5.32 g of the title compound was obtained from 6.38 g of the amide prepared in Example 225a. 1H-NMR (300 MHz, DMSO-d6): 8 = 2.70 (3H), 7.34 (1H), 7.90 (1H), 8.16 (1H), 8.46 (1H).
Example 225C: 5-bromo(difluoromethoxy)- l H-indazole usly to Example 212d, 4.12 g of the title compound was obtained from 5.32 g of the indazole prepared in Example 225b.
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 8 = 7.30 (1H), 7.44 (1H), 7.56 (1H), 8.06 (1H), 13.54 (1H).
Example 225d: Tert-butyl 4-{[5-bromo(difluoromethoxy)-2H-indazolyl]methyl}- dincarboxylate >VCH3 H30 CH3 0 F Analogously to Example 212e, 2.06 g of the title compound was obtained from 4.1 g of the indazole prepared in Example 225c and 8.7 g of tert-butyl 4-[(tosyloxy)methyl]piperidin carboxylate. 1H-NMR (300 MHz, CDCl3): 8 = 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 2256: Methyl 2- { [1 -butoxycarbonyl)piperidinyl]methyl} (difluoromethoxy)- 2H-indazol-5 -carboxylate >VCH3 3 CH3 H C/OYEF/ O OYF Analogously to Example 1e, after three runs 1.28 g of the title compound was obtained from 683 mg of the bromide prepared in Example 225d and 0.18 ml of methanol. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.96-1.22 (2H), 1.28-1.47 (11H), 2.14 (1H), 2.54-2.74 (2H), 3.81 (3H), 3.87 (2H), 4.36 (2H), 7.17 (1H), 7.58 (1H), 7.65 (1H), 8.62 (1H).
Example 225f: 2- {[1 -(tert-butoxycarbonyl)piperidinyl]methyl} (difluoromethoxy)-2H- indazolcarboxylic acid HO \ Analogously to Example 1d, 1.05 g of the title compound was ed from 1.28 g of the ester Dpared in Example 225e.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 1H-NMR (300 MHz, 6): 8 = 0.97-1.16 (2H), 1.28-1.47 (11H), 2.13 (1H), 2.63 (2H), 3.87 (2H), 4.35 (2H), 7.14 (1H), 7.54 (1H), 7.65 (1H), 8.58 (1H), 13.05 (1H).
Example 225g: Tert-butyl 4-( {4-(difluoromethoxy)-5 - [N—(2-methoxyethyl)carbamoyl] -2H- indazolyl } methyl)piperidin— l -carboxylate HC+O H30 >=o H N H3C\O/\/N \ o OYF ously to Example 1, 503 mg of the title compound was obtained from 520 mg of the compound prepared in Example 225f and 92 mg of 2-methoxyethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.01-1.13 (2H), 1.34 (9H), 1.38 (2H), 2.13 (1H), 2.59-2.71 (6H), 3.24 (3H), 3.34-3.44 (2H), 3.87 (2H), 4.34 (2H), 7.14 (1H), 7.33 (1H), 7.54 (1H), 8.21 (1H), 8.50 (1H).
Example 225h: 4-(difluoromethoxy)-N—(2-methoxyethyl)(4-piperidylmethyl)-2H-indazol carboxamide hydrochloride H N HSC\O/\/N \ o OYF F Analogously to Example la, from 122 mg of the amide ed in Example 225g, 106 mg of the title compound was obtained, which was reacted without further purification.
Example 226: 4-(difluoromethoxy)( { l - [4-(4-fluorophenoxy)benzoyl]piperidin—4-yl} methyl) - N—(2-methoxyethyl)-2H-indazolcarboxamide \/N \ O O F dallogously to Example 1, 11 mg of the title compound was obtained from 106 mg of the pound prepared in Example 225h and 59 mg of 4-(4-fluorophenoxy)benzoic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 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—712(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)( { l - [(4'-fluorobiphenylyl)carbonyl]piperidin—4-yl} methyl)-N—(2-methoxyethyl)-2H-indazolcarboxamide Analogously to e 1, 38 mg of the title compound was obtained from 106 mg of the compound prepared in Example 225h and 55 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, 6): 8 = 1.14-1.62 (4H), 2.23-2.35 (1H), 2.68-2.85 (1H), .09 (1H), 3.24 (3H), 3.32-3.48 (5H), .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)piperidinyl]methyl} (difluoromethoxy)-N—(2- methoxyethyl)-2H-indazolcarboxamide of C ] H N ch\O/\/N \ o OYF Analogously to Example 1, 75 mg of the title compound was obtained from 106 mg of the compound prepared in Example 225h and 41 mg of 4-cyclopropylbenzoic acid. 1H-NMR (300 MHZ, DMSO-d6): 8 = 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). e 229: 2- {[1 -(4-chlorobenzoyl)piperidin—4-yl]methyl} -N-[2-(cyclopropylmethoxy)- ethyl] (difluoromethoxy)-2H-indazolcarboxamide O>—©—CI mowrggO 19 H N O F F [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 55, 170 mg of the title compound was obtained from 127 mg of the compound prepared in Example 22% and 53 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.14 (2H), 0.42 (2H), 0.96 (1H), .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 229a: Tert-butyl 4- {[5- {N— [2-(cyclopropylmethoxy)ethyl]carbamoyl} (difluoro- methoxy)-2H-indazolyl]methyl} piperidin—l -carboxylate H if?)O>=O H N V/\0/\/N \ O O F Analogously to Example 1, 453 mg of the title compound was obtained from 520 mg of the compound prepared in Example 225f and 185 mg of lopropylmethoxy)ethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.14 (2H), 0.42 (2H), 0.97 (1H), 1.07 (2H), 1.34 (9H), 1.39 (2H), 2.13 (1H), .72 (2H), 3.23 (2H), 3.37 (2H), 3.48 (2H), 3.87 (2H), 4.34 (2H), 7.15 (1H), 7.34 (1H), 7.55 (1H), 8.21 (1H), 8.50 (1H).
Example 229b: N-[(2-cyclopropylmethoxy)ethyl](difluoromethoxy)(4-piperidylmethyl)- 2H-indazolcarboxamide hydrochloride H N v/\o/\/N \ o OYF F Analogously to Example la, from 145 mg of the amide prepared in Example 229a, 127 mg of the title compound was obtained, which was d without further ation. e 230: N— [2-(cyclopropylmethoxy)ethyl] (difluoromethoxy)( { l - [4-(4-fluoro- phenoxy)benzoyl]piperidin—4-yl} methyl)-2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp fodrgjj Analogously to Example 1, 156 mg of the title compound was obtained from 127 mg of the compound prepared in Example 22% and 64 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 23 1: N— [2-(cyclopropylmethoxy)ethyl] (difluoromethoxy)( { l - [(4'-fluoro- biphenylyl)carbonyl]piperidin—4-yl} )-2H-indazolcarboxamide 535MF VAJNYEE? Analogously to Example 1, 164 mg of the title compound was ed from 127 mg of the compound prepared in Example 22% and 60 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, 6): 8 = 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), .75 (4H), 8.21 (1H), 8.52 (1H).
Example 232: 2- {[1 -(4-chlorobenzoyl)piperidin—4-yl]methyl} -N-(2-methoxyethyl)(2,2,2- trifluoroethoxy)-2H-indazolcarboxamide Owool HSC\O/\/N\n/<;E/1pH N o o F Analogously to Example 55, 113 mg of the title compound was obtained from 109 mg of the ”pound prepared in Example 232h and 46 mg of 4-chlorobenzoyl chloride.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 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: e 232a: N-[4-bromomethyl(2,2,2-trifluoroethoxy)phenyl]acetamide Br/QCHSN\n/CH3o FJ\F Analogously to Example 225a, 6.13 g of the title compound was obtained from 5.0 g of 2-methyl(2,2,2-trifluoroethoxy)aniline. 1H-NMR (300 MHZ, DMSO-d6): 8 = 2.07 (3H), 2.18 (3H), 4.55 (2H), 7.29 (1H), 7.45 (1H), 9.42 (1H).
Example 232b: l- [5-bromo(2,2,2-trifluoroethoxy)- l H-indazol-l -yl] ethan— 1 -one Br@/N Analogously to Example 212C, 5.08 g of the title compound was obtained from 6.13 g of the amide prepared in Example 232a. 1H-NMR (300 MHz, 6): 8 = 2.69 (3H), 5.14 (2H), 7.80 (1H), 7.99 (1H), 8.64 (1H).
Example 232C: 5-bromo(2,2,2-trifluoroethoxy)- l H-indazole Analogously to Example 212d, 3.57 g of the title nd was obtained from 5.08 g of the indazole ed in Example 232b. 1H-NMR (300 MHz, DMSO-d6): 8 = 5.05 (2H), 7.24 (1H), 7.45 (1H), 8.26 (1H), 13.38 (1H).
Example 232d: Tert-butyl 4- {[5-bromo(2,2,2-trifluoroethoxy)-2H-indazolyl]methyl} - Deridin- l -carboxylate ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp N >VCH3 H30 CH3 Analogously to Example 212e, 1.77 g of the title compound was ed from 3.57 g of the indazole prepared in Example 232c and 6.7 g of tert-butyl 4-[(tosyloxy)methyl]piperidin carboxylate. 1H-NMR (300 MHz, CDCl3): 5 = 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 2326: Methyl 2-{[1-(tert-butoxycarbonyl)piperidinyl]methyl} (2,2,2-trifluoro- ethoxy)-2H-indazolecarboxylate N >VCH3 H30 CH3 0 \ H30’ 0 o F Analogously to Example 1e, after three runs 857 mg of the title compound was obtained from 590 mg of the bromide prepared in Example 232d and 0.15 ml of methanol. 1H-NMR (300 MHz, DMSO-d6): 8 = .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). e 232f: 2- {[1 -(tert-butoxycarbonyl)piperidinyl]methyl} (2,2,2-trifluoroethoxy)-2H- indazolecarboxylic acid N >VCH3 H30 CH3 HO \ o o Analogously to e 1d, 724 mg of the title compound was obtained from 854 mg of the ester prepared in Example 232e. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.01-1.17 (2H), 1.34 (9H), 1.40 (2H), 2.13 (1H), 2.53-2.75 Di), 3.87 (2H), 4.32 (2H), 4.84 (2H), 7.37 (1H), 7.58 (1H), 8.60 (1H), 12.74 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 232g: Tert-butyl 4-( {5- methoxyethyl)carbamoyl] (2,2,2-trifluoroethoxy)-2H- indazolyl}methyl)piperidin— 1 -carboxylate HSC+O H30 >=o H N HSC\O/\/N \ o o FJ\F Analogously to Example 1, 386 mg of the title compound was obtained from 360 mg of the compound prepared in Example 232f and 59 mg of 2-methoxyethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.98-1.18 (2H), 1.34 (9H), 1.43 (2H), 2.14 (1H), 2.65 (2H), 3.23 (3H), 3.35-3.47 (4H), 3.88 (2H), 4.30 (2H), 4.96 (2H), 7.35 (1H), 7.43 (1H), 7.99 (1H), 8.65 (1H).
Example 232h: N—(2-methoxyethyl)(4-piperidylmethyl)(2,2,2-trifluoroethoxy)-2H- indazolcarboxamide hydrochloride H N HSC\O/\/N \ o o Analogously to Example la, from 109 mg of the amide prepared in Example 232g, 113 mg of the title compound was obtained, which was reacted without r purification. e 233: 2-({1 -[4-(4-fluorophenoxy)benzoyl]piperidin—4-yl}methyl)-N—(2-methoxyethyl)- ,2-trifluoroethoxy)-2H-indazolcarboxamide O: C O H C H \ 3 \O/\/ O O Analogously to Example 1, 51 mg of the title compound was obtained from 109 mg of the compound prepared in Example 232h and 56 mg of 4-(4-fluorophenoxy)benzoic acid.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 1.10-1.31 (1H), 1.48 (2H), .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-( { l - [(4'-fluorobiphenylyl)carbonyl]piperidinyl} methyl)-N-(2-methoxyethyl )(2,2,2-trifluoroethoxy)-2H-indazolcarboxamide HSC\O/\/NY<;E/H 3.9 o o Analogously to Example 1, 61 mg of the title compound was obtained from 109 mg of the nd prepared in Example 232h and 52 mg of 4-(4-fluorophenyl)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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 lorobenzoyl)piperidinyl]methyl} (cyclopropylmethoxy)- ethyl](2,2,2-trifluoroethoxy)-2H-indazolcarboxamide O800' «Mr?N\ Analogously to Example 55, 122 mg of the title compound was obtained from 122 mg of the compound prepared in Example 235b and 48 mg of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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: e 235a: Tert-butyl 4- {[5- {N- [2-(cyclopropylmethoxy)ethyl]carbamoyl} (2,2,2- fluoroethoxy)-2H-indazolyl]methyl} piperidin-l -carboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp HSC+O3 H30 >=o pN H N v/\o/\/N \ Analogously to Example 1, 429 mg of the title compound was obtained from 360 mg of the compound prepared in Example 232f and 119 mg of 2-(cyclopropylmethoxy)ethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 0.13 (2H), 0.42 (2H), 0.95 (1H), 1.08 (2H), 1.34 (9H), 1.41 (2H), 2.14 (1H), 3.22 (2H), 3.41 (2H), 3.48 (2H), 3.88 (2H), 4.30 (2H), 4.95 (2H), 7.35 (1H), 7.42 (1H), 8.00 (1H), 8.65 (1H).
Example 235b: N-[2-(cyclopropylmethoxy)ethyl](4-piperidylmethyl)(2,2,2-trifluoroethoxy )-2H-indazolcarboxamide hydrochloride /N\p CIH H N v/\o/\/N \ o o F Analogously to Example 1a, from 138 mg of the amide prepared in Example 235a, 122 mg of the title compound was obtained, which was reacted without further purification.
Example 236 : N—[2-(cyclopropylmethoxy)ethyl] ( {1-[4-(4-fluorophenoxy)benzoyl]piperidin— 4-yl} methyl)(2,2,2-trifluoroethoxy)-2H-indazol-5 -carboxamide Analogously to Example 1, 95 mg of the title compound was ed from 122 mg of the compound prepared in Example 235b and 58 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHz, 6): 8 = 0.13 (2H), 0.41 (2H), 0.95 (1H), 1.09-1.60 (3H), .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 Di), 7.17-7.27 (2H), 7.30-7.38 (3H), 7.42 (1H), 7.99 (1H), 8.65 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 237: N— [2-(cyclopropylmethoxy)ethyl] ( { l - [(4'-fluorobiphenylyl)carbonyl] dinyl} methyl)(2,2,2-trifluoroethoxy)-2H-indazol-5 -carboxamide v/\O/\/N\n/<;E/H imp O O Analogously to Example 1, 98 mg of the title compound was obtained from 122 mg of the compound prepared in Example 235b and 54 mg of 4-(4-fluorophenoxy)benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)piperidinyl]methyl}-N-[2-(3 -methoxyazetidin—l -yl) ethyl] methyl-2H-indazolcarboxamide owool A JO N/\/H N //:l 0 ‘13 CH3 ously to Example 1, 33 mg of the title compound was obtained from 120 mg of the nd prepared in Example 23 8c and 40 mg of 2-(3-methoxyazetidin—1-yl)ethylamine (prepared analogously to W02006/104406). 1H-NMR (300 MHz, CDCl3): 8 = 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), .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 238a: methyl 4-methyl(4-piperidylmethyl)-2H-indazolcarboxylate hydrochloride J p CIH ’0 \ 0 CH3 Analogously to Example la, from 3.0 g of the ester prepared in e 1e, 2.51 g of the title Dripound was obtained, which was reacted without further purification.
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 238b: Methyl 2- {[1-(4-chlorobenzoyl)piperidinyl]methyl} methyl-2H-indazol carboxylate A JO 0 \ H30’ 0 CH3 Analogously to Example 55, 3.27 g of the title compound was obtained from 2.5 g of the compound prepared in e 238a and 1.5 g of 4-chlorobenzoyl chloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.16-1.63 (4H), .33 (1H), 2.73 (4H), 2.90-3.05 (1H), 3.44-3.55 (1H), 3.79 (3H), 4.32 (2H), 4.36-4.47 (1H), 7.36 (2H), 7.42 (1H), 7.46 (2H), 7.63 (1H), 8.67 (1H).
Example 238C: 2- {[1 -(4-chlorobenzoyl)piperidinyl]methyl} methyl-2H-indazol carboxylic acid HO \ O CH Analogously to Example 1d, 470 mg of the title compound was ed from 485 mg of the ester prepared in Example 23 8b.
Example 239: (+/-) {[1-(4-chlorobenzoyl)piperidin—4-yl]methyl}methyl-N—(3 ,4,5,6-tetrahydro-2H-pyran —2-ylmethyl)-2H-indazolcarboxamide 0.. YonpH N N \ 0 CH3 Analogously to Example 1, 188 mg of the title compound was obtained from 300 mg of the compound prepared in Example 238c and 92 mg of 3,4,5,6-tetrahydro-2H-pyran—2-ylmethyl- amine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.01-1.27 (3H), .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 DJ), 8.46 (1H). ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 240: (R or [1-(4-chlorobenzoyl)piperidin—4-yl]methyl}methyl-N—(3,4,5,6- tetrahydro-2H-pyran—2-ylmethyl)-2H-indazolcarboxamide O O O ”9N ”9N H N 0VH N 0 CH3 0 CH3 From 185 mg of the racemate prepared in Example 239, 51 mg of the title nd together with 53 mg of the -eluting enantiomer (Example 241) were obtained by racemate separation by means of preparative chiral HPLC (Method B).
Analytical chiral HPLC: 7.02 min.
Example 241: (S or R){[1-(4-chlorobenzoyl)piperidin—4-yl]methyl}methyl-N—(3,4,5,6- tetrahydro-2H-pyran—2-ylmethyl)-2H-indazolcarboxamide o o N N Ap Ap H N N \ H \ o o ”“/ 0 CH3 0 CH3 From 185 mg of the racemate prepared in Example 239, 53 mg of the title compound together with 51 mg of the faster-eluting enantiomer (Example 240) were obtained by racemate separation by means of preparative chiral HPLC (Method B).
Analytical chiral HPLC: 8.24 min.
Example 242: 2- {[1-(4-chlorobenzoyl)piperidin—4-yl]methyl} -N-ethylmethyl-2H-indazol carboxamide H N HSCVN \ 0 CH3 Analogously to Example 1, 85 mg of the title compound was obtained from 300 mg of the compound prepared in e 23 8c and 43 mg of ethylarnine 2M in THF. 1H-NMR (300 MHz, DMSO-d6): 8 = 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).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 243: 2- -chlorobenzoyl)piperidin—4-yl]methyl} -N-isobutylmethyl-2H-indazol- -carboxamide J\/H N N \ 0 CH3 Analogously to Example 1, 92 mg of the title compound was ed from 300 mg of the nd prepared in Example 23 8c and 69 mg of isobutylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = .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-mesylethyl)methyl-2H- indazolcarboxamide 0a0.
H N Analogously to Example 1, 132 mg of the title compound was obtained from 300 mg of the compound prepared in Example 23 8c and 151 mg of 2-mesylethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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: esylethyl)methyl [(1 - {4-[4-(trifluoromethyl)phenoxy]benzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide H30\ /\/N /S\I \ wimp O O 0 CH3 Analogously to Example 1, 67 mg of the title compound was obtained from 137 mg of the compound prepared in Example 245b and 41 mg of 2-mesylethylamine hydrochloride.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-d6): 5 = 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 ng material was prepared as follows: Example 245a: Methyl 4-methyl[(1- {4- [4-(trifluoromethyl)phenoxy]benzoyl} piperidin yl)methyl] -2H-indazolcarboxylate A JO 0 \ H30/ 0 CH3 ously to Example 1, 2.73 g of the title compound was obtained from 3.76 g of the compound prepared in e 238a and 3.28 g of 4-[4-(trifluoromethyl)phenoxy]benzoic acid. 1H-NMR (300 MHz, DMSO-d6): 8 = 1.25 (2H), 1.35-1.70 (2H), 2.20-2.37 (1H), 2.65-2.70 (3H), 2.75-3.10 (2H), .72 (1H), 3.82 (4H), 4.36 (2H), 7.14 (2H), 7.20 (2H), 7.39-7.48 (3H), 7.66 (1H), 7.75 (2H), 8.70 (1H).
Example 245b: 4-methyl[(1- {4- [4-(trifluoromethyl)phenoxy]benzoyl} piperidinyl)- methyl]-2H-indazolcarboxylic acid HO \ 0 CH3 Analogously to Example 1d, 1.1 g of the title compound was obtained from 2.73 g of the ester prepared in Example 245a.
Example 246 : N—(2-cyanoethyl)methyl [(1 - {4- [4-(trifluoromethyl)phenoxy]benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O800 . J0 N N 0 CH3 Analogously to Example 1, 144 mg of the title compound was obtained from 137 mg of the compound ed in Example 245b and 18 mg of 3-aminopropanenitrile. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)methyl [(1 - {4- ifluoromethyl)phenoxy]benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide O>LOO . JO H N N¢/\/N \ 0 CH3 Analogously to Example 1, 125 mg of the title compound was obtained from 137 mg of the compound prepared in Example 245b and 24 mg of 2-aminoacetonitrile hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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), .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)[(1-{4-[4- (trifluoromethyl)phenoxy]benzoyl } piperidinyl)methyl] -2H-indazolcarboxamide ($00 64669 ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 231 mg of the title compound was obtained from 254 mg of the compound prepared in Example 245b and 72 mg of 3,4,5,6-tetrahydro-2H-pyran—2-ylmethyl- amine. 1H-NMR (300 MHz, DMSO-d6): 8 = .66 (10H), 2.24-2.32 (1H), 2.70-3.15 (4H), 3.21 (3H), 3.34-3.43 (1H), .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—(l ,4-dioxan—2-ylmethyl)methyl [( l - {4- [4-(trifluoromethyl)phenoxy] benzoyl} piperidin—4-yl)methyl] -2H-indazolcarboxamide ($00 (we? Analogously to e 1, 280 mg of the title compound was obtained from 254 mg of the nd prepared in Example 245b and 73 mg of l,4-dioxan—2-ylmethylamine. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)methyl- 2H-indazolcarboxamide mH N N \ 0 CH3 Analogously to Example 1, 79 mg of the title compound was obtained from 300 mg of the compound prepared in Example 23 8c and 115 mg of cyclobutylmethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-d6): 8 = 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) nthyl-ZH-indazol-S-carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp HSCX/HN \ 0 CH3 Analogously to Example 1, 108 mg of the title compound was obtained from 300 mg of the compound prepared in Example 23 8c and 83 mg of 2,2-dimethylpropanamine. 1H-NMR (300 MHz, 6): 8 = 0.91 (9H), .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- -chlorobenzoyl)piperidin—4-yl]methyl}-N-(2-hydroxyethyl)methyl- 2H-indazolcarboxamide O>—©—CI “Ni/(PH N 0 CH3 Analogously to e 1, 84 mg of the title compound was obtained from 370 mg of the nd prepared in Example 23 8c and 54 mg of 2-aminoethanol. 1H-NMR (300 MHz, DMSO-d6): 8 = 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)methyl- 2H-indazolcarboxamide A JC) H N HO\/\/N \ 0 CH3 Analogously to Example 1, 95 mg of the title compound was obtained from 370 mg of the compound prepared in e 23 8c and 66 mg of 3-aminopropanol. 1H-NMR (300 MHz, DMSO-d6): 8 = 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).
Dample 254: 4-methoxy-N—(2-methoxyethyl)( { l - [4-(trifluoromethoxy)benzoyl] azetidin—3 - yl} methyl)-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1, 90 mg of the title compound was obtained from 100 mg of the compound prepared in Example 214C and 97 mg of 4-(trifluoromethoxy)benzoic acid in DMF. 1H-NMR (400 MHz, a): 8 [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-( { l - ro(trifluoromethyl)benzoyl] azetidin—3 -yl} methyl)methoxy-N— (2-methoxyethyl)-2H-indazol-5 -carboxamide o O/CH3 H30’ \/\N / H N O >: F F F Analogously to Example 1, 40 mg of the title compound was obtained from 100 mg of the compound prepared in Example 214C and 98 mg of 2-fluoro(trifluoromethyl)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [4-chloro-3 -(trifluoromethyl)benzoyl] azetidin—3 -yl} methyl)methoxy-N— hoxyethyl)-2H-indazol-5 -carboxamide o O/CH3 H C’ \/\N / 3 H N N 33 F Analogously to Example 1, 40 mg of the title compound was obtained from 100 mg of the compound prepared in Example 214C and 106 mg of 4-chloro(trifluoromethyl)benzoic acid in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-ds): 5 [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-chlorofluorobenzoyl)azetidin—3 -yl]methyl} methoxy-N-(2- yethyl)-2H-indazolcarboxamide O O,CHS /O\/\ H C N / 3 H N N Eb ously to Example 1, 20 mg of the title compound was obtained from 100 mg of the compound prepared in Example 214c and 82 mg of 4-chlorofluorobenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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} methoxy-N-(2-morpholino- ethyl)-2H-indazolcarboxamide 0/\ ICH3 o 0 K/NWNKCE\H \ IN N 17 N>—©—CI ously to Example 1b Version B, 67 mg of the title nd was obtained from 66 mg of the compound prepared in Example 258d and 32 mg of 2-morpholinoethylamine in DMF. 1H-NMR (400 MHz, DMSO-da): 5 [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: e 258a: Methyl 2- {[1 -(tert-butoxycarbonyl)azetidin—3-yl]methyl} methoxy-2H- indazolcarboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ously to Example 1e, 448 mg of the title compound was obtained from 750 mg of the nd prepared in Example 214a and 546 mg of methanol. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.27 - 1.44 (9H), 3.01 - 3.22 (1H), 3.78 (5H), 3.85 - 3.99 (2H), 4.14 (3H), 4.64 (2H), 7.24 (1H), 7.51 (1H), 8.94 (1H).
Example 258b: Methyl 2-(azetidin—3-ylmethyl)methoxy-2H-indazolcarboxylate o O/CH3 800 mg of 258a were first placed in 40 ml acetone, treated with 40 ml of semiconcentrated hydrochloric acid, d until complete conversion and concentrated to dryness. Yield: 414 mg of the title compound. 1H-NMR (400 MHz, DMSO-ds): 8 [ppm]= 3.39 (1H), 3.79 (3H), 3.84 - 3.95 (2H), 3.96 - 4.07 (2H), 4.15 (3H), 4.72 (2H), 7.25 (1H), 7.52 (1H), 8.92 (1H).
Example 258C: Methyl 2- {[1-(4-chlorobenzoyl)azetidin—3-yl]methyl}methoxy-2H-indazol carboxylate O O,CH3 HSC\OJ\::E\N\ / N E Nx00 404 mg of 258b were first placed in 30 ml DCM at 0°C, treated with 0.21 ml of 4-chloro- benzoyl chloride and 0.75 ml of N—ethyldiisopropylamine and stirred at room temperature until complete conversion. For the work-up, the reaction solution was treated with saturated sodium hydrogen carbonate solution, extracted with DCM and the ed organic phases dried with sodium sulphate and concentrated to dryness. This yielded 608 mg of the title nd, which was used in the next step without further purification.
Example 258d: 2- {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} methoxy-2H-indazol dboxylic acid [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O O/CH3 N Eb Nx001 550 mg of 258c were first placed in 20 ml ethanol, treated with 20 ml of 2N sodium hydroxide and stirred until complete conversion. For the work-up, the reaction solution was adjusted to a pH of 3 with 1N hydrochloric acid, extracted with ethyl acetate, and the combined organic phases dried with sodium sulphate and concentrated to dryness. Yield after purification by column chromatography on silica gel with a hexane/ ethyl acetate gradient: 213 mg of the title compound. 1H-NMR (400 MHz, DMSO-da): 8 [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)methoxy-2H- indazolcarboxamide O O,CH3 HSCVO\/\NJ\<EE\H N N 17 Nxcw Analogously to e 1b Version B, 30 mg of the title compound was obtained from 66 mg of the nd prepared in Example 258d and 22 mg of 2-ethoxyethylamine in DMF. 1H-NMR (400 MHz, DMSO-da): 5 [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— l - yl) ethyl] methoxy-2H-indazolcarboxamide Fi‘ O O’CH3 NkaCf\H N N 7b ously to Example 1b Version B, 58 mg of the title nd was obtained from 66 mg of the nd prepared in Example 258d and 37 mg of 2-(3,3-difluoropyrrolidin-l-yl)ethyl- amine in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 1H—NMR (400 MHz, DMSO-da): 8 [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)piperidinyl]methyl} methoxy-N-(2-morpholino- ethyl)-2H-indazolcarboxamide OW / 3 0 o H \N N400' Analogously to Example 1b, Version B, 77 mg of the title compound was obtained from 100 mg of the compound prepared in e 261 e and 46 mg of 2-morpholinoethylamine in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 ng material was prepared as follows: Example 261a: Tert-butyl 4-[(5-bromomethoxy-2H-indazolyl)methyl]piperidin carboxylate Analogously to Example 1c, 5.57 g of the title compound was obtained from 9.65 g of 5-bromo- 4-methoxy-1H-indazole and 23.55 g of tert-butyl[(tosyloxy)methyl]piperidincarboxylate. 1H-NMR (400 MHZ, chloroform-d): 8 [ppm]: 1.16 - 1.31 (2H), 1.39 - 1.49 (9H), 1.52 - 1.64 (2H), 2.16 - 2.36 (1H), 2.56 - 2.80 (2H), 4.11 (5H), 4.26 (2H), 7.28 - 7.33 (1H), 7.34 - 7.39 (1H), 7.99 (1H).
Example 261b: Methyl 2-{[1-(tert-butoxycarbonyl)piperidinyl]methyl}methoxy-2H- indazolcarboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 1e, 1.1 g of the title compound was obtained from 2.4 g of the compound prepared in Example 261a and 1.63 g of methanol.
Example 261C: Methyl 4-methoxy(4-piperidylmethyl)-2H-indazolcarboxylate /CH3 HSC\O / \ /“ Analogously to Example 258b, from 1.1 g of the compound prepared in Example 26lb 1.1 g of the title compound was obtained, which was reacted in the next step t further purification.
Example 261 (1: Methyl 2- { [l -(4-chlorobenzoyl)piperidinyl]methyl} methoxy-2H-indazol- -carboxylate O O/CH3 HSC\O / \ IN Analogously to Example 258c, from 1.1 g of the compound ed in Example 26lc and 762 mg of 4-chlorobenzoyl chloride, 980 mg of the title nd was obtained after purification by column chromatography on silica gel with a hexane/ethyl acetate gradient. 1H-NMR (300 MHz, DMSO-da): 8 [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). e 261 e: 2- { [l -(4-chlorobenzoyl)piperidinyl]methyl} hoxy-2H-indazol carboxylic acid HO / ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 258d, 547 mg of the title compound was obtained from 980 mg of the compound prepared in e 261d. 1H-NMR (400 MHz, DMSO-ds): 8 [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)piperidinyl]methyl} methoxy-N—(2-methoxyethyl)- 2H-indazolcarboxamide O O,CHS /O\/\ H30 N / H N Analogously to Example 1b, Version B, 50 mg of the title compound was obtained from 100 mg of the compound prepared in Example 261 e and 26 mg of 2-methoxyethylamine in DMF. 1H-NMR (400 MHz, a): 8 [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)piperidinyl]methyl} methoxy-N—(2,2,2-trifluoro- ethyl)-2H-indazolcarboxamide O O’CH3 F\\/\N / F \ /N Analogously to Example 1b, Version B, 68 mg of the title compound was obtained from 100 mg of the compound prepared in Example 261 e and 35 mg of trifluoroethylamine in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)piperidinyl]methyl} -N-(2-ethoxyethyl)methoxy- 2H-indazolcarboxamide ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O O/CH3 HSCVO\/\N / \ IN Nx00 Analogously to Example lb, Version B, 60 mg of the title compound was obtained from 100 mg of the compound prepared in Example 261 e and 31 mg of 2-ethoxyethylamine in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)piperidinyl]methyl} methoxy-N— {2- [(trifluoro- methyl)sulphanyl] ethyl} -2H-indazolcarboxamide O O’CH3 FY3%N%\F H F “NbN O Analogously to Example lb, n B, 68 mg of the title compound was obtained from 100 mg of the compound prepared in Example 26le and 51 mg of 2-[(trifluoromethyl)sulphanyl]- ethylamine in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)( { l - ifluoromethoxy)benzoyl]piperidin yl} methyl)-2H-indazolcarboxamide Analogously to Example lb, Version B, 84 mg of the title compound was obtained from 100 mg of the compound prepared in e 266b and 89 mg of 4-(trifluoromethoxy)benzoic acid in DMF.
LC-MS: R1 = 1.16 min, MS (ES+): m/Z = 435 (M+H)+.
The starting material was prepared as follows: [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp e 266a: utyl 4-( {4-methoxy-5 - [N-(2-methoxyethyl)carbamoyl] -2H-indazol yl} methyl)piperidincarboxylate o O,CH3 HC’ \/\N / 3 H N $— 3 o >LCH3 3 g of compound 261a, 1.59 g of 2-methoxyethylamine, 1.87 g of molybdenum hexacarbonyl, 204 mg of tri-tert-butylphosphine tetrafluoroborate and 316 mg of palladium(ll) acetate were first ded in 100 ml 1,4-dioxan. Then 2.25 g of sodium carbonate and a few drops of water were added, and the mixture stirred for 25 mins at 140°C and 150 watts in the microwave. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel using a hexane/ ethyl acetate/ methanol gradient. Yield: 1.3 g of the title compound. 1H-NMR (300 MHz, DMSO-da): 8 [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 266b: 4-methoxy-N-(2-methoxyethyl)(4-piperidylmethyl)-2H-indazolcarbox- amide 0 o’ H30’ kaCE\ H N Analogously to Example 258b, from 1.3 g of the compound prepared in Example 266a, 1.48 g of the title compound was obtained, which was used in the subsequent reactions t further purification.
Example 267: 2-({1-[2-fluoro(trifluoromethyl)benzoyl]piperidinyl}methyl)methoxy-N- hoxyethyl)-2H-indazol-5 -carboxamide O O’CH3 /O\/\ H30 N / H N O >: F F [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example lb, Version B, 20 mg of the title compound was obtained from 100 mg of the compound prepared in Example 266b and 90 mg of 2-fluoro(trifluoromethyl)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)( { l - [4-(pentafluoro-W—sulphanyl)benzoyl] - piperidinyl} methyl)-2H-indazolcarboxamide O O’CH3 /O\/\ H c N / 3 H N N F\ IF O F F Analogously to Example lb, n B, 39 mg of the title compound was obtained from 100 mg of the compound prepared in Example 266b and 107 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid in DMF.
LC-MS: R1 = 1.18 min, MS (ES+): m/z = 577 .
Example 269: 4-methoxy-N—(2-methoxyethyl)[(1 - {4-[(trifluoromethyl)sulphanyl]benzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide Analogously to Example lb, Version B, 25 mg of the title compound was ed from 100 mg of the compound ed in Example 266b and 96 mg of 4-[(trifluoromethyl)sulphanyl]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [4-chloro-3 -(trifluoromethyl)benzoyl]piperidinyl} methyl)methoxy- D2-methoxyethyl)-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O O/CH3 /O\/\ HSC N / H N Analogously to Example lb, Version B, 27 mg of the title compound was obtained from 100 mg of the compound prepared in Example 266b and 97 mg of 4-chloro(trifluoromethyl)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-ds): 8 [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-chlorofluorobenzoyl)piperidinyl]methyl} methoxy-N-(2- methoxyethyl)-2H-indazolcarboxamide O O’CH3 /O\/\ H30 N / \ i“ ously to e lb, Version B, 17 mg of the title compound was obtained from 100 mg of the compound prepared in e 266b and 75 mg of 4-chlorofluorobenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [3 -fluoro(trifluoromethoxy)benzoyl]piperidinyl} methyl)methoxy- N-(2-methoxyethyl)-2H-indazolcarboxamide O/CH3 O”1:5? H N O >l—F F F [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Analogously to Example lb, Version B, 12 mg of the title nd was obtained from 100 mg of the compound prepared in Example 266b and 97 mg of 3-fluoro(trifluoromethoxy)benzoic acid in DMF.
LC-MS: R1 = 1.18 min, MS (ES+): m/Z = 553 (M+H)+. e 273: 4-methoxy-N-(2-methoxyethyl)( { l - [(1 -methyl- 1 H-indol-3 -yl)carbonyl] - piperidinyl} )-2H-indazolcarboxamide O’CH3 H N N / 3 Analogously to Example lb, Version B, 19 mg of the title compound was obtained from 100 mg of the compound prepared in Example 266b and 76 mg of yl-lH-indolcarboxylic acid in DMF. 1H—NMR (300 MHz, DMSO-da): 8 [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)piperidinyl]methyl} ethoxy-N-(2-methoxyethyl)- 2H-indazolcarboxamide H N \/N \ 0 r0 o>—©—CI Analogously to Example lb, Version B, 47 mg of the title compound was obtained from 110 mg of the compound prepared in Example 274c and 72 mg of 4-chlorobenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 274a: Tert-butyl 4- [(5-bromoethoxy-2H-indazolyl)methyl]piperidin- l - carboxylate [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp \/Nb >—o CH3 0 >LCH3 Analogously to Example 74c, 285 mg of the title compound was obtained from 484 mg of -bromoethoxy-lH-indazole and 1.11 g of tert-butyl[(5-bromoethoxy-2H-indazolyl)- methyl]piperidin- l -carboxylate. 1H-NMR (400 MHZ, chloroform-d): 8 [ppm]: 1.13 - 1.34 (2H), 1.46 (9H), 1.49 (3H), 1.56 - 1.63 (2H), 2.16 — 2.37 (1H), 2.54 — 2.80 (2H), 4.02 — 4.21 (2H), 4.26 (2H), 4.33 (2H), 7.28 — 7.43 (2H), 7.93 (1H).
Example 274b: Tert-butyl 4-( {4-ethoxy [N—(2-methoxyethyl)carbamoyl] -2H-indazolyl} - methyl)piperidin- l -carboxylate o o HSC’ \/\N / H N >—o CH3 0 CH Analogously to Example 266a, 235 mg of the title compound was obtained from 285 mg of the compound prepared in e 274a and 146 mg of 2-methoxyethylamine. 1H-NMR (300 MHz, DMSO-da): 8 [ppm]: 0.97 - 1.22 (2H), 1.29 - 1.56 (14H), 2.06 - 2.31 (1H), 2.59 - 2.86 (2H), 3.33 (3H), 3.49 (4H), 3.80 - 4.02 (2H), 4.30 (2H), 4.51 (2H), 7.26 (1H), 7.71 (1H), 8.31 (1H), 8.79 (1H).
Example 274C: 4-ethoxy-N—(2-methoxyethyl)(4-piperidylmethyl)-2H-indazolcarboxamide o o ch/ kaCE\ H N Analogously to Example 258b, from 235 mg of the compound prepared in e 274b, 237 mg of the title compound was obtained, which was reacted in the next step without r purification.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 275: 4-ethoxy-N-(2—methoxyethyl)( { l - [4-(pentafluoro-k6-sulphanyl)benzoyl] - piperidinyl} )-2H-indazolcarboxamide “W“ \ b O O r N F F I F O F F Analogously to Example lb, Version B, 30 mg of the title compound was obtained from 110 mg of the compound prepared in Example 274c and 113 mg of 4-(pentafluoro-7t6-sulphanyl)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 5 [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} ethoxy-N-(2—methoxyethyl)-2H- indazolcarboxamide H N H C \ 3 \O/\/ 0 r0 ‘b CH3 o%©—CI Analogously to Example lb, Version B, 25 mg of the title nd was obtained from 50 mg of the compound prepared in Example 276C and 35 mg of 4-chlorobenzoic acid in DMF. 1H-NMR (400 MHz, s): 8 [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 276a: Tert-butyl 3 - [(5 -bromoethoxy-2H-indazolyl)methyl] azetidin—l -carboxylate Br\::f\\ [1%N Analogously to Example 74c, 204 mg of the title nd was obtained from 500 mg of oethoxy-lH-indazole and 1.06 g of tert-butyl[(tosyloxy)methyl]azetidin—l- aboxylate.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (600 MHz, chloroform-d): 8 [ppm]= 1.44 (9H), 1.49 (3H), 3.14 - 3.30 (1H), 3.72 - 3.83 (2H), 4.07 (2H), 4.33 (2H), 4.59 (2H), 7.29 (1H), 7.37 (1H), 7.98 (1H).
Example 276b: Tert-butyl 3 -( {4-ethoxy methoxyethyl)carbamoyl] -2H-indazolyl} - methyl)azetidin— l -carboxylate 0 O O”*Cf H N N ‘b ;_o CH3 0 CH3 Analogously to e 266a, from 191 mg of the compound prepared in Example 276a and 105 mg of 2-methoxyethylamine, 121 mg of the title compound was obtained, which was reacted in the next step without further purification.
Example 276C: tidin—3-ylmethyl)ethoxy-N-(2-methoxyethyl)-2H-indazolcarbox- amide 0 O /O\/\ HSC N / H N N 7b Analogously to Example 258b, from 121 mg of the compound ed in Example 276b, 93 mg of the title compound was obtained, which was reacted in the next step without further purification.
Example 277: 4-ethoxy-N-(2-methoxyethyl)( { l - [4-(pentafluoro-k6-sulphanyl)benzoyl] - azetidin—3 -yl} methyl)-2H-indazolcarboxamide H N H3C\o/\/N \ ‘b O O V WF 0 F/ \F Analogously to Example 1b, Version B, 35 mg of the title compound was obtained from 50 mg of 276c and 56 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-ds): 8 [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).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 278: 2- {[1-(4-chlorobenzoyl)azetidin—3 -yl]methyl} methyl-N-(2-morpholinoethyl)- 2H-indazolcarboxamide fi 0 K/NwN)E<jf\H \ IN~14 Analogously to Example lb, Version B, 23 mg of the title compound was obtained from 100 mg of 278b and 66 mg of 4-chlorobenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 278a: Tert-butyl 3 -( {6-methyl [N—(2-morpholinoethyl)carbamoyl] dazol yl} methyl)azetidin— l -carboxylate ON\/\NH)E<:E\N%17% O >l—CH3 HSC Analogously to Example lb, Version B, 418 mg of the title compound was obtained from 410 mg of 178C and 232 mg of 2-morpholinoethylamine in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.36 (9H), 2.39 (3H), 2.44 (4H), 2.95 - 3.17 (1H), 3.24 - 3.43 (4H), 3.58 (4H), 3.64 - 3.79 (2H), 3.88 (2H), 4.62 (2H), 7.39 (1H), 7.68 (1H), 8.04 - 8.22 (1H), 8.45 (1H).
Example 278b: 2-(azetidin—3 -ylmethyl)methyl-N-(2-morpholinoethyl)-2H-indazol-5 - carboxamide HJ:::::\INNH Analogously to Example 258b, from 400 mg of the compound prepared in Example 278a, 372 mg of the title compound was obtained, which was reacted in the next step t further Dification.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 279: 6-methyl-N-(2-morpholinoethyl)( { 1 - [4-(trifluoromethoxy)benzoyl] azetidin—3 - yl} methyl)-2H-indazolcarboxamide OO%N)E<)TO H \ IN N >¢F Analogously to Example 1b, Version B, 44 mg of the title compound was obtained from 100 mg of 278b and 86 mg of 4-(trifluoromethoxy)benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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)( {1-[4-(pentafluoro-k6-sulphanyl)benzoyl]- azetidin—3 -yl} methyl)-2H-indazolcarboxamide OOVA/CfO \ IN N F \ 7F o F’ F ously to Example 1b, Version B, 37 mg of the title compound was obtained from 100 mg of 278b and 104 mg of 4-(pentafluoro-k6-sulphanyl)benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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)methyl-2 -( { 1 - [(1 -methyl- 1 H-indol-3 rbonyl] - piperidinyl} methyl)-2H-indazolcarboxamide /O\/\ H30 N / H N b CH N N/ 3 ously to e lb, Version B, 4.2 mg of the title compound was obtained from 150 mg of 205c and 119 mg of 1-methyl-1H-indolcarboxylic acid in DMF.
LC-MS: R1 = 1.01 min, MS (ES+): m/z = 489 (M+H)+.
D [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp e 282: N—(2-methoxyethyl)methyl( { l - [(1 -methyl-1H-indol-3 -yl)carbonyl] azetidin— 3 -yl} methyl)-2H-indazolcarboxamide O 6 N‘CH /N\ 3 H N HSC\O/\/N \ 0 CH3 Analogously to e lb, Version B, 35 mg of the title compound was ed from 175 mg of 117e and 122 mg of l-methyl-1H-indolcarboxylic acid in DMF.
LC-MS: R = 0.95 min, MS (ES+): m/z = 460 (M+H)+.
Example 283: 2-({1 - [4-(4-fluorophenoxy)benzoyl]piperidin—4-yl} methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide F Analogously to Example lb, Version B, 267 mg of the title compound was obtained from 250 mg of 71a and 246 mg of uorophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide Analogously to Example lb, Version B, 55 mg of the title compound was obtained from 100 mg of 71a and 105 mg of 4-(4-chlorophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.23 (2H), 1.34 - 1.72 (2H), 2.21 - 2.41 (1H), 2.54 ), 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 - . 3 (5H), 8.56 (1H), 8.84 (1H).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp ation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 285: 4-methyl( { 1 - methylphenoxy)benzoyl]piperidin—4-yl} methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide Analogously to Example 1b, Version B, 60 mg of the title compound was obtained from 100 mg of 71a and 97 mg of 4-(4-methylphenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 (slH).
Example 286 : 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidin—4-yl}methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazolcarboxamide Analogously to Example 1b, Version B, 39 mg of the title compound was obtained from 100 mg of 71a and 92 mg of 4-(4-fluorophenyl)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 {[1 -(4-morpholinobenzoyl)piperidinyl]methyl} -N-(2,2,2-trifluoro- ethyl)-2H-indazolcarboxamide Analogously to Example 1b, Version B, 45 mg of the title compound was obtained from 100 mg of 71a and 88 mg of 4-morpholinobenzoic acid in DMF.
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-ds): 5 [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). e 288: 4-methyl-N—(2,2,2-trifluoroethyl)[(1 - {4-[(trifluoromethyl)sulphanyl]benzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide . *Cob H21.
Analogously to Example lb, Version B, 67 mg of the title compound was obtained from 100 mg of 71a and 94 mg of 4-[(trifluoromethyl)sulphanyl]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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( { l - [(1 -methyl- 1 H-indol-3 -yl)carbonyl]piperidinyl} methyl)-N- (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide Analogously to Example lb, Version B, 43 mg of the title nd was ed from 100 mg of 71a and 74 mg of l-methyl-lH-indolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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( { l - [(1 -methyl- 1 H-indolyl)carbonyl]piperidinyl} methyl)-N- (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example lb, n B, 51 mg of the title compound was obtained from 100 mg of 71a and 74 mg of l-methyl-lH-indolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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) [(1 - {4- [4-(trifluoromethyl)phenoxy] - benzoyl} piperidin—4-yl)methyl] -2H-indazolcarboxamide O CH F\\/\N / F \ [N O C Analogously to Example lb, Version B, 156 mg of the title compound was obtained from 150 mg of 71a and 179 mg of 4-[4-(trifluoromethyl)phenoxy]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [(5 -fluoromethyl- 1 H-indolyl)carbonyl]piperidin—4-yl} ) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide Analogously to Example lb, n B, 28 mg of the title compound was obtained from 100 mg of 71a and 82 mg of o-l-methyl-lH-indolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [(5-methoxymethyl- 1 H-indolyl)carbonyl]piperidin—4-yl} methyl) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp o N Analogously to Example lb, Version B, 37 mg of the title compound was obtained from 100 mg of 71a and 87 mg of 5-methoxy-l-methyl-lH-indolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [(5 -chloromethyl- 1 H-indolyl)carbonyl]pip eridin—4-yl} ) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 xamide F *(Em O WCI H30 Analogously to Example lb, Version B, 43 mg of the title nd was obtained from 100 mg of 71a and 89 mg of 5-chloro-l-methyl-lH-indolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-ds): 8 [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-( { l - [(6-methoxymethyl- 1 H-indolyl)carbonyl]piperidin—4-yl} methyl) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide Analogously to Example lb, Version B, 36 mg of the title compound was obtained from 100 mg of 71a and 87 mg of 6-methoxy-l-methyl-lH-indolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 a”, 7.39 - 7.53 (2H), 8.57 (1H), 8.83 (tlH). ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 296 : 2- { [l -( l lylcarbonyl)pip eridin—4-yl]methyl} methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide F\‘AH N / \ IN F Analogously to Example lb, Version B, 43 mg of the title nd was obtained from 100 mg of 71a and 68 mg of indolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-ds): 5 [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: yl( { l - [(1 -methyl- 1 H-benzimidazolyl)carbonyl]piperidin—4-yl} - methyl)-N-(2,2,2-trifluoroethyl)-2H-indazolcarboxamide F *CQNb NHI)N 0 ,N Analogously to Example lb, Version B, 26 mg of the title compound was obtained from 100 mg of 71a and 75 mg of l-methyl-lH-benzimidazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-ds): 5 [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( { l - [(2-phenylthiazolyl)carbonyl]piperidin—4-yl} methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide O CH F\\/\NHkCfi\/ N F \N/b Analogously to Example lb, Version B, 53 mg of the title compound was obtained from 100 mg of 71a and 87 mg of 2-phenylthiazolcarboxylic acid in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-dg): 5 [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). e 299: 2- {[1-(benzoxazolylcarbonyl)piperidin—4-yl]methyl}methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 0 H3 F bN 0HI)O Analogously to Example lb, Version B, 20 mg of the title compound was obtained from 100 mg of 71a and 69 mg of benzoxazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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( { l - [(2-phenyloxazolyl)carbonyl]piperidin—4-yl} methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide ously to Example lb, Version B, 20 mg of the title compound was obtained from 100 mg of 71a and 80 mg of 2-phenyloxazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-dg): 8 [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) {[1-(4- {[5-(trifluoromethyl)pyridin—2-yl] - oxy} benzoyl)piperidin—4-yl]methyl} -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example lb, Version B, 23 mg of the title compound was obtained from 75 mg of 71a and 90 mg of 4- {[5-(trifluoromethyl)pyridinyl]oxy}benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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-(benzothiazolylcarbonyl)piperidinyl]methyl}methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide HI) Analogously to e 1b, n B, 35 mg of the title compound was obtained from 75 mg of 71a and 57 mg of hiazolcarboxylic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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) { [1 -(4- {[6-(trifluoromethyl)pyridin—3 -yl] - oxy} benzoyl)piperidinyl]methyl} -2H-indazolcarboxamide Analogously to Example lb, Version B, 42 mg of the title compound was obtained from 75 mg of 71a and 90 mg of the carboxylic acid prepared in Example 303b) in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-da): 5 [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 ed as follows: Example 303a: 4- {[6-(trifluoromethyl)pyridin-3 -yl] oxy} benzonitrile NZ—Q—O / \N 2.5 g of 5-bromo(trifluoromethyl)pyridine, 5.8 g of 4-hydroxybenzonitrile, 10.8 g of caesium carbonate and 1.87 g of molybdenum hexacarbonyl in 100 ml 1,4-dioxan were heated under reflux until complete conversion. The reaction mixture was d with water, extracted several times with ethyl acetate, and the combined organic phases washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by column chromatography on silica gel using a / ethyl e gradient. Yield: 1.35 g of the title compound. 1H-NMR (300 MHz, DMSO-da): 8 [ppm]= 7.35 (2H), 7.75 - 7.84 (1H), 7.89 - 8.03 (3H), 8.66 (1H).
Example 303b: 4- {[6-(trifluoromethyl)pyridin—2-yl]oxy}benzoic acid / \N FF 1.33 g of the compound prepared in Example 303a in 64 ml ethanol was treated with 32 ml of 40% potassium hydroxide solution and heated under reflux until complete sion. 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 sulphate and concentrated.
Yield: 1.32 g of the title compound. 1H-NMR (400 MHz, DMSO-ds): 8 [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) {[1-(4- {[6-(trifluoromethyl)pyridin—2-yl] - oyl)piperidinyl]methyl} -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 CH3 N / N2 C O / \ — F Analogously to Example 1b, Version B, 48 mg of the title compound was obtained from 75 mg of 71a and 90 mg of 4- {[6-(trifluoromethyl)pyridinyl]oxy}benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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({1-[(3 -phenyl-1,2,4-oxadiazolyl)carbonyl]piperidinyl}methyl)- N—(2,2,2-trifluoroethyl)-2H-indazolcarboxamide O CH F\)/\N / \ IN N N >—</ | o O,N Analogously to Example 1b, Version B, 40 mg of the title compound was obtained from 90 mg of 71a and 73 mg of 3-phenyl-1,2,4-oxadiazolcarboxylic acid in DMF. 1H-NMR (400 MHz, a): 8 [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)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide Analogously to Example 1b, Version B, 59 mg of the title compound was obtained from 110 mg of 71a and 101 mg of 4-(4-cyanophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.17 - 1.34 (2H), 1.35 - 1.70 (2H), 2.18 - 2.41 (1H), g), 7.794 (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- 7.94 (2H), 8.56 (s1H), 8.81 (s1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Example 307: 2-( { 1 - [4-(3 -fluorophenoxy)benzoyl]piperidin—4-yl} methyl)methyl-N—(2,2,2- trifluoroethyl)-2H-indazolcarboxamide Analogously to Example 1b, Version B, 40 mg of the title compound was obtained from 100 mg of 71a and 89 mg of 4-(3-fluorophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)[(1-{4-[3-(trifluoromethyl)phenoxy]- benzoyl} piperidin—4-yl)methyl] -2H-indazolcarboxamide Analogously to e 1b, Version B, 47 mg of the title compound was obtained from 100 mg of 71a and 119 mg of trifluoromethyl)phenoxy]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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( { 1 - [(5-phenyloxazolyl)carbonyl]piperidin—4-yl} methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide Analogously to e 1b, Version B, 10 mg of the title compound was obtained from 100 mg D71a and 73 mg of 5-phenyloxazolcarboxylic acid in DMF. ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 1H-NMR (400 MHz, DMSO-ds): 5 [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 3 1 0: 2-[(1- {4- [(5 -cyanopyridinyl)oxy]benzoyl} piperidinyl)methyl] methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide Analogously to Example 1b, Version B, 47 mg of the title compound was obtained from 100 mg of 71a and 119 mg of 4-[3-(trifluoromethyl)phenoxy]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 3 1 1: 2- [(1 - {4- [(5-chloropyridinyl)oxy]benzoyl} piperidinyl)methyl] methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide Analogously to Example 1b, Version B, 72 mg of the title compound was obtained from 100 mg of 71a and 96 mg of 4-[(5-chloropyridin—2-yl)oxy]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 3 1 2: 4-methyl-N—(2,2,2-trifluoroethyl) [(1 - {4- [5 -(trifluoromethyl)pyridinyl] - benzoyl} piperidin—4-yl)methyl] -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 H3 ._ .
Analogously to Example lb, Version B, 83 mg of the title compound was ed from 100 mg of 71a and 103 mg of trifluoromethyl)pyridin—2-yl]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 3 13: 2-( { l - [4-(2,4-difluorophenoxy)benzoyl]piperidin—4-yl} )methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide Analogously to Example lb, Version B, 87 mg of the title compound was obtained from 100 mg of 71a and 96 mg of 4-(2,4-difluorophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 3 14: 2-( { l - [4-(3 ,4-difluorophenoxy)benzoyl]piperidin—4-yl} methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide FY\N / F \ [N C O O Q.
Analogously to Example lb, Version B, 48 mg of the title compound was obtained from 100 mg of 71a and 96 mg of 4-(3,4-difluorophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.24 (2H), 1.36 - 1.72 (2H), 2.19 - 2.42 (1H), 2.54 fl), 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 - 1 (2H), 7.21 (1H), 7.29 (1H), 7.35 - 7.55 (4H), 8.55 (1H), 8.81 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 3 1 5: 4-methyl-N—(2,2,2-trifluoroethyl) [(1 - {[4'-(trifluoromethyl)biphenylyl] - carbonyl} dinyl)methyl] -2H-indazolcarboxamide O H FWAN / F \ [N N bfi F O ”.FI I Analogously to Example lb, Version B, 32 mg of the title compound was obtained from 100 mg of 71a and 102 mg of 4’-(trifluoromethyl)biphenylcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)piperidinyl]methyl} methyl-N-(2,2,2-trifluoro- ethyl)-2H-indazolcarboxamide >—< >—Br F 4. JO F>l\/NH N 0 CH3 ously to Example 1b, n B, 6.96 g of the title compound was obtained from 5.61 g 71a and 2.89 g of 4-bromobenzoic acid. 1H-NMR (300 MHz, DMSO-ds): 8 [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 3 1 7: 2-( { l - [4-(5-chloropyridinyl)benzoyl]piperidinyl} methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide /\CI N N— . ,9 5k) N N \ 0 CH3 80 mg of the aryl bromide prepared in Example 316 together with 32 mg of (5-chloropyridin—2- yl)boronic acid was first placed in 1 ml tetrahydrofuran, d with 17.3 mg of 1,1 ’-bis(diphenylphosphino)ferrocenodichloropalladium(11) and 0.17 ml of 1M potassium Dbonate solution and heated in the microwave for 10 minutes at 120°C (100 watts). After fresh addition of 11 mg of (5-chloropyridin—2-yl)boronic acid and 17.3 mg of the palladium(11) [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp catalyst, the reaction e was again heated in the microwave for 10 minutes at 120°C (100 watts) until complete conversion. The reaction mixture was concentrated. After HPLC ation, this yielded 15 mg of the title compound. 1H-NMR (300 MHz, DMSO-ds): 8 [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). e 3 18: 2-( { l - [(4'-methoxy-2'-methylbiphenylyl)carbonyl]piperidinyl} methyl) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide 0 I O Analogously to Example 317, 50 mg of the title compound was ed from 125 mg of 316 and 53 mg of (4-methoxymethyl-phenyl)boronic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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 3 19: 4-methyl( { l - [4-(6-methylpyridin—3 -yl)benzoyl]piperidinyl} methyl)-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide _ N N9 5K)N \ 0 CH3 Analogously to Example 317, 37 mg of the title compound was obtained from 125 mg of 316 and 44 mg of (6-methylpyridin—3-yl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-ds): 8 [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-( { l - uoro-2'-methoxybiphenylyl)carbonyl]piperidinyl} methyl) methyl-N—(2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp HSC—O Analogously to Example 317, 60 mg of the title compound was obtained from 125 mg of 316 and 75 g of (4-fluoromethoxyphenyl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [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: yl-N—(2,2,2-trifluoroethyl) [(1 - {4- [6-(trifluoromethyl)pyridin-3 -yl] - benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide — F F Ap BK) N N \ 0 CH3 Analogously to Example 317, 45 mg of the title compound was ed from 125 mg of 316 and 84 mg of [6-(trifluoromethyl)pyridin—3-yl]boronic acid under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [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-( { l - [4-(6-methoxypyridin-3 -yl)benzoyl]piperidinyl} methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide ’CH3 F Ap 0 CH3 Analogously to Example 317, 54 mg of the title compound was ed from 125 mg of 316 and 68 mg of (6-methoxypyridin—3-yl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [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).
D [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 323: 2-({1-[4-(6-methoxypyridinyl)benzoyl]piperidin—4-yl}methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide / \ N N— o—CH3 F /N\ 5K) N N \ 0 CH3 Analogously to Example 317, 55 mg of the title compound was ed from 125 mg of 316 and 49 mg of (6-methoxypyridin—2-yl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [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: yl( { 1 - [4-(5-methylpyridin—2-yl)benzoyl]piperidinyl} methyl)-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide N N— 5K) N9 N \ 0 CH3 Analogously to e 317, 9 mg of the title compound was obtained from 125 mg of 316 and 44 mg of (5-methylpyridin—2-yl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-ds): 8 [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-fluoropyridinyl)benzoyl]piperidin—4-yl}methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide N N— F A JO :X/H N 0 CH3 Analogously to Example 317, 35 mg of the title compound was obtained from 125 mg of 316 and 45 mg of (5-fluoropyridinyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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), D5 (1H), 8.04 - 8.17 (3H), 8.57 (1H), 8.68 (1H), 8.83 (1H).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Example 326 : 2-({1-[4-(5-methoxypyridinyl)benzoyl]piperidin—4-yl}methyl)methyl-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide OMN_ [OHS O F Ap 0 CH3 Analogously to Example 317, 94 mg of the title compound was obtained from 125 mg of 316 and 49 mg of (5-methoxypyridin—2-yl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [ppm]= 1.19 - 1.36 (2H), 1.37 - 1.69 (2H), 2.28 - 2.40 (1H), 2.54 (3H), 2.73 - 3.19 (2H), 3.48 - 3.79 (1H), 3.88 (3H), 4.07 (2H), 4.38 (3H), 7.20 (1H), 7.38 - 7.55 (4H), 7.96 (1H), 8.07 (2H), 8.39 (1H), 8.57 (1H), 8.82 (1H).
Example 327: 4-methyl({1-[4-(2-methylpyrimidin—5-yl)benzoyl]piperidin—4-yl}methyl)-N— (2,2,2-trifluoroethyl)-2H-indazol-5 -carboxamide N _N . / \N FX/HN \ 0 CH3 Analogously to e 317, 46 mg of the title compound was obtained from 125 mg of 316 and 102 mg of (2-methylpyrimidin—5-yl)boronic acid pinacol ester under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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) [( 1 - {4- [2-(trifluoromethyl)pyrimidin—5-yl] - benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide F J\ 5K) N N \ 0 CH3 Analogously to Example 317, 34 mg of the title compound was obtained from 125 mg of 316 and 89 mg of [2-(trifluoromethyl)pyrimidinyl]boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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 D1), 7.47 (1H), 7.57 (2H), 7.98 (2H), 8.57 (1H), 8.84 (1H), 9.44 (2H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 329: 4-methyl-N-(2,2,2-trifluoroethyl) [(1 - {4- [6-(trifluoromethyl)pyridinyl] - benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide / \ N N— F F F Ap 0 CH3 Analogously to Example 317, 70 mg of the title compound was obtained from 125 mg of 316 and 121 mg of [6-(trifluoromethyl)pyridin—2-yl]boronic acid pinacol ester under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [4-(4-cyanophenoxy)benzoyl]piperidinyl} methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide H \N HSC\O/\/N \ 0 CH3 Analogously to Example lb, n B, 151 mg of the title compound was obtained from 213 mg of 71a and 153 mg of 4-(4-cyanophenoxy)benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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 33 1: ethoxyethyl)methyl-2 -( { l - [(1 -methyl- 1 H-indol-3 -yl)carbonyl] - dinyl} methyl)-2H-indazolcarboxamide O CH /O\/\ H30 N / H \/N N 3 / N/ Analogously to Example lb, n B, 26 mg of the title compound was obtained from 38 mg fi7la and 36 mg of l-methyl-lH-indolcarboxylic acid in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-da): 5 [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)piperidinyl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide Analogously to Example lb, Version B, 498 mg of the title compound was obtained from 807 mg of 71a and 788 mg of omethylbenzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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 rt-butylbenzoyl)piperidin—4-yl]methyl} -N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide O H30 CH3 Analogously to Example lb, n B, 50 mg of the title compound was obtained from 100 mg of 71a and 81 mg of 4-tert-butylbenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [4-(1 -hydroxy- l -methylethyl)benzoyl]piperidin—4-yl} methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide O : H30 CH3 Dalogously to Example lb, Version B, 28 mg of the title compound was obtained from 100 mg of 71a and 82 mg of 4-(l-hydroxy-l -methylethyl)benzoic acid in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-ds): 5 [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). e 335: 2- {[1-(4-cyclohexylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide O CH H30] \/\N / H \/N Analogously to Example lb, Version B, 75 mg of the title compound was obtained from 100 mg of 71a and 93 mg of 4-cyclohexylbenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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) {[1-(6-methoxynaphthoyl)piperidinyl]methyl} methyl-2H-indazolcarboxamide Analogously to Example lb, Version B, 23 mg of the title compound was obtained from 100 mg of 71a) and 92 mg of 6-methoxy-naphthalen—2-carboxylic acid in DMF. 1H-NMR (400 MHz, a): 8 [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)methyl( { l - [(2-phenylthiazolyl)carbonyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example lb, Version B, 36 mg of the title compound was obtained from 100 mg of 71a and 93 mg of 2-phenylthiazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)methyl( { l - [(1 -methyl- 1 H-benzimidazolyl)carbonyl] - dinyl} methyl)-2H-indazolcarboxamide H30’ \/\N / H \/N N N Analogously to Example lb, Version B, 39 mg of the title compound was obtained from 100 mg of 71a and 80 mg of l-methyl-lH-benzimidazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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). e 339: N-(2-methoxyethyl)methyl( { l - [(2-phenyloxazol-5 -yl)carbonyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide Analogously to Example lb, n B, 30 mg of the title compound was obtained from 100 mg of 71a and 86 mg of 2-phenyloxazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-(benzoxazolylcarbonyl)piperidinyl]methyl}-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 CH3 0Wkéf H N NHI)N 0 O Analogously to Example lb, Version B, 37 mg of the title compound was obtained from 100 mg of 71a and 84 mg of benzoxazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 5 [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). e 341: 2-( { l - [4-(1 -cyano- l -methylethyl)benzoyl]piperidinyl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide H30” \/\N / \ IN N W 0 : H30 CH3 Analogously to Example lb, Version B, 20 mg of the title compound was obtained from 100 mg of 71a and 86 mg of 4-(l-cyano-l-methylethyl)benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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)methyl( { l - rimidinyloxy)benzoyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide Analogously to Example lb, Version B, 37 mg of the title compound was obtained from 100 mg of 71a and 98 mg of 4-(2-pyrimidinyloxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 343: N—(2-methoxyethyl)methyl( {1-[4-(3 -pyridyloxy)benzoyl]piperidin yl} methyl)-2H-indazolcarboxamide O CH H30’ \/\N / \ IN Analogously to Example 1b, Version B, 7 mg of the title nd was obtained from 75 mg of 71a and 73 mg of 4-(3-pyridyloxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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). e 344: N—(2-methoxyethyl) {[1-(7-methoxynaphthoyl)piperidinyl]methyl} methyl-2H-indazolcarboxamide O CH H C’ \/\N Analogously to Example 1b, Version B, 28 mg of the title compound was obtained from 75 mg of 71a and 69 mg of the ylic acid prepared in Example 344c) in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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 s: Example 344a: : 7-methoxynaphthalenyl-1,1,2,2,3,3,4,4,4-nonafluorobutan—1-sulphonate F F FW‘/0 O\ s CH3 F F n .12 g of 7-methoxynaphthol were dissolved in 50 ml toluene and cooled to 0°C. 30.7 ml of N,N—diisopropylethylamine and 17.6 ml of nonafluorobutanesulphonyl fluoride were successively added dropwise to this and the reaction mixture was then stirred at room ture until complete conversion. The reaction mixture was poured into 600 ml of saturated ammonium chloride solution, the deposited brown oil ted and the aqueous phase [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 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 / ethyl acetate gradient. Yield: 11.45 g of the title compound. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 3.89 (3H), 7.28 (1H), 7.41 (1H), 7.52 (1H), 7.90 - 8.00 (2H), 8.05 (1H).
Example 344b: Methyl 7-methoxynaphthalencarboxylate H C O Analogously to Example 1e, 2.34 g of the title compound was obtained from 11.0 g of 344a and 8.8 ml of methanol. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 3.89 (3H), 3.91 (3H), 7.31 (1H), 7.57 (1H), 7.82 (1H), 7.94 (2H), 8.54 (1H).
Example 344C: 7-methoxynaphthalencarboxylic acid H0 00 \CHs Analogously to Example 258d, 1.27 g of the title compound was obtained from 2.0 g of 344b. 1H-NMR (300 MHz, DMSO-ds): 8 [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: ethoxyethyl)methyl {[1-(4- {[5-(trifluoromethyl)pyridinyl] oxy} - benzoyl)piperidinyl]methyl} -2H-indazolcarboxamide Analogously to Example lb, n B, 221 mg of the title compound was obtained from 200 mg of 71a and 232 mg of 4- {[5-(trifluoromethyl)pyridinyl]oxy}benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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), D8 (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).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 346 : N-(2-methoxyethyl)methyl({1-[4-(2-pyridyloxy)benzoyl]piperidin—4-yl}- methyl)-2H-indazolcarboxamide 0 CH3 0%~*C€ H N o <\/ \> ously to Example 1b, Version B, 29 mg of the title compound was obtained from 100 mg of 71a and 98 mg of 4-(2-pyridyloxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-ds): 5 [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)methyl { [1 -(4- {[4-(trifluoromethyl)pyrimidinyl] - oxy} benzoyl)piperidin—4-yl]methyl} -2H-indazolcarboxamide Analogously to Example 1b, Version B, 11 mg of the title nd was obtained from 75 mg of 71a and 97 mg of 4- {[4-(trifluoromethyl)pyrimidin—2-yl]oxy}benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-dg): 8 [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 -(benzothiazolylcarbonyl)piperidinyl]methyl} -N-(2-methoxyethyl) methyl-2H-indazolcarboxamide O SI) Analogously to Example 1b, Version B, 28 mg of the title compound was obtained from 75 mg of 71a and 61 mg of benzothiazolcarboxylic acid in DMF.
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-ds): 5 [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)methyl {[1-(4- {[6-(trifluoromethyl)pyridin-3 -yl] oxy} - benzoyl)piperidin—4-yl]methyl} -2H-indazolcarboxamide Analogously to Example lb, Version B, 34 mg of the title nd was obtained from 75 mg of7la and 96 mg of 303b in DMF. 1H-NMR (400 MHz, DMSO-ds): 8 [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). e 350: N—(2-methoxyethyl)methyl {[1-(4- {[6-(trifluoromethyl)pyridinyl] oxy} - benzoyl)piperidin—4-yl]methyl} -2H-indazolcarboxamide Analogously to Example lb, Version B, 36 mg of the title compound was obtained from 100 mg of 71a and 129 mg of 4- {[6-(trifluoromethyl)pyridin—2-yl]oxy}benzoic acid in DMF. 1H—NMR (400 MHz, DMSO-ds): 5 [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-( { l - [(4'-methoxybiphenylyl)carbonyl]piperidinyl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 CH3 0”*CF H N ously to Example lb, Version B, 15 mg of the title compound was obtained from 100 mg of 71a and 104 mg of 4’-methoxy-biphenylcarboxylic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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)methyl( { l - [(3 l- l ,2,4-oxadiazolyl)carbonyl] - piperidinyl} methyl)-2H-indazolcarboxamide Analogously to Example lb, Version B, 12 mg of the title compound was obtained from 100 mg of 71a and 78 mg of 3-phenyl-l,2,4-oxadiazolcarboxylic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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: ethoxyethyl)methyl({l-[4-(3,4,5,6-tetrahydro-2H-pyran—4-yloxy)- benzoyl]pipoeridinyl}methyl)-2H-indazolcarboxamide Analogously to Example lb, Version B, 21 mg of the title compound was obtained from 100 mg of 71a and 91 mg of 4-(3,4,5,6-tetrahydro-2H-pyran—4-yloxy)benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp Example 354: N-(2-methoxyethyl)methyl( { l - [(5 -phenyloxazolyl)carbonyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide ously to Example lb, Version B, 10 mg of the title compound was obtained from 100 mg of 71a and 77 mg of 5-phenyl-oxazolcarboxylic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)methyl[(1- {4- [3 -(trifluoromethyl)phenoxy]benzoyl} - piperidinyl)methyl] dazolcarboxamide H N HSC\0/\/N \ 0 CH3 : O 0 W:F Analogously to Example lb, Version B, 40 mg of the title compound was obtained from 100 mg of 71a and 115 mg of 4-[(3-(trifluoromethyl)phenoxy]benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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)methyl-2H-indazolcarboxamide HgC’OwN/KEEE\0 H3 \ IN O C Q\\NN Analogously to Example lb, Version B, 15 mg of the title compound was obtained from 100 mg D71a and 98 mg of 4-[(5-cyanopyridinyl)oxy]benzoic acid in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-da): 5 [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)methyl-2H-indazolcarboxamide Analogously to Example lb, Version B, 40 mg of the title nd was obtained from 100 mg of 71a and 102 mg of 4-[(5-chloropyridin—2-yl)oxy]benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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-( { l - [4-(2,4-difluorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide 0 H3 H30] \/\N / H N O C O G Analogously to Example lb, Version B, 22 mg of the title compound was obtained from 100 mg of 71a and 102 mg of 4-(2,4-difluorophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [4-(3 uorophenoxy)benzoyl]piperidinyl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 CH3 H30’ V\N / H \fl N2 0 O O Q.
Analogously to Example lb, n B, 23 mg of the title compound was obtained from 100 mg of 71a and 102 mg of -difluorophenoxy)benzoic acid in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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)methyl [(1 - {[4'-(trifluoromethyl)biphenylyl] - carbonyl} piperidin—4-yl)methyl] -2H-indazolcarboxamide 0 H3 Ho” \/\N / 3 H N Analogously to Example lb, Version B, 44 mg of the title compound was obtained from 100 mg of 71a and 109 mg of 4’-(trifluoromethyl)biphenylcarboxylic acid in DMF LC-MS: R1 = 1.28 min, MS (ES+): m/z = 579 (M+H)+.
Example 361: 2-( { l - [4-(3 -fluorophenoxy)benzoyl]piperidin—4-yl} )-N—(2-methoxyethyl)- yl-2H-indazolcarboxamide H N HSC‘o/\/N \ b 0 CH3 N’; C 0 OD.
Analogously to Example lb, Version B, 43 mg of the title compound was obtained from 100 mg of 71a and 95 mg of 4-(3-fluorophenoxy)benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp e 362: 2- {[1-(2-fluoroisopropoxybenzoyl)piperidinyl]methyl}-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 H30 N >—CH3 Analogously to Example 1b, Version B, 31 mg of the title compound was obtained from 75 mg of 71a and 41 mg of 2-fluoroisopropoxybenzoic acid. 1H-NMR (300 MHz, chloroform-d): 8 [ppm]: 1.21 - 1.42 (8H), 1.51 (1H), 1.69 (1H), 2.38 (1H), 2.56 - 2.80 (4H), 2.87 - 3.08 (1H), 3.36 (3H), 3.48 - 3.73 (4H), 4.28 (2H), 4.51 (1H), 4.74 (1H), .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 -3 ',4'-dimethylbiphenylyl)carbonyl]piperidinyl} methyl)-N- (2-methoxyethyl)methyl-2H-indazolcarboxamide H N H,c\O/\/N \ 0 CH3 0 0 CH3 F CH3 Analogously to Example 1b, Version B, 35 mg of the title compound was obtained from 75 mg of 71a and 50 mg of 3-fluoro-3',4'-dimethylbiphenylcarboxylic acid. 1H-NMR (300 MHz, chloroform-d): 8 [ppm]: 1.25 - 1.51 (2H), 1.57 (1H), 1.76 (1H), 2.25 - 2.37 (6H), 2.45 (1H), 2.61 — 2.71 (3H), 2.79 (1H), 3.06 (1H), 3.40 (3H), 3.53 — 3.77 (5H), 4.34 (2H), 4.83 (1H), 6.04 — 6.30 (1H), 7.15 — 7.47 (7H), 7.55 (1H), 7.98 (1H).
Example 364: 2-({1-[(2',3 -difluoro-4'-methoxybiphenylyl)carbonyl]piperidin—4-yl} methyl)- ethoxyethyl)methyl-2H-indazolcarboxamide H N HSC\O/\/N \ 0 CH3 O O / O F F Analogously to Example 1b, Version B, 28 mg of the title compound was obtained from 90 mg of 71a and 65 mg of 3,2'-difluoro-4'-methoxybiphenylcarboxylic acid. 1H-NMR (300 MHz, chloroform-d): 8 [ppm]: 1.25 - 1.50 (2H), 1.50 - 1.84 (2H), 2.44 (1H), 2.66 (3H), 2.78 (1H), 3.03 (1H), 3.39 (3H), 3.53 - 3.76 (5H), 3.85 (3H), 4.23 - 4.45 (2H), 4.83 (1H), n7 (1H), 6.64 - 6.92 (2H), 7.18 - 7.48 (5H), 7.54 (1H), 7.97 (1H).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 365: 2-( { 1 - [4-(difluoromethoxy)benzoyl]piperidinyl} methyl)-N—(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide H N H3C\O/\/N \ 0 CH3 F: F o : Analogously to Example 1b, Version B, 23 mg of the title compound was obtained from 75 mg of 71a and 38 mg of 4-(difluoromethoxy)benzoic acid. 1H-NMR (300 MHz, chloroform-d): 8 [ppm]: 1.26 (2H), 1.59 (2H), 2.26 - 2.49 (1H), 2.62 (3H), 2.84 (2H), 3.36 (3H), 3.43 (1H), 3.50 - 3.96 (4H), 4.29 (2H), 4.46 - 5.02 (1H), 6.13 - 6.25 (1H), 6.26 - 6.82 (1H), 7.11 (2H), 7.22 - 7.43 (3H), 7.50 (1H), 7.93 (1H).
Example 366 : 2-( { 1 - fluorophenoxy)benzoyl]piperidinyl} methyl)-N—(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide H.99N HSC\O/\/N \ 0 CH3 b . d 120 mg of compound 54, 26 mg of o-fluorophenol, 152 mg of caesium carbonate, 6.7 mg of copper(1) bromide and 3.2 mg of (2-pyridyl)acetone were suspended in 6 ml dimethyl sulphoxide and stirred for 3 days at 80°C. The reaction mixture was filtered, the filter cake washed with water and ethyl acetate, and the aqueous phase extracted several times with ethyl acetate. The combined c phases were dried with sodium sulphate and trated. The residue was purified by HPLC and 12 mg of the title compound was obtained. 1H-NMR (300 MHz, chloroform-d): 8 [ppm]: 1.16 - 1.47 (2H), 1.62 (2H), 2.43 (1H), 2.66 (3H), 2.85 (2H), 3.39 (3H), 3.53 — 3.74 (4H), 3.79 — 4.19 (1H), 4.33 (2H), 4.47 — 5.02 (1H), 6.15 (1H), 6.96 (2H), 7.07 — 7.23 (3H), 7.30 — 7.45 (3H), 7.54 (1H), 7.96 (1H).
Example 367: [(4'-cyano-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide O CH H30” \/\N / galogously to e 317, 40 mg of the title compound was obtained from 80 mg of 54 andmg of (2-methylcyanophenyl)boronic acid under reflux. ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-ds): 8 [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 -chloropyridinyl)benzoyl]piperidinyl} methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 0 CH3 H30/ \AN / OH >—<\N_/>—CI 200 mg of the aryl bromide prepared in Example 54 together with 187 mg of (5-chloropyridin yl)boronic acid pinacol ester were first placed in 3 ml DMF, d with 48 mg of 1,1’-bis(diphenylphosphino)ferrocenodichloropalladium(ll), 39 mg of copper(l)chloride 254 mg of caesium carbonate and 22 mg of 1,1’-bis(diphenylphosphino)ferrocene and heated for ca. 1 day at 70°C, until further progress of the reaction could no longer be ed. The reaction mixture was treated with water and saturated sodium hydrogen carbonate solution, treated several times with ethyl acetate, and the combined organic phases dried with sodium sulphate and concentrated. After HPLC purification, this yielded 92 mg of the title compound. 1H-NMR (400 MHz, DMSO-ds): 8 [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)methyl [(1 - {4- [6-(trifluoromethyl)pyridinyl] - l} piperidinyl)methyl] -2H-indazolcarboxamide O CH HSC’ \AN / \N/ F WF_F \ / Analogously to Example 317, 33 mg of the title compound was obtained from 100 mg of 54 and 80 mg of [6-(trifluoromethyl)pyridinyl]boronic acid pinacol ester under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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). mple 370: N—(2-methoxyethyl)( { 1 - ethoxy—2'-methylbiphenylyl)carbonyl] - piperidinyl} methyl)methyl-2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 CH3 H N 0 CH Analogously to Example 317, 52 mg of the title compound was obtained from 100 mg of 54 and 48 mg of (4-methoxymethylphenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [(4'-chloro-2'-methylbiphenylyl)carbonyl]piperidinyl} methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide O CH H30’ \/\N / 2M0 Analogously to Example 317, 43 mg of the title compound was ed from 100 mg of 54 and 50 mg of oromethylphenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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'-(l -cyano- l lethyl)biphenylyl]carbonyl} piperidinyl)- methyl] -N-(2-methoxyethyl)methyl-2H-indazolcarboxamide Analogously to Example 317, 67 mg of the title compound was obtained from 100 mg of 54 and 55 mg of [4-(l-cyano-l -methylethyl)phenyl]boronic acid under reflux. 1H-NMR (400 MHz, a): 8 [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).
Dample 373: N—(2-methoxyethyl)( { l - [4-(5-methoxypyridin—2-yl)benzoyl]piperidinyl} - methyl)methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp 0 CH3 H30’ kaCE\ H N H >—<\ />—o\ o CH Analogously to Example 368, 12 mg of the title compound was obtained from 200 mg of 54 and 183 mg of (5-methoxypyridin—2-yl)boronic acid l ester under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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)methyl[(1-{4-[6-(trifluoromethyl)pyridinyl]- benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide 0 CH3 H30/ \/\N [\j C :_N F F \ / O F Analogously to Example 317, 37 mg of the title compound was obtained from 100 mg of 54 and 56 mg of [2-(trifluoromethyl)pyridinyl]boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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)( { l - [4-(6-methoxypyridin—3 -yl)benzoyl]piperidinyl} - methyl)methyl-2H-indazolcarboxamide 0 CH3 0“ACT H N \ / \ o CH Analogously to Example 317, 50 mg of the title compound was obtained from 100 mg of 54 and 47 mg of (2-methoxypyridin—5-yl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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), D6 (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).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 376 : 2-({1-[(4'-fluoro-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide Analogously to Example 317, 261 mg of the title compound was obtained from 300 mg of 54 and 135 mg of romethylphenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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)methyl( { 1 - [4-(6-methylpyridin-3 -yl)benzoyl]piperidin- 4-yl} methyl)-2H-indazolcarboxamide OH >—<\ >—_ CH3 Analogously to Example 317, 45 mg of the title nd was obtained from 80 mg of 54 and 32 mg of (2-methylpyridin—5-yl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [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)({1-[4-(6-methoxypyridin—2-yl)benzoyl]piperidin yl} methyl)methyl-2H-indazolcarboxamide HSC/ \/\N / \ )1 O—CH3 \ / Analogously to Example 317, 30 mg of the title compound was obtained from 100 mg of 54 and 45 mg of (6-methoxypyridin—2-yl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [ppm]= 1.26 (2H), 1.35 - 1.68 (2H), 2.32 (1H), 2.52 (3H), D0 - 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).
[Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 379: N-(2-methoxyethyl)methyl( { 1 - [4-(2-methylpyrimidinyl)benzoyl] - piperidinyl} methyl)-2H-indazolcarboxamide N _ OW¥N Analogously to Example 317, 36 mg of the title compound was obtained from 100 mg of 54 and 64 mg of (2-methylpyrimidinyl)boronic acid pinacol ester under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [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). e 380: 2-({1-[(4'-fluoro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide \N b [CH3 Analogously to Example 317, 47 mg of the title compound was obtained from 100 mg of 54 and 50 mg of (4-fluoromethoxyphenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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: [(4'-chloro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N- (2-methoxyethyl)methyl-2H-indazolcarboxamide O CH H30’ \/\N / H N N ’CH3 O O 0' Analogously to Example 317, 87 mg of the title compound was obtained from 100 mg of 54 and 54 mg of (4-fluoromethoxyphenyl)boronic acid under reflux.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, s): 8 [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)methyl [( l - {4- [2-(trifluoromethyl)pyrimidin—5-yl] - benzoyl} piperidin—4-yl)methyl] -2H-indazolcarboxamide _ .
O N/ F F Analogously to Example 317, 14 mg of the title compound was obtained from 100 mg of 54 and 56 mg of [2-(trifluoromethyl)pyrimidin—5-yl]boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - hloro-2'-fluorobiphenylyl)carbonyl]piperidin—4-yl} methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide o CH H30” \/\N / Analogously to Example 317, 51 mg of the title compound was obtained from 100 mg of 54 and 51 mg of (4-chlorofluorophenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [(2'-chloro-4'-fluorobiphenylyl)carbonyl]piperidin—4-yl} methyl)-N—(2- methoxyethyl)methyl-2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Analogously to Example 317, 26 mg of the title compound was obtained from 100 mg of 54 and 51 mg of (2-chlorofluorophenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [4-(5 -chloropyridin—3 -yl)benzoyl]pip eridinyl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide O CH H30’ \/\N / H \/N Analogously to e 317, 22 mg of the title compound was obtained from 100 mg of 54 and 46 mg of (5-chloropyridin—3-yl)boronic acid under reflux. 1H-NMR (300 MHz, DMSO-ds): 8 [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-( { l - fluoropyridin—3 -yl)benzoyl]piperidinyl} methyl)-N-(2-methoxy- ethyl)methyl-2H-indazolcarboxamide HKCEENbN _N \ / Analogously to e 317, 57 mg of the title compound was obtained from 100 mg of 54 and 41 mg of (5-fluoropyridin—3-yl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-ds): 8 [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)methyl[(1- {4-[5-(trifluoromethyl)pyridinyl]- UZOYI}piperidinyl)methyl] -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 0 CH3 0”0:5? H N N _N \ / Analogously to Example 317, 73 mg of the title compound was obtained from 100 mg of 54 and 56 mg of [5-(trifluoromethyl)pyridinyl]boronic acid under reflux. 1H-NMR (400 MHz, a): 8 [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'-(l -hydroxy- l -methylethyl)biphenylyl]carbonyl} dinyl)- methyl] methoxyethyl)methyl-2H-indazolcarboxamide H30/ \/\N / H \/N 0M0 H30 CH3 Analogously to Example 317, 46 mg of the title compound was obtained from 100 mg of 54 and 77 mg of (4-hydroxy-tert-butylphenyl)boronic acid pinacol ester under reflux. 1H-NMR (300 MHz, DMSO-da): 8 [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-( { l - [(3 ',5'-difluorobiphenylyl)carbonyl]piperidinyl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide Analogously to Example 317, 22 mg of the title compound was obtained from 100 mg of 54 and 46 mg of (3,5-difluorophenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-ds): 8 [ppm]= 1.18 - 1.35 (2H), 1.36 - 1.70 (2H), 2.19 - 2.39 (1H), D2 - 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 [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (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-( { l - [(4'-fluoromethylbiphenylyl)carbonyl]piperidinyl} methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 335,, Analogously to Example 317, 25 mg of the title compound was obtained from 60 mg of 332 and 19 mg of (4-fluorophenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [(3 ',5'-difluoromethylbiphenylyl)carbonyl]piperidinyl} methyl)-N- hoxyethyl)methyl-2H-indazolcarboxamide F ously to Example 317, 30 mg of the title compound was obtained from 60 mg of 332 and 27 mg of (3,5-difluorophenyl)boronic acid under reflux. 1H-NMR (400 MHz, DMSO-ds): 8 [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)methyl( { l - [3 -methyl(3 -pyridyl)benzoyl]piperidin yl} methyl)-2H-indazolcarboxamide O CH HSCI \/\N / \ IN Analogously to Example 317, 19 mg of the title compound was obtained from 60 mg of 332 and Dmg ofpyridineylboronic acid under reflux.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-ds): 8 [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)methyl( { l - [3 -methyl(4-pyridyl)benzoyl]piperidin—4- yl} methyl)-2H-indazolcarboxamide O CH H30’ \/\N / \ IN Analogously to Example 317, 19 mg of the title nd was obtained from 60 mg of 332 and 21 mg of pyridineylboronic acid under reflux. 1H-NMR (400 MHz, DMSO-da): 8 [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)methyl( { l - [(2-methylbiphenylyl)carbonyl]piperidin- 4-yl} )-2H-indazolcarboxamide O CH HSCI \/\N / Analogously to Example 317, 57 mg of the title compound was obtained from 60 mg of 332 and 21 mg of phenylboronic acid under reflux. 1H-NMR (400 MHz, DMSO-d6): 8 [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-mesylethyl)methyl-2H- indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example lb, Version B, 383 mg of the title nd was obtained from 1 g of 395b and 797 mg of 4-bromobenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 5 [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 395a: Tert-butyl 4-( {5- [N—(2-mesylethyl)carbamoyl] methyl-2H-indazolyl} - methyl)piperidin- l -carboxylate Analogously to Example 266a, 1.26 g of the title compound was obtained from 2.506 g of 1c and 3.022 g of 2-mesylethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-da): 5 [ppm]: 1.02 - 1.17 (2H), 1.34 — 1.54 (11H), 2.08 — 2.24 (1H), 2.55 (3H), 2.73 (2H), 3.06 (3H), 3.34 - 3.47 (2H), 3.57 - 3.76 (2H), 3.91 (2H), 4.32 (2H), 7.23 (1H), 7.43 (1H), 8.33 (1H), 8.52 (1H).
Example 395b: N-(2-mesylethyl)methyl(4-piperidylmethyl)-2H-indazolcarboxamide hydrochloride Analogously to Example 258b from 1.26 g of compound 395a, 1.29 g of the title compound was obtained, which was reacted t further ation.
Example 396 : esylethyl)methyl {[1-(4- {[5-(trifluoromethyl)pyridinyl] oxy} - benzoyl)piperidinyl]methyl} -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example lb, Version B, 30 mg of the title nd was obtained from 80 mg of 395b and 90 mg of 4- {[5-(trifluoromethyl)pyridin—2-yl]oxy}benzoic acid in DMF. 1H-NMR (400 MHz, DMSO-ds): 8 [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-mesylethyl)methyl {[1-(4- {[6-(trifluoromethyl)pyridin-3 -yl] oxy} - l)piperidin—4-yl]methyl} -2H-indazolcarboxamide Analogously to Example lb, Version B, 30 mg of the title compound was obtained from 80 mg of 395b and 90 mg of 303b in DMF. 1H-NMR (400 MHz, DMSO-da): 8 [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-( { l - [(2',4'-difluorobiphenylyl)carbonyl]piperidin—4-yl} methyl)-N—(2-mesyl- ethyl)methyl-2H-indazolcarboxamide Analogously to e lb, Version B, 25 mg of the title compound was obtained from 80 mg of 395b and 74 mg of 2',4'-difluoro-biphenylcarboxylic acid in DMF.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-ds): 5 [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)piperidinyl]methyl} -N-(3 -hydroxy-3 lbutyl) methyl-2H-indazolcarboxamide H30 CH CH3 HOX/\3 N / H N Analogously to e lb, Version B, 37 mg of the title compound was obtained from 160 mg of 39% and 105 mg of 4-chlorobenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 5 [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 399a: Tert-butyl 4-( {5 - [N—(3 -hydroxy-3 -methylbutyl)carbamoyl] methyl-2H- indazol-2—yl} methyl)piperidin— l -carboxylate O CH H30 CH3 3 HOXAN / H N >—o CH3 0 CH3 Analogously to Example lb, Version B, 150 mg of 1d and 69 mg of 4-amino-2—methylbutan-2—ol in DMF were reacted at 60°C. After phase separation and extraction, the ed organic phases were additionally washed with 0.1 N hydrochloric acid and saturated sodium en carbonate solution. This yielded 132 mg of the title compound, which was used in the next step without further purification.
Example 399b: N—(3-hydroxy—3-methylbutyl)methyl-2—(4-piperidylmethyl)-2H-indazol carboxamide H30 CH [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Analogously to Example 258b, from 132 mg of 399a, 162 mg of the title compound was obtained, which was used in the next step without further purification.
Example 400: 2- { [1 lorobenzoyl)piperidinyl]methyl} -N-(2-cyanoethyl)methyl-2H- indazolcarboxamide \\/\N H N Analogously to e 1b, Version B, 55 mg of the title compound was obtained from 177 mg of 400b and 128 mg of 4-chlorobenzoic acid in DMF. 1H-NMR (400 MHz, DMSO-da): 5 [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 400a: Tert-butyl 4-( {5- [N-(2-cyanoethyl)carbamoyl] methyl-2H-indazolyl} - methyl)-piperidincarboxylate \\/\N H N >/—o H. 0 CH3 ously to Example 1b, Version B, 150 mg of 1d and 42 mg of 3-aminopropannitrile in DMF were reacted at 60°C. After phase separation and extraction, the combined organic phases were onally washed with 0.1 N hydrochloric acid and saturated sodium hydrogen carbonate solution. This d 137 mg of the title compound, which was used in the next step without further purification.
Example 400b: N-(2-cyanoethyl)methyl(4-piperidylmethyl)-2H-indazolcarboxamide N / dalogously to Example 258b, from 137 mg of 400a 177 mg of the title compound was ained, which was used in the next step without further purification. ation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example 401: 2- {[1 -(4-chlorobenzoyl)piperidinyl]methyl} -N-(cyanomethyl)methyl-2H- indazolcarboxamide Analogously to Example 1b, Version B, 75 mg of the title compound was obtained from 90 mg of 23 8c and 29 mg of aminoacetonitrile in DMF. 1H-NMR (400 MHz, DMSO-dg): 8 [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)piperidinyl]methyl} -N-(cyclopropylmethyl)methyl- 2H-indazol-5 -carboxamide Analogously to Example lb, Version B, 44 mg of the title compound was obtained from 90 mg of 23 8c) and 19 mg of cyclopropylmethylamine in DMF. 1H-NMR (300 MHz, DMSO-da): 8 [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: lobutylmethyl)methyl [(1 - {4-[4-(trifluoromethyl)phenoxy]benzoyl} - piperidinyl)methyl] -2H-indazolcarboxamide mNWg/NN p/\ H 0 CH3 galogously to Example lb, Version B, 48 mg of the title compound was obtained from 137 mg0 403b and 31 mg of (cyclobutylamino)methylamine hydrochloride.
[Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-da): 8 [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 403a: Methyl 4-methyl[(1- {4- [4-(trifluoromethyl)phenoxy]benzoyl} piperidin yl)methyl] -2H-indazolcarboxylate Analogously to Example 1b, Version B, 2.73 g of the title compound was obtained from 3.76 g of 238a and 3.28 g of trifluoromethyl)phenoxy]benzoic acid. 1H-NMR (400 MHz, DMSO-ds): 8 [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). e 403b: 4-methyl-2— [(1 - {4- [4-(trifluoromethyl)phenoxy]benzoyl} piperidinyl)- methyl]-2H-indazolcarboxylic acid HO \ Analogously to Example 1d, from 1.05 g of 403a, 970 mg of the title compound was obtained, which was used in the next step without further purification.
Example 404: N—isobutylmethyl [(1 - {4- [4-(trifluoromethyl)phenoxy]benzoyl} piperidin yl)methyl] -2H-indazolcarboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp O C d.
,N‘ JO H.
H30Lnjfl/N 0 CH3 Analogously to Example lb, n B, 35 mg of the title compound was obtained from 100 mg of 403b and 14 mg of isobutylamine. 1H-NMR (300 MHz, DMSO-da): 8 [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 [(1 - {4- [4-(trifluoromethyl)phenoxy]benzoyl} piperidin— 4-yl)methyl] -2H-indazolcarboxamide Analogously to Example lb, Version B, 36 mg of the title compound was obtained from 100 mg of 403b and 16 mg of neopentylamine. 1H-NMR (400 MHz, DMSO-da): 8 [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: lopropylmethyl)methyl [(1 - {4- [4-(trifluoromethyl)phenoxy] - benzoyl} piperidin—4-yl)methyl] -2H-indazolcarboxamide A/NYg/NN p/\ H 0 CH3 Analogously to e lb, Version B, 33 mg of the title compound was obtained from 100 mg of 403b and 26 mg of cyclopropylmethylamine. ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (300 MHz, DMSO-ds): 8 [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)({1-[(4'-fluorobiphenylyl)carbonyl]piperidin—4-yl}- methyl)methyl-2H-indazolcarboxamide NWHYEF/N1Q 0 CH3 Analogously to Example 1b, Version B, 37 mg of the title compound was obtained from 140 mg of 407a and 84 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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 407a: N-(2-cyanoethyl)methyl(4-piperidylmethyl)-2H-indazolcarboxamide hydrochloride N / Analogously to Example 1a, from 165 mg of 400a, 140 mg of the title compound was obtained, which was used in the next step without further ation.
Example 408: 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidin—4-yl}methyl)-N—(2-mesylethyl )- 4-methyl-2H-indazolcarboxamide Analogously to Example 1b), Version B, 126 mg of the title compound was obtained from 300 mg of 408a) and 156 mg of 4’-fluorobiphenylcarboxylic acid.
D-MS: Rt = 1.20 min, MS (ES+): m/z = 577 (M+H)+.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp The starting material was prepared as follows: Example 408a: esylethyl)methyl(4-piperidylmethyl)-2H-indazolcarboxamide hydrochloride H30\S/\/NY<;E/N’/\‘O O Analogously to Example 1a, from 346 mg of 395a, 300 mg of the title compound was obtained, which was used in the next step without further purification.
Example 409: 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N—(3 -hydroxy- propyl)methyl-2H-indazolcarboxamide A JO H N HO\/\/N \ 0 CH3 Analogously to Example 1b, Version B, 20 mg of the title compound was obtained from 124 mg of 40%) and 73 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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: e 409a: Tert-butyl 4-( {5 - [N—(3 -hydroxypropyl)carbamoyl] methyl-2H-indazolyl} - methyl)piperidincarboxylate o >VCH3 >—O CH3 H N HOWN \ O CH ously to e 1b, n B, 151 mg of the title compound was obtained from 150 mg of 1d and 30 mg of 3-amino-propan—1-ol.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-dg): 5 [ppm]: 1.01 - 1.30 (3H), 1.32 - 1.49 (10H), 1.67 (2H), 2.08 - 2.27 (1H), 2.52 (3H), 2.57 - 2.80 (2H), 3.29 (2H), 3.41 — 3.54 (2H), 3.81 — 4.00 (2H), 4.32 (2H), 4.48 (1H), 7.18 (1H), 7.42 (1H), 8.10 (1H), 8.50 (1H).
Example 409b: ydroxypropyl)methyl(4-piperidylmethyl)-2H-indazolcarbox- amide H N HOWN \ 0 CH3 ously to Example 1a, from 246 mg of 409a, 124 mg of the title compound was obtained, which was used in the next step without further purification.
Example 41 0: [(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N—(2-hydroxy- methyl-2H-indazolcarboxamide W001” Analogously to Example 1b, Version B, 36 mg of the title compound was obtained from 117 mg of 410b and 72 mg of 4’-fluorobiphenylcarboxylic acid. 1H-NMR (300 MHz, DMSO-da): 8 [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 41 0a: Tert-butyl 4-( {5- [N—(2-hydroxyethyl)carbamoyl] methyl-2H-indazolyl} - methyl)piperidincarboxylate o >¢0H3 >—O CH3 H N HO/\/N \ o CH Analogously to Example 1b, Version B, 143 mg of the title compound was obtained from D) mg of 1d) and 25 mg of 2-aminoethan—1-ol.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-ds): 8 [ppm]= 1.01 — 1.30 (3H), 1.32 — 1.51 (10H), 2.07 — 2.26 (1H), 2.52 — 2.55 (3H), 2.58 — 2.82 (2H), 3.30 (2H), 3.45 — 3.58 (2H), 3.83 — 3.98 (2H), 4.32 (2H), 4.69 (1H), 7.21 (1H), 7.41 (1H), 8.05 (1H), 8.50 (1H).
Example 410b: N—(3-hydroxypropyl)methyl(4-piperidylmethyl)-2H-indazolcarbox- amide hydrochloride H N HOWN \ 0 CH3 Analogously to Example 1a) from 138 mg of 410a, 117 mg of the title compound was obtained, which was used in the next step without further ation.
Example 41 1: (+/-)—N—(1,4-dioxanylmethyl)({1-[(4'-fluorobiphenylyl)carbonyl]- piperidinyl} methyl)methyl-2H-indazol-5 -carboxamide J6?”F ously to Example 1b, Version B, 62 mg of the title compound was obtained from 226 mg of 41 lb) and 119 mg of robiphenylcarboxylic acid. 1H-NMR (400 MHz, DMSO-da): 8 [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 41 1 a: (+/-)—tert-butyl 4-( {5- [N—(l ,4-dioxan—2-ylmethyl)carbamoyl] methyl-2H- indazolyl} methyl)piperidin— 1 -carboxylate Dalogously to e 1b, n B, 267 mg of the title compound was obtained from 250 mg of 1d and 78 mg of (+/-)-1,4-dioxanylmethylamine.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 1H-NMR (400 MHz, DMSO-da): 5 [ppm]= 0.99 - 1.18 (2H), 1.38 (11H), 2.09 — 2.24 (1H), 2.53 (3H), 3.10 - 3.29 (4H), 3.41 - 3.52 (1H), 3.53 - 3.70 (4H), 3.70 - 3.81 (2H), 3.84 - 3.98 (2H), 4.32 (2H), 7.18 (1H), 7.41 (1H), 8.12 — 8.24 (1H), 8.51 (1H).
Example 411b: (+/—)—N—(1,4-dioxanylmethyl)methyl(4-piperidylmethyl)-2H-indazol carboxamide hloride O /N\ H N N \ 0 CH3 Analogously to Example 1a, from 261 mg of 41 1a, 226 mg of the title compound was ed, which was used in the next step without further purification.
Example 412: (+/—)—2- {[1 -(4-chlorobenzoyl)piperidin—4-yl]methyl} methyl-N—(oxetanyl- methyl)-2H-indazolcarboxamide o800' Ofl‘vnflNPN 0 CH3 Analogously to Example 1b, Version B, 55 mg of the title compound was obtained from 350 mg of 23 8c) and 83 mg of oxetan—2-ylmethylamine. 1H-NMR (300 MHz, DMSO-da): 8 [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-dioxanylmethyl)- 4-methyl-2H-indazolcarboxamide 2800' 9489 Analogously to Example 1b, Version B, 185 mg of the title compound was obtained from 376 mg of 23 8c and 111 mg of (+/-)-1,4-dioxan—2-ylmethylamine hydrochloride. 1H-NMR (300 MHz, DMSO-da): 8 [ppm]= 1.19 - 1.32 (2H), 1.33 - 1.66 (2H), 2.20 - 2.40 (1H), fi3 (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 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp (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-yl- methyl)methyl-2H-indazolcarboxamide {Slut/rurfipiwp .. ESL/“@1153 0 CH3 0 CH3 From 185 mg of the racemate ed in Example 413, 51 mg of the title compound together With 58 mg of the slower-eluting enantiomer (Example 415) were obtained by racemate separation by means of ative chiral HPLC (Method D).
Analytical chiral HPLC: 12.62 min.
Example 415: (S or R)-2—{[1-(4-chlorobenzoyl)piperidin—4-yl]methyl}-N-(1,4-dioxan—2-yl- methyl)methyl-2H-indazolcarboxamide o o N>—©—CI l O ”Np O E LH N p H \N N \ E j \ O 0 "I'M/N 0 CH3 0 CH3 From 185 mg of the racemate ed in Example 413, 58 mg of the title compound together With 51 mg of the faster-eluting omer (Example 414) were obtained by racemate separation by means of preparative chiral HPLC (Method D).
Analytical chiral HPLC: 13.68 min.
Example 416: (R or S)—4-methyl-N—(3,4,5,6-tetrahydro-2H-pyran—2-ylmethyl)[(1-{4-[4- (trifluoromethyl)phenoxy]benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide F F F F F F o o >—<: >—o >—< :>—o N N O A9 (iv A JG H N N \ H \ """"/ o o 0 CH3 0 CH3 [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp From 231 mg of the racemate prepared in Example 248, 24 mg of the title nd together with 24 mg of the slower-eluting omer (Example 417) were obtained by te tion by means of preparative chiral HPLC (Method E).
Analytical chiral HPLC: 7.08 min.
Example 417: (S or R)methyl-N—(3,4,5,6-tetrahydro-2H-pyran—2-ylmethyl)[(1-{4-[4- (trifluoromethyl)phenoxy]benzoyl} piperidinyl)methyl] -2H-indazolcarboxamide F F F F F F o o H >70 H >70 19N 19N QH \N 0 H N \N ,,,,,,,Wee o o 0 CH3 From 231 mg of the racemate prepared in Example 248, 24 mg of the title compound together with 24 mg of the faster-eluting enantiomer (Example 416) were obtained by racemate separation by means of preparative chiral HPLC (Method E).
Analytical chiral HPLC: 8.98 min.
Example 418: (R or S)-N—(l ,4-dioxan—2-ylmethyl)methyl [(1 - {4- [4-(trifluoromethyl)- phenoxy]benzoyl} piperidinyl)methyl] -2H-indazol-5 -carboxamide F F F F F F o o o C o N C N O , p o E j , p H \\N E LH \\N N o '“W/N o 0 CH, 0 CH, From 280 mg of the racemate prepared in Example 249, 65 mg of the title compound together with 75 mg of the slower-eluting enantiomer (Example 419) were obtained by racemate separation by means of preparative chiral HPLC (Method D (injection volume: 0.1 ml; detection: UV 210 nM)).
Analytical chiral HPLC: 13.66 min.
Example 419: (R or S)-N—(l ,4-dioxan—2-ylmethyl)methyl [(1 - {4- [4-(trifluoromethyl)- phenoxy]benzoyl} dinyl)methyl] -2H-indazol-5 -carboxamide [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp O O O : O N N O Ap O E LHNY©;/ Ap N E j H N “/N \ o o 0 CH3 0 CH3 From 280 mg of the racemate prepared in Example 249, 75 mg of the title nd together With 65 mg of the faster-eluting enantiomer (Example 418) were obtained by racemate separation by means of preparative chiral HPLC d D (injection volume: 0.1 ml; Detection: UV 210 nM)).
Analytical chiral HPLC: 14.90 min.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Biological es: 1. Detection of anta onism to the human rosta landin E2 sub e EPZ rece tor si nal 1. 1 ion principle The binding of PGE2 to the EP2 subtype of the human PGE2 receptor induces the activation of membrane-located adenylate cyclases and leads to the formation of CAMP. In the presence of the phosphodiesterase inhibitor IBMX, the CAMP accumulated owing to this ation and released by cell lysis is used in a competitive detection method. In this test, the CAMP present in the lysate competes with a fluorescence-labelled CAMP (CAMP-d2) for g to an Eu cryptate-labelled anti-CAMP antibody.
In the absence of ar CAMP, a maximal signal is produced, which is attributable to the binding of this CAMP-d2 molecule to the antibody. After excitation of the CAMP-d2 molecule at 337 nm, there is a fluorescence resonance energy transfer (FRET) to the Eu cryptate molecules of the anti-CAMP antibody (labelled therewith), followed by a long-lasting emission signal at 665 nm (and at 620 nM). Both signals are measured in a suitable measurement instrument with a time delay, i.e. after decay of the background fluorescence. Any increase in the low FRET signal caused by prostaglandin E2 administration red as well ratio Change = emisSion665nm/emiSSi0n620nm * 10000) indicates the action of antagonists. 1.2. Detection method 1.2.1. Test for antagonism (data per well of a ll : To a test plate with the nce solutions already added (0.05 pl; 100% DMSO, concentration range from 0.8 nM — 16.5 uM) were added 4 ul of a CAMP-d2/Cell suspension (625000 cells/m1). After a 20-minute preincubation at room temperature (RT), 2 ul of a 3xPGE2 solution (1.5 nM, in PBS-IBMX) were added and incubated in the presence of the agonist for a further 60 mins at RT (volume: N 6 ul). Next the reaction was stopped by on of 2 ul of lysis buffer and incubated for a further 20 mins at RT before the actual measurement (volume: N 8 ul).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 2. Detection of anta onism to the human rosta landin E2 sub e EP4 rece tor si nal 2. 1 Detection principle The binding of PGE2 to the EP4 subtype of the human PGE2 receptor induces the activation of membrane-located adenylate cyClases and leads to the formation of CAMP. In the presence of the phosphodiesterase inhibitor IBMX, the CAMP accumulated owing to this stimulation and released by cell lysis is used in a competitive detection method. In this test, the CAMP present in the lysate competes with a fluorescence-labelled CAMP (CAMP-d2) for binding to an Eu cryptate-labelled anti-CAMP antibody.
In the absence of cellular CAMP a maximal signal is produced, which is attributable to the binding of this CAMP-d2 molecule to the dy. After tion of the CAMP-d2 molecule at 337 nm, there is a fluorescence resonance energy transfer (FRET) to the Eu cryptate molecules of the anti-CAMP antibody (labelled therewith), followed by a long-lasting on signal at 665 nm (and at 620 nM). Both signals are measured in a suitable measurement instrument with a time delay, i.e. after decay of the background fluorescence. Any increase in the low FRET signal caused by prostaglandin E2 administration red as well ratio Change = emisSion665nm/emiSSi0n620nm * 10000) tes the action of antagonists. 2.2. Detection method 2.2.1. Test for antagonism (data per well of a 384-well plate): To a test plate with the substance solutions already added (0.05 pl; 100% DMSO, concentration range from 0.8 nM - 16.5 uM) were added 4 ul of a CAMP-d2/Cell suspension (312500 cells/ml).
After a 20-minute preincubation at room temperature (RT), 2 ul of a 3xPGE2 solution (0.3 nM, in MX) were added and incubated in the ce of the t for a further 60 mins at RT (volume: N 6 ul). Next the reaction was stopped by addition of 2 ul of lysis buffer and incubated for a further 20 mins at RT before the actual measurement (volume: N 8 ul).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 3. Detection of antagonism to the human prostaglandin D receptor signal 3. 1 Detection principle The binding of prostaglandin D2 to the human PGD receptor induces the activation of membrane-located adenylate cyclases and leads to the ion of CAMP. In the presence of the phosphodiesterase inhibitor IBMX, the CAMP accumulated owing to this stimulation and released by cell lysis is used in a competitive detection method. In this test, the CAMP t in the lysate competes with a fluorescence-labelled CAMP (CAMP-d2) for binding to an Eu cryptate-labelled AMP antibody.
In the absence of cellular CAMP, a maximal signal is produced, which is attributable to the binding of this CAMP-d2 molecule to the antibody. After excitation of the 2 molecule at 337 nm, there is a fluorescence resonance energy er (FRET) to the Eu cryptate molecules of the anti-CAMP antibody (labelled therewith), followed by a long-lasting emission signal at 665 nm (and at 620 nM). Both signals are measured in a suitable ement instrument with a time delay, i.e. after decay of the background fluorescence. Any increase in the low FRET signal caused by prostaglandin E2 administration (measured as well ratio Change = emisSion665nm/emiSSi0n620nm * 10000) indicates the action of antagonists. 3.2. Detection method 3.2.1. Test for antagonism (data per well of a ll plate): To a test plate with the substance solutions already added (0.05 pl; 100% DMSO, concentration range from 0.8 nM — 16.5 uM) were added 4 ul of a CAMP-d2/Cell suspension (625000 cells/ml). After a 20-minute preincubation at room temperature (RT), 2 ul of a 3xPGD2 solution (6 nM, in PBS-IBMX) were added and incubated in the ce of the agonist for a r mins at RT (volume: N 6 ul). Next the reaction was stopped by on of 2 ul of lysis buffer and incubated for a further 20 mins at RT before the actual measurement (volume: N 8 ul).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp 4. The EPz subtype of the PGEz receptor and the pre-ovulatogy cumulus expansion 4.1. Background: In the pre-ovulatory antral follicle, the oocyte is surrounded by cumulus cells, which form a dense cell crown around the oocyte. After the LH peak nizing hormone), a series of processes is activated, which results in a marked morphological change in this cell crown of cumulus cells. During this, the cumulus cells form an extracellular matrix, which leads to the so- called s expansion (Vanderhyden et al. Dev Biol. 1990 Aug;140(2): 7) This cumulus ion is an important component of the ovulatory process and the subsequent possibility of fertilization.
During the cumulus expansion, prostaglandins and here prostaglandin E2, synthesis whereof is induced by the LH peak, are of decisive importance. Prostanoid EP2 knockout mice i et al., 1999, Proc Natl Acad Sci U S A., Aug 31;96(18):10501-6.) show a markedly decreased cumulus expansion and severe subfertility, which demonstrates the importance of the prostanoid EP2 receptor for this process. 4.2. Cumulus expansions test in vitro In immature female mice (strain: B6D2F1 from Charles River), at an age of 14 - 18 days, the folliculogenesis was induced by a single administration (intraperitoneal) of 10 IU of PMSG (pregnant mare serum gonadotropin; Sigma G-4877, Lot 68H0909). 47-50 hours after the injection, the ovaries were removed and the cumulus-oocyte complexes removed. At this stage, the cumulus complex is not yet expanded.
The cumulus-oocyte xes were now ted for 20-24 hours with prostaglandin Eg (PGEQ (0.3 uM), vehicle l (ethanol) or test substances. Medium: MEM medium with 0.1 mM IBMX, te (0.23 mM), glutamine (2 mM), pen/strep 100 IU/ml pen. and 100 ug/ml strep), HSA (8 mg/ml) and foetal bovine serum (FBS, 10%). The cumulus expansion was then established h the subdivision into four stages (after Vanderhyden et al. Dev Biol. 1990 0(2):307-3l7). 4.3 In-vivo action on post-ovulatory in-vitro fertilization : Substances can exert an influence on fertility by sing the fertilizability of oocytes or cumulus-oocyte xes. In order to study such effects, substances can be administered in vivo and subjected to in vitro fertilization after ovulation of cumulus-oocyte complexes has taken place. The in-vitro fertilization rate, where no test substance is any longer present, allows conclusions as to the in-vivo effects of the test substances.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Immature female mice (strain: B6D2Fl, Charles River, Suelzfeld, age: 19-25 days) were kept in Macrolon cages in rooms with controlled illumination (12 hrs ss: 12 hrs , fed with a standard diet and provided with drinking water ad libitum.
The mice were primed with PMSG ant mare serum gonadotropin) (10 lU/animal i.p.).
After 48 hours, a stimulus triggering ovulation was created in the animals by one administration of 10 lU/animal i.p. (hCG, human chorionic gonadotropin). The test substances were dissolved in benzyl benzoate/castor oil (1+4 V/V) and administered in a volume of 0.1 ml s.c. 1 hour before hCG (n=5 animals per group). Fourteen hours after hCG administration, the animals were killed.
Ovulated oocytes and cumulus-oocyte complexes were obtained from the bursa ovarii and/or t and subjected to in-vitro fertilization, n for the fertilization a sperm count of 40000 sperms/0.5 ml was used for 1 hour. Twenty-four hours after the tion with the sperms, the number of fertilized oocytes is established and the percentage fertilization rate determined.
The results in Table 4 show that Example 17 according to the invention has a dose-dependent influence on the fertilizability of ovulated cumulus-oocyte complexes. 4.4 In-vivo action on fertility in non-human primates (Cynomolgus): In order to study the effect of substances on fertility, mating studies can be performed in s (Jensen et al. Contraception 81 (2010) 165—171). For this, the test substances are administered to female cynomolgus monkeys (Macaca ularis) which are being kept in groups, then the animals are mated with a male animal. s are checked for by sperm detection in daily vaginal smears. Pregnancies resulting rom are identified by hormone determinations and ultrasound examinations. Through the s in the serum oestradiol concentrations during the cycle, (rise before the le LH peak), the fertile phase within a cycle of the indiVidual animals can be determined. Matings in this fertile period are described as “timed matings” (matings in the fertile phase). Apart from the absolute number of pregnancies occurring, the effect on the fertility can also be expressed as ncies per “timed matings”.
To test the action of EP2 receptor antagonists on fertility in monkeys, Examples 17 and 56 according to the invention were administered over 6 months, dissolved in 0.5 ml castor oil. e 17 was administered once daily at a dosage of 10 mg/kg (n= 10 animals), while Example 56 was administered twice daily at a dosage of 10 mg/kg (n=9 s). Only the vehicle was administered to a control group (n=10 animals). In the first month of the treatment, no male animal was placed with the female animals. After this, female and male animals were kept together over 5 months, with detection of pregnancies and cycle monitoring.
Table 5 shows that both substances result in a marked reduction in the number of pregnancies Durring. These data for the first time show the strong contraceptive effect of EP2 receptor [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp antagonists in the primate. r results of the study show that the substances have no effects on hormone levels and cycle length. This confirms that the substances produce a contraceptive effect by non-hormonal mechanisms. The reversibility of the ity was demonstrated on some animals after discontinuation of the treatment.
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp . Determination of the pharmacokinetic parameters after intravenous administration . l . Intravenous administration: For this, the substances were administered in ved form, ible solubilizers such as PEG400 and/or l being used in tolerable ty. The substances were administered at a dosage of 0.1 -1 mg/kg. The administration was effected in the female rat as a bolus injection.
Here, at various times after bolus injection ca. 100-150 ul blood samples were withdrawn from the jugular vein via a catheter. The blood s were treated with lithium-heparin as anticoagulant and stored refrigerated until further work-up. After centrifugation of the samples for 15 mins at 3000 rpm, an aliquot of 100 pl was withdrawn from the supernatant (plasma) and precipitated by addition of 400 pl of cold acetonitrile or methanol (absolute). The precipitated samples were frozen overnight at -20°C, then centrifuged once again for 15 mins at 3000 rpm, before 150 pl of the clear supernatant was withdrawn for the concentration determination. The is was performed with an Agilent 1200 HPLC system with attached LCMS/MS detection. 5.2 Calculation of the PK parameters The calculation was performed by means of the PK calculation software WinNonLin®, where t1/2 means half-life within a specified interval (here: terminal t1/2, in hrs).
[Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Table 1: es for the biological activity of the compounds according to the invention on the hEP2 receptor (leo measured by cAMP antagonism test), selectivity towards hDP & hEP4 (leo measured by cAMP antagonism test): X: l - 10, XX: 10 - 100, XXX > 100 : ----Example Antagonism hEP2 Selectivity Selectivity n——— n——— [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 ivity Selectivity 3 0 XXX XXX 3 1 XXX XXX 32 XXX XXX 3 3 XXX XXX 34 XXX XXX 3 5 XXX XXX 3 6 XXX XXX 3 7 XXX XXX 3 8 XXX XXX 3 9 XXX XXX 40 XXX XXX 4 1 XXX XXX 42 XXX XXX 43 XXX XXX 44 XXX XXX 45 XXX XXX 46 XXX XXX 47 XXX XXX 48 XXX XXX 49 XXX XXX 50 XXX XXX 1 XXX XXX 52 X [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity ICso [M] hEP2/hEP4 63 XX [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity 97 XXX XXX 100 XXX XXX 101 XXX XXX 121 XXX XXX 122 XXX XXX 123 XXX XXX 124 XXX XXX 125 XXX XXX 126 XXX XXX 127 XXX XXX [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity 144 XXX 145 XXX 146 XXX 147 XXX 148 XXX 149 XXX 150 XXX 151 XXX 152 XXX 153 XXX 154 XXX 155 XXX 157 XXX 158 XXX 159 XXX 160 XXX 161 XXX [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp ation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity 162 XXX XXX 163 XXX XXX 164 XXX XXX 165 XXX XXX 166 XXX XXX 167 XXX XXX 168 XXX XXX 169 XXX XXX 170 XXX XXX 171 XXX XXX 172 XXX XXX 173 XXX XXX 174 XXX XXX 175 XXX XXX 176 XXX XXX 177 XXX XXX 178 XXX XXX [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Example Antagonism hEP2 Selectivity Selectivity 228 XXX XXX 229 XXX XXX 230 XXX XXX 23] XXX XXX 232 XXX XXX 233 XXX XXX 234 XXX XXX 235 XXX XXX 236 XXX XXX 237 XXX XXX 238 XXX XXX 239 XXX XXX 240 XXX XXX 24] XXX XXX [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp Example Antagonism hEP2 Selectivity Selectivity 261 XXX XXX 262 XXX XXX [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity 294 XXX XXX 295 XXX XXX 296 XXX XXX [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity 360 XXX XXX 361 XXX XXX 362 XXX XXX 363 XXX XXX 364 XXX XXX 365 XXX XXX 366 XXX XXX 367 XXX XXX 368 XXX XXX 369 XXX XXX 370 XXX XXX 371 XXX XXX 372 XXX XXX 373 XXX XXX 374 XXX XXX 375 XXX XXX [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp ionNone set by jennyp [Annotation] jennyp Unmarked set by jennyp Example Antagonism hEP2 Selectivity Selectivity 393 xxx xxx 394 xxx xxx 395 xxx xxx 396 xxx xxx 397 xxx xxx 398 xxx xxx 399 X 400 xxx 40] xxx 402 xxx 403 xxx 404 xxx 406 xxx 407 xxx 408 xxx 409 xxx 410 xxx 41 1 xxx 412 xxx 4 l 3 xxx 415 xxx Table 2: Reduction in the cumulus expansion in percent With use of 0.3 uM PGE2 for stimulation, reference 1: example 62 from 09049662A1 % reduction at 1 uM % reduction at 0.5 um ation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp ation] jennyp Unmarked set by jennyp [Annotation] jennyp None set by jennyp [Annotation] jennyp MigrationNone set by jennyp [Annotation] jennyp ed set by jennyp 6 25 ——7673 7 38 Table 3: Terminal ife (t1/2) after intravenous administration in the female rat, reference 1: example 62 from DE102009049662A1 Table 4: Reduction in in-vitro fertilization rate after in-vivo administration of the test substance: Example % fertilization % fertilization % fertilization % fertilization With vehicle With 1 mg/kg With 5 mg/kg With 10 mg/kg Table 5: Reduction in the pregnancy rates in the non-human primate (Cynomolgus) Group Animals Number of Pregnancies % Pregnancies/ per group “timed matings”* “timed mating” ———- *Detection of vaginal sperms in the fertile phase of the cycle

Claims (29)

Claims:
1. Compounds of the general formula (I) R2 N H N X N R4 ( )n O R1 m( ) Ar R3 5 wherein R1: means H, C 1-C2 alkyl or C1-C2 alkyloxy; R2: H or methyl; 10 subject to the o that one of the two residues R1 or R2 equals H; X: -(CH2)l-, -(CH2)k-O-, -CH2-S-, CH2-S(O)2-, -CH(CH3)-, -CH(CH3)-O- or )2-O-; 15 k: 1 or 2; l: 0, 1 or 2; R4: H, C 1-C4 alkyl, C3-C4 cycloalkyl or -C4 cycloalkyl; and in the case of X: -CH2- or -CH(CH3)- R4: additionally means a 4membered heterocyclyl r esidue; 25 and in the case of X: -(CH2)l- or -CH(CH3)- R4: additionally means CN; 7849490_1 (GHMatters) P97018.NZ X er with R4 form a 4membered heterocyclyl residue via a ring carbon linkage; m: 1 or 2; n: 1 or 2; Ar: a 6membered aryl or 5membered hetaryl residue, 10 R3: halogen, CN, SF 5, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C6 heterocyclyl, O-C1-C4 alkyl, O-C3-C6 cycloalkyl, O-C4-C6 heterocyclyl, S-C1-C4 alkyl, S(O)2-C1-C4 alkyl, Ar´, O-Ar´, C(CH3)2-CN or 2-OH; and Ar´: an optionally singly or doubly substituted 6-membered aryl or 5membered 15 heteroaryl residue; wherein the substituents are selected from F, Cl, CN, C1-C4 alkyl, O-C1-C4 alkyl, C(CH 3)2-CN, C(CH3)2-OH and C(O)NH2; and diastereomers, omers and salts or cyclodextrin clathrates thereof.
2. Compounds according to Claim 1, wherein R1, R2: mean H or methyl; 25 subject to the proviso that one of the two residues R1 or R2 equals H; X: -(CH2)l- or -(CH2)k-O-; k: 1 or 2; l: 0, 1 or 2; R4: C 1-C4 alkyl, C3-C4 lkyl or CH2-C3-C4 cycloalkyl; and 35 m, n: 2; 7849490_1 (GHMatters) P97018.NZ and diastereomers, enantiomers and salts or cyclodextrin clathrates thereof and R3, Ar and Ar´ have the meanings stated in Claim 1. 5
3. Compounds according to Claim 1, wherein R1, R2: mean H or ; subject to the proviso that one of the two residues R1 or R2 equals H; X: -(CH2)l- or -(CH2)k-O-; k: 1 or 2; 15 l: 0, 1 or 2; R4: C 1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; and m, n: 1; and diastereomers, enantiomers and salts or cyclodextrin clathrates thereof and R3, Ar and Ar´ have the meanings stated in Claim 1.
4. Compounds according to Claim 1 or 2, n R1: means methyl; R2: H; 30 X: -(CH2)l- or -(CH2)k-O-; k: 1; l: 0 or 1; 7849490_1 ters) P97018.NZ R4: C 1-C4 alkyl, C3-C4 cycloalkyl or -C4 cycloalkyl; m, n: 2; and 5 Ar: a phenyl residue; and diastereomers, enantiomers and salts or cyclodextrin ates thereof and R3 and Ar´ have the meanings stated in Claim 1. 5. Compounds according to Claim 1 or 3, wherein R1: means a methyl group; 15 R2: H; X: -(CH2)l- or -(CH2)k-O-; k: 1; l: 0 or 1; R4: C 1-C4 alkyl, C3-C4 cycloalkyl or CH2-C3-C4 cycloalkyl; 25 m, n: 1; and Ar: a phenyl residue; and diastereomers, omers and salts or cyclodextrin clathrates thereof and R3 and 30 Ar´ have the aforesaid meanings. 6. Compounds according to Claim 4 or 5 selected from a group which contains the following compounds: 35 1. 2-{[1-(4-cyanofluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 2. 2-{[1-(4-tert-butoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 3. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 5 4. N-(2-methoxyethyl)methyl{[1-(4-morpholinobenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide
5. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide
6. 2-{[1-(2-fluoromesylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 10 2H-indazolcarboxamide
7. 2-{[1-(2-fluoromethoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide
8. 2-{[1-(4-bromofluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 15
9. 2-{[1-(2-fluoromethylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide
10. [2-fluoro(trifluoromethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide
11. N-(2-methoxyethyl)methyl({1-[4-(pentafluoro-λ6-sulphanyl)benzoyl]piperidin 20 yl}methyl)-2H-indazolcarboxamide
12. N-(2-methoxyethyl)methyl{[1-(4-methylbenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide
13. 2-({1-[4-(4-chlorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 25
14. ethoxyethyl)methyl({1-[4-(4-methylphenoxy)benzoyl]piperidin yl}methyl)-2H-indazolcarboxamide
15. 2-({1-[4-(4-tert-butylphenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide
16. N-(2-methoxyethyl)methyl[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}piperidin 30 yl)methyl]-2H-indazolcarboxamide
17. N-(2-methoxyethyl)({1-[4-(4-methoxyphenoxy)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide
18. N-(2-methoxyethyl)methyl{[1-(4-phenoxybenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 35
19. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- lcarboxamide 7849490_1 (GHMatters) P97018.NZ
20. 2-{[1-(4-methoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide
21. 2-{[1-(4-fluorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 5
22. ethoxyethyl)methyl({1-[4-(trifluoromethyl)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide
23. 2-{[1-(2-methoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 24. N-(2-methoxyethyl)methyl[(1-{4-[(trifluoromethyl)sulphonyl]benzoyl}piperidin 10 yl)methyl]-2H-indazolcarboxamide 25. N-(2-methoxyethyl)methyl({1-[3-(trifluoromethyl)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 26. N-(2-methoxyethyl)methyl{[1-(3-methylbenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 15 27. 2-{[1-(3-chlorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 28. 2-({1-[4-(4-carbamoylphenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 29. 2-({1-[4-(cyclopentyloxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)methyl- 20 2H-indazolcarboxamide 30. 2-({1-[4-(difluoromethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 31. 2-{[1-(4-cyanobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H-indazol- 5-carboxamide 25 32. 2-({1-[4-(1H-imidazolyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 33. N-(2-methoxyethyl)methyl({1-[4-(oxazolyl)benzoyl]piperidinyl}methyl)-2H- indazolcarboxamide 34. ethoxyethyl)methyl({1-[4-(oxazolyl)benzoyl]piperidinyl}methyl)-2H- 30 indazolcarboxamide 35. ethoxyethyl)methyl({1-[4-(isoxazolyl)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 36. N-(2-methoxyethyl)methyl({1-[4-(1H-pyrazolyl)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 35 37. N-(2-methoxyethyl)methyl({1-[4-(1H-1,2,4-triazolyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 38. 2-({1-[4-(difluoromethoxy)fluorobenzoyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 39. 2-({1-[2-fluoro(pyrrolidinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 5 40. [(3,4'-difluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 41. 2-({1-[(3-fluoro-4'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 42. 2-({1-[(3-fluoro-4'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxy- 10 ethyl)methyl-2H-indazolcarboxamide 43. 2-[(1-{[3-fluoro-3'-(trifluoromethyl)biphenylyl]carbonyl}piperidinyl)methyl]-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 44. 2-[(1-{[3-fluoro-2'-(trifluoromethoxy)biphenylyl]carbonyl}piperidinyl)methyl]-N- (2-methoxyethyl)methyl-2H-indazolcarboxamide 15 45. 2-({1-[(2'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 46. 2-({1-[(2',4'-difluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 47. 2-({1-[(2-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl) 20 methyl-2H-indazolcarboxamide 48. N-(2-methoxyethyl)methyl({1-[(2'-methylbiphenylyl)carbonyl]piperidinyl}- methyl)-2H-indazolcarboxamide 49. N-(2-methoxyethyl)methyl({1-[4-(4-pyridyloxy)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 25 50. N-(2-methoxyethyl)methyl({1-[4-(4H-1,2,4-triazolyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 51. 2-{[1-(2-fluoromorpholinobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 52. 2-{[1-(4-bromobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- 30 indazolcarboxamide 53. N-(2-methoxyethyl)methyl({1-[4-(trifluoromethoxy)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 54. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 35 55. ethoxyethyl)methyl[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}piperidin yl)methyl]-2H-indazolcarboxamide 7849490_1 ters) P97018.NZ 56. 4-methyl({1-[4-(pentafluoro-λ6-sulphanyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 57. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-(2,2,2-trifluoroethyl)-2H- indazolcarboxamide 5 58. 4-methyl-N-(2,2,2-trifluoroethyl)({1-[4-(trifluoromethoxy)benzoyl]piperidin yl}methyl)-2H-indazolcarboxamide 59. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-[2-(cyclopropylmethoxy)ethyl] methyl-2H-indazolecarboxamide 60. N-[2-(cyclopropylmethoxy)ethyl]methyl{[1-(4-methylbenzoyl)piperidinyl]- 10 }-2H-indazolcarboxamide 61. N-[2-(cyclopropylmethoxy)ethyl]({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}- )methyl-2H-indazolcarboxamide 62. N-[2-(cyclopropylmethoxy)ethyl]methyl({1-[4-(trifluoromethyl)benzoyl]piperidin- 4-yl}methyl)-2H-indazolcarboxamide 15 63. cyclopropylmethoxy)ethyl]({1-[(4'-fluorobiphenylyl)carbonyl]piperidin yl}methyl)methyl-2H-indazolcarboxamide 64. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}-N-[2-(cyclopropylmethoxy)ethyl] methyl-2H-indazolcarboxamide 65. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-[2-(2,2,2-trifluoroethoxy)- 20 ethyl]-2H-indazolcarboxamide 66. 4-methyl{[1-(4-methylbenzoyl)piperidinyl]methyl}-N-[2-(2,2,2-trifluoroethoxy)- ethyl]-2H-indazolcarboxamide 67. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-[2-(2,2,2- trifluoroethoxy)ethyl]-2H-indazolcarboxamide 25 68. 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl]({1-[4-(trifluoromethyl)benzoyl]piperidin- 4-yl}methyl)-2H-indazolcarboxamide 69. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)methyl-N-[2-(2,2,2- trifluoroethoxy)ethyl]-2H-indazolcarboxamide 70. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}methyl-N-[2-(2,2,2-trifluoro- 30 ethoxy)ethyl]-2H-indazolcarboxamide 71. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-(2-isopropoxyethyl)methyl-2H- indazolcarboxamide 72. N-(2-isopropoxyethyl)methyl{[1-(4-methylbenzoyl)piperidinyl]methyl}-2H- indazolcarboxamide 35 73. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-isopropoxyethyl) methyl-2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 74. sopropoxyethyl)methyl({1-[4-(trifluoromethyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 75. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-isopropoxyethyl) -2H-indazolcarboxamide 5 76. 2-{[1-(4-cyclopropylbenzoyl)piperidinyl]methyl}-N-(2-isopropoxyethyl)methyl- 2H-indazolcarboxamide 77. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-[2-(trifluoromethoxy)ethyl]- 2H-indazolcarboxamide 78. [4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-[2-(trifluoro- 10 methoxy)ethyl]-2H-indazolcarboxamide 79. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)methyl-N-[2-(trifluoromethoxy )ethyl]-2H-indazolcarboxamide 80. 4-methyl-N-[2-(trifluoromethoxy)ethyl][(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 15 81. N-(2-tert-butoxyethyl){[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-2H- indazolcarboxamide 82. N-(2-tert-butoxyethyl)({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 83. N-(2-tert-butoxyethyl)({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl) 20 methyl-2H-indazolcarboxamide 84. N-(2-tert-butoxyethyl)methyl[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 85. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}methyl-N-{2-[( 2H3)methyloxy]- (2H4)ethyl}-2H-indazolcarboxamide 25 86. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-{2- [( 2H3)methyloxy]( 2H4)ethyl}-2H-indazolcarboxamide 87. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}-N-(2-methoxyethyl)methyl-2H-indazol- 5-carboxamide 88. N-(2-methoxyethyl)methyl[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}azetidin 30 yl)methyl]-2H-indazolcarboxamide 89. N-(2-methoxyethyl)methyl({1-[4-(trifluoromethoxy)benzoyl]azetidinyl}methyl)- 2H-indazolcarboxamide 90. [2-fluoro(trifluoromethyl)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 35 91. 2-{[1-(4-chlorofluorobenzoyl)azetidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 92. 2-({1-[3-fluoro(trifluoromethyl)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 93. 2-({1-[4-chloro(trifluoromethyl)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) -2H-indazolcarboxamide 5 94. 2-{[1-(4-cyclopropylbenzoyl)azetidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 95. N-(2-methoxyethyl)methyl[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}azetidin yl)methyl]-2H-indazolcarboxamide 96. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-N-(2,2,2-trifluoroethyl)-2H- 10 indazolcarboxamide 97. 4-methyl-N-(2,2,2-trifluoroethyl)({1-[4-(trifluoromethoxy)benzoyl]azetidinyl}- methyl)-2H-indazolcarboxamide 98. 2-({1-[2-fluoro(trifluoromethyl)benzoyl]azetidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 15 99. 4-methyl({1-[4-(pentafluoro-λ6-sulphanyl)benzoyl]azetidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 100. cyclopropyloxy)ethyl]methyl({1-[4-(trifluoromethoxy)benzoyl]azetidin yl}methyl)-2H-indazolcarboxamide 101. N-[2-(cyclobutyloxy)ethyl]methyl({1-[4-(trifluoromethoxy)benzoyl]azetidin 20 yl}methyl)-2H-indazolcarboxamide 102. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}-N-[2-(cyclopropylmethoxy)ethyl] methyl-2H-indazolcarboxamide 103. N-[2-(cyclopropylmethoxy)ethyl]({1-[4-(4-fluorophenoxy)benzoyl]azetidinyl}- methyl)methyl-2H-indazolcarboxamide 25 104. N-[2-(cyclopropylmethoxy)ethyl]methyl{[1-(4-methylbenzoyl)azetidinyl]- methyl}-2H-indazolcarboxamide 105. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-N-[2-(trifluoromethoxy)ethyl]- 2H-indazolcarboxamide 106. N-(2-tert-butoxyethyl){[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-2H- 30 lcarboxamide 107. N-[2-(cyclopropylmethoxy)ethyl]({1-[(4'-fluorobiphenylyl)carbonyl]azetidin yl}methyl)methyl-2H-indazolcarboxamide 108. 2-({1-[(4'-fluorobiphenylyl)carbonyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 35 109. 2-({1-[4-(4-fluorophenoxy)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 110. 2-({1-[4-(4-fluorophenoxy)benzoyl]azetidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 111. 2-({1-[(4'-fluorobiphenylyl)carbonyl]azetidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 5 112. 2-{[1-(4-chlorobenzoyl)azetidinyl]methyl}methyl-N-[2-(2,2,2-trifluoroethoxy)- -2H-indazolcarboxamide 113. 4-methyl-N-[2-(2,2,2-trifluoroethoxy)ethyl][(1-{4-[4-(trifluoromethyl)phenoxy]- benzoyl}azetidinyl)methyl]-2H-indazolcarboxamide 114. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- 10 azetidinyl)methyl]-2H-indazolcarboxamide 115. 2-({1-[4-(4-chlorophenoxy)benzoyl]azetidinyl}methyl)methyl-N-(2,2,2-trifluoroethyl )-2H-indazolcarboxamide 116. 2-({1-[4-(4-chlorophenoxy)benzoyl]azetidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 15 117. N-(2-methoxyethyl)methyl{[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}benzoyl)- azetidinyl]methyl}-2H-indazolcarboxamide 118. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}- l)azetidinyl]methyl}-2H-indazolcarboxamide 119. 2-{[1-(4-chlorobenzoyl)piperidinyl]methyl}-N-ethylmethyl-2H-indazol 20 carboxamide 120. 2-({1-[4-(4-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 121. 2-({1-[4-(4-chlorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 25 122. 4-methyl({1-[4-(4-methylphenoxy)benzoyl]piperidinyl}methyl)-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 123. 2-({1-[(4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)methyl-N-(2,2,2- oroethyl)-2H-indazolcarboxamide 124. 4-methyl{[1-(4-morpholinobenzoyl)piperidinyl]methyl}-N-(2,2,2-trifluoroethyl)- 30 2H-indazolcarboxamide 125. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[(trifluoromethyl)sulphanyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 126. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[4-(trifluoromethyl)phenoxy]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 35 127. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}- benzoyl)piperidinyl]methyl}-2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 128. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}- benzoyl)piperidinyl]methyl}-2H-indazolcarboxamide 129. 4-methyl-N-(2,2,2-trifluoroethyl){[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}- benzoyl)piperidinyl]methyl}-2H-indazolcarboxamide 5 130. 2-({1-[4-(4-cyanophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2-trifluoroethyl )-2H-indazolcarboxamide 131. 2-({1-[4-(3-fluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2-trifluoroethyl )-2H-indazolcarboxamide 132. yl-N-(2,2,2-trifluoroethyl)[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}- 10 piperidinyl)methyl]-2H-indazolcarboxamide 133. {4-[(5-cyanopyridinyl)oxy]benzoyl}piperidinyl)methyl]methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 134. {4-[(5-chloropyridinyl)oxy]benzoyl}piperidinyl)methyl]methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 15 135. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[5-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 136. 2-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 137. 2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- 20 trifluoroethyl)-2H-indazolcarboxamide 138. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{[4'-(trifluoromethyl)biphenylyl]carbonyl}- piperidinyl)methyl]-2H-indazolcarboxamide 139. 2-{[1-(4-bromobenzoyl)piperidinyl]methyl}methyl-N-(2,2,2-trifluoroethyl)-2H- indazolcarboxamide 25 140. 2-({1-[4-(5-chloropyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 141. 2-({1-[(4'-methoxy-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)methyl- N-(2,2,2-trifluoroethyl)-2H-indazolcarboxamide 142. 4-methyl({1-[4-(6-methylpyridinyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- 30 trifluoroethyl)-2H-indazolcarboxamide 143. 2-({1-[(4'-fluoro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)methyl-N- (2,2,2-trifluoroethyl)-2H-indazolcarboxamide 144. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 35 145. 2-({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 146. 2-({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 147. 4-methyl({1-[4-(5-methylpyridinyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- oroethyl)-2H-indazolcarboxamide 5 148. 2-({1-[4-(5-fluoropyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 149. 2-({1-[4-(5-methoxypyridinyl)benzoyl]piperidinyl}methyl)methyl-N-(2,2,2- trifluoroethyl)-2H-indazolcarboxamide 150. yl({1-[4-(2-methylpyrimidinyl)benzoyl]piperidinyl}methyl)-N-(2,2,2- 10 trifluoroethyl)-2H-indazolcarboxamide 151. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[2-(trifluoromethyl)pyrimidinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 152. 4-methyl-N-(2,2,2-trifluoroethyl)[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 15 153. 2-({1-[4-(4-cyanophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 154. 2-{[1-(4-bromomethylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl- 2H-indazolcarboxamide 155. 2-{[1-(4-tert-butylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- 20 indazolcarboxamide 156. 2-({1-[4-(1-hydroxymethylethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 157. 2-{[1-(4-cyclohexylbenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl)methyl-2H- indazolcarboxamide 25 158. 2-({1-[4-(1-cyanomethylethyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 159. ethoxyethyl)methyl({1-[4-(pyrimidinyloxy)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 160. N-(2-methoxyethyl)methyl({1-[4-(3-pyridyloxy)benzoyl]piperidinyl}methyl)- 30 2H-indazolcarboxamide 161. N-(2-methoxyethyl)methyl{[1-(4-{[5-(trifluoromethyl)pyridinyl]oxy}benzoyl)- piperidinyl]methyl}-2H-indazolcarboxamide 162. N-(2-methoxyethyl)methyl({1-[4-(2-pyridyloxy)benzoyl]piperidinyl}methyl)- 2H-indazolcarboxamide 35 163. N-(2-methoxyethyl)methyl{[1-(4-{[4-(trifluoromethyl)pyrimidinyl]oxy}- benzoyl)piperidinyl]methyl}-2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 164. N-(2-methoxyethyl)methyl{[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}benzoyl)- piperidinyl]methyl}-2H-indazolcarboxamide 165. N-(2-methoxyethyl)methyl{[1-(4-{[6-(trifluoromethyl)pyridinyl]oxy}benzoyl)- piperidinyl]methyl}-2H-indazolcarboxamide 5 166. 2-({1-[(4'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl)- 4-methyl-2H-indazolcarboxamide 167. N-(2-methoxyethyl)methyl({1-[4-(3,4,5,6-tetrahydro-2H-pyranyloxy)benzoyl]- piperidinyl}methyl)-2H-indazolcarboxamide 168. N-(2-methoxyethyl)methyl[(1-{4-[3-(trifluoromethyl)phenoxy]benzoyl}piperidin- 10 4-yl)methyl]-2H-indazolcarboxamide 169. 2-[(1-{4-[(5-cyanopyridinyl)oxy]benzoyl}piperidinyl)methyl]-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 170. 2-[(1-{4-[(5-chloropyridinyl)oxy]benzoyl}piperidinyl)methyl]-N-(2-methoxyethyl thyl-2H-indazolcarboxamide 15 171. 2-({1-[4-(2,4-difluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 172. 2-({1-[4-(3,4-difluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 173. N-(2-methoxyethyl)methyl[(1-{[4'-(trifluoromethyl)biphenylyl]carbonyl}- 20 piperidinyl)methyl]-2H-indazolcarboxamide 174. 2-({1-[4-(3-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 175. 2-{[1-(2-fluoroisopropoxybenzoyl)piperidinyl]methyl}-N-(2-methoxyethyl) -2H-indazolcarboxamide 25 176. 2-({1-[(3-fluoro-3',4'-dimethylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 177. 2-({1-[(2',3-difluoro-4'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 178. 2-({1-[4-(difluoromethoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) 30 methyl-2H-indazolcarboxamide 179. 2-({1-[4-(2-fluorophenoxy)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 180. 2-({1-[(4'-cyano-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 35 181. 2-({1-[4-(5-chloropyridinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 0_1 (GHMatters) P97018.NZ 182. N-(2-methoxyethyl)methyl[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 183. N-(2-methoxyethyl)({1-[(4'-methoxy-2'-methylbiphenylyl)carbonyl]piperidin yl}methyl)methyl-2H-indazolcarboxamide 5 184. 2-({1-[(4'-chloro-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 185. 2-[(1-{[4'-(1-cyanomethylethyl)biphenylyl]carbonyl}piperidinyl)methyl]-N-(2- yethyl)methyl-2H-indazolcarboxamide 186. N-(2-methoxyethyl)({1-[4-(5-methoxypyridinyl)benzoyl]piperidinyl}methyl) 10 methyl-2H-indazolcarboxamide 187. N-(2-methoxyethyl)methyl[(1-{4-[6-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 188. ethoxyethyl)({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl) methyl-2H-indazolcarboxamide 15 189. 2-({1-[(4'-fluoro-2'-methylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 190. N-(2-methoxyethyl)methyl({1-[4-(6-methylpyridinyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 191. N-(2-methoxyethyl)({1-[4-(6-methoxypyridinyl)benzoyl]piperidinyl}methyl) 20 methyl-2H-indazolcarboxamide 192. N-(2-methoxyethyl)methyl({1-[4-(2-methylpyrimidinyl)benzoyl]piperidin yl}methyl)-2H-indazolcarboxamide 193. [(4'-fluoro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 25 194. 2-({1-[(4'-chloro-2'-methoxybiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- methoxyethyl)methyl-2H-indazolcarboxamide 195. N-(2-methoxyethyl)methyl[(1-{4-[2-(trifluoromethyl)pyrimidinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 196. 2-({1-[(4'-chloro-2'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxy- 30 ethyl)methyl-2H-indazolcarboxamide 197. 2-({1-[(2'-chloro-4'-fluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 198. 2-({1-[4-(5-chloropyridinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 35 199. 2-({1-[4-(5-fluoropyridinyl)benzoyl]piperidinyl}methyl)-N-(2-methoxyethyl) methyl-2H-indazolcarboxamide 7849490_1 (GHMatters) P97018.NZ 200. N-(2-methoxyethyl)methyl[(1-{4-[5-(trifluoromethyl)pyridinyl]benzoyl}- piperidinyl)methyl]-2H-indazolcarboxamide 201. 2-[(1-{[4'-(1-hydroxymethylethyl)biphenylyl]carbonyl}piperidinyl)methyl]-N- hoxyethyl)methyl-2H-indazolcarboxamide 5 202. 2-({1-[(3',5'-difluorobiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 203. 2-({1-[(4'-fluoromethylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2-methoxyethyl )methyl-2H-indazolcarboxamide 204. 2-({1-[(3',5'-difluoromethylbiphenylyl)carbonyl]piperidinyl}methyl)-N-(2- 10 methoxyethyl)methyl-2H-indazolcarboxamide 205. N-(2-methoxyethyl)methyl({1-[3-methyl(3-pyridyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide 206. N-(2-methoxyethyl)methyl({1-[3-methyl(4-pyridyl)benzoyl]piperidinyl}- methyl)-2H-indazolcarboxamide and 15 207. N-(2-methoxyethyl)methyl({1-[(2-methylbiphenylyl)carbonyl]piperidinyl}- )-2H-indazolcarboxamide 7. Use of a compound according to any one of Claims 1-6 for the production of a drug containing suitable formulation and carrier substances. 8. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for use in the treatment of a medical condition. 9. Use of a nd according to any one of Claims 1-6 in the manufacture of a drug for 25 fertility control/contraception. 10. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for the prophylaxis and treatment of endometriosis. 30 11. Use of a compound according to any one of Claims 1-6 in the cture of a drug for the prophylaxis and treatment of menstrual complaints, where the menstrual problems can be severe and tent bleeding, irregular bleeding and pains. 12. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for 35 the prophylaxis and treatment of fibroids (myomas). 7849490_1 (GHMatters) P97018.NZ 13. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for the prophylaxis and treatment of cancer, where the cancer diseases can be lung, intestinal, breast, skin, prostate or oesophageal cancer and leukaemia. 5 14. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for the prophylaxis and treatment of arteriosclerosis. 15. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for the prophylaxis and treatment of 10 - neurodegenerative, neuroinflammatory and ischaemic diseases, where the diseases can be Alzheimer’s disease, Parkinson’s disease, ALS, stroke and multiple sclerosis, - pain, where the pain can be inflammatory hyperalgesia, - infectious diseases of the lung, - chronic obstructive pulmonary diseases, 15 - intestinal inflammatory diseases, where the intestinal matory diseases can be Crohn’s disease and ulcerative colitis, - bone marrow transplantation operations, - aneurysms, - ar damage and the Kawasaki syndrome, or 20 - arthritis. 16. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for the prophylaxis and treatment of polycystic kidney diseases. 25 17. Use of a compound according to any one of Claims 1-6 in the manufacture of a drug for the prophylaxis and treatment of pathological eye diseases, where the pathological eye diseases can be Graves’ disease. 18. Drug containing a compound according to any one of Claims 1-6 in combination with a 30 Cyclooxygenase (COX) inhibitor for the treatment of diseases, n the COX inhibitors can be selected from the following list: n, naproxen, indomethacin, meloxicam, ibuprofen, ketoprofen, piroxicam, tenoxicam, nimesulide, mic acid, lac, celecoxib (4-[5-(4-methylphenyl)(trifluoromethyl)-1H-pyrazol zenesulphonamide), parecoxib (N-[4-(5-methylphenyl 35 isoxazolyl)phenyl]sulphonylpropionamide), rofecoxib (4-(4-mesylphenyl) phenylfuran-(5H)-one), oxib methylphenyl 0_1 (GHMatters) P97018.NZ isoxazoyl)benzenesulphonamide), NS-398 (N-methylcyclohexanoxynitrobenzenesulphonamide ), lumiracoxib [2-(2'-chloro-6'-fluorophenyl)-aminomethylbenzeneacetic acid], ceracoxib and etoricoxib. 5 19. Drug according to Claim 18, where the es are infectious diseases, cancer, vascular diseases, angiogenic diseases, uterine contraction disorders, pain, inflammatory es, neuroinflammatory diseases, neurodegenerative diseases, autoimmune diseases, immunodependent diseases/therapies, nephrological diseases and ophthalmological diseases and where the drugs can also be used for the treatment of pain 10 and in transplantation and for fertility control. 20. Use of a compound according to any one of Claims 1-6, in the manufacture of a pharmaceutical preparation for enteral, parenteral, vaginal, intrauterine and oral administration. 21. Method for the preparation of the compounds of the l formula (I) according to Claim 1, characterized in that a compound of the general formula (VIII) Formula (VIII) where R1, R2, R3, Ar, m and n have the meaning as stated in Claim 1, 20 is reacted with an amine of the general formula (XI), Formula (XI) where R4 and X have the meaning stated in Claim 1. 22. Method for the preparation of the compounds of the general formula (I) according to 25 Claim 1, characterized in that a compound of the general a (VI) Formula (VI) where R1, R2, R3, Ar, m and n have the meaning stated in Claim 1, is reacted with an amine of the general formula (XI), 7_1 (GHMatters) P97018.NZ Formula (XI) where R4 and X have the meaning stated in Claim 1, and carbon monoxide or a carbon monoxide source, under palladium (0) catalysis. 5 23. Method according to Claim 22, wherein the carbon monoxide source is molybdenum rbonyl.
24. Method for the preparation of the compounds of the general formula (I) according to Claim 1, characterized in that a compound of the general formula (XV) 10 Formula (XV) where R1, R2, R4, X, m, n have the meaning stated in Claim 1, is reacted with a compound of the general formula (IX), Formula (IX) where R3 and Ar have the meaning stated in Claim 1 15 and where either Y = OH resulting in a carboxylic acid or Y = Cl resulting in a carboxylic acid chloride or Y = O-C(O)-O-CH2(CH 3)CH 3 resulting in an anhydride.
25. Method for the preparation of the compounds of the general formula (I) according to 20 Claim 1, characterized in that a compound of the general formula (XVI), Formula (XVI) where R1, R2, R4, X, Ar, m and n have the meaning stated in Claim 1 and wherein LG´ means Br or I, is reacted with a boronic acid or a boronic acid ester of the l a (XVIII), 25 (Formular XVIII) where R3 means aryl or heteroaryl and Met means OH, boronic acids or – boronic acid pinacol esters. 8017637_1 (GHMatters) P97018.NZ
26. Compound according to any one of Claims 1-6 substantially as herein bed with reference to any one of the Examples.
27. Use according to any one of Claims 7 to 17 and 20 substantially as herein described with 5 reference to any one of the es.
28. Drug according to Claim 18 or 19 substantially as herein described with reference to any one of the Examples. 10
29. Method according to any one of Claims 21-25 substantially as herein described with reference to any one of the Examples. 8017637_1 (GHMatters) P97018.NZ
NZ624722A 2011-11-28 2012-11-26 Novel 2h-indazoles as ep2 receptor antagonists NZ624722B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE102011087170 2011-11-28
DE102011087170.5 2011-11-28
DE102012206715.9 2012-04-24
DE102012206715 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
NZ624722A NZ624722A (en) 2016-08-26
NZ624722B2 true NZ624722B2 (en) 2016-11-29

Family

ID=

Similar Documents

Publication Publication Date Title
US11931350B2 (en) Opioid receptor ligands and methods of using and making same
CN111225665B (en) Macrocyclic immunomodulators
EP2785707B1 (en) Novel 2h-indazoles as ep2 receptor antagonists
CA3124898C (en) Heterocyclic compound, intermediate, preparation method therefor and application thereof
ES2911888T3 (en) Heteroaryl compounds as IRAK inhibitors and uses thereof
JP5816635B2 (en) Nuclear transport regulator and use thereof
JPH05294961A (en) Hydantoin and succinmide substituted derivatives of spiroindanylcamphorsulfonyloxytocin antagonist
SK277923B6 (en) 3-imidazolymethyl-1,2,3,9-tetrahydro-4h-carbazole-4-on derivatives, method of their preparation and pharmaceutical agents containing this agents
EP2003118A1 (en) Cinnamic acid derivatives as modulators of EP2 receptors
TW200307678A (en) Substituted pyridines having antiangiogenic activity
JP2006505552A (en) Azaindole derivatives as p38 kinase inhibitors
HU230123B1 (en) Substituted indoleoxoacetic piperazine derivatives, pharmaceutical compositions containing them and their antiviral use
KR20180094938A (en) Combination of opioid receptor ligand and cytochrome P450 inhibitor
KR20220141331A (en) P2X3 modifier
CA3047812A1 (en) Tetrazole containing compounds
CN103402995A (en) Novel indole or indazole derivative or salt thereof
WO2021045159A1 (en) Therapeutic or prophylactic method for diabetes using combination medicine
EP2003119A1 (en) Substituted acetamides as modulators of EP2 receptors
NZ624722B2 (en) Novel 2h-indazoles as ep2 receptor antagonists
EP2999469A1 (en) Pharmaceutical composition and the use thereof, and application regime of said pharmaceutical composition for on-demand contraception
Bräuer et al. 2H-indazoles as EP 2 receptor antagonists
WO2010012399A1 (en) Indolylamides as modulators of the ep&lt;sb&gt;2&lt;/sb&gt; receptor
ES2314288T3 (en) DERIVED FROM 1,2,4-TRIAZOL, METHOD FOR PREPARATION AND PHARMACEUTICAL COMPOSITION THAT CONTAINS.
TW201910325A (en) Indole derivatives and uses thereof
WO2014187793A1 (en) Use of a pharmaceutical composition for emergency contraception