WO2015044072A1

WO2015044072A1 - Indol and indazol derivatives

Info

Publication number: WO2015044072A1
Application number: PCT/EP2014/070092
Authority: WO
Inventors: Theresa Maria Ballard; Katrin Groebke Zbinden; Emmanuel Pinard; Thomas Ryckmans; Herve Schaffhauser
Original assignee: F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.
Priority date: 2013-09-27
Filing date: 2014-09-22
Publication date: 2015-04-02
Also published as: HK1220199A1; JP6185660B2; EP3049391B1; JP2016534026A; KR20160044039A; BR112016006154A2; EP3049391A1; US9708259B2; RU2016112952A; CN105593211A; US20160207885A1; CN105593211B; MX2016001942A; CA2918925A1

Abstract

The present invention relates to indole and indazole derivatives of the following formula (I) wherein A is (AA) and the remaining variables are as defined in the specification. The compounds may be used for the treatment or prophylaxis of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

Description

INDOL AND INDAZOL DERIVATIVES

The present invention relates to compounds of formula

H

R is lower alkyl, -(CH₂)_z-C3_7-cycloalkyl or -(CH₂)_Z- C4_6-heterocycloalkyl, which are

optionally substituted by one to three hydroxy, lower alkyl, lower alkoxy or halogen, or is (endo)-7-oxabicyclo[2.2.1]heptan-2-yl;

X is CH or N;

Y¹ is CR³ or N; Y² is CR⁴; or or Y 1'and Y 2" may form together with the carbon atoms to which they are attach

Y³ is N;

Y⁴ is N; is NR⁷; is hydrogen or halogen; is hydrogen, halogen, cycloalkyl, lower alkyl or lower alkoxy;

R is hydrogen, halogen, , CN, -C(0)NH₂, -C(0)NHCH₃ or -C(0)N(CH₃)₂; is hydrogen, a 5 or 6 membered heteroaryl or heterocyclyl group, selected from the group

c

or is phenyl, -C(0)NH₂, -CH₂C(0)NH₂, -C(0)NHCH₃, -C(0)NH-cycloalkyl,

-C(0)N(CH₃)₂, -NHC(0)0-lower alkyl, CN, lower alkoxy, lower alkoxy substituted by halogen, halogen or S(0)₂CH ;

R⁵ is phenyl; R⁶ is phenyl or thiazol-2-yl;

R is pyridin-2-yl or pyrimidin-4-yl; p is 0 or 1 ; m is 1, 2 or 3; z is 0 or 1;

or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its

corresponding enantiomer and/or optical isomers thereof. WO 2013/106795 describes a very broad scope of partially similar compounds for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The activity (EC_50, in nM) is very low between 2400 and > 10000, and therefore these compounds are not suitable for the development of corresponding drugs.

The compounds of the present invention are muscarinic Ml receptor positive allosteric modulators (PAM) and hence are useful in the treatment of diseases, mediated by the muscarinic Ml receptor, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

Acetylcholine (ACh) is a neurotransmitter which activates both nicotinic (ligand-gated ion channel) and muscarinic (metabotropic) receptors in the CNS and in the periphery.

The muscarinic receptors (mAChRs) are members of the class A G-protein-coupled receptors. To date, five distinct subtypes of mAChRs (M1-M5) have been cloned and sequenced. The muscarinic Ml receptors are predominantly distributed in the brain, with the highest expression in the cortex, thalamus, striatum and hippocampus. In clinical studies, Xanomeline, a Ml/M4-preferring agonist, demonstrated robust efficacy on positive, negative and cognitive symptoms in schizophrenic patients and improved cognitive scores and reduced psychotic-like behaviors in patients with Alzheimer's disease (AD). The Ml receptor has been implicated in memory and learning processes, regulation of dopamine and NMDA receptor activity and has thus been proposed as a potential target for the treatment of AD and schizophrenia. AD is the most common cause of dementia in later life. Pathologically AD is characterized by the deposition in the brain of amyloid in extracellular plaques and intracellular neurofibrillary tangles. The amyloid plaques are mainly composed of amyloid peptides (Abeta peptides) which originate from the β-Amyloid Precursor Protein (APP) by a series of proteolytic cleavage steps. Several forms of APP have been identified of which the most abundant are proteins of 695, 751 and 770 amino acids length. They all arise from a single gene through differential splicing. The Abeta peptides are derived from the same domain of the APP but differ at their N- and C- termini, the main species are of 40 and 42 amino-acid length by processing of the beta-amyloid precursor protein (APP) by the beta-amyloid protein cleaving enzyme. The processing leads to accumulation of Abeta in the brain.

Ml receptors are abundantly expressed postsynaptically in cortex, hippocampus and striatum which are important brain regions involved for cognition. Based on the cholinergic hypothesis i.e. degeneration of presynaptic cholinergic nerve terminals in hippocampus and cortical regions, Ml activation should rescue the cognitive deficits which occur in AD, thus providing symptomatic treatment of this neurodegenerative disorder. Postmortem studies in AD cortical tissues have shown that Ml receptor expression are not reduced, thus providing evidence for target availability in a critical brain region. Moreover, preclinical studies have shown that Ml activation has potential as a disease-modifying therapy for AD by shifting the APP processing towards the non-amyloido genie a-secretase pathway and by decreasing tau hyperphosphorylation. Therefore, Ml PAMs provide an approach to target both symptomatic and disease-modifying treatment of AD.

Schizophrenia is a severe, disabling, lifelong disorder that affects 1% of the population and is characterized by positive symptoms (such as hallucinations, delusions and paranoia), negative symptoms (such as social withdrawal and apathy) and cognitive impairment (for example, deficits in working memory, executive function and attention). Schizophrenia is a

neurodevelopmental disorder with genetic risk factors and neuropathological changes. Aberrant activity occurs within the prefrontal - hippocampal - thalamic network in brains of

schizophrenia patients. Positive symptoms of schizophrenia are suggested to be caused by dopaminergic system dysfunction, particularly increased dopamine activity within subcortical brain regions such as the striatum. Negative symptoms are thought to occur due to impaired signaling within the neurocircuitry of the ventral tegmental area and ventral striatum. Decreased NMDA receptor function in pyramidal neurons coupled with sub-optimal dopamine release in critical regions such as dorsolateral prefrontal cortex may account for some of the cognitive deficits.

Ml receptors are located in regions which are affected in schizophrenia, such as the hippocampus, cortex and striatum, in particular in the medium spiny neurons. Several reports have shown a reduction in muscarinic receptors in the prefrontal cortex and hippocampus, regions where Ml is densely expressed, in a subset of schizophrenic patients. Furthermore, preclinical studies have shown that Ml knockout mice have enhanced amphetamine-induced activity and increased striatal dopamine levels. Electrophysiology studies have revealed that activation of Ml receptors potentiates NMDA mediated hippocampal activity, modulates activity of medium spiny neurons and increases activity of medial prefrontal cortex neurons. Overall, activation of Ml receptors should modulate dysfunctional dopaminergic and glutamatergic signaling within the underlying neurocircuitry resulting in improvements in the symptoms of schizophrenia. The clinical effects of Xanomeline and other muscarinic Ml agonist agents were however always associated with adverse effects attributed to their insufficient Ml muscarinic receptor subtype selectivity The typical observed side effects, including sweating, salivation,

gastrointestinal distress and bradycardia have been attributed to the non-specific activation of peripheral M2 and M3 mAChRs. Despite a tremendous effort from a number of companies, the search for highly Ml selective agonists has failed because of the high degree of conservation between muscarinic receptor subtypes at their orthosteric acetylcholine ligand binding sites.

To circumvent the selectivity and safety issues associated with targeting the highly conserved orthosteric ACh site, an alternative approach consists of developing Ml PAMs that act at the less highly conserved allosteric binding sites.

Recently. Merck and Vanderbilt University reported M I PAMs from different chemical classes exhibiting, as rationalized, a good level of Ml subtype selectivity. Importantly, similar to the preclinical profile of Xanomeline and other un selective M 1 agonists, these M 1 allosteric agents demonstrated pro-cognitive effects (in scopolamine-induced memory deficit in mice.

scopolamine impaired non-human primates and in transgenic AD mice). PQCA and ML ! 69 have been shown to promote non-amyloidogenic APP processing. Electrophysiology studies have shown that Ml PAMs potentiate carbachol-induced activity in the medial prefrontal cortex and medium spiny neurons. Moreover, unlike unselective agonists. M 1 PA s do not appear to produce side effects such as salivation at therapeutic effective doses. Additionally, they are expected to be devoid of liabilities such as receptor desensitization/intemalization following chronic dosing previously reported for orthosteric receptor agonists. In summary, the PAM approach, by activating in a truly selective manner M 1 receptors, is a highly promising novel strategy to deliver both efficacious and safe therapeutic agents for the treatment of schizophrenia (positive, negative and cognitive symptoms ) as well as AD (symptomatic and disease modifying).

Thus, the compounds of the invention, which are muscarinic Ml receptor positive allosteric modulators, are believed to be useful in the treatment of Alzheimer's disease and other diseases mediated by the muscarinic Ml receptor, without side effects.

Therefore, the object of the present invention was to identify compounds that are muscarinic Ml receptor positive allosteric modulators. It has been found that the compounds of formula I are active in this area and they may therefore be used for the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders The present invention relates to compounds of formula I and to their pharmaceutically acceptable salts, to these compounds as pharmaceutically active substances, to the processes for their production, as well as to the use in the treatment or prevention of disorders, relating to muscarinic Ml receptor positive allosteric modulators, and to pharmaceutical compositions containing the compounds of formula I.

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

As used herein, the term "lower alkyl" denotes a saturated, i.e. aliphatic hydrocarbon group including a straight or branched carbon chain with 1 - 7 carbon atoms. Examples for "alkyl" are methyl, ethyl, n-propyl, isopropyl, n- butyl, i-butyl, 2-butyl, t-butyl and the like.

As used therein, the term "C3_7-cycloalkyl" denotes a saturated carbon ring, containing from 3 to 7 carbon ring atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "alkoxy" denotes a group -O-R' wherein R' is lower alkyl as defined above. The term "halogen" denotes chlorine, bromine, fluorine or iodine.

The term "lower alkoxy substituted by halogen" denotes an alkyl group as defined above, wherein at least one hydrogen atoms is replaced by halogen, for example OCF₃, OCH₂F,

OCH₂CF₃, OCH₂CH₂CF₃, OCH₂CF₂CF₃ and the like.

The term "C4_6-heterocycloalkyl" denotes a non-aromatic heterocyclic ring with 4 to 6 ring atoms, containing at least one O atom, for example tetrahydropyran-4-yl,

tetrahydrothiopyran, thiane 1,1 -dioxide, tetrahydropyran-3-yl, oxolan-3-yl, oxetan-3-yl, oxetan-2-yl or tetrahydrofuran-2-yl.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable acid addition salt" embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane- sulfonic acid, p-toluenesulfonic acid and the like

One embodiment of the present invention are compounds of formula I, wherein R is -(CH₂)_z-C4_6-cycloalkyl, which is optionally substituted by one to three hydroxy, lower alkyl, lower alkoxy or halogen or 8endo)-7-oxabicyclo[2.2.1]heptan-2-yl; and p is 0 or 1, and the other substituents are as described above, for example the following compounds:

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(( lS,2S)-2-hydroxycyclohexyl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(( lR,2R)-2-hydroxycyclohexyl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(( lS,2S)-2-hydroxycyclohexyl)- 1 H-indazole- 3 -c arboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(( lR,2R)-2-hydroxycyclohexyl)- 1 H-indazole- 3 -c arboxamide

N-(3,3-difluorocyclobutyl)-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3- carboxamide

N-cyclobutyl-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide 4-fluoro- 1 - (2-fluoro-4- ( 1 -methyl- 1 H-pyrazol-4-yl)benzyl)- N-((lS,2S)-2-hydroxycyclopentyl)-lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lSR,2SR)-2-hydroxy-2- methylcyclohexyl)-lH-indole-3-carboxamide

N-cyclohexyl-4-fluoro- 1 -(2-fluoro-4-( 1 -methyl- 1 H-pyrazol-4-yl)benzyl)- 1 H-indole-3- carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lSR,2RS)-2-hydroxy-2- methylcyclohexyl)- lH-indole-3-carboxamide

4-fluoro- 1 -(2-fluoro-4-( 1 -methyl- 1 H-pyrazol-4-yl)benzyl)-N-(( 1 S,2R)-2-hydroxycyclopentyl)- lH-indole-3-carboxamide

N-(2,2-difluorocyclohexyl)-4-fluoro- 1 -(2-fluoro-4-( 1-methyl- lH-pyrazol-4-yl)benzyl)- 1H- indole-3-carboxamide

4,5,6,7-tetrafluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)-lH-indole-3-carboxamide

4,5,6,7-tetrafluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l-methyl-lH-pyrazol-4-yl)pyridin-

3- yl)methyl)-lH-indole-3-carboxamide

4- fluoro- l-(2-fluoro-4-methoxybenzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

l-(4-(difluoromethoxy)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-( 1-methyl- lH-pyrazol-4-yl)pyridin-3- yl)methyl)- 1 H-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-methoxybenzyl)-lH-indole-3-carboxamide l-(4-cyanobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide 4-fluoro-l-(3-fluoro-4-methoxybenzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(trifluoromethoxy)benzyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(3-(l -methyl- lH-pyrazol-4-yl)benzyl)-lH-indole- 3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(4-methyl-lH-imidazol-l-yl)benzyl)-lH-indole-

3- carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-methyl-lH-indazol-5-yl)methyl)-lH-indole-3- carboxamide

l-(4-chlorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3-chlorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3-cyanobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3,4-difluorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide 4-fluoro-l-(4-fluorobenzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3,5-difluorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide 4-fluoro-N-(( 1 S,2S)-2-hydroxycyclohexyl)- 1 -(4-( 1 -methyl- 1 H-pyrazol-4-yl)benzyl)- 1 H-indole-

3- carboxamide

4- fluoro- l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-7- methyl- lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-7-methyl-l-(4-(l -methyl- lH-pyrazol-4-yl)benzyl)- lH-indole-3-carboxamide

l-benzyl-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide

4-fluoro-N-(( 1 S,2S)-2-hydroxycyclohexyl)- 1 -(4- (3 -methyl- 1 H-pyrazol- 1 -yl)benzyl)- 1 H-indole-

3- carboxamide

4,5,6,7-tetrafluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)- lH-indole-3-carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-methyl-lH-benzo[d]imidazol-5-yl)methyl)-lH- indole-3-carboxamide

4,5-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH- indole-3-carboxamide

4,5-difluoro-N-(( lS,2S)-2-hydroxycyclohexyl)-l-((6-(l -methyl- lH-pyrazol-4-yl)pyridin-3- yl)methyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(methylcarbamoyl)benzyl)-lH-indole-3- carboxamide

4,5-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(4-methyl-lH-imidazol-l-yl)benzyl)-lH- indole-3-carboxamide

4,5-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(3-methyl-lH-pyrazol-l-yl)benzyl)-lH- indole-3-carboxamide

4,7-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)-lH-indazole-3-carboxamide

4,7-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l -methyl- lH-pyrazol-4-yl)pyridin-3- yl)methyl)-lH-indazole-3-carboxamide

l-(4-carbamoylbenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide 1 -(4- (2-amino-2-oxoethyl)benzyl)-4-fluoro-N- (( 1 S ,2S)-2-hydroxycyclohexyl)- 1 H-indole-3 - carboxamide

l-(3-carbamoylbenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(methylsulfonyl)benzyl)-lH-indole-3- carboxamide

ethyl 4-((4-fluoro-3-((lS,2S)-2-hydroxycyclohexylcarbamoyl)-lH-indol-l- yl)methyl)phenylcarbamate

4-fluoro-l-(2-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole- 3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(methylcarbamoyl)pyridin-3-yl)methyl)-lH- indole-3-carboxamide

4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole- 3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(3-(methylcarbamoyl)benzyl)-lH-indole-3- carboxamide

l-(3-(dimethylcarbamoyl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide 2-(4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol-3-yl)-N-((lS,2S)-2- hydroxycyclohexyl)acetamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-((l-hydroxycyclopropyl)methyl)- lH-indole-3-carboxamide

4-((4-fluoro-3-(2-((lS,2S)-2-hydroxycyclohexylamino)-2-oxoethyl)-lH-indol-l-yl)methyl)-N- methylbenzamide

N-((lR,2S)-3,3-difluoro-2-hydroxycyclohexyl)-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide

N-((lS,2R)-3,3-difluoro-2-hydroxycyclohexyl)-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide

N-((lR,2S)-3,3-difluoro-2-hydroxycyclohexyl)-4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide

N-((lS,2R)-3,3-difluoro-2-hydroxycyclohexyl)-4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide

7-cyclopropyl-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide

N-cyclopropyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide N-cyclobutyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-cyclopentyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-cyclohexyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-(cyclopropylmethyl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide N-(4,4-difluorocyclohexyl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3- carboxamide

N-(3,3-difluorocyclohexyl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3- carboxamide

4-fluoro-N-(2-fluorocyclohexyl)-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide 4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(2-fluorocyclohexyl)-lH-indole-3- carboxamide

4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(2-fluorocyclohexyl)-lH-indole-3- carboxamide 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-phenylpyridin-3-yl)methyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(pyrimidin-2-yl)benzyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(oxazol-5-yl)benzyl)-lH-indole-3-carboxamide 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(isoxazol-5-yl)benzyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((2-phenylpyrimidin-5-yl)methyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((5-phenylpyridin-2-yl)methyl)-lH-indole-3- carboxamideyl)benzyl) - 1 H-indole- 3 -c arboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((5-(thiazol-2-yl)pyridin-2-yl)methyl)-lH-indole-

3- carboxamide

l-((6-(lH-imidazol-l-yl)pyridin-3-yl)methyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH- indole-3-carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-(pyriirddin-4-yl)piperidin-4-yl)methyl)-i indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(imidazo[l,2-a]pyridin-7-ylmethyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(imidazo[l,2-a]pyridin-6-ylmethyl)-lH-indole-3- carboxamide

l-(4-(cyclopropylcarbamoyl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-7-methoxy-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-7- methoxy-lH-indole-3-carboxamide

l-(4-(lH-Pyrazol-5-yl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

l-(4-(lH-l,2,4-triazol-3-yl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(pyrimidin-5-yl)benzyl)-lH-indole-3- carboxamide 4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(pyridin-3-yl)benzyl)-lH-indole-3- carboxamide

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-(pyridin-2-yl)piperidin-4-yl)methyl)-lH- indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(pyrrolidin-l-yl)benzyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(pyrrolidin-l-yl)pyridin-3-yl)methyl)-lH- indole-3-carboxamide or

N-(2,2-difluorocyclohexyl)-4-fluoro- 1 -(3-fluoro-4-(methylcarbamoyl)benzyl)- lH-indole-3- carboxamide.

One further embodiment of the present invention are compounds of formula I, wherein R is -(CH₂)_Z- C4_6-heterocycloalkyl, which are optionally substituted by one to three hydroxy, lower alkyl, lower alkoxy or halogen or (endo)-7-oxabicyclo[2.2.1]heptan-2-yl; p is 0 or 1; and the other substituents are as described above, for example the following compounds:

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3RS,4RS)-3-hydroxytetrahydro- 2H-pyran-4-yl)-lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3RS,4SR)-3-hydroxytetrahydro- 2H-pyran-4-yl)-lH-indazole-3-carboxamide

4-fluoro-N-[(3S,4R)-4-methoxyoxolan-3-yl]-l-[[4-(l-methylpyrazol-4-yl)phenyl]methyl]indole 3-carboxamide

(R)-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((tetrahydrofuran-2-yl)methyl)-lH- indole-3-carboxamide

4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-lH-indole-3- carboxamide

4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(oxetan-3-ylmethyl)-lH-indole-3- carboxamide

4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(oxetan-2-ylmethyl)-lH-indole-3- carboxamide

l-(4-carbamoylbenzyl)-4-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole 3- carboxamide

l-(4-cyanobenzyl)-4-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

4- fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-lH indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3S,4S)-4-hydroxytetrahydro-2H pyran-3-yl)-lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH indole-3-carboxamide

4-fluoro-7-methyl-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-lH indole-3-carboxamide

4-fluoro-7-methyl-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH indole-3-carboxamide

4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(4-methyl-lH imidazol-l-yl)benzyl)-lH-indole-3-carboxamide

4- fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((l-methyl-lH-indazol

5- yl)methyl)-lH-indole-3-carboxamide

l-(4-cyanobenzyl)-4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH indole-3-carboxamide

4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl-lH pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

4,5,6,7-tetrafluoro-N-((3S,4R) or (3R,4S))-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl- lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

4,5,6,7-tetrafluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl- lH-pyrazol-4-yl)benzyl)- lH-indole-3-carboxamide

4,5,6,7-tetrafluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S) or (3S,4R))-3- hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide 4-fluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

4-fluoro-l-(4-(4-methyl-lH-imidazol-l-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

4-fluoro-l-((6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)- lH-indole-3-carboxamide

4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indazole-3- carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3S,4R) or (3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S) or (3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

4,7-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro- 2H-pyran-4-yl)-lH-indazole-3-carboxamide

4,7-difluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((6-(l-methyl-lH-pyrazol-4- yl)pyridin-3-yl)methyl)-lH-indazole-3-carboxamide

1- ((6-(lH-l,2,4-triazol-l-yl)pyridin-3-yl)methyl)-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H- pyran-4-yl)-lH-indole-3-carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(thiazol-2-yl)benzyl)-lH-indole- 3-carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(5-methyl-l,2,4-oxadiazol-3- yl)benzyl)-lH-indole-3-carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(2-oxopyrrolidin-l-yl)benzyl)- lH-indole-3-carboxamide

2- [4-fluoro-l-[[2-fluoro-4-(l-methylpyrazol-4-yl)phenyl]methyl]indol-3-yl]-N-[(3R,4S)-3- hydroxyoxan-4-yl] acetamide

4,7-difluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

4,7-difluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-

3- carboxamide

4,7-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)- lH-indole-3-carboxamide

4-((4-fluoro-3-(2-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-ylamino)-2-oxoethyl)-lH-indol-l- yl)methyl)-N-methylbenzamide

7-cyclopropyl-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl-lH- pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

7-cyclopropyl-4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

7-ethyl-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

7-ethyl-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide

N-(2,2-dimethyloxan-4-yl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3- carboxamide

4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(oxan-3-yl)indole-3-carboxamide

4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(4-methyloxan-4-yl)indole-3-carboxamide 4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(thian-4-yl)indole-3-carboxamide

N-(l,l-dioxothian-4-yl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide 4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(3-methyloxan-4-yl)indole-3-carboxamide 4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(2-methyloxan-4-yl)indole-3-carboxamide 7-ethyl-4-fluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

4-fluoro-l-(4-(methylcarbamoyl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-7-methyl-N-(tetrahydro-2H-pyran-4- yl)-lH-indole-3 -carboxamide

4-fluoro-7-methyl- 1 -((1 -methyl- lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)- 1H- indole-3-carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((l-(pyridin-2-yl)piperidin-4- yl)methyl)-lH-indole-3-carboxamide

4-fluoro-l-((6-(methylcarbamoyl)pyridin-3-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-

3- carboxamide

4- fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methoxy-l-(4-(l-methyl-lH- pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide 4-fluoro-7-methoxy-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-7-methoxy-N-(tetrahydro-2H-pyran- 4-yl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S)-3-hydroxytetrahydro-2H- pyran-4- yl) -7 -methoxy- 1 H-indole- 3 -c arboxamide

4-fluoro-7-methoxy-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

l-(4-(lH-l,2,4-triazol-3-yl)benzyl)-4-fluoro-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

4-Fluoro- 1 -(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)- lH-indole-3- carboxamide

4-Fluoro- 1 -(2-fluoro-4-(methylcarbamoyl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)- lH-indole-3- carboxamide

N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)- lH-indole-3-carboxamide

4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(tetrahydro-2H-thiopyran-4-yl)-lH-indole-

3- carboxamide or

4- fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(3-methyltetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide.

One embodiment of the invention are compounds of formula I, wherein X is N, for example the following compounds

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl) 1 H-indazole- 3 -c arboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lR,2R)-2-hydroxycyclohexyl) 1 H-indazole- 3 -c arboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3RS,4SR)-3-hydroxytetrahydro 2H-pyran-4-yl)-lH-indazole-3-carboxamide

4,7-difluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((6-(l-methyl-lH-pyrazol-4- yl)pyridin-3-yl)methyl)-lH-indazole-3-carboxamide or

4,7-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l -methyl- lH-pyrazol-4-yl)pyridin-3- yl)methyl) - 1 H-indazole- 3 -carboxamide .

One embodiment of the invention are compounds of formula I, wherein Y¹ is N, for example the following compounds

4,5,6,7-tetrafluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l-methyl-lH-pyrazol-4-yl)pyridine

3- yl)methyl)-lH-indole-3-carboxamide

4,5-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l -methyl- lH-pyrazol-4-yl)pyridine-3- yl)methyl)-lH-indole-3-carboxamide

4- fluoro-l-((6-(l-methyl-lH-pyrazol-4-yl)yridine-3-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)- lH-indole-3-carboxamide

4,7-difluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((6-(l-methyl-lH-pyrazol-4- yl)yridine-3-yl)methyl)-lH-indazole-3-carboxamide

4,7-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l -methyl- lH-pyrazol-4-yl)yridine-3- yl)methyl)-lH-indazole-3-carboxamide

l-((6-(lH-l,2,4-triazol-l-yl)yridine-3-yl)methyl)-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro- 2H-pyran-4-yl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(methylcarbamoyl)yridine-3-yl)methyl)-lH- indole-3-carboxamide

One embodiment of the invention are compounds of formula I, wherein Y 1 and Y 2 may form together with the carbon atoms to which they are attach

for example the following compounds

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-methyl-lH-indazol-5-yl)methyl)-lH-indole-3- carboxamide

4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((l-methyl-lH-indazol- 5-yl)methyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-methyl-lH-benzo[d]yridine-5-yl)methyl) lH-indole-3-carboxamide

4-fluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- Carboxamide

4,7-difluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3 carboxamide

7-ethyl-4-fluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH indole-3-carboxamide

4-fluoro-7-methyl- 1 -((1 -methyl- lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)- 1H indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(imidazo[l,2-a]pyridin-7-ylmethyl)-lH-indole-3 carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(imidazo[l,2-a]pyridin-6-ylmethyl)-lH-indole-3 Carboxamide

4-fluoro-7-methoxy-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH indole-3-carboxamide

One embodiment of the invention are compounds of formula I, wherein the five-membered heteroaryl group for R⁴ is not a pyrazole group, substituted by methyl, for example the following compounds

l-(4-carbamoylbenzyl)-4-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole- 3-carboxamide

4-fluoro-l-(2-fluoro-4-methoxybenzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(3-(l -methyl- lH-pyrazol-4-yl)benzyl)-lH-indole

3- carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(4-methyl-lH-imidazol-l-yl)benzyl)-lH-indole 3-carboxamide

l-(4-chlorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3-chlorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3-cyanobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3,4-difluorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide 4-fluoro-l-(4-fluorobenzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-(3,5-difluorobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-benzyl-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide

4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(4-methyl-lH- yridine-l-yl)benzyl)-lH-indole-3-carboxamide

l-(4-cyanobenzyl)-4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-methyl-lH-benzo[d]yridine-5-yl)methyl)- lH-indole-3-carboxamide

l-(4-carbamoylbenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-((6-(lH-l,2,4-triazol-l-yl)yridine-3-yl)methyl)-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-

2H-pyran-4-yl)-lH-indole-3-carboxamide

1 -(4- (2-amino-2-oxoethyl)benzyl)-4-fluoro-N- (( 1 S ,2S)-2-hydroxycyclohexyl)- 1 H-indole-3 - carboxamide

l-(3-carbamoylbenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(methylsulfonyl)benzyl)-lH-indole-3- carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(5-methyl-l,2,4-oxadiazol-3- yl)benzyl)- lH-indole-3-carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(2-oxopyrrolidin-l-yl)benzyl)- lH-indole-3-carboxamide ethyl 4-((4-fluoro-3-((lS,2S)-2-hydroxycyclohexylcarbamoyl)-lH-indol-l- yl)methyl)phenylcarbamate

4-fluoro-l-(2-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-

3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)- l-((6-(methylcarbamoyl)yridine-3-yl)methyl)- 1H- indole-3-carboxamide

4- fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-

3- carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(3-(methylcarbamoyl)benzyl)-lH-indole-3- carboxamide

l-(3-(dimethylcarbamoyl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(oxazol-5-yl)benzyl)-lH-indole-3-carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(isoxazol-5-yl)benzyl)-lH-indole-3- carboxamide

l-(4-(lH-l,2,4-triazol-3-yl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide or

l-(4-(lH-l,2,4-triazol-3-yl)benzyl)-4-fluoro-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide.

One further embodiment of the invention are compounds of formula IA

H

R

IA, which compounds are

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(( lS,2S)-2-hydroxycyclohexyl)- lH-indazole-3-carboxamide 4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N- ((lR,2R)-2-hydroxycyclohexyl)-lH-indazole-3-carboxamide

4,6-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)- lH-indole-3-carboxamide

4-fluoro-N-[(3S,4R)-4-methoxyoxolan-3-yl]-l-[[4-(l-methylpyrazol-4-yl)phenyl]methyl]indole-

3- carboxamide

N-cyclobutyl-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

4- fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-lH-indole-3- carboxamide

l-(4-carbamoylbenzyl)-4-fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-

3- carboxamide

4- fluoro- 1 - (2-fluoro-4- ( 1 -methyl- 1 H-pyrazol-4-yl)benzyl)- N-((lS,2S)-2-hydroxycyclopentyl)-lH-indole-3-carboxamide 4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lSR,2SR)-2-hydroxy-2- methylcyclohexyl)-lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-lH- indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3S,4S)-4-hydroxytetrahydro-2H- pyran-3-yl)-lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)- 1H- indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lSR,2RS)-2-hydroxy-2- methylcyclohexyl)-lH-indole-3-carboxamide

N-(2,2-difluorocyclohexyl)-4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH- indole-3-carboxamide

4,5,6 J-tetrafluoro-l-(2-fluoro-4-(l-methyl-lH-p razol-4-yl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)-lH-indole-3-carboxamide

4,5,6,7-tetrafluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l-methyl-lH-pyrazol-4-yl)pyridine- 3-yl)methyl)-lH-indole-3-carboxamide

4-fluoro- l-(2-fluoro-4-methoxybenzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l-methyl-lH-pyrazol-4-yl)pyridine-3- yl)methyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-methoxybenzyl)-lH-indole-3-carboxamide l-(4-cyanobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide 4-fluoro- l-(3-fluoro-4-methoxybenzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(3-(l -methyl- lH-pyrazol-4-yl)benzyl)-lH-indole- 3- carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(4-methyl-lH-imidazol-l-yl)benzyl)-lH-indole-

3- carboxamide

4- fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(( lS,2S)-2-hydroxycyclohexyl)-7- methyl- lH-indole-3-carboxamide

l-benzyl-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide

4-fluoro-7-methyl-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-lH- indole-3-carboxamide

4-fluoro-7-methyl-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

3- carboxamide

4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(4-methyl-lH- imidazol-l-yl)benzyl)-lH-indole-3-carboxamide

4- fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((l-methyl-lH-indazol-

5- yl)methyl)-lH-indole-3-carboxamide

4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl-lH- pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-methyl-lH-benzo[d]yridine-5-yl)methyl)-lH- indole-3-carboxamide

4,5,6,7-Tetrafluoro-N-((3S,4R) or (3R,4S))-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl- lH-pyrazol-4-yl)benzyl)- lH-indole-3-carboxamide

4,5,6,7-Tetrafluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)- l-(4-(l-methyl- lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

Fluoro-l-(4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

4-fluoro-l-((6-(l-methyl-lH-pyrazol-4-yl)yridine-3-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3S,4R) or

(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S) or (3S,4R)-3- hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide 4,7-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)-lH-indazole-3-carboxamide

4,7-difluoro-N-(( lS,2S)-2-hydroxycyclohexyl)-l-((6-(l -methyl- lH-pyrazol-4-yl)yridine-3- yl)methyl)- 1 H-indazole-3-carboxamide

l-(4-carbamoylbenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide l-((6-(lH-l,2,4-triazol-l-yl)yridine-3-yl)methyl)-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H- pyran-4-yl)-lH-indole-3-carboxamide

3- carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(methylcarbamoyl)pyridin-3-yl)methyl)-lH- indole-3-carboxamide

4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-

3- carboxamide

1- (3-(dimethylcarbamoyl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

2- (4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol-3-yl)-N-((lS,2S)-2- hydroxycyclohexyl)acetamide

3- carboxamide

4- ((4-fluoro-3-(2-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-ylamino)-2-oxoethyl)-lH-indol-l- yl)methyl)-N-methylbenzamide

N-((lS,2R)-3,3-difluoro-2-hydroxycyclohexyl)-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4- yl)benzyl)- lH-indole-3-carboxamide

N-((endo)-7-oxabicyclo[2.2.1]heptan-2-yl)-4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide

7-cyclopropyl-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(l-methyl-lH-pyrazol-4- yl)benzyl)-lH-indole-3-carboxamide 7-cyclopropyl-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l-methyl-lH- pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

4-fluoro-N-methyl- 1 -[ [4- (methylcarbamoyl)phenyl] methyl] indole-3-carboxamide

N-cyclopropyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-cyclobutyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-cyclohexyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-cycloheptyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-(cyclopropylmethyl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-(4,4-difluorocyclohexyl)-4-fluoro- 1 - [ [4- (methylcarbamoyl)phenyl] methyl] indole-3 - carboxamide

N-(2,2-difluorocyclohexyl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3- carboxamide

4-fluoro-N-(2-fluorocyclohexyl)-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(4-methyloxan-4-yl)indole-3-carboxamide

4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(thian-4-yl)indole-3-carboxamide

N-(l,l-dioxothian-4-yl)-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(3-methyloxan-4-yl)indole-3-carboxamide

4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]-N-(2-methyloxan-4-yl)indole-3-carboxamide

7-ethyl-4-fluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(2-fluorocyclohexyl)-lH-indole-3- carboxamide

N-(3,3-difluorocyclohexyl)-4-fluoro- 1 -(3-fluoro-4-(methylcarbamoyl)benzyl)- lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-phenylpyridin-3-yl)methyl)-lH-indole-3- carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-7-methyl-N-(tetrahydro-2H-pyran-4- yl)- lH-indole-3 -carboxamide

3- carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-7-methoxy-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(( lS,2S)-2-hydroxycyclohexyl)-7- methoxy-lH-indole-3-carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methoxy-l-(4-(l-methyl-lH- pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

4-fluoro-7-methoxy-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(pyrimidin-5-yl)benzyl)-lH-indole-3- carboxamide

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(pyridin-3-yl)benzyl)-lH-indole-3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(pyrrolidin-l-yl)pyridin-3-yl)methyl)-lH- indole-3-carboxamide

N-(2,2-difluorocyclohexyl)-4-fluoro- 1 -(3-fluoro-4-(methylcarbamoyl)benzyl)- lH-indole-3- carboxamide

3- carboxamide or

4- fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(3-methyltetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide. One further embodiment of the invention are compounds of formula IB

H

which compound is

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((2-phenylpyrimidin-5-yl)methyl)-lH-indole-3- carboxamide.

One further embodiment of the invention are compounds of formula IC

H

which compounds are

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((2-phenylpyrimidin-5-yl)methyl)-lH-indole-3- carboxamide or

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((5-(thiazol-2-yl)pyridin-2-yl)methyl)-lH-indole- 3-carboxamide.

One further embodiment of the invention are compounds of formula ID H

which compounds are

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-(pyrimidin-4-yl)piperidin-4-yl)methyl)-lH- indole-3-carboxamide or

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-(pyridin-2-yl)piperidin-4-yl)methyl)-lH- indole-3-carboxamide.

The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises a) reacting a compound of formula

IIB,

with a compound of formula

RNH₂ in the presence of an activating agent such as BOP (benzotriazol- 1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or thionyl chloride to a compound of formula

N-R N-R

wherein the substituents are as defined above,

b) reacting a compound of formula

with a compound of formula

in the presence of base like cesium carbonate or sodium hydride to a compound of formula

wherein Hal is halogen and the other substituents are as defined above, and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

The compounds of formula I may be prepared in accordance with process variant a) or b) and with the following schemes 1- 2. The starting material is commercially available or may be prepared in accordance with known methods.

Scheme 1

= ower a y

The substituents are as described above. Compounds of general formula I can be prepared by reacting ester derivatives of formula IV with an alkylating agent in the presence of a base such as sodium hydride to provide V followed by a saponification of V in the presence of a base such as lithium hydroxide and coupling of the resulting acid II with an amine RNH₂. Scheme 2

The substituents are as described above.

Compounds of general formula I can be prepared by coupling acid derivatives of formula VI with an amine RNH₂ to provide amide III followed by reaction of III with an alkylating agent in the presence of a base such as cesium carbonate or sodium hydride.

All reactions are typically performed in a suitable solvent and under an atmosphere of argon or nitrogen.

Some substituents substituents R¹ may be derived from another precursor substituent at the end of the reaction sequence. For instance, a compound of formula I may be synthesized bearing an ester group as R¹, which is converted to a carboxamide substituent by standard procedures.

Insofar as their preparation is not described in the examples, the compounds of formula (I) as well as all intermediate products can be prepared according to analogous methods or according to the methods set forth above. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.

Isolation and purification of the compounds

Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick- layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.

Salts of compounds of formula I The compounds of formula I are basic and may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.

The acid addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like. The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the

compounds of the present invention have an activity as neurogenic agents.

The compounds were investigated in accordance with the test given hereinafter.

Ml PAM assay The assay is designed to select compounds that possess modulator activity at the acetylcholine muscarinic receptor expressed in CHO cells by measuring the intracellular calcium with a Fluorometric Imaging Plate Reader System (FLIPR, Molecular Devices). The assay study the effect of several concentrations of test compounds on basal or acetylcholine- stimulated Ca²⁺ levels using FLIPR. CHO human Ml are plated the day before the experiments at 2 x 10⁵ cells/ml in PDL BioCoat 96 well black/clear plate (Becton 35 4640). The cells are grown at 37°C and 5% C0₂ in the following medium: F12 Nut Mix (Gibco 21765), 10% FCS heat inactivated (GIBCO 16000-044), 1 % Pen Strep (Gibco,15140) and 200 μg/ ml Geneticin (Gibco 11811). On the day of the experiment, the medium was removed and replaced by 100 ml of dye loading buffer containing Hanks Balanced Salt solution (HBSS, 14065-049, Gibco) with 20 mM HEPES (Gibco 15630- 056), 2 mM Probenicid (Sigma P8761), 2mM Fluo-4AM ester (Molecular Probes F-14202), 10% Pluronic acid Molecular Probes P-3000) pH=7.4 and incubated at 37°C. After 60 minutes extracellular dye was removed and the cells were washed five times with FLIPR buffer containing HBSS (Gibco 14065-049) with 20 mM HEPES (Gibco, 15630-056), 2 mM

Probenicid (Sigma P8761) pre-warmed at 37°C using and Ebml cell washer leaving 100 ml of FLIPR buffer in each well. The cell plate and the diluted compounds (1% DMSO final concentration) are placed on the platform of the FLIPR and the door closed. A signal test to check background fluorescence and basal fluorescence signal is performed. Laser intensity is adjusted if necessary. Two minutes preincubation with the diluted test compounds is provide to determine any agonist activity on the Ml receptor by comparison to 30 nM Acetylcholine control. In order to determine any modulator activity the diluted compounds were added to cells and after two minutes preincubation, the EC₂o of acetylcholine is added followed by another two minutes preincubation before the measurement of intracellular Ca²⁺ with a FLIPR (Molecular Devices).

Table with activity data

Example hMl EC₅₀/ Example hMl ECso/ Example hMl ECso/ ratMl ECso ratMl ECso ratMl ECso

1 0.00564/ 58 0.17359/ 114 0.017/

0.06265 10

0.015

2 0.03897/ 59 0.00433/ 115 0.05/

0.20758 0.00435

0.028

3 0.02518/ 60 0.10092/ 116 0.074/

0.09056 0.18255

0.32 0.29451/ 61 0.34281/ 117 0.014/ 1.29408 0.51525

0.029

0.08375/ 62 0.43262/ 118 0.009/ 0.23056 0.56325

0.029

0.07002/ 63 0.01955/ 119 0.006/ 0.14723 0.05425

0.012

0.07002/ 64 0.0547/ 120 0.015/ 0.14723 0.07993

0.032

0.27812/ 65 0.03236/ 121 0.006/ 0.4268 0.05995

0.017

0.36503/ 66 0.21649/ 122 0.062/ 0.41052 0.41204

0.154

0.25567/ 67 0.08278/ 123 0.364/ 0.39796 0.18328

0.68

0.41296/ 68 0.26659/ 124 0.011/ 0.61775 0.18163

0.024

0.12931/ 69 0.34401/ 125 0.166/ 0.39801

0.623

0.19182/ 70 0.10203/ 126 0.019/ 0.24956 0.28411

0.051

0.12088/ 71 0.00592/ 127 0.019/ 0.19809 0.01202

0.026 0.01243/ 72 0.0428/ 128 0.289/ 0.00961 0.133

1.238

0.23702/ 73 0.0658/ 129 0.027/ 0.3368 0.0943

0.066

0.1004/ 74 0.0548/ 130 0.034/ 0.1694 0.0489

0.058

0.06116/ 75 0.0401/ 131 0.036/ 0.18456 0.046

0.152

0.22859/ 76 0.00433/ 132 0.003/ 0.57922 0.00435

0.022

0.20379/ 77 0.00221/ 133 0.048/ 0.42486 0.00247

0.084

0.06054/ 78 0.522/ 134 0.025/ 0.175 0.728

0.076

0.01776/ 79 0.0168/ 135 0.097/ 0.06046 0.0256

0.384

0.01495/ 80 0.11/ 136 0.134/ 0.02579 0.263

0.428

0.04629/ 81 0.351/ 137 0.009/ 0.08446

0.034

0.35873/ 82 0.435/ 138 0.016/ 0.038 0.08061/ 83 0.184/ 139 0.423/ 0.20053 0.16

2.627

0.05596/ 84 0.182/ 140 0.103/ 0.08072 0.169

0.518

0.27196/ 85 0.0429/ 141 0.155/ 0.453

0.22564/ 86 0.00691/ 142 0.075/

0.013

0.21

0.01324/ 87 0.0734/ 143 0.409/ 0.01411 0.12

1.072

0.09063/ 88 0.0143/ 144 0.07/ 0.16046 0.0158

0.172

0.1047/ 89 0.319/ 145 0.017/ 0.22344

0.036

0.10375/ 90 0.341/ 146 0.002/ 0.22165

0.005

0.34213/ 91 0.0249/ 147 0.197/ 0.323

0.22606/ 92 0.035/ 148 0.084/

0.057

0.139

0.01546/ 93 0.191/ 149 0.438/ 0.02591 1.881

0.348 0.04381/ 94 0.066/ 150 0.05/ 0.03954

0.141 0.034

0.13074/ 95 0.027/ 151 0.194/ 0.38163

0.05 0.299

0.20524/ 96 0.028/ 152 0.26/ 0.073 0.609

0.47648/ 97 0.465/ 153 0.056/ 1.886 0.056

0.21875/ 98 0.032 154 0.272/ 0.45572

0.134 0.837

0.11046/ 99 0.054/ 155 0.011/ 0.20003

0.195 0.005

0.48838/ 100 0.004/ 156 0.003/ 0.63158

0.015 0.01

0.006/ 101 0.014/ 157 0.095/ 0.0098

0.042 0.117

0.03613/ 102 0.029/ 158 0.023/ 0.07408

0.088 0.061

0.0103/ 103 0.007/ 159 0.02/ 0.02216

0.032 0.047

0.11766/ 104 0.165/ 160 0.196/ 0.39292

0.196 48 0.25074/ 105 0.288/ 161 0.121/ 0.52781

0.627 0.307

49 0.04448/ 106 0.189/ 162 0.214/

0.05247

0.187 0.751

50 0.01831/ 107 0.482/ 163 0.059/

0.01388

0.767 0.082

51 0.01228/ 108 0.414/ 164 0.048/

0.01116

0.952 0.088

52 0.01786/ 109 0.061/ 165 0.043/

0.027

0.079

53 0.04414/ 110 0.141/ 166 0.035/

0.04752

0.482

54 0.06964/ 111 0.127/ 167 0.047/

0.1218

0.408

55 0.00211/ 112 0.072/ 168 0.097/

0.00282

0.168

56 0.13603/ 113 0.034/

0.28466

0.077

57 0.13923/

The 168 compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelantine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions. The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelantine capsules. Suitable carriers for soft gelantine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelantine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

As mentioned earlier, medicaments containing a compound of formula (I) or

pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula (I) or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.

As further mentioned earlier, the use of the compounds of formula (I) for the preparation of medicaments useful in the prevention and/or the treatment of the above recited diseases is also an object of the present invention. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/ kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 per day.

Pharmaceutical compositions comprising compounds of the invention:

Tablet Formulation (Wet Granulation)

Item Ingredients mg/tablet

5 mg 25 mg 100 mg 500 mg

1. Compound of formula I 5 25 100 500

2. Lactose Anhydrous DTG 125 105 30 150

3. Sta-Rx 1500 6 6 6 30

4. Microcrystalline Cellulose 30 30 30 150

5. Magnesium Stearate 1 1 1 1

Total 167 167 167 831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50°C.

3. Pass the granules through suitable milling equipment.

4. Add item 5 and mix for three minutes; compress on a suitable

Capsule Formulation

Item Ingredients mg/capsule

5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500

2. Hydrous Lactose 159 123 148 —

3. Corn Starch 25 35 40 70

4. Talc 10 15 10 25

5. Magnesium Stearate 1 2 2 5

Total 200 200 300 600

Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

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

3. Fill into a suitable capsule. Experimental part

Preparation of intermediates

Example A.l

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

Step 1 :Methyl 4-fluoro- 1 -(2-fluoro-4-( 1 -methyl- lH-pyrazol-4-yl)benzyl)- lH-indole-3- carboxylate

A suspension of methyl 4-fluoro- lH-indole-3-carboxylate (150 mg, 777 μιηοΐ) in N,N- dimethylformamide (2 ml) was cooled in ice-bath. Sodium hydride 60% dispersion in oil (37.3 mg, 932 μιηοΐ) was added at once. The mixture was stirred at 0°C for 15 minutes. 4-(4- (chloromethyl)-3-fluorophenyl)-l-methyl-lH-pyrazole (example B.2) (174 mg, 777 μιηοΐ) was added at once. The mixture was stirred at 0°C for 1 hour, quenched with a 20% ammonium chloride solution, diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with a flash column chromatography on silica (10 g) eluting with a gradient formed from n- heptane and ethyl acetate (0 to 100 %) to provide 208 mg (70 %) of the title compound as a light brown solid. MS (m/e): 382.5 (M+H)⁺.

Step 2: 4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid To a solution of methyl 4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3- carboxylate (195.9 mg, 514 μιηοΐ) in THF (1.6 ml), MeOH (0.8 ml) and water (0.8 ml) was added lithium hydroxide monohydrate (64.7 mg, 1.54 mmol). The mixture was stirred at room temperature for 1 hr, then heated to 50°C for 5 hrs and finally stirred at room temperature for 2 days. The mixture was diluted with water and the solvent was evaporated in vacuo. The residue was taken up in water and HC1 2N was added dropwise to adjust the pH to 2-3. The solid was filtered and dried to provide the title compound (170 mg, 90 %) as a white solid. MS (m/e): 366.2 (M-H)^~.

Example A.2

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indazole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A. l, the title compound was prepared from methyl 4-fluoro-lH-indazole-3-carboxylate (CAS 1427504-03-7) and 4-(4- (chloromethyl)-3-fluorophenyl)-l-methyl-lH-pyrazole (example B.2) White solid. MS (m/e): 369.4 (M+H)⁺.

Example A.3

4,6-Difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A. l, the title compound was prepared from ethyl 4,6-difluoro-lH-indole-3-carboxylate and 4-(4-(chloro-methyl)-3- fluorophenyl)-! -methyl- lH-pyrazole (example B.2). White solid. MS (m/e): 386.4 (M+H)⁺.

Example A.4

4,5,6,7-Tetrafluoro-lH-indole-3-carboxylic acid ((lS,2S)-2-hydroxy-cyclohexyl)-amide

In a 10 mL pear-shaped flask, 4,5,6,7-tetrafluoro-lH-indole-3-carboxylic acid (200 mg, 815 μιηοΐ), (lS,2S)-(+)-2-aminocyclohexanol hydrochloride (136 mg, 897 μιηοΐ) and (1H- benzo[d][l,2,3]triazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (469 mg, 1.1 mmol) were combined with CH₂CI₂ (4.9 ml) and triethylamine (330 mg, 452 μΐ, 3.26 mmol) to give an off-white suspension. The reaction mixture was stirred at r.t. for 2 days. The reaction mixture diluted with H₂0 and extracted with CH₂C1₂. The aqueous layer extracted with EtOAc. This organic layer was dried over MgS0₄, filtrated and concentrated to give the title compound (390 mg, 70% pure) as an off-white solid. MS (m/e): 331.4 (M+H)⁺.

Example A.5

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carbonyl chloride

To a solution of 4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3- carboxylic acid (Example A. l) (200 mg, 544 μιηοΐ) in dichloroethane (2 ml) under nitrogen at room temperature, was added 1 drop of N,N-dimethylformamide, followed by oxalyl chloride (212 mg, 143 μΐ, 1.63 mmol). The reaction mixture was stirred at room temperature for 3.5 hours. The mixture was evaporated to dryness to provide the title compound (222 mg, 106 %) as an off-white solid.

Example A.6

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide

To a stirred suspension of 4-fluoro-lH-indole-3-carboxylic acid (1 g, 5.58 mmol; CAS 23077- 42-1) at r.t. in dichloromethane (60 ml) under an argon atmosphere were added (lS,2S)-2- aminocyclohexanol hydrochloride (931 mg, 6.14 mmol), BOP (2.96 g, 6.7 mmol) and triethylamine (2.26 g, 3.1 ml, 22.3 mmol). The resulting light brown solution was stirred at r.t. for 17 hrs. The mixture was concentrated and the residue was purified by silica gel

chromatography (50 g) chromatography using a CH₂Cl₂/MeOH 9: 1 gradient as eluent. The product-containing fractions were combined and concentrated to leave a viscous oil. It was triturated in CH₂Cl₂/n-heptane 3:2 (25 ml). The resulting suspension was stirred at r.t. for 1 hr. The product was collected by filtration, washed with a 1 : 1 mixture of CH₂C1₂ and n-heptane, and dried to give the title compound (1.2 g, 75%) as an off-white solid. MS (m/e): 275.3 (M-H)^~ Example A.7

4-Fluoro-7-methyl-lH-indole-3-carboxylic acid ((lS,2S)-2-hydroxy-cyclohexyl)-amide

In analogy to the procedure described for the synthesis of example A.6, the title compound prepared from 4-fluoro-7-methyl-lH-indole-3-carboxylic acid and (lS,2S)-(+)-2-amino- cyclohexanol hydrochloride. White solid.

Example A.8

4-Fluoro-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

In analogy to the procedure described for the synthesis of example A.6, the title compound prepared from 4-fluoro-lH-indole-3-carboxylic acid (CAS 23077-42-1) and tetrahydro-2H- pyran-4-amine. White solid. MS (m/e): 263.2 (M+H)⁺.

Example A.9

4-Fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A. l, the title compound prepared from methyl 4-fluoro-lH-indole-3-carboxylate and 4-(4-(chloromethyl)phenyl)-l- methyl-lH-pyrazole (example B.5). Off-white solid. MS (m/e): 350.6 (M+H)⁺.

Example A.10

4-Fluoro-7-methyl-lH-indole-3-carboxylic acid (tetrahydro-pyran-3-yl)-amide

In analogy to the procedure described for the synthesis of example A.6, the title compound was prepared from 4-fluoro-7-methyl-lH-indole-3-carboxylic acid and tetrahydro-pyran-3-ylamine. Light yellow solid. Example A.ll

4-Fluoro-7-methyl-lH-indole-3-carboxylic acid (tetrahydro-pyran-4-yl)-amide

In analogy to the procedure described for the synthesis of example A.6, the title compound was prepared from 4-fluoro-7-methyl-lH-indole-3-carboxylic acid and tetrahydro-pyran-4-ylamine. White foam. MS (m/e): 277.2 (M+H)⁺.

Example A.12

4-fluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

Step 1 : 4-Fluoro-N-((3RS,4SR)-3-hvdroxytetrahvdro-2H-pyran-4-yl)-lH-indole-3-carboxamide In analogy to the procedure described for the synthesis of example A.6, the title compound was prepared from methyl 4-fluoro-lH-indole-3-carboxylate and (3RS,4SR)-4-aminotetrahydro-2H- pyran-3-ol (CAS 215940-92-4). Light yellow solid. MS (m/e): 279.4 (M+H)⁺.

Step 2: 4-Fluoro-N-((3R,4S) or (3S,4R -3-hvdroxytetrahvdro-2H-pyran-4-yl -lH-indole-3- carboxamide

4-Fluoro-N-((3RS,4SR)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide (310 mg, 1.1 mmol) was separated on a Reprosil Chiral NR column to provide 136 mg (44%) of the title compound as an off-white solid (+ enantiomer). MS (m/e): 279.4 (M+H)⁺.

Example A.13

4,5,6,7-Tetrafluoro-lH-indole-3-carboxylic acid ((3RS,4SR)-3-hydroxy-tetrahydro-pyran-

4-yl)-amide

In analogy to the procedure described for the synthesis of example A.6, the title compound prepared from 4,5,6,7-tetrafluoro-lH-indole-3-carboxylic acid and (3RS,4SR)-4-amino- tetrahydro-2H-pyran-3-ol (CAS 215940-92-4). White solid. Example A.14

4,5-Difluoro-lH-indole-3-carboxylic acid ((lS,2S)-2-hydroxy-cyclohexyl)-amide

In analogy to the procedure described for the synthesis of example A.6, the title compound was prepared from 4,5-difluoro-lH-indole-3-carboxylic acid and (lS,2S)-(+)-2-aminocyclohexanol hydrochloride. Light brown solid.

Example A.15

4,7-Difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indazole-3-carboxylic acid

Step 1: 4,7-Difluoro-lH-indazole-3-carboxylic acid

A solution of 4,7-difluoroindoline-2,3-dione (2.0 g, 10.9 mmol) in IN NaOH (11.8 ml) was stirred at 50°C for 30 mins. The solution was allowed to cool to r,t. and maintained for lhr. The reaction mixture was cooled to 0°C and treated with a pre-cooled (0°C) solution of sodium nitrite (754 mg in 2.8 ml H₂0). This solution was added to a stirred solution of H₂S0₄ (1.2 ml in 22 ml H₂0) at 0°C and the reaction mixture was maintained at that temperature for 30 min. A cold (0°C) solution of SnCl₂ (5.9 g, 26.2 mmol) in concentrated HCl (4.2 ml) was slowly added to the reaction mixture within 10 min; and the reaction mixture was maintained for 60 min. The reaction mixture was extracted with 15% MeOH/CH₂Cl₂. Evaporation of the solvent provided the title compound as a brown sticky solid (600 mg, 55%) which was used in the next step without purification. Step 2: Methyl 4,7-difluoro-lH-indazole-3-carboxylate

A solution of 4,7-difluoro-lH-indazole-3-carboxylic acid (4.5 g, 22.7 mmol) in MeOH (45 ml) was treated with H₂S0₄ (0.41 ml) and stirred at 50°C over night. After completion of the reaction, the reaction mixture was concentrated. The crude product was purified by silica gel chromatography using 15% EtOAc in hexane as eluent to provide the title compound as an off- white solid (500 mg, 10%).

Step 3: Methyl 4,7-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indazole-3- carboxylate

To a stirred solution of methyl 4,7-difluoro-lH-indazole-3-carboxylate (250 mg, 1.2 mmol) at 0°C in DMF (3.00 ml) under an argon atmosphere was added sodium hydride 60% dispersion in mineral oil (47.1 mg, 1.2 mmol) in one portion. After stirring for 15 min at 0°C, 4-(4- (chloromethyl)-3-fluorophenyl)-l-methyl-lH-pyrazole (example B.2; 265 mg, 1.2 mmol) was added in one portion. The ice bath was removed, and stirring at r.t. was continued for 17 hrs. The reaction mixture was taken up in H₂0 (10 ml) and sat. aq. NaCl (10 ml) and extracted with EtOAc. The aqueous phase was back-extracted with EtOAc (10 ml). The combined organics were washed with water (20 ml) and brine (20 ml), dried over MgS0₄, filtered and concentrated. The crude product was purified by silica gel chromatography using a EtO Ac/heptane gradient as eluent providing the title compound (251 mg, 53 mg) as yellow solid, along with its regioisomer (103 mg, 22 mg) methyl 4,7-difluoro-2-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-2H- indazole-3-carboxylate. MS (m/e): 401.1 (M+H)⁺.

Step 4: 4,7-Difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indazole-3-carboxylic acid

To a stirred solution of methyl 4,7-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)- lH-indazole-3-carboxylate (246mg, 614 μιηοΐ) at r.t. in THF (2 ml) and methanol (1 ml) under an argon atmosphere were added water (1.7 ml) and 1 N NaOH (1.23 ml, 1.23 mmol). Stirring at r.t. was continued for 17 hrs. The mixture (clear orange solution) was treated with 1 N HCl (1.2 ml). The light yellow suspension was stirred at r.t. for 1 hr. The solid was collected by filtration, washed with H₂0 and dried to provide the title compound (221 mg, 93%) as light yellow solid. MS (m/e): 385.1 (M-H)^~. Example A.16

4,7-Difluoro-l-[[6-(l-methylpyrazol-4-yl)pyridine-3-yl]methyl]indazole-3-carboxylic acid

The title compound was prepared in analogy to the procedures described in example A.15, using 5-(chloromethyl)-2-(l-methyl-lH-pyrazol-4-yl)pyridine (example B.l) as alkylating agent in the 3^rd step. Off-white solid. MS (m/e): 368.2 Example A.17

4,7-Difluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-lH-indole-3-carboxylic acid

Step 1: Methyl 4,7-difluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-lH-indole-3-carboxylate The title compound was obtained in analogy to the procedure described in example 26, reacting methyl 4,7-difluoro-lH-indole-3-carboxylate and 5-(bromomethyl)-l-methyl-lH-indazole hydrobromide. White solid. MS (m/e): 356.5 (M+H)⁺.

Step 2: 4,7-Difluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-lH-indole-3-carboxylic acid

The title compound was obtained in analogy to the procedure described in example A. l, step 2.

White solid. MS (m/e): 342.5 (M+H)⁺. Example A.18

4,7-Difluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from methyl 4,7-difluoro-lH-indole-3-carboxylate and 4-(4- (chloromethyl)phenyl)-l-methyl-lH-pyrazole (example B.5). White solid. MS (m/e): 368.5 (M+H)⁺. Example A.19

4,7-Difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from methyl 4,7-difluoro-lH-indole-3-carboxylate and 4-(4-(chloromethyl)-3- fluorophenyl)- 1 -methyl- lH-pyrazole (example B.2). White solid. MS (m/e): 386.5 (M+H)⁺.

Example A.20

2-(4-Fluoro-l-(4-(methylcarbamoyl)benzyl)-lH-indol-3-yl)acetic acid

In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from ethyl 2-(4-fluoro-lH-indol-3-yl)acetate (CAS 919295-78-6) and 4-

(chloromethyl)-N-methylbenzamide (example B.6). Brown solid. MS (m/e): 341.2 (M+H)⁺. Example A.21

7-Cyclopropyl-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

Step 1 : l-(7-Bromo-4-fluoro- lH-indol-3-yl)-2,2,2-trifluoro-ethanone

To a solution of 7-bromo-4-fluoro-lH-indole (23 g, 107.4 mmol) in DMF (220 ml) under nitrogen at room temperature was added trifluoro acetic anhydride (29.8 ml, 214.95 mmol). The reaction mixture was stirred at 40°C for 8 hours, cooled to room temperature, diluted with water (250 ml) and extracted with ethyl acetate (2x500 ml). The combined organic layers were washed with brine (250 ml), aqueous sodium carbonate solution (200 ml) and dried over sodium sulfate, filtered and concentrated. The residue was purified with flash column chromatography on silica eluting with 15% ethyl acetate in hexane to provide 20 g (60 %) of the title compound as an off- white solid. LC-MS (ESI): 310 (M).

Step 2: 7-Bromo-4-fluoro-lH-indole-3-carboxylic acid

To a solution of l-(7-bromo-4-fluoro-lH-indol-3-yl)-2,2,2-trifluoro-ethanone (5 g, 16.12 mmol) in methanol (60 ml) and water (60 ml) under nitrogen at room temperature was added NaOH (9.6 g, 241.93 mmol). The mixture was stirred at 140°C for 16 hours, cooled to room temperature and concentrated. The residue was diluted with water (150 ml) and washed with ethyl acetate (100 ml). The aqueous layer was treated with 50% aqueous HC1 until pH~4 and extracted with ethyl acetate (2x 200 ml). The combined organics were washed with brine (100 ml) and aqueous sodium carbonate solution (100 ml), dried over sodium sulfate, filtered and concentrated to provide the title compound as a off white- solid (2.3 g, 55 %). LC-MS (ESI): 256 (M-H)^~.

Step 3: Methyl 7-bromo-4-fluoro-lH-indole-3-carboxylate

HC1 gas was bubbled through a solution of 7-bromo-4-fluoro-lH-indole-3-carboxylic acid (11.2 g, 43.4 mmol) in methanol (200 ml) at room temperature for 30 min. The reaction mixture was then stirred at 60°C for 16 hours and concentrated. The residue was diluted with water (200 ml) and extracted with ethyl acetate (2x 500 ml). The combined organics were washed with brine (250 ml) and aqueous sodium carbonate solution (250 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified with flash column chromatography on silica eluting with 20% ethyl acetate in hexane to provide the title compound as a brown solid (7.1 g, 60 %). LC-MS (ESI): 271 (M-H)^~.

Step 4: Methyl 7-cyclopropyl-4-fluoro-lH-indole-3-carboxylate

To a solution of 7-bromo-4-fluoro-lH-indole-3-carboxylic acid methyl ester (4.5 g, 16.5 mmol) in toluene (200 ml) were added cyclopropyl boronic acid (2.8 g, 33.08 mmol),

tricyclohexylphosphine (0.232 g, 0.827 mmol), and K₃PO₄ (7.01 g, 33.08 mmol). The reaction mixture was purged with argon for 20 min. Pd(OAc)₂ (0.371 g, 1.65 mmol) was added and the mixture was purged with argon for another 10 min. The reaction mixture was then heated to 100°C and stirred at this temperature for 16 hours in a sealed tube. The mixture was cooled to room temperature and filtered through a celite pad which was washed with EtOAc (100 ml). Water (200 ml) was added to the filtrate. The aqueous layer was extracted with EtOAc (3x 200 ml). The combined organics were washed with water (100 ml) and brine (100 ml), dried over Na₂S0₄ and concentrated. The residue was purified with flash column chromatography on silica eluting with 20% ethyl acetate in hexane to provide the title compound as a grey solid (2.3 g, 60 %). LC-MS (ESI): 234 (M+H)⁺.

Step 5: 7-Cyclopropyl-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from methyl 7-cyclopropyl-4-fluoro-lH-indole-3-carboxylate and 4-(4- (chloromethyl)phenyl)-l-methyl-lH-pyrazole (example B.5). Off-white solid. MS (m/e): 388.3 (M-H)^".

Example A.22

7-Cyclopropyl-4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3- carboxylic acid

In analogy to the procedures described for the synthesis of example A.21, the title compound was prepared from methyl 7-cyclopropyl-4-fluoro-lH-indole-3-carboxylate and 4- (4- (chloromethyl)-3-fluorophenyl)-l-methyl-lH-pyrazole (example B.2). Off-white solid. MS (m/e): 406.2 (M-H)^~.

Example A.23

7-Ethyl-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid

Step 1: Methyl 4-fluoro-7-vinyl-lH-indole-3-carboxylate

To a solution of methyl 7-bromo-4-fluoro-lH-indole-3-carboxylate (example A.21, step 3) (1.0 g, 3.68 mmol) and 4,4,5, 5-tetramethyl-2-vinyl-[l,3,2]dioxaborolane (1.13 g, 7.35 mmol) at room temperature in 1,4-dioxane (30 ml) and water (3 ml) was added CS₂CO₃ (2.39 g, 7.35 mmol) and the mixture was purged with argon for 10 min. [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane adduct (0.08 g, 0.37 mmol) was added and the reaction mixture was purged with argon for another 10 min. The reaction mixture was then heated to 80°C and stirred at this temperature for 16 hours under argon. The reaction mixture was cooled to room temperature, filtered through a celite pad which was washed with EtOAc (50 ml). The filtrate was diluted with water (100 ml) and extracted with EtOAc (2x100 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried over Na₂S0₄ and

concentrated. The residue was purified with flash column chromatography on silica eluting with 20% ethyl acetate in hexane to provide the title compound as a white solid (500 mg, 62 %). LC- MS (ESI): 220 (M+H)⁺.

Step 2: Methyl 7-ethyl-4-fluoro-lH-indole-3-carboxylate

A mixture of methyl 4-fluoro-7-vinyl-lH-indole-3-carboxylate (500 mg, 2.28 mmol) and 10% palladium on activated charcoal (4 mg, 0.039 mmol) in methanol (10 ml) was stirred for 4 hours at room temperature under hydrogen atmosphere (balloon pressure). The palladium catalyst was filtered off and the filtrate was concentrated. The residue was purified with flash column chromatography on silica eluting with 20% ethyl acetate in hexane to provide the title compound as an off- white solid (450 mg, 89 %). LC-MS (ESI):220 (M-H)^~. Step 3: 7-Ethyl-4-fluoro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxylic acid In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from methyl 7-ethyl-4-fluoro-lH-indole-3-carboxylate and 4-(4- (chloromethyl)phenyl)-l-methyl-lH-pyrazole (example B.5). White solid. MS (m/e): 378.2 (M+H)⁺. Example A.24

4-Fluoro-l-{[4-(methylcarbamoyl) phenyl] methyl}-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from methyl 4-fluoro-lH-indole-3-carboxylate and 4-(chloromethyl)-N- methylbenzamide (example B.6). Off-white solid. LC-MS (ESI): 327.0 (M+H)⁺.

Example A.25

7-Ethyl-4-fluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from methyl 7-ethyl-4-fluoro-lH-indole-3-carboxylate and 5-(bromomethyl)-l- methyl-lH-indazole hydrobromide. White solid. MS (m/e): 355.2 (M+H)⁺. Example A.26

4-Fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-lH-indole-3-carboxylic acid

In analogy to the procedures described for the synthesis of example A.17, the title compound was prepared from methyl 4-fluoro-lH-indole-3-carboxylate and 4-(chloromethyl)-2-fluoro-N- methylbenzamide (example B.7). Off-white solid. MS (m/e): 345.1 (M+H)⁺.

Example A.27

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-7-methoxy-lH-indole-3-carboxamide

To a stirred solution of (lS,2S)-2-aminocyclohexanol hydrochloride (CAS 13374-30-6) (111 mg, 734 μιηοΐ) at room temperature in dichloromethane (5 ml) under an argon atmosphere were added 4-fluoro-7-methoxy-lH-indole-3-carboxylic acid (150 mg, 667 μιηοΐ), (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (354 mg, 800 μιηοΐ) and triethylamine (270 mg, 370 μΐ, 2.67 mmol). Stirring at r.t. was continued for 17 hours. The reaction mixture was concentrated and the residue was purified with flash column

chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 10%) to provide the title compound as an off-white solid (162 mg, 79 %). MS (m/e): 305.2 (M-H)^~.

Example A.28

4-Fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methoxy-lH-indole-3- carboxamide

In analogy to the procedure described for the synthesis of example A.27, the title compound was prepared from 4-fluoro-7-methoxy-lH-indole-3-carboxylic acid and (3R,4S)-4- aminotetrahydropyran-3-ol hydrochloride (example C. l). Off-white solid. MS (m/e): 307.1 (M-

Example A.29

4-Fluoro-7-methoxy-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

In analogy to the procedure described for the synthesis of example A.27, the title compound was prepared from 4-fluoro-7-methoxy-lH-indole-3-carboxylic acid and 4-aminotetrahydropyran. Off-white solid. MS (m/e): 291.2 (M-H)^~.

Example A.30

l-(4-Bromobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide

In analogy to the procedure described for the synthesis of example A.17, step 1, the title compound was prepared from 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide (example A.6) and l-bromo-4-(bromomethyl)benzene. White solid. MS (m/e): 445.3 (M+H)⁺.

Example A.31

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(piperidin-4-ylmethyl)-lH-indole-3- carboxamide

Step 1: tert-Butyl 4-((4-fluoro-3-((lS,2S -2-hvdroxycvclohexylcarbamoyl -lH-indol-l- yPmethyPpiperidine- 1 -carboxylate

In analogy to the procedure described for the synthesis of example A.17, step 1, the title compound was prepared from 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide (example A.6) and 4-methanesulfonyloxymethylpiperidine-l-carboxylic acid tert- butyl ester (CAS 161975-39-9). White solid. MS (m/e): 474.4 (M+H)⁺. Step 2: 4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(piperidin-4-ylmethyl)-lH-indole-3- carboxamide

To a solution of tert-butyl 4-((4-fluoro-3-((lS,2S)-2-hydroxycyclohexylcarbamoyl)-lH-indol-l- yl)methyl)piperidine-l-carboxylate (200 mg, 422 μmol) at 0°C in dioxane (5 ml) under an argon atmosphere was added HCl 4M solution in dioxane (528 μΐ, 2.11 mmol). The mixture was stirred at room temperature for 5 hours. The reaction mixture was cooled again to 0°C and HCl 4M solution in dioxane (528 μΐ, 2.11 mmol) was added and the mixture was stirred at room temperature for another 17 hours. The mixture was concentrated. The residue was dissolved in CH₂Cl₂/MeOH (95:5) and washed with aqueous saturated Na₂C0₃ solution. The organic layer was dried over MgS0₄, filtered and concentrated to provide the title compound as a light yellow solid (149 mg, 89%). MS (m/e): 374.3 (M+H)⁺.

Example A.32

l-((6-Bromopyridin-3-yl)methyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

In analogy to the procedure described for the synthesis of example A.17, step 1, the title compound was prepared from 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide (example A.6) and 2-bromo-5-pyridylmethyl chloride. White solid. MS(m/e) 448.2 (M+H)⁺.

Example A.33

Methyl 2-fluoro-4-((4-fluoro-3-(tetrahydro-2H-pyran-4-ylcarbamoyl)-lH-indol-l- yl)methyl)benzoate

In analogy to the procedure described for the synthesis of example A.17, step 1, the title compound was prepared from 4-fluoro-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide (example A.8) and methyl 4-(bromomethyl)-2-fluorobenzoate. White solid. MS (m/e): 429.3 (M+H)⁺.

Example A.34

4-Fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

In analogy to the procedure described for the synthesis of example A.27, the title compound was prepared from 4-fluoro-indole-3-carboxylic acid (CAS 23077-42-1) and (3R,4S)-4- aminotetrahydropyran-3-ol hydrochloride (example C. l). Light- yellow solid. MS (m/e): 279.1 (M+H)⁺.

Example A.35

l-(4-Carbamoyl-benzyl)-4-fluoro-lH-indole-3-carboxylic acid

In analogy to the procedure described for the synthesis of example A. l (step: 1 and 2), the title compound was prepared from methyl 4-fluoro-lH-indole-3-carboxylate and 4-chloromethyl - benzonitrile. MS (m/e): 313.4 (M+H)⁺.

Example A.36

l-(4-Cyanobenzyl)-4-fluoro-lH-indole-3-carboxylic acid

Stepl: Methyl l-(4-cyanobenzyl)-4-fluoro-lH-indole-3-carboxylate

In analogy to the procedure described for the synthesis of example A.l (step 1), the title compound was prepared from methyl 4-fluoro-lH-indole-3-carboxylate and 4-chloromethyl- benzonitrile.

Step 2: l-(4-Cyanobenzyl)-4-fluoro-lH-indole-3-carboxylic acid

In a sealed tube, methyl l-(4-cyanobenzyl)-4-fluoro-lH-indole-3-carboxylate (187 mg, 607 μιηοΐ) and lithium iodide (812 mg, 6.1 mmol) were combined with pyridine (8.7 ml). The reaction mixture was stirred at 135°C for 19 hrs, then treated with water and HC1 2N. The precipitate was filtered, washed with water and dried to provide 85 mg (48%) of the title compound as an off white solid. MS (m/e): 295.4 (M+H)⁺.

Example A.37

4-Fluoro-N-tetrahydropyran-4-yl-lH-indazole-3-carboxamide

In analogy to the procedure described for the synthesis of example A.6, the title compound was prepared from 4-fluoro-lH-indazole-3-carboxylic acid and tetrahydro-pyran-4-ylamine. MS (m/e): 264.4 (M+H)⁺.

Example B.l

5-(Chloromethyl)-2-(l-methyl-lH-pyrazol-4-yl)pyridine

Step 1: (6-(l-Methyl-lH-pyrazol-4-yl)pyridine-3-yl)methanol

To a solution of (6-chloropyridin-3-yl)methanol (1 g, 6.8 mmol) in dioxane (20 ml) under nitrogen at room temperature was added l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (2.16 g, 10.2 mmol) followed by [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane adduct (276 mg, 341 μιηοΐ). A solution of sodium carbonate (2.17 g, 20.5 mmol) in water (16 ml) was added to the mixture. The reaction mixture was stirred at 80°C for 1 hour and cooled to room temperature. Ethyl acetate (20 ml) and water (10 ml) were added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude brown solid was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate (0 to 100%) to provide 1 g (77%) of the title compound as a grey solid. MS (m/e): 190.2 (M+H)⁺.

Step 2: 5-(Chloromethyl)-2-(l-methyl-lH-pyrazol-4-yl)pyridine

To a 0°C solution of (6-(l-methyl-lH-pyrazol-4-yl)pyridine-3-yl)methanol (1 g, 5.3 mmol) in dichloromethane (30 ml) was added a solution of thionyl chloride (1.27 g, 775 μΐ, 10.6 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 3 hours and quenched with a saturated solution of sodium hydrogen carbonate (30 ml). The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and evaporated. The crude material was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate (0 to 20%) to provide 930 mg (85%) of the title compound as a light grey solid. MS (m/e): 208.2 (Μ+Η)^+' Example B.2

4-(4-(Chloromethyl)-3-fluorophenyl)-l-methyl-lH-pyrazole

In analogy to the procedures described for the synthesis of example B. l, the title compound was prepared from 4-bromo-2-fluorophenyl)-methanol. MS (m/e): 225.4 (M+H)⁺.

Example B.3

4-(3-(Chloromethyl)phenyl)-l-methyl-lH-pyrazole

In analogy to the procedure described for the synthesis of example B.l, the title compound was prepared from 3-bromophenyl-methanol. MS (m/e): 207.4 (M+H)⁺.

Example B.4

l-(4-Chloromethyl-phenyl)-4-methyl-lH-imidazole

In analogy to the procedure described for the synthesis of example B.l (step 2), the title compound was prepared from (4-(4-methyl-lH-imidazol-l-yl)phenyl)methanol. MS (m/e): 207.3 (M+H)⁺.

Example B.5

4-(4-(Chloromethyl)phenyl)-l-methyl-lH-pyrazole

In analogy to the procedure described for the synthesis of example B.l, the title compound was prepared from 4-bromophenyl-methanol. MS (m/e): 207.4 (M+H)⁺.

Example B.6

4-(Chloromethyl)-N-methylbenzamide

To a stirred, cooled solution of 4-(chloromethyl)benzoyl chloride (1.6 g, 8.49 mmol) at 0°C in dichloromethane (15 ml) under an argon atmosphere were added methylamine hydrochloride (521 mg, 7.72 mmol). A solution of triethylamine (3.12 g, 4.28 ml, 30.9 mmol) in

dichloromethane (15 ml) was added dropwise. Stirring at 0°C was continued for 44 hrs. The mixture was concentrated and the residue was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 10 %) to provide 10 mg (y: 0.6%) of the title compound as a white solid. MS (m/e): 184.2 (M+H)⁺.

Example B.7

4-(Chloromethyl)-2-fluoro-N-methylbenzamide

Step 1: 2-Fluoro-4-formyl-N-methylbenzamide

To a stirred suspension of 2-fluoro-4-formylbenzoic acid (1 g, 5.95 mmol) at r.t. in

dichloromethane (3 ml) under an argon atmosphere was added dropwise thionyl chloride (849 mg, 521 μΐ, 7.14 mmol). DMF (0.25 ml) was then added dropwise. The mixture was then refluxed for 2 hours. The mixture was cooled to room temperature and it was added dropwise to stirred, cooled (0°C) methylamine 40% solution in water (1.66 g, 1.85 ml, 21.4 mmol) for 15 min. When the addition was complete, stirring at 0°C was continued for 1 hour. The mixture was concentrated and the residue was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 10 %) to provide the title compound as an off-white solid (330 mg, 36 %). MS (m/e): 182.1 (M+H)⁺.

Step 2: 2-Fluoro-4-(hvdroxymethyl)-N-methylbenzamide

To a stirred, cooled (0°C) solution of 2-fluoro-4-formyl-N-methylbenzamide (320 mg, 1.77 mmol) in dichloromethane (8 ml) and methanol (2 ml) under an argon atmosphere was added portionwise sodium borohydride (134 mg, 3.53 mmol). The cooling bath was removed and stirring at room temperature was continued for 6 hours. The mixture was concentrated and the residue was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 10 %) to provide the title compound as an off-white solid (288 mg, 89 %). MS (m/e): 184.1 (M+H)⁺.

Step 3: 4-(Chloromethyl)-2-fluoro-N-methylbenzamide

To a stirred, cooled (0°C) suspension of 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide (275 mg, 1.5 mmol) in dichloromethane (10 ml) under an argon atmosphere was added dropwise a solution of thionyl chloride (357 mg, 219 μΐ, 3.00 mmol) in dichloromethane (2 ml). The cooling bath was removed and stirring at room temperature was continued for 6 hours.

The mixture was concentrated and the residue was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 10 %) to provide the title compound as a white solid (255 mg, 84 %). MS (m/e): (M+H)⁺.

Example B.8

5-(4-Bromomethyl-phenyl)-oxazole

To a stirred solution of 5-(4-methylphenyl)-l,3-oxazole (2 g) at room temperature in

tetrachloromethane (60 ml) were added NBS (2.9 g) and dibenzoylperoxide (150 mg). The mixture was stirred at 77°C under a 150 watt lamp for 6 hours and then cooled to room temperature. The insoluble material was filtered off. The filtrate was washed with water and aqueous NaHC0₃ solution, dried (MgS0₄), filtered and concentrated. The residue was purified with flash column chromatography on silica eluting with 50 % heptane in diisopropylether to provide the title compound (1.35 g, 45 %). MS (m/e): 237 (M).

Example B.9

2-(4-(Chloromethyl)phenyl)thiazole

To a solution at 0° of (5-(thiazol-2-yl)pyridin-2-yl)methanol (65 mg, 338 μιηοΐ) in

dichloromethane (5 ml) was added under an argon atmosphere sulfurous dichloride (80.5 mg, 49.1 μΐ, 676 μιηοΐ). The mixture was stirred at r.t for 3 h. The solvent was evaporated. The residue was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 5 %) to provide the title compound (40 mg, 56%) as light yellow solid. MS (m/e): 211.1 (M+H)⁺.

Example B.10

(l-(Pyrimidin-4-yl)piperidin-4-yl)methyl methanesulfonate

Step 1: Ethyl l-(pyrimidin-4-yl)piperidine-4-carboxylate

A mixture of 4-bromopyrimidine hydrochloride (200 mg, 1.02 mmol), cesium carbonate (333 mg, 1.02 mmol) and ethyl piperidine-4-carboxylate (161 mg, 158 μΐ, 1.02 mmol) in 1,4-dioxane (5 ml) under an argon atmosphere was stirred at 100° for 17 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified with flash column

chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 5 %) to provide the title compound as a light yellow viscous oil (153 mg, 63 %). MS (m/e): 236.3 (M+H)⁺.

Step 2: (l-(Pyrimidin-4-yl)piperidin-4-yl)methanol

To a solution of ethyl l-(pyrimidin-4-yl)piperidine-4-carboxylate (150 mg, 638 μιηοΐ) in methanol (5 ml) and dichloromethane (5 ml) at 0°C under argon was added sodium borohydride (145 mg, 3.83 mmol) in one portion. The cooling bath was removed and the mixture was stirred at room temperature for 4 hours. The mixture was cooled again to 0°C and sodium borohydride (145 mg, 3.83 mmol) was added in one portion. The mixture was stirred at room temperature for 17 hr and concentrated. The residue was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 5 %) to provide the title compound as a white solid (80 mg, 65 %). MS (m/e): 194.2 (M+H)⁺.

Step 3: (l-(Pyrimidin-4-yl)piperidin-4-yl)methyl methanesulfonate

To a stirred solution of (l-(pyrimidin-4-yl)piperidin-4-yl)methanol (80 mg, 414 μιηοΐ) and triethylamine (83.8 mg, 115 μΐ, 828 μιηοΐ) in dichloromethane (2 ml) at 0°C under argon was added dropwise a solution of methanesulfonyl chloride (94.8 mg, 64.3 μΐ, 828 μιηοΐ) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 3 hours.

Sodium bicarbonate (34.8 mg, 414 μιηοΐ) was added and the mixture was stirred for 5 min and filtered. The filtrate was concentrated and the residue was purified with flash column

chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 5 %) to provide the title compound as a yellow viscous oil (34.5 mg, 31 %). MS (m/e): 272.2

(M+H)⁺.

Example B.ll

5-(Chloromethyl)-N-methylpicolinamide

In analogy to the procedures described for the synthesis of example B.10, step 2 and example B.9, the title compound was prepared from methyl 6-(methylcarbamoyl)nicotinate (CAS

173371-36-3). Off-white solid. MS (m/e): 185.1 (M+H)⁺.

Example B.12

5-(4-(Chloromethyl)phenyl)-l-(4-methoxybenzyl)-lH-pyrazole

Step 1: 5-Iodo-l-(4-methoxybenzyl)-lH-pyrazole

To a solution of 5-iodo-lH-pyrazole (0.2 g, 1.03 mmol) in dimethyl acetamide (3 ml) at 0°C under argon was added sodium hydride 60% dispersion in mineral oil (41.2 mg, 1.03 mmol) in one portion. After stirring at 0°C for 15 min, l-(bromomethyl)-4-methoxybenzene (207 mg, 1.03 mmol) was added in one portion. The cooling bath was removed and the mixture was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, and washed with water. The aqueous phase was back extracted with ethyl acetate. The combined organics were washed with water, dried over MgS0₄, filtered and evaporated. The residue was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate (0 to 50 %) to provide the title compound as a colorless viscous oil (270 mg, 83 %). MS (m/e): 315.1 (M+H)⁺.

Step 2: (4-(l-(4-Methoxybenzyl)-lH-pyrazol-5-yl)phenyl)methanol

A mixture of 5-iodo-l-(4-methoxybenzyl)-lH-pyrazole (0.27 g, 860 μιηοΐ) and 4- (hydroxymethyl)phenylboronic acid (170 mg, 1.12 mmol) at room temperature in 1,2- dimethoxyethane (6 ml) and 2M aqueous Na₂C0₃ solution (1.43 ml, 2.86 mmol) was purged with argon in an ultrasonic bath for 5 min. Then triphenylphosphine (45.1 mg, 172 μιηοΐ) and palladium(II) acetate (19.3 mg, 86.0 μιηοΐ) were added and the mixture was stirred at 85°C under argon for 17 hr. The mixture was cooled to room temperature, poured onto water and extracted with ethyl acetate. The organic layer was washed with water, dried with MgS0₄, filtered and evaporated. The residue was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate (0 to 50 %) to provide the title compound as a colorless viscous oil (160 mg, 63 %). MS (m/e): 295.2 (M+H)⁺.

Step 3: 5-(4-(Chloromethyl)phenyl)-l-(4-methoxybenzyl)-lH-pyrazole

In analogy to the procedures described for the synthesis of example B.9, the title compound was prepared from (4-(l-(4-methoxybenzyl)-lH-pyrazol-5-yl)phenyl)methanol. Off-white solid. MS (m/e): 313.2 (M+H)⁺.

Example B.13

3-(4-(Chloromethyl)phenyl)-l-(4-methoxybenzyl)-lH-l,2,4-triazole

In analogy to the procedures described for the synthesis of example B.13, the title compound prepared from 5-bromo-lH-l,2,4-triazole.White solid. MS (m/e): 314.2 (M+H)⁺.

Example C.l

(3R,4S)-4-Aminotetrahydropyran-3-ol hydrochloride

Step 1 : Methanesulfonic acid tetrahvdro-pyran-4-yl ester

To a solution of tetrahydro-2H-pyran-4-ol (25 g, 245 mmol) and triethyl amine (40.1 ml, 294 mmol) in CH₂CI₂ (500 ml) at 0°C was added dropwise methanesulfonylchloride (20.7 ml, 269 mmol) over a period of 40 min, keeping the temperature between 0° - 4°C. The reaction mixture was then allowed to stir at 0°C for lhr. The cooling bath was removed and the mixture was stirred for another 90 mins at 25°C. The mixture was washed with water (2 x 125ml), dried over anhydrous Na₂S0₄, filtered and concentrated under vacuum to get methanesulfonic acid tetrahydro-pyran-4-yl ester (38 g, 86%; crude) as a liquid that was used in the next step without any further purification. Step 2: 3, 6-Dihydro-2H-pyran

A mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (20 g, 111 mmol) and DBU (18.8 ml, 125.6 mmol) was distilled under normal atmospheric pressure. The fraction at 90° - 96°C was 6- dihydro-2H-pyran (6 g, 64%) as a colourless liquid. Step 3: (1SR, 6RS)-3 J-Dioxa-bicycloK.l.Olheptane

To a solution of 3,6-dihydro-2H-pyran (6 g, 71.4 mmol,) in CH₂CI₂ (300 ml) was added 3- chloroperbenzoic acid (25 g, 107.1 mmol) portionwise at 25°C, and stirred at that temperature for 21 hrs. The resultant white suspension was diluted with water (250 ml) and then with aqueous solution of Na₂S0₃. The mixture was stirred at 25°C for 10 min, then basified by addition of saturated aqueous solution of NaHC0₃. The organic layer was separated, and the aqueous layer was re-extracted with CH₂CI₂. The combined organic layers were washed with saturated aqueous solution of NaHC0₃ (100 ml), and brine (80 ml), dried over anhydrous Na₂SC"4, filtered and concentrated in vacuo to afford the title compound (5 g, 70%; crude) as a yellow liquid. Step 4: (3SR,4RS)-4-Azidotetrahydropyran-3-ol

To a solution of (lSR,6RS)-3,7-dioxabicyclo[4.1.0]heptane (5 g, 49.9 mmol) in MeOH (50ml) were added sodium azide (24.3 g, 374.6 mmol), ammonium chloride (20 g, 374.6 mmol) and water (5 ml), and the resultant mixture was stirred at 25°C for 19 hrs, and then at 70°C for 2 hrs. The mixture was cooled 0°C, and the precipitated solid was filtered and washed with methanol. The filtrate was concentrated in vacuo. Resultant residue was taken in ethyl acetate, and filtered. Removal of the filtrate in vacuo yielded the title compound (5 g, 70%; crude) as a yellow liquid.

Step 5: (3SR,4RS)-4-Aminotetrahvdropyran-3-ol

To a solution of (3SR,4RS)-4-azidotetrahydropyran-3-ol (5g, 35 mmol) in ethyl acetate (50 ml), was added Pd(OH)₂ on charcoal (1.25 g, 1.4 mmol). The mixture was purged with argon, and then allowed to stir under a balloon pressure of hydrogen for 21 hrs at 25°C. Removal of the catalyst by filtration followed by evaporation of the filtrate in vacuo afforded the title compound (4 g, crude).

Step 6: (3S, 4R)-3-Hvdroxy-tetrahvdro-pyran-4-yl)-carbamic acid benzyl ester and ((3R, 4S)-3- hvdroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester

To a solution of (3SR,4RS)-4-aminotetrahydropyran-3-ol (10 g, 85.4 mmol) and Et N (23.6 ml, 170.9 mmol) in CH₂CI₂ (100 ml) was added benzyl chloroformate (9.8 ml, 59.9 mmol) dropwise at 0°C. After completion of addition, the mixture was stirred at 25°C for 2 hrs. The mixture was washed with water (60 ml). The aqueous layer was re-extracted with CH₂CI₂. The combined organic layers were dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo to get the mixture the two regioisomeric pairs of enantiomers (16 g). This crude product was purified by silica gel chromatography using 45% EtOAc in hexane as eluent to get the pair of enantiomers with the desired regioisomery as white solid (4.5 g, 21%). This enantiomeric mixture was subject to chiral separation by SFC to afford (3S,4R)-3-hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester (1.7 g, 8%) and ((3R,4S)-3-hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester (1.7 g, 8 %) both as a white solid. Step 7: (3R,4S)-4-Amino-tetrahydro-pyran-3-ol hydrochloride

To a solution of ((3R,4S)-3-hydroxy-tetrahydro-pyran-4-yl)-carbamic acid benzyl ester (1.1 g, 4.4 mmol) in MeOH (50 ml) was added 10% palladium on charcoal (140 mg, 0.13 mmol), and stirred the reaction mixture under hydrogen atmosphere for lhr. The catalyst was filtered off. The filtrate was acidified with 1.25 M HCl in MeOH and concentrated in vacuo to get (3R,4S)-4- amino-tetrahydro-pyran-3-ol hydrochloride as an off white solid (500 mg, 97%).

Description of examples

Example 1

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)-lH-indole-3-carboxamide

To a suspension of 4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3- carboxylic acid (example A. l) (30 mg, 81.7 μιηοΐ) in Ν,Ν-dimethylformamide (1 ml) was added triethylamine (41.3 mg, 56.8 μΐ, 408 μιηοΐ). The mixture was stirred at room temperature for 15 minutes. (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (47.0 mg, 106 μιηοΐ) was added. The suspension was stirred at room temperature for 1 hour. (lS,2S)-2-Aminocyclohexanol hydrochloride (12.4 mg, 81.7 μιηοΐ) was added. The mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was taken in water. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate (0 to 100%) to provide 10 mg (25%) of the title compound as a light yellow solid. MS (m/e): 465.5 (M+H)⁺.

In analogy to example 1, examples 2 to 16 of the following table were prepared by coupling an acid derivative with an amine.

Example 17

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)- N-((lS,2S)-2-hydroxycyclopentyl)-lH-indole-3-carboxamide

To a solution of 4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3- carbonyl chloride (example A.5) (30 mg, 77.8 μιηοΐ) and triethylamine (31.5 mg, 43.3 μΐ, 311 μιηοΐ) in dichloromethane (1.2 ml) was added (lS,2S)-2-aminocyclopentanol hydrochloride (12.3 mg, 85.5 μιηοΐ). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo. Water was added. The resulting precipitate was filtrated, washed with diethyl ether and dried to provide 26 mg (74%) of the title compound as an off-white solid. MS (m/e): 451.4 (M+H)⁺.

In analogy to Example 17, compounds 18 to 25 of the following table were prepared from 4- fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carbonyl chloride

(example A.5) and an amine derivative:

MW

Expl.

Structure Systematic Name Starting materials found No.

(MH⁺)

4-fluoro- 1 - (2-fluoro -4- ( 1 -

4-fluoro-l-(2-fluoro-4- methyl- lH-pyrazol-4- ( 1 -methyl- 1 H-pyrazol- yl)benzyl)- lH-indole-3- 4-yl)benzyl)-N- carbonyl chloride (example

18 ((lSR,2SR)-2- 479.5

A.5) and (lSR,2SR)-2- hydroxy-2- amino-1- rac _ methylcyclohexyl)- 1H- methylcyclohexanol

indole-3-carboxamide

hydrochloride

4-fluoro-l-(2-fluoro-4- 4-fluoro- 1 - (2-fluoro -4- ( 1 - ( 1 -methyl- 1 H-pyrazol- methyl- lH-pyrazol-4- 4-yl)benzyl)-N- yl)benzyl)- lH-indole-3-

24 ((lS,2R)-2- carbonyl chloride (example 451.4 hydroxycyclopentyl)- A.5) and (lS,2R)-2- lH-indole-3- aminocyclopentanol

carboxamide hydrochloride

4-fluoro- 1 - (2-fluoro -4- ( 1 -

N-(2,2- methyl- lH-pyrazol-4- difluorocyclohexyl)-4- yl)benzyl)- lH-indole-3- fluoro- l-(2-fluoro-4-

25 carbonyl chloride (example 485.4

( 1 -methyl- 1 H-pyrazol-

A.5) and 2,2-

4-yl)benzyl)-lH- difluorocyclohexanamine indole-3-carboxamide

hydrochloride

Example 26

In a microwave tube, 4,5,6,7-tetrafluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide (50 mg, 104 μιηοΐ; example A.4), 4-(4-(chloromethyl)-3-fluorophenyl)-l-methyl- lH-pyrazole (34 mg, 151 μιηοΐ; example B.2) and cesium carbonate (98.7 mg, 303 μιηοΐ) were combined with N,N-dimethylaceamide (633 μΐ) to give a colorless suspension. The reaction mixture was stirred at r.t. for 2 days, then was taken up in H₂0 and extracted with EtOAc. The organic layers were washed H₂0 and then with saturated NaCl solution, dried over MgS04 and concentrated in vacuo. The crude material was purified by silica gel chromatography using a CH₂Cl₂/MeOH gradient as eluent to provide the title compound (39 mg, 72%) as colorless solid. MS (m/e): 519.4 (M+H)⁺ In analogy to Example 26, compounds 27 to 61 of the following table were prepared by reaction of the indicated amides with an alkylating agent.

l-(3-cyanobenzyl)-4- 4-fluoro-N-((lS,2S)-2- fluoro-N-((lS,2S)-2- hydroxycyclohexyl)- 1H- hydroxycyclohexyl)- indole-3-carboxamide 392.5 lH-indole-3- (example A.6) and 3- carboxamide (bromomethyl)benzonitrile

4-fluoro-N-((lS,2S)-2-

F γ₍ ^'0Η l-(3,4-difhiorobenzyl)- hydroxycyclohexyl)- 1H- 4-fluoro-N-((lS,2S)-2- indole-3-carboxamide

hydroxycyclohexyl)- 403.4

'JJLN F (example A.6) and 4- lH-indole-3- (chloromethyl)- 1 ,2- carboxamide

difluorobenzene

4-fluoro-l-(4- 4-fluoro-N-((lS,2S)-2-

F o yrT ^oH fluorobenzyl)-N- hydroxycyclohexyl)- 1H- ((lS,2S)-2- indole-3-carboxamide

385.5 hydroxycyclohexyl)- (example A.6) and 1- lH-indole-3- (chloromethyl)-4- carboxamide fluorobenzene

4-fluoro-N-((lS,2S)-2- l-(3,5-difhiorobenzyl)- hydroxycyclohexyl)- 1H- 4-fluoro-N-((lS,2S)-2- indole-3-carboxamide

hydroxycyclohexyl)- 403.5

(example A.6) and 1- lH-indole-3- (chloromethyl) -3 , 5 - carboxamide

difluorobenzene

Example 62

4,5,6,7-Tetrafluoro-N-((3S,4R) or (3R,4S))-3-hydroxytetrahydro-2H-pyran-4-yl)-l- (4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

and

Example 63

4,5,6,7-Tetrafluoro-N-((3R,4S) or (3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(l- methyl-lH-pyrazol-4-yl)benzyl)-lH-indole-3-carboxamide

In analogy to the procedure described for the synthesis of example 26, the title compounds were prepared from 4,5,6,7-tetrafluoro-lH-indole-3-carboxylic acid ((3RS,4SR)-3-hydroxy- tetrahydro-pyran-4-yl)-amide (example A.13) and 4-(4-(chloromethyl)phenyl)-l-methyl-lH- pyrazole (example B.5) followed by chiral separation on a Reprosil chiral NR column. Example 62: (-) enantiomer, MS (m/e): 503.4 (M+H)⁺ and example 63: (+) enantiomer, MS (m/e): 503.4 (M+H)⁺.

Example 64

4,5,6,7-Tetrafluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S) or (3S,4R))-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

In analogy to the procedure described for the synthesis of example 26, the title compound was prepared from the chiral version of 4,5,6,7-tetrafluoro-lH-indole-3-carboxylic acid ((3RS,4SR)- 3-hydroxy-tetrahydro-pyran-4-yl)-amide (example A.13) and 4-(4-(chloromethyl)-3- fluorophenyl)- 1 -methyl- lH-pyrazole (example B.2) followed by purification with separation chromatography with a gradient formed from methylene chloride and methanol (0-5%) to provide 53 mg (44%) of the title compound as a white solid. MS (m/e): 519.5 (M+H)⁺.

Example 65

Fl ro-l-(4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-

To a suspension of 4-fluoro-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide (example A.8) (50 mg, 191 μιηοΐ) in N,N-dimethylformamide (500 μΐ) under nitrogen at 0°C was added sodium hydride 60% dispersion in oil (9.15 mg, 229 μιηοΐ). The mixture was stirred at 0°C for 15 minutes. After this time, 4-(4-(chloromethyl)phenyl)-l-methyl-lH-pyrazole (example B.5) (39.4 mg, 191 μιηοΐ) was added at once. The mixture was stirred under ice-bath cooling for 5 hours, quenched with a 20% ammonium chloride solution and diluted with water. The crude material was purified with flash column chromatography on amine eluting with a gradient formed from n-heptane and ethyl acetate (0 to 80%) to provide 60 mg (73 %) of the title compound as a white solid. MS (m/e): 433.5 (M+H)⁺. In analogy to Example 65, compounds 66 to 69 of the following table were prepared by reaction of the indicated amides with an alkylating agent.

MW

Expl.

Structure Systematic Name Starting materials found No.

(MH⁺)

4-fluoro- 1 - (( 1 -methyl- 4-fluoro-N-(tetrahydro-2H- lH-indazol-5- pyran-4- yl) - 1 H-indole- 3 - yl)methyl)-N- carboxamide (example A.8)

66 407.5

(tetrahydro-2H-pyran- and 5-(bromomethyl)-l- 4-yl)-lH-indole-3- methyl- lH-indazole

carboxamide hydrobromide

4-fluoro-l-(4-(4- 4-fluoro-N-(tetrahydro-2H- methyl- lH-imidazol- 1- pyran-4- yl) - 1 H-indole- 3 - yl)benzyl)-N- carboxamide (example A.8)

67 433.5

(tetrahydro-2H-pyran- and l-(4-chloromethyl- 4-yl)-lH-indole-3- phenyl)-4-methyl- 1H- carboxamide imidazole (example B.4)

4-fluoro-l-((6-(l-

4-fluoro-N-(tetrahydro-2H- methyl- lH-pyrazol-4- pyran-4- yl) - 1 H-indole- 3 - yl)yridine-3- carboxamide (example A.8)

68 yl)methyl)-N- 434.4 and 5-(chloromethyl)-2-(l- (tetrahydro-2H-pyran- methyl- lH-pyrazol-4- 4-yl)-lH-indole-3- yl)pyridine (example B.l) carboxamide

4-fluoro-N-(tetrahydro-2H-

4-fluoro-l-(4-(l- pyran-4- yl) - 1 H-indazole- 3 - methyl- lH-pyrazol-4- carboxamide (example

yl)benzyl)-N-

69 A.37) and 4-(4- 434.5

(tetrahydro-2H-pyran- (chloromethyl)phenyl)- 1 - 4-yl)-lH-indazole-3- methyl- 1 H-pyrazole

carboxamide

(example B.5) Example 70

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3S,4R) or (3R,4S)-3- hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

and

Example 71

4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3RS,4SR)-3-hydroxytetrahydro- 2H-pyran-4-yl)-lH-indole-3-carboxamide (example 6) (220 mg) was separated on a Reprosil

Chiral NR column to provide 94 mg (43%) of the title compound (example 81, (-) enantiomer) as an off-white solid, MS (m/e): 467.3 (M+H)⁺ and 91 mg (41%) of the compound (example 82, (+) enantiomer) as an off-white solid. MS (m/e): 467.4 (M+H)⁺.

In analogy to example 1, examples 72 to 75 of the following table were prepared by coupling acid derivative with an amine.

Exampl MW found

Structure Systematic Name Starting materials

e No. (MH⁺)

4,7-difluoro-l-(2- 4,7-difluoro-l-(2- fluoro-4-(l- fluoro-4-( 1 -methyl- methyl-lH- lH-pyrazol-4- pyrazol-4- yl)benzyl)-lH-

72 yl)benzyl)-N- indazole-3-carboxylic 484.2

((lS,2S)-2- acid (example A.15)

hydroxycyclohexyl and (lS,2S)-2- )-lH-indazole-3- aminocyclohexanol

carboxamide hydrochloride

carboxamide (example C.l)

In analogy to Example 26, compounds 76 to 85 following table were prepared by reaction of the indicated amides with an alkylating agent.

Example 86

Preparation of 4-fluoro-l-(2-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)-lH-indole-3-carboxamide

Step 1: Methyl 3-fluoro-4-((4-fluoro-3-((lS,2S)-2-hydroxycyclohexylcarbamoyl)-lH-indol-l- yl)methyl)benzoate

The title compound was obtained in analogy to the procedure described in example 26, reacting 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide (example A.6) and 4- bromomethyl-3-fluoro-benzoic acid methyl ester (CAS 128577-47-9). Off-white solid. MS (m/e): 443.5 (M+H)⁺.

Step 2: 4-Fluoro-l-(2-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)- lH-indole-3-carboxamide

To a stirred suspension of methylamine hydrochloride (22.9 mg, 339 μιηοΐ) at r.t. in dioxane (3 ml) under an argon atmosphere was added trimethylaluminum 2M solution in toluene (170 μΐ, 339 μιηοΐ) in one portion. After stirring for 2 hrs at r.t., methyl 3-fluoro-4-((4-fluoro-3-((lS,2S)- 2-hydroxycyclohexylcarbamoyl)-lH-indol-l-yl)methyl)benzoate (50 mg, 113 μιηοΐ) was added in one portion. The reaction mixture was heated to 100°C and stirring at that temperature was continued overnight. The orange slurry was cooled to r.t. and treated with 0.5 ml of water. Then, MgS0₄ was added. After stirring for 15 min at r.t., the mixture was filtered and the cake was washed with methanol. The filtrate was concentrated. The crude product was purified by silica gel chromatography using a CH₂Cl₂/MeOH gradient as eluent to provide the title compound (18 mg, 36 %) as white solid. MS (m/e): 442.2 (M+H)⁺.

In analogy to Example 86, compounds 87 to 90 of the following table were prepared by reaction of the indicated amides with an alkylating agent, followed by conversion of the ester with methyl- or dimethylamine hydrochloride in the presence of trimethylaluminium.

4-fluoro-N-((lS,2S)-2- l-(3- hydroxycyclohexyl)- 1H-

(dimethylcarbamoyl)be

indole-3-carboxamide

nzyl)-4-fluoro-N- (example A.6) and methyl

90 ((lS,2S)-2- 3 - (bromomethyl)benzoate hydroxycyclohexyl)- (CAS 1129-28-8), then

lH-indole-3- dimethylamine

carboxamide

o \ hydrochloride

Example 91

Step 1: l-(4-Bromobenzyl)-4-fluoro-N-((3R,4S)-3-hvdroxytetrahvdro-2H-pyran-4-yl)-lH- indole-3-carboxamide

The title compound was obtained in analogy to the procedures described in example 26, reacting 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide (example A.12) and 1- bromo-4-(chloromethyl)benzene. White solid. MS (m/e): 447.1 (M+H)⁺.

Step 2: 4-fluoro-N-((3R,4S)-3-hvdroxytetrahydro-2H-pyran-4-yl)- l-(4-(6-methoxypyridin-2- yl)benzyl)-lH-indole-3-carboxamide

To a solution of l-(4-bromobenzyl)-4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)- lH-indole-3-carboxamide (128 mg, 286 μιηοΐ) and 6-methoxypyridin-2-ylboronic acid (65.7 mg, 429 μιηοΐ) in 1 ,2-dimethoxyethane (2 ml) under an argon atmosphere was added cesium carbonate (186 mg, 572 μιηοΐ), water (0.2 ml) and tetrakis(triphenylphosphine)palladium(0) (9.9 mg, 8.6 μιηοΐ). The reaction mixture was stirred at 90° overnight, cooled to r.t and concentrated. The crude product was purified by silica gel chromatography using a CH₂Cl₂/MeOH gradient as eluent to provide the title compound (92 mg, 68%) as a white solid. MS (m/e): 476.3 (M+H)⁺.

Step 3: 4-Fluoro-l-(2-fluoro-4-(methylcarbamoyl)benzyl)-N-((lS,2S)-2-hvdroxycvclohexyl)- lH-indole-3-carboxamide

To a solution of 4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(6-methoxy- pyridin-2-yl)benzyl)-lH-indole-3-carboxamide (50 mg, 105 μιηοΐ) in acetonitrile (0.6 ml) at r.t under an argon atmosphere was added sodium iodide (23 mg, 155 μιηοΐ) and

trimethylchlorosilane (17 mg, 20.2 μΐ, 158 μιηοΐ). To this mixture was added dropwise a solution of acetonitrile (0.1 ml)/water (52 μΐ). The mixture was stirred at 60° for 7 hrs. After cooling to r.t. the mixture was poured on 10% aqueous Na₂S20₃ solution and extracted with CH₂C1₂. The organic phase was washed with water, dried over MgS0₄, filtered and concentrated. The crude product was purified by silica gel chromatography using a CH₂Cl₂/MeOH gradient as eluent to provide the title compound (15 mg, 28%) as a white solid. MS (m/e): 462.3 (M+H)⁺.

Example 92

2-[4-Fluoro-l-[[2-fluoro-4-(l-methylpyrazol-4-yl)phenyl]methyl]indol-3-yl]-N-[(3R,4S)-3- hydroxyoxan-4-yl]acetamide

Step 1: Ethyl 2-(4-fluoro-lH-indol-3-yl)acetate

To a stirred mixture of 4-fluoro-lH-indole (1 g, 7.4 mmol) and ethyl 2-diazoacetate (1.06 g, 973 μΐ, 9.25 mmol) in dichloromethane (50 ml) was added at r.t. and under an argon atmosphere copper(II)trifluoromethanesulfonate (134 mg, 370 μιηοΐ) (exothermic). The mixture was stirred at r.t overnight, then diluted with CH₂C1₂, washed with water, dried over MgS0₄, filtered and evaporated. The crude product was purified by silica gel chromatography using a

heptane/EtOAc gradient as eluent to obtain the title compound as a mixture with the isomeric ethyl 2-(4-fluoroindol-l-yl)acetate (815 mg) which was used in the next step without further purification. MS (m/e): 222.2 (M+H)⁺.

Step 2: Ethyl 2-(4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol-3-yl)acetate To a stirred solution of ethyl 2-(4-fluoro-lH-indol-3-yl)acetate (0.8 g, 2.17 mmol) in N,N- dimethylacetamide (10 ml) was added at r.t. and under an argon atmosphere 4-(4-

(chloromethyl)-3-fluorophenyl)-l-methyl-lH-pyrazole (487 mg, 2.17 mmol) and cesium carbonate (707 mg, 2.2 mmol). The mixture was stirred at r.t overnight, then diluted with EtOAc and washed with water. The aqueous layer was back extracted with EtOAc. The combined organics were washed with water, dried over MgS04, filtered and evaporated. The crude product was purified by silica gel chromatography using a heptane/EtOAc gradient as eluent to obtain the title compound (548 mg, 62%) as a colorless viscous oil. MS (m/e): 410.3 (M+H)⁺.

Step 3: 2-(4-Fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol-3-yl)acetic acid To a suspension of ethyl 2-(4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol- 3-yl)acetate (0.54 g, 1.32 mmol) in MeOH (1.5 ml) and THF (1.5 ml) was added at r.t. and under an argon atmosphere potassium hydroxide solution 1 M in water (2.64 ml, 2.64 mmol). The mixture was stirred at 75° for 4 hrs, then cooled to r.t.. 2M HC1 in water (2.64 ml, 5.3 mmol) was added under stirring at 0°. The mixture was stirred at r.t for 30 min. The precipitate was filtered, washed with water, collected and dried to provide the title compound (475 mg, 94%) as an off-white solid. MS (m/e): 382.3 (M+H)⁺. Step 4: 2-r4-Fluoro- l-rr2-fluoro-4-(l-methylpyrazol-4-yl)phenyllmethyllindol-3-yll-N-r(3R,4S)- 3-hydroxyoxan-4-yll acetamide

To a solution of 2-(4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol-3- yl)acetic acid (50 mg, 131 μιηοΐ) in DMF (1 ml) was added at r.t. and under an argon atmosphere (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (20.1 mg, 131 μιηοΐ), DIEA (50.8 mg, 68.7 μΐ, 393 μιηοΐ) and HATU (59.8 mg, 157 μιηοΐ). The yellow solution was stirred at r.t overnight. The mixture was poured on water and extracted with EtOAc. The organic layer was washed with water, dried with MgS0₄, filtered and evaporated. The crude product was purified by silica gel chromatography using a CH₂Cl₂/MeOH gradient as eluent to obtain the title compound (30 mg, 48%) as a white solid. MS (m/e): 481.3 (M+H)⁺. Example 93

Preparation of 2-(4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol-3-yl)-

N-((lS,2S)-2-hydroxycyclohexyl)acetamide

The title compound was obtained in analogy to the procedures described in example 92. Off- white solid. MS (m/e): 479.3 (M+H)⁺.

Examples 94 to 131

In analogy to example 1, examples 94 to 131 of the following table were prepared by coupling an acid derivative with an amine.

4,7-difluoro-l-(2- 4,7-difluoro-l-(2- fluoro-4-(l- fluoro-4-( 1 - methyl - methyl-lH- lH-pyrazol-4- pyrazol-4- yl)benzyl)-lH-indole-

96 yl)benzyl)-N- 3-carboxylic acid 469.3

(tetrahydro-2H- (example A.19) and

pyran-4-yl)-lH- tetrahydro-pyran-4-yl- indole-3- amine

carboxamide

4-fluoro-l-(2-

4-fluoro- l-(2-fluoro- fluoro-4-(l-

4-(l-methyl-lH- methyl-lH- pyrazol-4-yl)benzyl)- pyrazol-4- lH-indole-3-

97 yl)benzyl)-N-((l- 437.3 carboxylic acid

hydroxycyclopropy

(example A. l) and 1- I)methyl)-1H- (aminomethyl)cyclopr indole-3- opanol

carboxamide

4-((4-fluoro-3-(2- 2-(4-fluoro-l-(4-

((3R,4S)-3- (methylcarbamoyl)ben hydroxytetrahydro- zyl)-lH-indol-3- 2H-pyran-4- yl)acetic acid

98 ylamino)-2- (example A.20) and 440.3 oxoethyl)-lH- (3R,4S)-4-

indol- 1 -yl)methyl)- aminotetrahydropyran

N- -3-ol hydrochloride

methylbenzamide (example C.l)

2-(4-fluoro-l-(4-

4-((4-fluoro-3-(2- (methylcarbamoyl)ben

((lS,2S)-2- zyl)-lH-indol-3- hydroxycyclohexyl

yl) acetic acid

I T amino)-2-

99 (example A.20) and 438.4 oxoethyl)-lH-

(3R,4S)-4- indol- 1 -yl)methyl)- aminotetrahydro-2H- N- pyran-3-ol hydrogen

methylbenzamide

chloride N-((lR,2S)-3,3-

4-fluoro-l-(4-(l- difluoro-2- methyl- lH-pyrazol-4- hydroxycyclohexyl

yl)benzyl)-lH-indole- )-4-fluoro-l-(4-(l-

3-carboxylic acid

100 methyl-lH- 483.3

(example A.9) and

pyrazol-4- (lS,6R)-6-amino-2,2- yl)benzyl)-lH- difluorocyclohexanol indole-3- (CAS 1109284-40-3) carboxamide

N-((lS,2R)-3,3- difluoro-2- (R)4-fluoro-l-(4-(l- hydroxycyclohexyl methyl- lH-pyrazol-4- )-4-fluoro-l-(4-(l- yl)benzyl)-lH-indole-

101 methyl-lH- 3-carboxylic acid 483.3 pyrazol-4- (example A.9) and

yl)benzyl)-lH- (lR,6S)-6-amino-2,2- indole-3- difluorocyclohexanol carboxamide

N-((lR,2S)-3,3-

4-fluoro- l-(2-fluoro- difluoro-2-

4-(l-methyl-lH- hydroxycyclohexyl

pyrazol-4-yl)benzyl)- )-4-fluoro-l-(2- lH-indole-3- fluoro-4-(l-

102 carboxylic acid 501.3 methyl-lH- (example A.l) and

pyrazol-4- (lS,6R)-6-amino-2,2-

yl)benzyl)-lH- difluorocyclohexanol indole-3- (CAS 1109284-40-3) carboxamide

N-((lS,2R)-3,3- difluoro-2- 4-fluoro- 1- (2-fluoro- hydroxycyclohexyl 4-(l-methyl-lH- )-4-fluoro-l-(2- pyrazol-4-yl)benzyl)- fluoro-4-(l- lH-indole-3-

103 501.3 methyl-lH- carboxylic acid

pyrazol-4- (example A.l) and

yl)benzyl)-lH- (lR,6S)-6-amino-2,2- indole-3- difluorocyclohexanol carboxamide

4-fluoro-l-{ [4- N-cyclobutyl-4- (methylc arb amoyl) fluoro-l-[[4- phenyl] methyl}- 1H- (methylc arb amoyl) 380 indole-3-carboxylic phenyl] methyl] ind

acid (example A.24) ole-3-carboxamide

and cyclobutylamine

4-fluoro-l-{ [4-

N-cyclopentyl-4- (methylc arb amoyl) fluoro-l-[[4- phenyl] methyl}- 1H- (methylc arb amoyl) 394 indole-3-carboxylic phenyl] methyl] ind

acid (example A.24) ole-3-carboxamide

and cyclopentylamine

4-fluoro-l-{ [4-

N-cyclohexyl-4- (methylc arb amoyl) fluoro-l-[[4- phenyl] methyl}- 1H- (methylc arb amoyl) 408 indole-3-carboxylic phenyl] methyl] ind

acid (example A.24) ole-3-carboxamide

and cyclohexylamine

4-fluoro-l-{ [4-

N-cycloheptyl-4- (methylc arb amoyl) fluoro-l-[[4- phenyl] methyl}- 1H- (methylc arb amoyl) 422 indole-3-carboxylic phenyl] methyl] ind

acid (example A.24) ole-3-carboxamide

and cycloheptylamine

0

4-fluoro-l-{ [4-

N- (methylc arb amoyl)

(cyclopropylmethy phenyl] methyl}- 1H- l)-4-fluoro-l-[[4- indole-3-carboxylic

380 (methylc arb amoyl) acid (example A.24) phenyl] methyl] ind and o ole-3-carboxamide (cyclopropylmethyl)

amine

4-fluoro-l-{ [4- 4-fluoro-l-[[4- (methylc arb amoyl)

(methylcarbamoyl)

phenyl] methyl}- 1H- phenyl] methyl] -N- 410 indole-3-carboxylic

(oxan-3-yl)indole- acid (example A.24)

3-carboxamide

and oxan-3-amine

4-fluoro-l-{ [4-

4-fluoro-l-[[4- (methylc arb amoyl)

(methylcarbamoyl)

phenyl] methyl}- 1H- phenyl] methyl] -N- indole-3-carboxylic 424 (4-methyloxan-4- acid (example A.24) yl)indole-3- and 4-methyloxan-4-

carboxamide

amine

4-fluoro-l-{ [4-

4-fluoro-l-[[4- (methylc arb amoyl)

(methylc arb amoyl)

phenyl] methyl}- 1H- phenyl] methyl] -N- 426 indole-3-carboxylic

(thian-4-yl)indole- acid (example A.24)

3-carboxamide

and thian-4- amine

4-fluoro-l-{ [4-

N-(l,l- (methylc arb amoyl) dioxothian-4-yl)-4- phenyl] methyl}- 1H- fluoro-l-[[4- indole-3-carboxylic

458 (methylc arb amoyl) acid (example A.24) phenyl] methyl] ind and 4- ole-3-carboxamide aminotetrahydrothiop

0

yrandioxide

4-fluoro-l-{ [4-

4-fluoro-l-[[4- (methylc arb amoyl)

(methylc arb amoyl)

phenyl] methyl}- 1H- phenyl] methyl] -N- indole-3-carboxylic 424 (3-methyloxan-4- acid (example A.24) yl)indole-3- and 3-methyloxan-4- carboxamide

amine

amine hydrochloride

Examples 131 to 154

In analogy to example 26, examples 131 to 154 of the following table were prepared by reaction of the indicated amides with an alkylating agent.

-ile

4-fluoro-7- 4-fluoro-7-methoxy- methoxy-l-(4-(l- N-(tetrahydro-2H- methyl-lH- pyran-4-yl)-lH- pyrazol-4- indole-3-carboxamide

151 yl)benzyl)-N- (example A.29) and 5- 463.2

(tetrahydro-2H- (chloromethyl) -2- ( 1 - pyran-4-yl)-lH- methyl- lH-pyrazol-4-

indole-3- yl)pyridine (example

carboxamide B.l)

4-fluoro-l-(2-

4-fluoro-7-methoxy- fluoro-4-(l- N-(tetrahydro-2H- methyl-lH- pyran-4-yl)-lH- pyrazol-4- indole-3-carboxamide yl)benzyl)-7-

152 (example A.29) and 4- 481.2 methoxy-N- (4- (chloromethyl) - 3 - (tetrahydro-2H- fluorophenyl)- 1-

pyran-4-yl)-lH- methyl- 1 H-pyrazole

indole-3- (example B.2)

carboxamide

4-fluoro-l-(2-

4-fluoro-N-((3R,4S)- fluoro-4-(l- 3-hydroxytetrahydro- methyl-lH-

2H-pyran-4-yl)-7- pyrazol-4- methoxy- 1 H-indole- 3 - yl)benzyl)-N- carboxamide (example

153 ((3R,4S)-3- 497.2

A.28) and 4-(4- hydroxytetrahydro- (chloromethyl)- 3 - 2H-pyran-4-yl)-7- fluorophenyl)- 1- methoxy-lH- methyl- 1 H-pyrazole

indole-3- (example B.2)

carboxamide

4-fluoro-7-

4-fluoro-7-methoxy- methoxy-l-((l- N-(tetrahydro-2H- methyl-lH- pyran-4-yl)-lH- indazol-5- indole-3-carboxamide

154 yl)methyl)-N- 437.2

(example A.29) and 5- (tetrahydro-2H- (bromomethyl)- 1 - pyran-4-yl)-lH- methyl- lH-indazole

indole-3- hydrobromide

carboxamide Example 155

l-(4-(lH-Pyrazol-5-yl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-

3-carboxamide

Step 1: 4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(l-(4-methoxybenzyl)-lH-pyrazol-5- yl)benzyl)-lH-indole-3-carboxamide

In analogy to the procedure described for the synthesis of example 26, the title compound was prepared from 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide (example A.6) and 5-(4-(chloromethyl)phenyl)-l-(4-methoxybenzyl)-lH-pyrazole (example B.12). White solid. MS (m/e): 553.5 (M+H)⁺.

Step 2: l-(4-( lH-pyrazol-5-yl)benzyl)-4-fluoro-N-(( lS,2S)-2-hvdroxycvclohexyl)-lH-indole-3- carboxamide

A mixture of 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(l-(4-methoxybenzyl)-lH- pyrazol-5-yl)benzyl)-lH-indole-3-carboxamide (95 mg, 172 μmol) and 10 % palladium on activated charcoal (91.5 mg, 86.0 μιηοΐ) at room temperature in EtOH (3 ml) and acetic acid

(3.00 ml) was stirred under a hydrogen atmosphere (balloon pressure) for 17 hours. The catalyst was filtered and rinsed with EtOH. The filtrate was concentrated and the residue was purified with flash column chromatography on silica eluting with a gradient formed from

dichloromethane and methanol (0 to 5 %) to provide the title compound as a white solid (11.9 mg, 16 %). MS (m/e): 433.3 (M+H)⁺.

Examples 156 and 157

In analogy to the procedures described for the synthesis of example 155, examples 156 and 157 of the following table were prepared by the reaction of the indicated amides with an alkylating agent, followed by hydrogenation. Exampl MW found

Structure Systematic Name Starting materials e No. (MH⁺)

4-fluoro-N-((lS,2S)-

2- l-(4-(lH-l,2,4- hydroxycyclohexyl)- triazol-3- lH-indole-3- yl)benzyl)-4- carboxamide (example

fluoro-N-((lS,2S)-

156

z o A.6) and 3-(4- 433.5 -

(chloromethyl)phenyl)

hydroxycyclohexyl _1.(₄.

)-lH-indole-3- methoxybenzyl)- 1H- carboxamide

1,2,4-triazole

(example B.13)

4-Fluoro-N- l-(4-(lH-l,2,4- (tetrahydro-2H-pyran- triazol-3- 4-yl)-lH-indole-3- yl)benzyl)-4- carboxamide (example

157 ifS ? fluoro-N- A.8) and 3-(4-

420.3

(tetrahydro-2H- (chloromethyl)phenyl)

pyran-4-yl)-lH- .1.(4.

indole-3- methoxybenzyl)- 1H- carboxamide 1,2,4-triazole

(example B.13)

Example 158

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(pyrimidin-5-yl)benzyl)-lH-indole-

3-carboxamide

To a solution of l-(4-bromobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide (example A.30) (0.1 g, 225 μιηοΐ) and pyrimidin-5-ylboronic acid (41.7 mg, 337 μηιοΐ) in 1 ,2-dimethoxyethane (2 ml) under argon was added cesium carbonate (146 mg, 449 μιηοΐ), water (0.2 ml) and tetrakis(triphenylphosphine)palladium(0) (7.78 mg, 6.74 μιηοΐ). The mixture was stirred at 90°C for 17 hours, cooled to room temperature and filtered. The cake was rinsed with dchloromethane. The filtrate was concentrated and the residue was purified with flash column chromatography on silica eluting with a gradient formed from dichloromethane and methanol (0 to 5 %) to provide the title compound as a white solid (48.3 mg, 43 %). MS (m/e): 445.3 (M+H)⁺.

Example 159

In analogy to the procedure described for the synthesis of example 158, the title compound was prepared by the reaction of l-(4-bromobenzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH- indole-3-carboxamide (example A.30) and pyridin-3-ylboronic acid. Off-white solid. MS (m/e): 444.3 (M+H)⁺.

Example 160

4-Fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((l-(pyridin-2-yl)piperidin-4- yl)methyl)-lH-indole-3-carboxamide

To a stirred mixture of 4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(piperidin-4-ylmethyl)-lH- indole-3-carboxamide (example A.31) (150 mg, 402 μιηοΐ), 2-bromopyridine (63.5 mg, 38.5 μΐ, 402 μmol), potassium carbonate (99.9 mg, 723 μιηο) and water (15.2 mg, 15.2 μΐ, 843 μιηοΐ) in xylene (9 ml) at room temperature under argon were added palladium(II) acetate (3.61 mg, 16.1 μιηοΐ) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (11.6 mg, 20.1 μιηοΐ). The reaction mixture was degassed and back-filled with argon (3 times). The mixture was then heated to 140°C for 17 hours, cooled to room temperature, diluted with dichloromethane, stirred at room temperature for 5 min and filtered. The filtrate was concentrated and the residue was purified with flash column chromatography on silica eluting with a gradient formed from

dichloromethane and methanol (0 to 5 %) to provide the title compound as an off-white solid (27 mg, 15 %). MS (m/e): 451.3 (M+H)⁺.

Example 161 and 162

In analogy to the procedure described for the synthesis of example 160, examples 161 and 162 of the following table were prepared.

Example 163

4-Fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

The title compound was obtained in analogy to the procedure described in example 86, reacting methyl 2-fluoro-4-((4-fluoro-3-(tetrahydro-2H-pyran-4-ylcarbamoyl)-lH-indol-l- yl)methyl)benzoate (example A.33) and methylamine hydrochloride. White solid. MS (m/e): 423.3 (M+H)⁺.

Example 164 4-Fluoro-l-(2-fluoro-4-(methylcarbamoyl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

Step 1: methyl 3-fluoro-4-((4-fluoro-3-(tetrahydro-2H-pyran-4-ylcarbamoyl)-lH-indol-l- yPmethyPbenzoate

The title compound was obtained in analogy to the procedure described in example 26, reacting 4-fluoro-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide (example A.8) and methyl 4- (bromomethyl)-3-fluorobenzoate (CAS 128577-47-9). Off-white solid. MS (m/e): 429.3 (M+H)⁺. Step 2: 4-Fluoro-l-(2-fluoro-4-(methylcarbamoyl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

The title compound was obtained in analogy to the procedure described in example 86, reacting methyl 3-fluoro-4-((4-fluoro-3-(tetrahydro-2H-pyran-4-ylcarbamoyl)-lH-indol-l- yl)methyl)benzoate and methylamine hydrochloride. White solid. MS (m/e): 428.3 (M+H)⁺.

Examples 165 to 168

In analogy to example 1, examples 165 to 168 of the following table were prepared by coupling an acid derivative with an amine.

Example MW found

Structure Systematic Name Starting materials No. (MH⁺)

4-Fluoro- 1 -(3-fluoro-

N-(2,2- 4- difluorocyclohexyl (methylcarbamoyl)ben

)-4-fluoro-l-(3- zyl)-lH-indole-3-

165 fluoro-4- carboxylic acid 462.2

(methylc arb amoyl) (example A.26) and

benzyl)- lH-indole- 2,2- 3-carboxamide difluorocyclohexan- 1 - amine

N-(2,2- 4-Fluoro- 1 -(3-fluoro- dimethyltetrahydro 4- -2H-pyran-4-yl)-4- (methylcarbamoyl)ben

fluoro- 1 - (3 -fluoro- zyl)-lH-indole-3-

166 456.2

4- carboxylic acid

(methylc arb amoyl) (example A.26) and

benzyl)- lH-indole- 2,2-dimethyloxan-4- 3-carboxamide amine

4-fluoro-l-(3-

4-Fluoro- 1 -(3-fluoro- fluoro-4- 4- (methylc arb amoyl)

(methylcarbamoyl)ben

benzyl)-N-

167 zyl)-lH-indole-3- 444.2

(tetrahydro-2H- carboxylic acid

thiopyran-4-yl)- (example A.26) and

lH-indole-3- thian-4-amine

carboxamide

Claims

1. A compound of formula I

wherein

R is lower alkyl, -(CH₂)_z-C₃_7-cycloalkyl or -(CH₂)_Z- C₄_6-heterocycloalkyl, which are

optionally substituted by one to tree hydroxy, lower alkyl, lower alkoxy or halogen, or is (endo)-7-oxabicyclo[2.2.1]heptan-2-yl;

X is CH or N; Y¹ is CR³ or N;

Y² is CR⁴; or or Y^l which they are attach

Y is N; Y⁴ is N; Y⁵ is NR⁷

R is hydrogen or halogen; R is hydrogen, halogen, cycloalkyl, lower alkyl or lower alkoxy;

R³ is hydrogen, halogen, ^N , CN, -C(0)NH₂, -C(0)NHCH₃ or -C(0)N(CH₃)₂;

R⁴ is hydrogen, a 5 or 6 membered heteroaryl or heterocyclyl group, selected from the group

or is phenyl, -C(0)NH₂, -CH₂C(0)NH₂, -C(0)NHCH₃, -C(0)NH-cycloalkyl,

-C(0)N(CH₃)₂, -NHC(0)0-lower alkyl, CN, lower alkoxy, lower alkoxy substituted by halogen, halogen or S(0)₂CH ; R⁵ is phenyl;

R⁶ is phenyl or thiazol-2-yl;

R is pyridin-2-yl or pyrimidin-4-yl; p is 0 or 1 ; m is 1, 2 or 3; z is 0 or 1;

or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

2. Compounds of formula IA according to claim 1

wherein

R is lower alkyl, -(CH₂)_z-C₃-₇-cycloalkyl or -(CH₂)_Z- C₄-6-heterocyclo alkyl, which are

optionally substituted by one to three hydroxy, lower alkyl, lower alkoxy or halogen, or is (endo)-7-oxabicyclo[2.2. l]heptan-2-yl;

X is CH or N;

Y¹ is CR³ or N;

Y² is CR⁴; or or Y and Y² ma form together with the carbon atoms to which they are attach

Y is N;

R is hydrogen, halogen, , CN, -C(0)NH₂, -C(0)NHCH₃ or -C(0)N(CH₃)₂; R⁴ is hydrogen, a 5 or 6 membered heteroaryl or heterocyclyl group, selected from the group

or is phenyl, -C(0)NH₂, -CH₂C(0)NH₂, -C(0)NHCH₃, -C(0)NH-cycloalkyl,

-C(0)N(CH₃)₂, -NHC(0)0-lower alkyl, CN, lower alkoxy, lower alkoxy substituted by halogen, halogen or S(0)₂CH₃;

R⁵ is phenyl;

R⁶ is phenyl or thiazol-2-yl; R is pyridin-2-yl or pyrimidin-4-yl; p is 0 or 1 ; m is 1, 2 or 3; z is 0 or 1;

3. A compound of formula IA according to claim 2, which compounds are

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lR,2R)-2-hydroxycyclohexyl)- lH-indole-3-carboxamide

4,6-difluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2- hydroxycyclohexyl)-lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3RS,4SR)-3-hydroxytetrahydro- 2H-pyran-4-yl)- lH-indazole-3-carboxamide

3- carboxamide

4-fluoro- 1 - (2-fluoro-4- ( 1 -methyl- 1 H-pyrazol-4-yl)benzyl)- N-((lS,2S)-2-hydroxycyclopentyl)-lH-indole-3-carboxamide

4-fluoro- l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-3-yl)-lH- indole-3-carboxamide

4-fluoro- l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-(tetrahydro-2H-pyran-4-yl)-lH- indole-3-carboxamide

4,5,6,7-tetrafluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l-methyl-lH-pyrazol-4-yl)pyridine-

3- yl)methyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-( 1-methyl- lH-pyrazol-4-yl)pyridine-3- yl)methyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(3-(l -methyl- lH-pyrazol-4-yl)benzyl)- lH-indole- 3-carboxamide

3- carboxamide

4-fluoro- l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-7- methyl- lH-indole-3-carboxamide

4- fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-7-methyl-l-(4-(l -methyl- lH-pyrazol-4-yl)benzyl)- lH-indole-3-carboxamide

l-benzyl-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3-carboxamide

4-fluoro-N-(( 1 S,2S)-2-hydroxycyclohexyl)- 1 -(4- (3 -methyl- 1 H-pyrazol- 1 -yl)benzyl)- 1 H-indole- 3-carboxamide

5- yl)methyl)-lH-indole-3-carboxamide

4,5-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-((6-(l-methyl-lH-pyrazol-4-yl)pyridine-3- yl)methyl)-lH-indole-3-carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(methylcarbamoyl)benzyl)-lH-indole-3- carboxamide 4,5-difluoro-N-((lS,2S)-2-hydroxycyclohexyl)-l-(4-(4-methyl-lH-imidazol-l-yl)benzyl)-lH- indole-3-carboxamide

4,5,6,7-Tetrafluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3R,4S) or (3S,4R))-3- hydroxytetrahydro-2H-pyran-4-yl)- lH-indole-3-carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((3S,4R) or

(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-lH-indole-3-carboxamide

4,7-difluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-((6-(l-methyl-lH-pyrazol-4- yl)yridine-3-yl)methyl)- lH-indazole-3-carboxamide

4-fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(thiazol-2-yl)benzyl)-lH-indole-

3- carboxamide

4- fluoro-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-l-(4-(5-methyl-l,2,4-oxadiazol-3- yl)benzyl)-lH-indole-3-carboxamide

3- carboxamide

4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)- l-((6-(methylcarbamoyl)pyridin-3-yl)methyl)- 1H- indole-3-carboxamide

3- carboxamide

2-[4-fluoro-l-[[2-fluoro-4-(l-methylpyrazol-4-yl)phenyl]methyl]indol-3-yl]-N-[(3R,4S)-3- hydroxyoxan-4-yl] acetamide

2- (4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-lH-indol-3-yl)-N-((lS,2S)-2- hydroxycyclohexyl)acetamide 4,7-difluoro-l-((l-methyl-lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)-lH-indole-3- carboxamide

3- carboxamide

N-((lS,2R)-3,3-difluoro-2-hydroxycyclohexyl)-4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4- yl)benzyl)- lH-indole-3-carboxamide

4-fluoro-N-methyl- 1 -[ [4- (methylcarbamoyl)phenyl] methyl] indole-3-carboxamide N-cyclopropyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-cyclobutyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-cyclohexyl-4-fluoro-l-[[4-(methylcarbamoyl)phenyl]methyl]indole-3-carboxamide

N-(3,3-difluorocyclohexyl)-4-fluoro-l-(3-fluoro-4-(methylcarbamoyl)benzyl)-lH-indole-3- carboxamide

4-fluoro-l-(2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)benzyl)-7-methyl-N-(tetrahydro-2H-pyran-4- yl)- lH-indole-3 -carboxamide 4-fluoro-7-methyl- 1 -((1 -methyl- lH-indazol-5-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)- 1H- indole-3-carboxamide

3- carboxamide

4-fluoro-l-(2-fluoro-4-(l-methyl-lH-pyrazol-4-yl)benzyl)-N-((lS,2S)-2-hydroxycyclohexyl)-7- methoxy- 1 H-indole-3-carboxamide

l-(4-(lH-Pyrazol-5-yl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide l-(4-(lH-l,2,4-triazol-3-yl)benzyl)-4-fluoro-N-((lS,2S)-2-hydroxycyclohexyl)-lH-indole-3- carboxamide

3- carboxamide or

4. A compound of formula IB according to claim 1, H

wherein

R is lower alkyl, -(CH₂)_z-C₃-7-cycloalkyl or -(CH₂)_Z- C₄-6-heterocycloalkyl, which are optionally substituted by one to tree hydroxy, lower alkyl, lower alkoxy or halogen, or (endo)-7-oxabicyclo[2.2.1]heptan-2-yl;

X is CH or N;

Y¹ is CR³ or N;

Y² is CR⁴; or or Y a ² may form together with the carbon atoms to which they are attach

is N; is N; is NR⁷;

R is hydrogen or halogen; is hydrogen, halogen, cycloalkyl, lower alkyl or lower alkoxy;

or is phenyl, -C(0)NH₂, -CH₂C(0)NH₂, -C(0)NHCH₃, -C(0)NH-cycloalkyl,

R⁵ is phenyl;

5. A compound of formula IB according to claim 4, which compound is

6. A compound of formula IC according to claim 1 H

R

wherein

R is lower alkyl, -(CH₂)_z-C_3-7-cycloalkyl or -(CH₂)_Z- C₄-6-heterocycloalkyl, which are optionally substituted by one to tree hydroxy, lower alkyl, lower alkoxy or halogen, or (endo)-7-oxabicyclo[2.2.1]heptan-2-yl;

X is CH or N;

Y¹ is CR³ or N;

Y² is CR⁴; or or Y^!a ² may form together with the carbon atoms to which they are attach

Y³ is N;

Y⁴ is N;

Y⁵ is NR⁷;

R¹ is hydrogen or halogen;

R² is hydrogen, halogen, cycloalkyl, lower alkyl or lower alkoxy;

is hydrogen, halogen, , CN, -C(0)NH₂, -C(0)NHCH₃ or -C(0)N(CH₃)₂; R⁴ is hydrogen, a 5 or 6 membered heteroaryl or heterocyclyl group, selected from the group

or is phenyl, -C(0)NH₂, -CH₂C(0)NH₂, -C(0)NHCH₃, -C(0)NH-cycloalkyl,

R⁵ is phenyl;

7. A compound of formula IC according to claim 6, which compounds are

8. A compound of formula ID according to claim 1 H

wherein

R is lower alkyl, -(CH₂)_z-C₃_₇-cycloalkyl or -(CH₂)_Z- C_4-6-heterocycloalkyl, which are optionally substituted by one to tree hydroxy, lower alkyl, lower alkoxy or halogen, or (endo)-7-oxabicyclo[2.2.1]heptan-2-yl;

X is CH or N;

Y¹ is CR³ or N;

Y³ is N;

Y⁴ is N;

Y⁵ is NR⁷;

R¹ is hydrogen or halogen;

R² is hydrogen, halogen, cycloalkyl, lower alkyl or lower alkoxy;

\

or is phenyl, -C(0)NH₂, -CH₂C(0)NH₂, -C(0)NHCH₃, -C(0)NH-cycloalkyl,

R⁵ is phenyl;

9. A compound of formula ID according to claim 8, which compounds are

10. A process for the manufacture of a compound of formula I as defined in any one of claims 1 to 9, which process comprises a) reacting a compound of formula

with a compound of formula

RNH₂ in the presence of an activating agent such as BOP (benzotriazol- 1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate or thionyl chloride to a compound of formulas

wherein the substituents are as defined in claim 1, or

b) reacting a compound of formula

with a compound of formulas

in the presence of base like cesium carbonate or sodium hydride to a compound of formulas

wherein Hal is halogen and the other substituents are as defined in claim 1, and, if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

11. A compound according to any one of claims 1 to 9, when manufactures by a process according to claim 10.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutical acceptable carrier and/or adjuvant.

13. Pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutical acceptable carrier and/or adjuvant for use in the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

14. Compounds according to any one of claims 1 to 9 for use as therapeutic active substances.

15. Compounds according to any one of claims 1 to 9 for use as therapeutic active substances in the treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

16. The use of a compound according to any one of claims 1 to 9 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

17. A method for the treatment or prophylaxis of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders, .which method comprises administering an effective amount of a compound as defined in any one of claim 1 to 9.

18. The use of a compound according to any one of claims 1 to 9 for the treatment or prophylaxis of Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders.

19. The invention as hereinbefore described.