HK1220178B - Indol-carboxamide derivatives - Google Patents

Description

Indole-carboxamide derivatives

The invention relates to compounds of the general formula I

Wherein

R¹Is aryl or heteroaryl, said aryl or heteroaryl being optionally substituted by one, two or three substituents selected from the group consisting of lower alkyl, halogen, lower alkyl substituted by halogen, hydroxy, lower alkyl substituted by hydroxy, lower alkoxy substituted by halogen, cyano or nitro;

R²is halogen, lower alkyl or cyano;

R³is hydrogen, lower alkyl or lower alkyl substituted by halogen;

R⁴is hydrogen or lower alkyl;

R⁵、R⁶is hydrogen, lower alkyl or may form together with the N atom to which they are attached a heterocycloalkyl ring;

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

It has now been shown that the compounds of the present invention stimulate neurogenesis from Neural Stem Cells (NSCs). Neurogenesis occurs during development and in the adult brain. Conceptually, the neurogenesis process can be divided into four steps: (i) proliferation of NSCs; (ii) neuronal fate determination of NSCs; (iii) survival and maturation of new neurons; and (iv) the integration of new neuron functionality into the neuronal network.

Adult neurogenesis is a developmental process that occurs throughout life in the adult brain whereby new functional neurons are generated from adult neural stem cells. Constitutive adult neurogenesis under physiological conditions occurs predominantly in two "neurogenic" brain regions, 1) the sub-granule region (SGZ) in the hippocampal dentate gyrus, where new dentate granule cells are generated, 2) the sub-ventricular region (SVZ) of the lateral ventricles, where new neurons are generated and subsequently migrate to the olfactory bulb via the Rostral Migration Stream (RMS), becoming interneurons.

Extensive evidence suggests that adult neurogenesis of the hippocampus plays an important role in cognitive and emotional states, although precise function remains elusive. It has been claimed that relatively small numbers of neonatal granule neurons can affect overall brain function as they innervate many interneurons within the dentate gyrus, each of which inhibits hundreds of mature granule cells, resulting in neurogenesis-dependent feedback inhibition. In combination with a low firing threshold, the nascent neurons elicit a response to very subtle changes in the environment. Disorders in this process can manifest in behavior as a lack of pattern separation associated with mental illness. For example, neurogenesis in the hippocampus of adults is associated with cognitive and emotional abilities, e.g., physical exercise, exposure to rich external environments and typical antidepressants concurrently promoting neurogenesis and cognitive and/or emotional states in the hippocampus of adults, while chronic stress, depression, sleep deprivation and aging reduce neurogenesis in adults and are associated with negative cognitive and/or emotional states (Neuron70, 26.2011.5.26, pp 582-. It is of interest that antidepressants promote hippocampal adult neurogenesis and their effect on certain behaviors requires stimulation of neurogenesis. It is generally believed that neurogenesis in other regions of the adult CNS is very limited under normal physiological conditions, but can be induced following injury such as stroke (stroke), and central and peripheral brain injury.

Thus, it is believed that stimulation of neurogenesis in adults represents a target for neuroregenerative therapy for normal aging, particularly for a variety of neurodegenerative and neuropsychiatric disorders including schizophrenia (schizophrenia), obsessive-compulsive personality disorder (obsessive-complex cognitive disorder), major depression (major depression), bipolar disorders (bipolar disorders), anxiety disorders (anxiety disorders), epilepsy (epilepsy), retinal degeneration (degenerative degeneration), traumatic brain injury (traumatic brain injury), spinal cord injury (spinal cord injury), post-traumatic stress disorder (post-traumatic stress disorder), panic disorder (systemic disorder), Parkinson's disease (Parkinson's disease), dementia (cognitive dementia), cognitive impairment (cognitive impairment), post-cognitive impairment (mild cognitive impairment), chemotherapy-induced dysfunction (chemotherapy-induced chemotherapy), down syndrome, autism spectrum disorders, hearing loss (hearing loss) (Neuroscience, 167(2010) 1216-1226; Nature Medicine, Vol.11, No.3, (2005), 271-276) tinnitus (tinitus), spinocerebellar ataxia (spinocerebellar ataxia), amyotrophic lateral sclerosis (amyotrophic lateral sclerosis), multiple sclerosis (multiple sclerosis), Huntington's disease, stroke (ote), and disorders resulting from the abuse of radiation therapy (radiotherapy), chronic stress (chronstressful), or neuro-active drugs such as alcohol, opiates, methamphetamine, phencyclidine and cocaine (US 2012/0022096).

Thus, chemical stimulation of adult neurogenesis provides new regenerative means and opportunities to develop new drugs for the treatment of neurological and neuropsychiatric disorders.

Accordingly, an object of the present invention is a compound that modulates neurogenesis. 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 schizophrenia (schizophrenia), obsessive-compulsive personality disorder (obsessive-compulsive personality disorder), major depression (major depression), bipolar disorders (bipolar disorders), anxiety disorders (anxiety disorders), normal aging, epilepsy (epidys), retinal degeneration (degenerative degeneration), traumatic brain injury (traumatic brain injury), spinal cord injury (spinal cord injury), post-traumatic stress disorder (post-traumatic stress disorder), panic disorder (cerebral dysfunction), Parkinson's disease (Parkinson's disease), dementia (dementias), Alzheimer's disease (Alzheimer's disease), cognitive impairment (cognitive impairment), cognitive dysfunction (cognitive dysfunction), post-chemotherapy induced cerebral dysfunction (chemotherapy), post-chemotherapy induced syndrome (chemotherapy induced dysfunction syndrome), Hearing loss (hearing loss), tinnitus (tinitus), spinocerebellar ataxia (spinocerebellar ataxia), amyotrophic lateral sclerosis (amyotrophic lateralsis), multiple sclerosis (multiple sclerosis), Huntington's disease, stroke (stroke), and disorders resulting from radiation therapy (radiation therapy), chronic stress (chronic stress) or abuse of neuro-active drugs such as alcohol, opiates, methamphetamine, phencyclidine and cocaine.

The most preferred indications for the compounds of formula I are Alzheimer's disease, depression, anxiety and stroke.

One object of the present invention is a pharmaceutical composition comprising a compound of formula I.

A further object of the present invention is the use of a compound of formula I for the preparation of a medicament for the therapeutic and/or prophylactic treatment of the above-mentioned diseases.

Another object of the present invention is a method for the treatment of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, parkinson's disease, dementia, alzheimer's disease, cognitive impairment, chemotherapy-induced cognitive dysfunction, down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and cocaine, comprising administering an effective amount of a compound of formula I.

An embodiment of the invention are compounds of formula I, wherein R⁵And R⁶Is hydrogen.

Another embodiment of the present invention are compounds of formula I, wherein R is¹Is aryl, e.g. phenyl, said phenyl being optionally substituted by one, two or three substituents selected from lower alkyl, halogen, lower alkyl substituted by halogen,Hydroxy, hydroxy-substituted lower alkyl, lower alkoxy, halogen-substituted lower alkoxy, cyano or nitro; for example the following compounds:

7- (4-chlorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -1-methylindole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-1, 3-dimethyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-3-methyl-7- [4- (trifluoromethyl) phenyl ] -1H-indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

7- (4-chlorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-chlorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (4-chlorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (3, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-3-methyl-7- [4- (trifluoromethyl) -phenyl ] -1H-indole-2-carboxamide

5-chloro-7- (3, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-1, 3-dimethyl-7- [4- (trifluoromethyl) phenyl ] indole-2-carboxamide

5-cyano-3-methyl-7- [4- (trifluoromethoxy) -phenyl ] -1H-indole-2-carboxamide

5-cyano-7- (4-cyanophenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-1, 3-dimethyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

5-cyano-7- (4-cyanophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (4-cyanophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-3-methyl-7- [4- (trifluoromethoxy) phenyl ] -1H-indole-2-carboxamide

5-chloro-7- (2, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (2, 4-dichlorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-1, 3-dimethyl-7- [4- (trifluoromethoxy) -phenyl ] indole-2-carboxamide

5-chloro-7- (4-cyanophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (2, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (2, 4-dichlorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (4-chloro-3-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-chloro-3-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -1H-indole-2-carboxamide

7- (4-chlorophenyl) -5-cyano-1H-indole-2-carboxamide

5-cyano-7- [4- (trifluoromethyl) phenyl ] -1H-indole-2-carboxamide

5-cyano-1-methyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -1-methylindole-2-carboxamide

7- (4-chlorophenyl) -5-cyano-1-methylindole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -1-methylindole-2-carboxamide

5-cyano-7- (2, 4-difluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-cyanophenyl) -1H-indole-2-carboxamide

5-cyano-7- [4- (trifluoromethoxy) -phenyl ] -1H-indole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

7- (4-chlorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

7- (3, 4-difluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

5-fluoro-3-methyl-7- [4- (trifluoromethyl) -phenyl ] -1H-indole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chlorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-fluoro-1, 3-dimethyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

7- (3, 4-difluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

7- (4-cyanophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

5-fluoro-3-methyl-7- [4- (trifluoromethoxy) phenyl ] -1H-indole-2-carboxamide

7- (2, 4-difluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

7- (2, 4-dichlorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-1-methylindole-2-carboxamide

7- (4-cyanophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-fluoro-1, 3-dimethyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

7- (2, 4-dichlorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2, 4-difluorophenyl) -1-methylindole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -1-methylindole-2-carboxamide

7- (2, 4-difluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -1-methylindole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -1H-indole-2-carboxamide

5-cyano-1-methyl-7- (4-nitrophenyl) -indole-2-carboxamide

5-cyano-7- (4-nitrophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-methoxyphenyl) -1-methylindole-2-carboxamide

5-cyano-7- (4-methoxyphenyl) -1H-indole-2-carboxamide

5-cyano-1-methyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

5-fluoro-3-methyl-7- (4-methylphenyl) -1H-indole-2-carboxamide

5-fluoro-3-methyl-7- (2, 3, 4-trifluorophenyl) -1H-indole-2-carboxamide

5-fluoro-7- (4-methoxyphenyl) -3-methyl-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

5-fluoro-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

5-fluoro-1, 3-dimethyl-7- (4-methylphenyl) indole-2-carboxamide

5-fluoro-7- (4-methoxyphenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-fluoro-3-methyl-7-phenyl-1H-indole-2-carboxamide

5-fluoro-7- (4-fluoro-3-methylphenyl) -3-methyl-1H-indole-2-carboxamide

5-fluoro-1, 3-dimethyl-7-phenylindole-2-carboxamide

5-fluoro-7- (4-fluoro-3-methylphenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- (3, 4, 5-trifluorophenyl) -1H-indole-2-carboxamide

5-cyano-1-methyl-7- (3, 4, 5-trifluorophenyl) indole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-1H-indole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-1-methylindole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1H-indole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1-methylindole-2-carboxamide

5-cyano-1, 3-dimethyl-7- (3, 4, 5-trifluorophenyl) indole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1, 3-dimethylindole-2-carboxamide

5-cyano-3-methyl-7- (3, 4, 5-trifluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -3-methyl-1H-indole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide, or

5-cyano-7- (2, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide.

An embodiment of the invention is further a compound of formula I, wherein R is¹Is heteroaryl, e.g. pyridinyl, optionally substituted with one, two or three substituents selected from lower alkyl, halogen, lower alkyl substituted by halogen, hydroxy, lower alkyl substituted by hydroxy, lower alkoxy substituted by halogen, cyano or nitro; example (b)Such as the following compounds:

7- (2-chloropyridin-4-yl) -5-cyano-1-methylindole-2-carboxamide

7- (2-chloropyridin-4-yl) -5-cyano-1H-indole-2-carboxamide

5-fluoro-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

5-cyano-7- (6-fluoropyridin-3-yl) -1H-indole-2-carboxamide

5-fluoro-1, 3-dimethyl-7-pyridin-4-ylindole-2-carboxamide

5-cyano-7-pyridin-4-yl-1H-indole-2-carboxamide

5-cyano-1-methyl-7-pyridin-4-ylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -1-methylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -1H-indole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-1H-indole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-1-methylindole-2-carboxamide

7- (2-chloropyridin-4-yl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -1, 3-dimethylindole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (6-fluoropyridin-3-yl) -1, 3-dimethylindole-2-carboxamide

5-cyano-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

5-cyano-1, 3-dimethyl-7-pyridin-4-ylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -3-methyl-1H-indole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-3-methyl-1H-indole-2-carboxamide

5-cyano-7- (6-fluoropyridin-3-yl) -3-methyl-1H-indole-2-carboxamide, or

7- (2-chloropyridin-4-yl) -5-cyano-3-methyl-1H-indole-2-carboxamide.

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

As used herein, the term "aryl" denotes a carbocyclic ring system comprising 6 to 10 carbon atoms forming one or more rings, and wherein at least one ring is aromatic, such as phenyl or naphthyl. The most preferred aryl group is phenyl.

The term "heteroaryl" denotes a carbocyclic ring system comprising 5 to 10 ring atoms forming one or more rings, wherein at least one carbon atom is replaced by a heteroatom selected from the group consisting of O, N or S, and wherein at least one ring is aromatic, e.g., oxazolyl, pyridyl, thienyl, quinolinyl, pyrrolyl, furanyl, benzimidazolyl, imidazolyl, and the like. The most preferred group is pyridyl.

The term "lower alkyl" denotes a saturated, i.e. aliphatic, hydrocarbon group comprising a straight or branched carbon chain having 1-4 carbon atoms. Examples of "alkyl" are methyl, ethyl, n-propyl and isopropyl.

The term "halogen-substituted lower alkyl" denotes a lower alkyl group wherein at least one hydrogen atom is replaced by a halogen atom.

The term "hydroxy-substituted lower alkyl" denotes a lower alkyl group wherein at least one hydrogen atom is replaced by a hydroxy group.

The term "alkoxy" denotes the group-O-R ', wherein R' is lower alkyl as defined above.

The term "halogen-substituted lower alkyl" denotes lower as defined aboveAn alkyl group in which at least one hydrogen atom is replaced by a halogen atom. Preferred groups are CF₃。

The term "halogen-substituted lower alkoxy" denotes a lower alkoxy group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom. Preferred groups are OCF₃。

The term "halogen" denotes chlorine, bromine, fluorine or iodine.

The term "heterocycloalkyl" denotes an unsaturated carbocyclic ring wherein one or two carbon atoms are replaced by N, O or S, such as piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl.

The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable acid addition salts" include 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, methanesulfonic acid, p-toluenesulfonic acid and the like.

The novel compounds of formula I and pharmaceutically acceptable salts thereof of the present invention may be prepared by methods known in the art, for example, by a method comprising

a) Reacting a compound of formula 1 with a compound of formula 2

NHR⁵R⁶2

To form a compound of formula I

And, if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt, or

b) Reacting a compound of formula 3 with a compound of formula 4

To form a compound of formula I

And, if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt.

The preparation of the compounds of formula I according to the invention can be carried out in a sequential or convergent synthetic route. The synthesis of the compounds of the present invention is shown in scheme 1 below. Techniques for carrying out the reaction and purifying the resulting product are known to those skilled in the art. Unless stated to the contrary, substituents and indices used in the following description of the methods have the meanings given above.

In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The order of the reaction is not limited to the order shown in scheme 1, but the order of the reaction steps may be varied at will depending on the starting materials and their respective reactivities. Starting materials are commercially available or can be prepared by methods analogous to those given below, by methods described in the references cited in the specification or in the examples, or by methods known in the art.

Scheme 1

Starting from the aniline of formula 9 the corresponding hydrazine of formula 8 is prepared. These derivatives are the starting point for the classical indole synthesis which yields the indole-2-carboxylate ester of formula 6 via an intermediate of formula 7. Amide synthesis using classical methods yields the building blocks of formula 3. Reaction with, for example, commercially available boric acid yields the final compound of formula I. Amide formation and coupling reactions can also be exchanged by the reaction of a compound of formula 5 to a carboxylic acid of formula 1, which is subsequently converted to the final compound of formula I.

Isolation and purification of Compounds

Isolation and purification of the compounds and intermediates described herein may, if desired, be carried out by any suitable isolation or purification method 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 methods. A detailed description of suitable separation and isolation methods may be obtained by reference to the preparations and examples below. However, other equivalent separation or isolation methods may of course be used. Chiral HPLC can be used to separate racemic mixtures of chiral compounds of formula I.

Salts of compounds of formula I

The compounds of formula I are basic and can be converted into the corresponding acid addition salts. The conversion is achieved by treatment with at least stoichiometric amounts of appropriate acids 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 is added to a similar solvent. The temperature was maintained between 0 ℃ and 50 ℃. The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.

Acid addition salts of the basic compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of an appropriate base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, aqueous ammonia, and the like.

The compounds of formula I and their pharmaceutically acceptable addition salts have beneficial pharmaceutical properties. In particular, the compounds of the present invention have been found to have activity as neurogenic agents.

The compounds were studied according to the tests given below.

Neurogenesis assay

Neural stem cell proliferation assay

The neurogenic properties of small molecules are determined based on the proliferation of Neural Stem Cells (NSCs) derived from human embryonic stem cells by the dual SMAD inhibition described previously (Chambers, S.M., et al, high effective neural transformation of human ES and iPS cells by dual inhibition of SMAD signalling, Nature biotechnology 2009.27 (3): p.275-80.)

After an incubation period of 4 days, the cells were increased by ATP-based levels (Promega:) Compound responses were measured.

NSCs were thawed and expanded for 3 passages. On day 14, NSCs were plated out at 21' 000 cells/cm in 38. mu.l medium volume²The cell density of (A) was seeded into Polyornithin/Lamin-coated 384-well plates.

4 hours after cell seeding, compound solution was added in a volume of 2. mu.l. Compound stocks (water, 5% DMSO) were diluted to obtain dose responses (11 points, dilution factor 2) ranging from 8 μ M to 8 nM. Controls were run to constantly determine the neurogenic nature of the cells:

the negative (neutral) control was cell culture medium (final DMSO concentration: 0.25%).

The positive controls were:

1. cell culture Medium +100ng/ml FGF2 (final DMSO concentration: 0.1%)

2. Cell culture Medium +20ng/ml EGF (final DMSO concentration: 0.1%)

3. Cell culture Medium +100ng/ml Wnt3a (final DMSO concentration: 0.1%)

At 37 ℃ 5% CO₂After 4 days of incubation, the amount of ATP per well was quantified. ATP concentration is proportional to cell number. By using PromegaThe kit quantifies ATP.The reagent contains cell lysis buffer, thermostable luciferase (UltraGlo)^TMRecombinant luciferase), magnesium, and luciferin. Luciferin reacts with ATP to produce oxyluciferin, AMP and light. The luminescence signal is proportional to the ATP content.

For each assay plate, negative (neutral) control values were determined by taking the average of 16 negative control wells. For each compound, the neurogenic compound response was calculated as (compound/negative control) × 100.

Determining EC from dose response curves for each test compound₁₅₀The value is obtained. EC (EC)₁₅₀Is the concentration of compound that achieves 150% activity of the control (100%).

Preferred compounds show an EC in the range < 3.7. mu.M₁₅₀(. mu.M), as shown in Table 1 below.

TABLE 1

₁₅₀Examples of novel Compounds and List of EC data

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

The compounds of formula I can be treated with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, however, in the case of soft gelatin capsules, no carriers are generally required. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like. 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 may also contain other therapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as are processes for their preparation, which comprise bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The most preferred indications according to the invention are those comprising disorders of the central nervous system, such as the treatment or prevention of depression, psychosis, parkinson's disease, anxiety, Attention Deficit Hyperactivity Disorder (ADHD) and diabetes.

The dosage can vary within wide limits and will of course be adapted to the individual requirements in each particular case. In the case of oral administration, the dosage for an adult may vary from about 0.01mg to about 1000mg per day of a compound of formula I or a corresponding amount of a pharmaceutically acceptable salt thereof. The daily dose can be administered as a single dose or in divided doses, and, in addition, the upper limit can also be exceeded when this is found to be necessary.

Tablet formulation (Wet granulation)

Manufacturing process

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

2. The granules were dried at 50 ℃.

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

4. Add item 5 and mix for three minutes; pressing in a suitable press.

Capsule preparation

Manufacturing process

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. Packaging into appropriate capsule.

Intermediate 1

7-bromo-5-fluoro-1-methylindole-2-carboxamide

Step A

To commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [ CAS No.396076-60-1 ] at room temperature](150mg, 524. mu. mol) and a stirred solution of cesium carbonate (530mg, 1.63mmol) in DMF (2.5ml) was added methyl iodide (930mg, 410. mu.l, 6.55mmol) and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (30ml) and extracted with ethyl acetate (2 × 40 ml). The combined organic layers were washed with brine (1 × 30ml) and dried (MgSO)₄) And evaporated to give 7-bromo-5-fluoro-1-methylindole-2-carboxylic acid ethyl ester as a light brown solid (157mg, 99%), ms (isp) M/z 300.4[ (M + H)⁺]，mp 58℃。

Step B

A solution of ethyl 7-bromo-5-fluoro-1-methylindole-2-carboxylate (step A) (150mg, 500. mu. mol) in 1M potassium hydroxide solution in MeOH (5ml, 5.0mmol) and water (2.5ml) was stirred at 60 ℃ for 45 min. The reaction mixture was cooled to room temperature and acidified with 2M hydrochloric acid solution (3ml), the solid filtered off, diluted in dichloromethane/MeOH 9: 1 and the solution dried (MgSO 1)₄) And evaporated to give 7-bromo-5-fluoro-1-methylindole-2-carboxylic acid as an off-white solid (132mg, 97%), ms (isn) M/z 272.4[ (M-H)^-]，mp 245℃。

Step C

A stirred solution of 7-bromo-5-fluoro-1-methylindole-2-carboxylic acid (step B) (125mg, 459. mu. mol) in THF (2ml) was cooled to 0 ℃ before DMF (20. mu.l) and oxalyl chloride (117mg, 80.4. mu.l, 919. mu. mol) were added and the reaction mixture was allowed to stir at room temperature for 90 min. The reaction mixture was evaporated to dryness and the residue was suspended in THF (3ml) and cooled to 0 ℃. 25% ammonium hydroxide solution (546mg, 600. mu.l, 4.01mmol) was then added and the reaction mixture was allowed to stir at 0 ℃ for 10min, and then at room temperature for 30 min. Water (3ml) was added and the mixture was stirred at room temperature for 30min, the precipitated solid was filtered off, washed with water and dried in vacuo to give the title compound as an off-white solid (125mg, 100%), ms (isn) M/z 271.2[ (M-H)^-]，mp 232℃。

Intermediate 2

7-bromo-5-fluoro-1H-indole-2-carboxamide

Step A

Following the general procedure of intermediate 1, step B, starting from commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [ CAS No.396076-60-1](0.15g, 0.52mmol) preparation of 7-bromo-5-fluoro-1H-indole-2-carboxylic acidOff-white solid (129mg, 95%), ms (isn) M/z 256.4[ (M-H)^-]，mp 282℃。

Step B

Following the general method of intermediate 1, step C, from 7-bromo-5-fluoro-1H-indole-2-carboxylic acid (step a) (125mg, 0.48mmol) the title compound was prepared as an off-white solid (125mg, 100%), ms (isn) M/z-257.2 [ (M-H)^-]，mp 188℃。

Intermediate 3

7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide

Step A

To a stirred hydrochloric acid solution (25%, 50ml) was added commercially available 4-amino-3-bromobenzonitrile (10g, 50.8 mmol). The reaction mixture was cooled to 0 ℃ and a solution of sodium nitrite (4.03g, 58.4mmol) in water (33ml) was added dropwise over a period of 20min while maintaining the temperature below 10 ℃. The reaction mixture was allowed to stir at 0 ℃ for 1h, after which a solution of tin (II) chloride dihydrate (51.5g, 228mmol) in hydrochloric acid (25%, 75.3ml) was added slowly dropwise at 0 ℃ while keeping the temperature of the reaction mixture below 10 ℃. The reaction was stirred at 0 ℃ for 1h, basified with sodium hydroxide solution (32%, 220ml), diluted with water (500ml) and extracted with dichloromethane (3 × 500 ml). The combined organic layers were washed with water (2 × 500ml) and dried (MgSO)₄) And evaporated. The crude product (-10 g brown solid) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 3: 2) and trituration (diethyl ether/heptane) to yield (2-bromo-4-cyano-phenyl) -hydrazine as a light brown solid (5.05g, 47%), ms (isn) M/z 210.1[ (M-H)^-]，mp 115℃。

Step B

Following the general procedure for intermediate 5, step B, from (2-bromo-4-cyano-phenyl) -hydrazine (step a) (2-bromo-4-cyano-phenyl) -hydrazine5.04g, 23.8mmol) of (Z) -2- [ (2-bromo-4-cyano-phenyl) -hydrazono-l]-methyl butyrate (7.33g, 99%) as a brown solid, ms (isn) M/z 310.3[ (M-H)^-]，mp 103℃。

Step C

Following the general procedure of intermediate 5, step C, starting from (Z) -2- [ (2-bromo-4-cyano-phenyl) -hydrazono]Methyl butyrate (step B) (7.22g, 23.3mmol) preparation of methyl 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxylate as an off-white solid (3.44g, 50%), ms (isn) M/z 293.4[ (M-H)^-]，mp 248℃。

Step D

Following the general procedure of intermediate 1, step B, from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxylic acid methyl ester (step C) (0.6g, 2.05mmol) was prepared 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxylic acid as a white solid (560mg, 98%), ms (isn) M/z 277.2[ (M-H)^-]，mp 288℃。

Step E

The title compound was prepared according to the general method of intermediate 1, step C from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxylic acid (step D) (560mg, 2.01mmol) as an off-white solid (457mg, 82%), ms (isn) M/z ═ 276.4[ (M-H)^-]，mp 310℃。

Intermediate 4

7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide

Step A

Following the general procedure of intermediate 1, step a, from methyl 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxylate (intermediate 3, step C) (0.6g, 2.05mmol) was prepared methyl 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxylate as a white solid (0.6g, 95%), ms (isp) M/z 309.4[ (M + H)⁺]，mp 170℃。

Step B

Following the general procedure of intermediate 1, step B, from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxylic acid methyl ester (step a) (595mg, 1.94mmol) was prepared 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxylic acid as a white solid (0.56g, 99%), ms (isn) M/z 293.0[ (M-H)^-]，mp 259℃。

Step C

The title compound was prepared according to the general method of intermediate 1, step C from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxylic acid (step B) (564mg, 1.92mmol) as an off-white solid (482mg, 86%), ms (isn) M/z 292.4[ (M-H)^-]，mp 281℃。

Intermediate 5

7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide

Step A

According to the general method of intermediate 3, step a, (2-bromo-4-chloro-phenyl) -hydrazine was prepared from commercially available 2-bromo-4-chloro-aniline (3.1g, 15.0mmol) as an off-white solid (1.98g, 60%), ms (isp) M/z ═ 223.3[ (M + H)⁺]，mp102℃。

Step B

A stirred solution of (2-bromo-4-chloro-phenyl) -hydrazine (step a) (1.98g, 8.94mmol) in ethanol (6.5ml) was cooled to 0 ℃ and a commercially available solution of methyl 2-ketobutyrate (1.08g, 1.04ml, 9.3mmol) in ethanol (2ml) was added dropwise at 0 ℃ over 15 min. After the mixture was stirred at room temperature for 3h, it was evaporated. The crude material (3.01g) was purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield (Z) -2- [ (2-bromo-4-chloro-phenyl) -hydrazono)]-methyl butyrate (2.67g, 94%) as a pale yellow solid, ms (isp) M/z 321.3[ (M + H)⁺]，mp 67℃。

Step C

To (Z) -2- [ (2-bromo-4-chloro-phenyl) -hydrazono) at room temperature]-methyl butyrate (step B) (2.67g, 8.35mmol) in acetic acid (30ml) was added zinc chloride (6.26g, 46.0mmol) and the mixture was stirred under reflux for 1 h. The reaction mixture was then poured into ice/water (50ml) and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine (50ml), dried (MgSO4) and evaporated. The crude product (2.5g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) and trituration with diethyl ether (5ml) and heptane (15ml) to give 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxylic acid methyl ester as an off-white solid (2.02g, 80%), ms (isn) M/z 302.3[ (M-H)^-]，mp 163.5℃。

Step D

Following the general procedure of intermediate 1, step B, from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxylic acid methyl ester (step C) (0.79g, 2.61mmol) was prepared 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxylic acid as an off-white solid (0.75g, 100%), ms (isn) M/z 288.4[ (M-H)^-]，mp 277℃。

Step E

The title compound was prepared according to the general method of intermediate 1, step C from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxylic acid (step D) (745mg, 2.58mmol) as a white solid (736mg, 99%), ms (isn) M/z 287.4[ (M-H)^-]，mp 303℃。

Intermediate 6

7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide

Step A

General procedure according to intermediate 1, step A, from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxylic acid methyl ester (intermediate 5, step C) (0.8g, 2.64mmol) preparation of 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxylic acid methyl ester as a white solid (0.83g, 99%), ms (isp) M/z 318.3[ (M + H)⁺]，mp 113℃。

Step B

Following the general procedure of intermediate 1, step B, from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxylic acid methyl ester (step a) (0.82g, 2.59mmol) was prepared 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxylic acid as an off-white solid (0.78g, 99%), ms (isn) M/z 302.4[ (M-H)^-]，mp 251℃。

Step C

According to the general method of intermediate 1, step C, the title compound was prepared from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxylic acid (step B) (775mg, 2.56mmol) as a white solid (766mg, 99%), ms (isn) M/z ═ 301.4[ (M-H)^-]，mp 253℃。

Intermediate 7

7-bromo-5-cyano-1H-indole-2-carboxamide

Step A

To a stirred solution of commercially available 4-amino-3-bromo-5-iodobenzonitrile (0.5g, 1.55mmol) in THF (7.7ml) were added Boc-anhydride (0.71g, 755. mu.l, 3.25mmol) and 4-dimethylaminopyridine (18.9mg, 155. mu. mol) and the solution was stirred at room temperature for 3 h. The reaction mixture was evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 0-50%) to give a pale yellow solid (0.74g), which was subsequently dissolved in dichloromethane (2.2ml) and cooled to 0 ℃. Trifluoroacetic acid (318mg, 215 μ l, 2.79mmol) was then added and the solution was stirred at 0 ℃ for 3 h. Saturated sodium carbonate solution (5ml) was added and the mixture was extracted with dichloromethane (2 × 20 ml). The combined organic layers were washed with brine (30ml), dried (MgSO₄) And evaporated. The crude product (0.69g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) and crystallization (heptane) to yield (2-bromo-4-cyano-6-iodo-phenyl) -carbamic acid tert-butyl ester (0.42g, 64%) as an off-white solid, ms (isn) M/z 421.3[ (M-H)^-]，mp 117.5℃。

Step B

A mixture of (2-bromo-4-cyano-6-iodo-phenyl) -carbamic acid tert-butyl ester (step A) (413mg, 0.98mmol), 3, 3-diethoxyprop-1-yne (125mg, 140. mu.l, 0.98mmol), triethylamine (395mg, 544. mu.l, 3.9mmol), copper (I) iodide (5.58mg, 29.3. mu. mol) and bis (triphenylphosphine) -palladium (II) chloride (34.3mg, 48.8. mu. mol) was stirred at room temperature for 3 h. Then adding 2, 3, 4, 6, 7, 8, 9, 10-octahydropyrimido [1, 2-a ] into the mixture]Aza derivatives(297mg, 292. mu.l, 1.95mmol) and DMF (1.58ml) and the reaction mixture was stirred at room temperature for 17h, poured into water (10ml) and extracted with ethyl acetate (2X20 ml). The combined organic layers were washed with brine and dried (MgSO)₄) And evaporated. The crude product (0.51g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield 7-bromo-5-cyano-2-diethoxymethyl-indole-1-carboxylic acid tert-butyl ester (0.29g, 64%) as a light yellow oil, ms (ei) M/z 422[ (M)⁺]。

Step C

7-bromo-5-cyano-2-diethoxymethyl-indole-1-carboxylic acid tert-butyl ester (0.29g, 685. mu. mol) was dissolved in THF (2ml) and cooled to 0 ℃. Hydrochloric acid (37%, 1.35g, 1.14ml, 13.7mmol) was then added rapidly and the mixture was stirred at 0 ℃ for 15min and at room temperature for 5 h. The mixture was cooled (ice bath), saturated sodium carbonate solution (10ml) was added and the mixture was extracted with ethyl acetate (2 × 25 ml). The combined organic layers were washed with brine (30ml) and dried (MgSO)₄) And evaporated. The crude product (0.18g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%), to yieldTo give 7-bromo-2-formyl-1H-indole-5-carbonitrile (0.17g, 100%) as an orange solid, ms (isn) M/z 247.4[ (M-H)^-]，mp 117.5℃。

Step D

To a stirred solution of 7-bromo-2-formyl-1H-indole-5-carbonitrile (0.17g, 683. mu. mol) in MeOH (6.03ml) were added sodium cyanide (167mg, 3.41mmol) and manganese dioxide (297mg, 3.41mmol) and the reaction mixture was stirred at room temperature for 17H. The mixture was evaporated, water (20ml) was added and the mixture was extracted with ethyl acetate (2 × 15 ml). The combined organic layers were washed with brine and dried (MgSO)₄) And evaporated. The crude product (0.11g) was further purified by flash chromatography on silica gel (heptane/ethyl acetate 0-20%) to yield 7-bromo-5-cyano-1H-indole-2-carboxylic acid methyl ester (0.105g, 55%) as an orange solid, ms (isn) M/z 279.3[ (M-H)^-]，mp 248℃。

Step E

Following the general procedure for intermediate 1, step B, from 7-bromo-5-cyano-1H-indole-2-carboxylic acid methyl ester (step D) (997mg, 2.61mmol) was prepared 7-bromo-5-cyano-1H-indole-2-carboxylic acid as a white solid (0.9g, 100%), ms (isn) M/z 265.0[ (M-H)^-]，mp 310℃。

Step F

According to the general method of intermediate 1, step C, from 7-bromo-5-cyano-1H-indole-2-carboxylic acid (step E) (896mg, 3.38mmol) the title compound was prepared as a white solid (880mg, 99%), ms (isn) M/z ═ 264.0[ (M-H)^-]，mp 283.5℃。

Intermediate 8

7-bromo-5-cyano-1-methylindole-2-carboxamide

Step A

According to intermediatesGeneral procedure for step a from 7-bromo-5-cyano-1H-indole-2-carboxylic acid ethyl ester (intermediate 7, step D) (0.44g, 1.5mmol) to prepare 7-bromo-5-cyano-1-methylindole-2-carboxylic acid ethyl ester as an off-white solid (0.44g, 96%), ms (isp) M/z 309.0[ (M + H)⁺]，mp138℃。

Step B

Following the general procedure of intermediate 1, step B, from 7-bromo-5-cyano-1-methylindole-2-carboxylic acid ethyl ester (step a) (0.44g, 1.43mmol) was prepared 7-bromo-5-cyano-1-methylindole-2-carboxylic acid as a white solid (0.4g, 100%), ms (isn) M/z 277.3[ (M-H)^-]，mp 287℃。

Step C

According to the general method of intermediate 1, step C, from 7-bromo-5-cyano-1-methylindole-2-carboxylic acid (step B) (0.4g, 1.43mmol) the title compound was prepared as a white solid (370mg, 93%), ms (isn) M/z ═ 276.0[ (M-H)^-]，mp 237.5℃。

Intermediate 9

7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide

Step A

According to the general procedure for intermediate 3, step a, (2-bromo-4-fluoro-phenyl) -hydrazine was prepared from commercially available 2-bromo-4-fluoro-aniline (1.7g, 8.95mmol) as a white solid (1.63g, 89%), ms (isp) M/z ═ 205.1[ (M + H)⁺]，mp 76℃。

Step B

Preparation of (Z) -2- [ (2-bromo-4-fluoro-phenyl) -hydrazono according to the general procedure for intermediate 5, step B, from (2-bromo-4-fluoro-phenyl) -hydrazine (step A) (1.62g, 7.9mmol)]Methyl butyrate (2.03g, 85%) as an orange solid, ms (isp) M/z 303.3[ (M + H)⁺]，mp 44℃。

Step C

Following the general procedure of intermediate 5, step C, starting from (Z) -2- [ (2-bromo-4-fluoro-phenyl) -hydrazono]Methyl butyrate (step B) (2.02g, 6.66mmol) preparation of methyl 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxylate as a pale yellow solid (1.62g, 85%), ms (isn) M/z 286.3[ (M-H)^-]，mp127℃。

Step D

Following the general procedure of intermediate 1, step B, from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxylic acid methyl ester (step C) (0.8g, 2.8mmol) was prepared 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxylic acid as a brown solid (0.73g, 96%), ms (isn) M/z ═ 272.1[ (M-H)^-]，mp 265℃。

Step E

The title compound was prepared according to the general method of intermediate 1, step C from 7-bromo-5-cyano-1-methylindole-2-carboxylic acid (step D) (0.73g, 2.68mmol) as a grey solid (613mg, 84%), ms (isp) M/z ═ 271.3[ (M + H)⁺]，mp 273℃。

Intermediate 10

7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide

Step A

Following the general procedure of intermediate 1, step a, from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxylic acid methyl ester (intermediate 9, step C) (0.8g, 2.8mmol) was prepared 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxylic acid methyl ester as a pale yellow solid (0.75g, 89%), ms (isp) M/z 302.3[ (M + H)⁺]，mp 76℃。

Step B

Following the general procedure for intermediate 1, step B, starting from 7-bromo-5-fluoro-1, 3-dimethylindole-Methyl 2-carboxylate (step a) (0.74g, 2.47mmol) preparation of 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxylic acid as a white solid (687mg, 97%), ms (isp) M/z 286.4[ (M + H)⁺]，mp 225℃。

Step C

The title compound was prepared according to the general method of intermediate 1, step C from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxylic acid (step B) (687mg, 2.4mmol) as a white solid (628mg, 92%), ms (isp) M/z 287.3[ (M + H)⁺]，mp 248℃。

Example 1

7- (4-chloro-phenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

To a stirred solution of 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (98mg, 335 μmol) and commercially available 4-chlorophenylboronic acid (68.2mg, 436 μmol) in 1, 2-dimethoxyethane (2.3ml) was added 2M sodium carbonate solution (559 μ l, 1.12mmol) at room temperature and the reaction mixture was then purged with argon in an ultrasonic bath for 5 min. Triphenylphosphine (17.6mg, 67.1. mu. mol) and palladium (II) acetate (7.53mg, 33.5. mu. mol) were then added and the reaction mixture was stirred under reflux for 2 h. The reaction mixture was cooled to room temperature over MgSO₄Filtration and purification by flash chromatography on silica gel (dichloromethane/MeOH 0-5%), crystallization from dichloromethane/heptane yielded the title compound as a gray solid (90mg, 83%), ms (isn) M/z ═ 324.5[ (M + H)⁺]，mp 237℃。

Example 2

5-fluoro-7- (4-fluoro-phenyl) -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1-methylindole-2-carboxamide (intermediate 1) (120mg, 0.443mmol) and commercially available 4-fluoro-phenylboronic acid (80.5mg, 0.575mmol) as a brown solid (117mg, 92%), ms (isp) M/z 287.5[ (M + H)⁺]，mp 156℃。

Example 3

5-fluoro-7- (4-fluoro-phenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1H-indole-2-carboxamide (intermediate 2) (120mg, 0.467mmol) and commercially available 4-fluoro-phenylboronic acid (84.9mg, 0.607mmol) as a light brown solid (117mg, 92%), ms (isp) M/z 273.5[ (M + H)⁺]，mp 162℃。

Example 4

5-cyano-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) as a white solid (63mg, 82%), ms (isp) M/z 308.5[ (M + H)⁺]，mp 216℃。

Example 5

5-cyano-7- (3, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 3, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a light grey solid (62mg, 76%), ms (isp) M/z 326.5[ (M + H)⁺]，mp 212℃。

Example 6

5-cyano-1, 3-dimethyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as a light yellow solid (74mg, 83%), ms (isp) M/z 358.5[ (M + H)⁺]，mp 195℃。

Example 7

5-cyano-7- (3, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

According to the general method of example 1,the title compound was prepared from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 3, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a light brown solid (66mg, 85%), ms (isp) M/z 312.5[ (M + H)⁺]，mp 222℃。

Example 8

5-cyano-3-methyl-7- [4- (trifluoromethyl) phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as a light brown solid (67mg, 78%), ms (isp) M/z 344.5[ (M + H)⁺]，mp 243℃。

Example 9

5-cyano-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) as a light brown solid (57mg, 78%), ms (isp) M/z 292.4[ (M + H)⁺]，mp 268℃。

Example 10

7- (4-chlorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-chloro-phenylboronic acid (50.8mg, 0.325mmol) as a light brown solid (66mg, 85%), ms (isp) M/z ═ 308.4[ (M + H)⁺]，mp 291℃。

Example 11

5-chloro-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) as an off-white solid (62mg, 82%), ms (isp) M/z 301.5[ (M + H)⁺]，mp 173℃。

Example 12

5-chloro-7- (4-chlorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 4-chloro-phenylboronic acid (50.8mg, 0.325mmol) as an off-white solid (63mg, 79%), ms (isp) m/z 317.5[ ((isp) [ ((317.5) ]M+H)⁺]，mp 252℃。

Example 13

5-chloro-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) as an off-white solid (63mg, 80%), ms (isp) M/z 317.5[ (M + H)⁺]，mp 178℃。

Example 14

5-chloro-7- (4-chlorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 4-chloro-phenylboronic acid (50.8mg, 0.325mmol) as an off-white solid (66mg, 79%), ms (isp) M/z 333.5[ (M + H)⁺]，mp 195℃。

Example 15

5-chloro-7- (3, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 3, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a light brown solid (64mg, 80%), ms (isp) M/z ═ 321.4[ (M + H)⁺]，mp 206℃。

Example 16

5-chloro-3-methyl-7- [4- (trifluoromethyl) -phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as an off-white solid (62mg, 70%), ms (isp) M/z 353.4[ (M + H)⁺]，mp 184℃。

Example 17

5-chloro-7- (3, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 3, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as an off-white solid (56mg, 67%), ms (isp) M/z 335.4[ (M + H)⁺]，mp 196℃。

Example 18

5-chloro-1, 3-dimethyl-7- [4- (trifluoromethyl) phenyl ] indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as a white solid (59mg, 64%), ms (isp) M/z 367.4[ (M + H)⁺]，mp 206℃。

Example 19

5-cyano-3-methyl-7- [4- (trifluoromethoxy) -phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as a light brown solid (36mg, 40%), ms (isp) M/z ═ 360.4[ (M + H)⁺]，mp 207℃。

Example 20

5-cyano-7- (4-cyanophenyl) -3-methyl-1H-indole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg,250 μmol) and commercially available 4-cyanophenylboronic acid (47.8mg, 0.325mmol) the title compound was prepared as a light yellow solid (54mg, 72%), ms (isp) M/z 299.4[ (M + H)⁺]，mp 294℃。

Example 21

5-cyano-1, 3-dimethyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as an off-white solid (75mg, 80%), ms (isp) M/z 374.4[ (M + H)⁺]，mp 106℃。

Example 22

5-cyano-7- (4-cyanophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-cyanophenylboronic acid (47.8mg, 0.325mmol) as an off-white solid (60mg, 76%), ms (isp) M/z 315.4[ (M + H)⁺]，mp 226℃。

Example 23

5-chloro-7- (4-cyanophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 4-cyanophenylboronic acid (47.8mg, 0.325mmol) as an off-white solid (60mg, 78%), ms (isp) M/z 310.4[ (M + H)⁺]，mp 267℃。

Example 24

5-chloro-3-methyl-7- [4- (trifluoromethoxy) phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as an off-white solid (57mg, 62%), ms (isp) M/z 369.4[ (M + H)⁺]，mp 149℃。

Example 25

5-chloro-7- (2, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as an off-white solid (70mg, 87%), ms (isp) M/z ═ 321.4[ (M + H)⁺]，mp 196℃。

Example 26

5-chloro-7- (2, 4-dichlorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as a yellow solid (65mg, 74%), ms (isp) M/z 353.3[ (M + H)⁺]，mp 195℃。

Example 27

5-chloro-1, 3-dimethyl-7- [4- (trifluoromethoxy) -phenyl ] indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as an off-white solid (60mg, 63%), ms (isp) M/z 383.4[ (M + H)⁺]，mp 181℃。

Example 28

5-chloro-7- (4-cyanophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 4-cyanophenylboronic acid (47.8mg, 0.325mmol) as an off-white solid (67mg, 83%), ms (isp) M/z 324.4[ (M + H)⁺]，mp 199℃。

Example 29

5-chloro-7- (2, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a white solid (27mg, 32%), ms (isp) M/z 335.4[ (M + H)⁺]，mp 220℃。

Example 30

5-chloro-7- (2, 4-dichlorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as a white solid (62mg, 67%), ms (isp) M/z 367.3[ (M + H)⁺]，mp 221℃。

Example 31

5-chloro-7- (4-chloro-3-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-3-methyl-1H-indole-2-carboxamide (intermediate 5) (71.9mg, 250 μmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as an off-white solid (50mg, 59%), ms (isp) M/z ═ 335.3[ (M + H)⁺]，mp 283℃。

Example 32

5-chloro-7- (4-chloro-3-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-chloro-1, 3-dimethylindole-2-carboxamide (intermediate 6) (75.4mg, 250 μmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as an off-white solid (68mg, 77%), ms (isp) M/z 351.4[ (M + H)⁺]，mp 192℃。

Example 33

5-cyano-7- (3, 4-difluorophenyl) -1H-indole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250. mu. mol) and commercially available 3, 4-Difluoro-phenylboronic acid (51.3mg, 0.325mmol) the title compound was prepared as a light gray solid (53mg, 71%), ms (isp) M/z 335.4[ (M + H)⁺]，mp 262℃。

Example 34

5-cyano-7- (4-fluorophenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) as a light grey solid (52mg, 75%), ms (isp) M/z 280.1[ (M + H)⁺]，mp 234℃。

Example 35

7- (4-chlorophenyl) -5-cyano-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-chloro-phenylboronic acid (50.8mg, 0.325mmol) as an off-white solid (58mg, 79%), ms (isp) M/z 296.0[ (M + H)⁺]，mp 267.5℃。

Example 36

5-cyano-7- [4- (trifluoromethyl) phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as an off-white solid (60mg, 73%), ms (isp) M/z 330.4[ (M + H)⁺]，mp 277.5℃。

Example 37

5-cyano-1-methyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as an off-white solid (68mg, 79%), ms (isp) M/z 344.5[ (M + H)⁺]，mp 171℃。

Example 38

5-cyano-7- (4-fluorophenyl) -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) as a grey solid (60mg, 82%), ms (isp) M/z 294.4[ (M + H)⁺]，mp 203.5℃。

Example 39

7- (4-chlorophenyl) -5-cyano-1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-chloro-phenylboronic acid (50.8mg, 0.325mmol) as a white solid (63mg, 81%), ms (isp) M/z 310.4[ (M + H)⁺]，mp 176℃。

Example 40

5-cyano-7- (3, 4-difluorophenyl) -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 3, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as an off-white solid (58mg, 75%), ms (isp) M/z 312.5[ (M + H)⁺]，mp 184.5℃。

EXAMPLE 41

5-cyano-7- (2, 4-difluorophenyl) -1H-indole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and ethyl acetateCommercial 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) the title compound was prepared as a light brown solid (50mg, 67%), ms (isp) M/z 298.5[ (M + H)⁺]，mp 289.5℃。

Example 42

5-cyano-7- (2, 4-dichlorophenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as a light yellow solid (59mg, 72%), ms (isp) M/z 330.4[ (M + H)⁺]，mp 276.5℃。

Example 43

5-cyano-7- (4-cyanophenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-cyanophenylboronic acid (47.8mg, 0.325mmol) as an off-white solid (35mg, 49%), ms (isp) M/z 287.5[ (M + H)⁺]，mp 299℃。

Example 44

5-cyano-7- [4- (trifluoromethoxy) -phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as a light brown solid (61mg, 71%), ms (isp) M/z 346.4[ (M + H)⁺]，mp 247℃。

Example 45

5-fluoro-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) as a white solid (43mg, 60%), ms (isp) M/z 287.4[ (M + H)⁺]，mp 219℃。

Example 46

7- (4-chlorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-chloro-phenylboronic acid (50.8mg, 0.325mmol) as a white solid (30mg, 40%), ms (isp) M/z 303.4[ (M + H)⁺]，mp 230℃。

Example 47

7- (3, 4-difluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

Following the general method of example 1, the title compound was prepared from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 3, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a light yellow solid (46mg, 60%), ms (isp) M/z 305.1[ (M + H)⁺]，mp 208℃。

Example 48

5-fluoro-3-methyl-7- [4- (trifluoromethyl) -phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as a light brown solid (51mg, 61%), ms (isp) M/z 337.1[ (M + H)⁺]，mp 200℃。

Example 49

5-fluoro-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-fluoro-1, 3-dimethylBenzylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-fluoro-phenylboronic acid (45.5mg, 0.325mmol) the title compound was prepared as a light yellow solid (58mg, 77%), ms (isp) M/z ═ 301.1[ (M + H)⁺]，mp 202℃。

Example 50

7- (4-chlorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-chloro-phenylboronic acid (50.8mg, 0.325mmol) as a light yellow solid (55mg, 69%), ms (isp) M/z 317.1[ (M + H)⁺]，mp 210℃。

Example 51

5-fluoro-1, 3-dimethyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7mg, 0.325mmol) as a white solid (61mg, 70%), ms (isp) M/z 351.1[ (M + H)⁺]，mp 222℃。

Example 52

7- (3, 4-difluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 3, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a white solid (57mg, 72%), ms (isp) M/z 319.1[ (M + H)⁺]，mp 186℃。

Example 53

7- (4-cyanophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-cyanophenylboronic acid (47.8mg, 0.325mmol) as a light yellow solid (49mg, 67%), ms (isp) M/z 294.1[ (M + H)⁺]，mp 230℃。

Example 54

5-fluoro-3-methyl-7- [4- (trifluoromethoxy) phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as a grey solid (50mg, 57%), ms (isp) m/z＝353.1[(M+H)⁺]，mp 108℃。

Example 55

7- (2, 4-difluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a white solid (35mg, 46%), ms (isp) M/z 305.2[ (M + H)⁺]，mp 200℃。

Example 56

7- (2, 4-dichlorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as a white solid (40mg, 47%), ms (isp) M/z 339.1[ (M + H)⁺]，mp 198℃。

Example 57

7- (4-chloro-2-fluorophenyl) -5-cyano-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as an off-white solid (51mg, 65%), ms (isp) M/z 314.0[ (M + H)⁺]，mp 286.5℃。

Example 58

7- (4-chloro-2-fluorophenyl) -5-cyano-1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as a white solid (34mg, 42%), ms (isp) M/z 328.1[ (M + H)⁺]，mp 192℃。

Example 59

7- (4-cyanophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-cyanophenylboronic acid (47.8mg, 0.325mmol) as a white solid (52mg, 68%), ms (isp) M/z 308.2[ (M + H)⁺]，mp 245℃。

Example 60

5-fluoro-1, 3-dimethyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as a light grey solid (56mg, 61%), ms (isp) M/z 367.2[ (M + H)⁺]，mp 171℃。

Example 61

7- (2, 4-dichlorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as a white solid (52mg, 59%), ms (isp) M/z 353.1[ (M + H)⁺]，mp 169℃。

Example 62

5-cyano-7- (2, 4-difluorophenyl) -1-methylindole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250. mu. mol) and commercially availableCommercial 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) the title compound was prepared as a white solid (43mg, 55%), ms (isp) M/z 312.1[ (M + H)⁺]，mp 206.5℃。

Example 63

5-cyano-7- (2, 4-dichlorophenyl) -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as a white solid (39mg, 45%), ms (isp) M/z 344.1[ (M + H)⁺]，mp 222.5℃。

Example 64

7- (2, 4-difluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a white solid (16mg, 20%), ms (isp) M/z 319.1[ (M + H)⁺]，mp 192℃。

Example 65

5-cyano-7- (4-fluoro-3-methylphenyl) -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0mg, 0.325mmol) as a white solid (56mg, 73%), ms (isp) M/z 308.1[ (M + H)⁺]，mp 220℃。

Example 66

5-cyano-7- (4-fluoro-3-methylphenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0mg, 0.325mmol) as a light brown solid (53mg, 72%), ms (isp) M/z 294.1[ (M + H)⁺]，mp 247℃。

Example 67

5-cyano-1-methyl-7- (4-nitrophenyl) -indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-nitro-phenylboronic acid (54.3mg, 0.325mmol) as a yellow solid (64mg, 80%), ms (isp) M/z 321.1[ (M + H)⁺]，mp 236℃。

Example 68

5-cyano-7- (4-nitrophenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-nitro-phenylboronic acid (54.3mg, 0.325mmol) as a yellow solid (30mg, 39%), ms (isp) M/z 307.1[ (M + H)⁺]，mp 269℃。

Example 69

7- (2-chloropyridin-4-yl) -5-cyano-1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1mg, 0.325mmol) as an off-white solid (46mg, 59%), ms (isp) M/z 311.1[ (M + H)⁺]，mp 209℃。

Example 70

7- (2-chloropyridin-4-yl) -5-cyano-1H-indole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-1H-indoleIndole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1mg, 0.325mmol) the title compound was prepared as a pale red solid (17mg, 23%), ms (isp) M/z 297.1[ (M + H)⁺]，mp 297℃。

Example 71

5-cyano-7- (4-methoxyphenyl) -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-methoxy-phenylboronic acid (49.4mg, 0.325mmol) as an off-white solid (61mg, 80%), ms (isp) M/z 306.1[ (M + H)⁺]，mp 206.5℃。

Example 72

5-cyano-7- (4-methoxyphenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-methoxy-phenylboronic acid (49.4mg, 0.325mmol) as a light grey solid (49mg, 67%), ms (isp) M/z 292.1[ (M + H)⁺]，mp 255℃。

Example 73

5-cyano-1-methyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9mg, 0.325mmol) as an off-white solid (66mg, 74%), ms (isp) M/z 360.1[ (M + H)⁺]，mp 176℃。

Example 74

5-fluoro-3-methyl-7- (4-methylphenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available p-tolylboronic acid (44.2mg, 0.325mmol) as an off-white solid (52mg, 74%), ms (isp) M/z 283.1[ (M + H)⁺]，mp 192℃。

Example 75

5-fluoro-3-methyl-7- (2, 3, 4-trifluorophenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 2, 3, 4-trifluorophenylboronic acid (57.2mg, 0.325mmol) as a white solid (19mg, 24%), ms (isp) M/z ═ 323.1[ (M + H)⁺]，mp 209℃。

Example 76

5-fluoro-7- (4-methoxyphenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-methoxy-phenyl boronic acid (49.4mg, 0.325mmol) as a white solid (47mg, 63%), ms (isp) M/z 299.1[ (M + H)⁺]，mp 217℃。

Example 77

7- (4-chloro-2-fluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as a white solid (41mg, 51%), ms (isp) M/z ═ 321.1[ (M + H)⁺]，mp 216℃。

Example 78

5-fluoro-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available pyridin-4-ylboronic acid (39.9mg, 0.325mmol) as a light orange solid (29mg, 43%), ms (isp) M/z 270.2[ (M + H)⁺]，mp 270℃。

Example 79

5-fluoro-1, 3-dimethyl-7- (4-methylphenyl) indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available p-tolylboronic acid (44.2mg, 0.325mmol) as a white solid (43mg, 58%), ms (isp) M/z 297.2[ (M + H)⁺]，mp 174℃。

Example 80

5-fluoro-7- (4-methoxyphenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-methoxy-phenylboronic acid (49.4mg, 0.325mmol) as a light grey solid (49mg, 63%), ms (isp) M/z 313.2[ (M + H)⁺]，mp 156℃。

Example 81

7- (4-chloro-2-fluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as an off-white solid (28mg, 33%), ms (isp) M/z 335.2[ (M + H)⁺]，mp 194℃。

Example 82

5-fluoro-3-methyl-7-phenyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available phenylboronic acid (39.6mg, 0.325mmol) as an off-white solid (48mg, 72%), ms (isp) M/z 269.2[ (M + H)⁺]，mp 151℃。

Example 83

5-fluoro-7- (4-fluoro-3-methylphenyl) -3-methyl-1H-indole-2-carboxamide

Following the general method of example 1, a standard was prepared from 7-bromo-5-fluoro-3-methyl-1H-indole-2-carboxamide (intermediate 9) (67.8mg, 250 μmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0mg, 0.325mmol)The title compound, grey solid (48mg, 64%), ms (isp) M/z 301.2[ (M + H)⁺]，mp 200℃。

Example 84

5-fluoro-1, 3-dimethyl-7-phenylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available phenylboronic acid (39.6mg, 0.325mmol) as a white solid (50mg, 71%), ms (isp) M/z 283.2[ (M + H)⁺]，mp 191℃

Example 85

5-fluoro-7- (4-fluoro-3-methylphenyl) -1, 3-dimethylindole-2-carboxamide

Following the general method of example 1, the title compound was prepared from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0mg, 0.325mmol) as a light yellow solid (55mg, 70%), ms (isp) M/z 315.2[ (M + H)⁺]，mp 194℃。

Example 86

5-cyano-7- (6-fluoropyridin-3-yl) -1H-indole-2-carboxamide

Following the general method of example 1, from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8mg, 0.325mmol) the title compound was prepared as a light yellow solid (30mg, 43%), ms (isp) M/z 281.1[ (M + H)⁺]，mp 331℃。

Example 87

5-fluoro-1, 3-dimethyl-7-pyridin-4-ylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-fluoro-1, 3-dimethylindole-2-carboxamide (intermediate 10) (71.3mg, 250 μmol) and commercially available pyridin-4-ylboronic acid (39.9mg, 0.325mmol) as a white solid (39mg, 55%), ms (isp) M/z 284.2[ (M + H)⁺]，mp 217℃。

Example 88

5-cyano-7-pyridin-4-yl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available pyridin-4-ylboronic acid (39.9mg, 0.325mmol) as a light yellow solid (33mg, 50%), ms (isp) M/z 263.1[ (M + H)⁺]，mp 341℃。

Example 89

5-cyano-1-methyl-7-pyridin-4-ylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available pyridin-4-ylboronic acid (39.9mg, 0.325mmol) as a white solid (40mg, 58%), ms (isp) M/z 277.1[ (M + H)⁺]，mp 208.5℃。

Example 90

5-cyano-7- (3, 4, 5-trifluorophenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 3, 4, 5-trifluoro-phenylboronic acid (57.2mg, 0.325mmol) as a white solid (54mg, 69%), ms (isp) M/z 316.1[ (M + H)⁺]，mp 274℃。

Example 91

5-cyano-1-methyl-7- (3, 4, 5-trifluorophenyl) indole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 3, 4, 5-trifluoro-phenylboronic acid (57).2mg, 0.325mmol) the title compound is prepared as a light grey solid (50mg, 61%), ms (isp) M/z 330.1[ (M + H)⁺]，mp 217.5℃。

Example 92

7- (4-chloro-3-fluorophenyl) -5-cyano-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as a light yellow solid (63mg, 80%), ms (isn) M/z 312.1[ (M-H)^-]，mp 260.5℃。

Example 93

7- (4-chloro-3-fluorophenyl) -5-cyano-1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as an off-white solid (53mg, 65%), ms (isp) M/z 328.1[ (M + H)⁺]，mp 183.5℃。

Example 94

5-cyano-7- (2-fluoropyridin-4-yl) -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8mg, 0.325mmol) as an off-white solid (49mg, 67%), ms (isp) M/z 295.1[ (M + H)⁺]，mp 203.5℃。

Example 95

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4mg, 0.325mmol) as a light brown solid (22mg, 30%), ms (isp) M/z 292.1[ (M + H)⁺]，mp 279.5℃。

Example 96

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1-methylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1-methylindole-2-carboxamide (intermediate 8) (69.5mg, 250 μmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4mg, 0.325mmol) as an off-white solid (48mg, 63%), ms (isp) M/z 306.1[ (M + H)⁺]，mp 240℃。

Example 97

5-cyano-7- (2-fluoropyridin-4-yl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8mg, 0.325mmol) as a light yellow solid (14mg, 20%), ms (isp) M/z 281.1[ (M + H)⁺]，mp 285℃。

Example 98

7- (6-chloropyridin-3-yl) -5-cyano-1H-indole-2-carboxamide

Following the general method of example 1, from 7-bromo-5-cyano-1H-indole-2-carboxamide (intermediate 7) (66mg, 250 μmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1mg, 0.325mmol) the title compound was prepared as a light yellow solid (35mg, 47%), ms (isp) M/z 297.1[ (M + H)⁺]，mp 266.5℃。

Example 99

7- (6-chloropyridin-3-yl) -5-cyano-1-methylindole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-1-methylindole-2-carboxamide (medium)Intermediate 8) (69.5mg, 250 μmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1mg, 0.325mmol) the title compound was prepared as a white solid (51mg, 66%), ms (isp) M/z 311.1[ (M + H)⁺]，mp 189℃。

Example 100

5-cyano-1, 3-dimethyl-7- (3, 4, 5-trifluorophenyl) indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 3, 4, 5-trifluoro-phenylboronic acid (57.2mg, 0.325mmol) as an off-white solid (30mg, 35%), ms (isp) M/z 344.1[ (M + H)⁺]，mp 232.5℃。

Example 101

5-cyano-7- (4-fluoro-3-methylphenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0mg, 0.325mmol) as a light grey solid (25mg, 31%), ms (isp) M/z 322.2[ (M + H)⁺]，mp 223℃。

Example 102

7- (4-chloro-3-fluorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as an off-white solid (29mg, 44%), ms (isp) M/z 342.1[ (M + H)⁺]，mp 179℃。

Example 103

5-cyano-7- (2, 4-dichlorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as an off-white solid (25mg, 28%), ms (isp) M/z 358.1[ (M + H)⁺]，mp 177.5℃。

Example 104

7- (4-chloro-2-fluorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as an off-white colored productSolid (46mg, 54%), ms (isp) M/z 342.1[ (M + H)⁺]，mp 213.5℃。

Example 105

5-cyano-7- (2, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as an off-white solid (44mg, 54%), ms (isp) M/z 326.1[ (M + H)⁺]，mp 219℃。

Example 106

7- (2-chloropyridin-4-yl) -5-cyano-1, 3-dimethylindole-2-carboxamide

Following the general method of example 1, from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1mg, 0.325mmol) the title compound was prepared as a pale yellow solid (55mg, 68%), ms (isp) M/z 325.1[ (M + H)⁺]，mp 160℃。

Example 107

5-cyano-7- (2-fluoropyridin-4-yl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8mg, 0.325mmol) as a light yellow solid (62mg, 80%), ms (isp) M/z 309.1[ (M + H)⁺]，mp 163℃。

Example 108

7- (6-chloropyridin-3-yl) -5-cyano-1, 3-dimethylindole-2-carboxamide

Following the general method of example 1, from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1mg, 0.325mmol) the title compound was prepared as a pale yellow solid (65mg, 80%), ms (isp) M/z 325.1[ (M + H)⁺]，mp 197℃。

Example 109

5-cyano-7- (6-fluoropyridin-3-yl) -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8mg, 0.325mmol) as an off-white solid (65mg, 84%), ms (isp) M/z 309.1[ (M + H)⁺]，mp 183℃。

Example 110

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1, 3-dimethylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4mg, 0.325mmol) as an off-white solid (62mg, 78%), ms (isp) M/z 320.2[ (M + H)⁺]，mp 166.5℃。

Example 111

5-cyano-3-methyl-7- (3, 4, 5-trifluorophenyl) -1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 3, 4, 5-trifluoro-phenylboronic acid (57.2mg, 0.325mmol) as an off-white solid (24mg, 29%), ms (isp) M/z 330.2[ (M + H)⁺]，mp 240℃。

Example 112

5-cyano-7- (4-fluoro-3-methylphenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0mg, 0.325mmol) as an off-white solid (11mg, 14%), ms (isp) M/z ═ 308.2[ (M + H)⁺]，mp 212.5℃。

Example 113

5-cyano-7- (2, 4-dichlorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 2, 4-dichloro-phenylboronic acid (62.0mg, 0.325mmol) as an off-white solid (25mg, 29%), ms (isp) M/z ═ 344.1[ (M + H)⁺]，mp 272.5℃。

Example 114

5-cyano-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available pyridin-4-ylboronic acid (39.9mg, 0.325mmol) as a yellow solid (30mg, 43%), ms (isp) M/z 277.1[ (M + H)⁺]，mp 316.5℃。

Example 115

5-cyano-1, 3-dimethyl-7-pyridin-4-ylindole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-1, 3-dimethylindole-2-carboxamide (intermediate 4) (73mg, 250 μmol) and commercially available pyridin-4-ylboronic acid (39.9mg, 0.325mmol) as a light yellow solid (49mg, 68%), ms (isp) M/z 291.1[ (M + H)⁺]，mp 259℃。

Example 116

5-cyano-7- [4- (hydroxymethyl) phenyl ] -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4mg, 0.325mmol) as an off-white solid (58mg, 76%), ms (isp) M/z ═ 306.1[ (M + H)⁺]，mp 224℃。

Example 117

7- (4-chloro-3-fluorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide

Following the general procedure of example 1, starting from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-chloro-3-fluoro-benzeneBoronic acid (56.7mg, 0.325mmol) the title compound was prepared as a white solid (51mg, 62%), ms (isp) M/z ═ 328.0[ (M + H)⁺]，mp 299℃。

Example 118

7- (4-chloro-2-fluorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide

Following the general method of example 1, the title compound was prepared from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7mg, 0.325mmol) as a light yellow solid (30mg, 37%), ms (isp) M/z ═ 328.1[ (M + H)⁺]，mp 297℃。

Example 119

5-cyano-7- (2, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 2, 4-difluoro-phenylboronic acid (51.3mg, 0.325mmol) as a white solid (22mg, 28%), ms (isp) M/z 312.1[ (M + H)⁺]，mp 266.5℃。

Example 120

5-cyano-7- (2-fluoropyridin-4-yl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8mg, 0.325mmol) as a white solid (24mg, 33%), ms (isp) M/z 295.1[ (M + H)⁺]，mp 248.5℃。

Example 121

7- (6-chloropyridin-3-yl) -5-cyano-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1mg, 0.325mmol) as an off-white solid (37mg, 48%), ms (isp) M/z 311.1[ (M + H)⁺]，mp 265℃。

Example 122

5-cyano-7- (6-fluoropyridin-3-yl) -3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8mg, 0.325mmol) as an off-white solid (55mg, 75%), ms (isp) M/z ═ 295.1[ (M + H)⁺]，mp 298℃。

Example 123

7- (2-chloropyridin-4-yl) -5-cyano-3-methyl-1H-indole-2-carboxamide

The title compound was prepared according to the general method of example 1 from 7-bromo-5-cyano-3-methyl-1H-indole-2-carboxamide (intermediate 3) (69.5mg, 250 μmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1mg, 0.325mmol) as a pale red solid (19mg, 25%), ms (isp) M/z ═ 311.0[ (M + H)⁺]，mp 253℃。

Claims (15)

1. A compound of formula I

Wherein

R¹Is phenyl or pyridyl, optionally substituted by one, two or three, selected from C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkyl radical, C_1-4Alkoxy, halogen substitutedC_1-4Alkoxy, cyano, or nitro;

R²is halogen, C_1-4Alkyl or cyano;

R³is hydrogen, C_1-4Alkyl or halogen substituted C_1-4An alkyl group;

R⁴is hydrogen or C_1-4An alkyl group;

R⁵、R⁶is hydrogen or C_1-4An alkyl group;

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

2. A compound of formula I according to claim 1, wherein R⁵And R⁶Is hydrogen.

3. A compound of formula I according to claim 1 or 2, wherein R¹Is phenyl optionally substituted by one, two or three groups selected from C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkoxy, cyano or nitro.

4. A compound of formula I according to claim 2, which is

7- (4-chlorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -1-methylindole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-1, 3-dimethyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-3-methyl-7- [4- (trifluoromethyl) phenyl ] -1H-indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

7- (4-chlorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-chlorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (4-chlorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (3, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-3-methyl-7- [4- (trifluoromethyl) -phenyl ] -1H-indole-2-carboxamide

5-chloro-7- (3, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-1, 3-dimethyl-7- [4- (trifluoromethyl) phenyl ] indole-2-carboxamide

5-cyano-3-methyl-7- [4- (trifluoromethoxy) -phenyl ] -1H-indole-2-carboxamide

5-cyano-7- (4-cyanophenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-1, 3-dimethyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

5-cyano-7- (4-cyanophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (4-cyanophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-3-methyl-7- [4- (trifluoromethoxy) phenyl ] -1H-indole-2-carboxamide

5-chloro-7- (2, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (2, 4-dichlorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-1, 3-dimethyl-7- [4- (trifluoromethoxy) -phenyl ] indole-2-carboxamide

5-chloro-7- (4-cyanophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (2, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (2, 4-dichlorophenyl) -1, 3-dimethylindole-2-carboxamide

5-chloro-7- (4-chloro-3-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

5-chloro-7- (4-chloro-3-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -1H-indole-2-carboxamide

7- (4-chlorophenyl) -5-cyano-1H-indole-2-carboxamide

5-cyano-7- [4- (trifluoromethyl) phenyl ] -1H-indole-2-carboxamide

5-cyano-1-methyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

5-cyano-7- (4-fluorophenyl) -1-methylindole-2-carboxamide

7- (4-chlorophenyl) -5-cyano-1-methylindole-2-carboxamide

5-cyano-7- (3, 4-difluorophenyl) -1-methylindole-2-carboxamide

5-cyano-7- (2, 4-difluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-cyanophenyl) -1H-indole-2-carboxamide

5-cyano-7- [4- (trifluoromethoxy) -phenyl ] -1H-indole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -3-methyl-1H-indole-2-carboxamide

7- (4-chlorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

7- (3, 4-difluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

5-fluoro-3-methyl-7- [4- (trifluoromethyl) -phenyl ] -1H-indole-2-carboxamide

5-fluoro-7- (4-fluorophenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chlorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-fluoro-1, 3-dimethyl-7- [4- (trifluoromethyl) -phenyl ] -indole-2-carboxamide

7- (3, 4-difluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

7- (4-cyanophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

5-fluoro-3-methyl-7- [4- (trifluoromethoxy) phenyl ] -1H-indole-2-carboxamide

7- (2, 4-difluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

7- (2, 4-dichlorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-1-methylindole-2-carboxamide

7- (4-cyanophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-fluoro-1, 3-dimethyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

7- (2, 4-dichlorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2, 4-difluorophenyl) -1-methylindole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -1-methylindole-2-carboxamide

7- (2, 4-difluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -1-methylindole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -1H-indole-2-carboxamide

5-cyano-1-methyl-7- (4-nitrophenyl) -indole-2-carboxamide

5-cyano-7- (4-nitrophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-methoxyphenyl) -1-methylindole-2-carboxamide

5-cyano-7- (4-methoxyphenyl) -1H-indole-2-carboxamide

5-cyano-1-methyl-7- [4- (trifluoromethoxy) phenyl ] indole-2-carboxamide

5-fluoro-3-methyl-7- (4-methylphenyl) -1H-indole-2-carboxamide

5-fluoro-3-methyl-7- (2, 3, 4-trifluorophenyl) -1H-indole-2-carboxamide

5-fluoro-7- (4-methoxyphenyl) -3-methyl-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-fluoro-3-methyl-1H-indole-2-carboxamide

5-fluoro-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

5-fluoro-1, 3-dimethyl-7- (4-methylphenyl) indole-2-carboxamide

5-fluoro-7- (4-methoxyphenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-fluoro-1, 3-dimethylindole-2-carboxamide

5-fluoro-3-methyl-7-phenyl-1H-indole-2-carboxamide

5-fluoro-7- (4-fluoro-3-methylphenyl) -3-methyl-1H-indole-2-carboxamide

5-fluoro-1, 3-dimethyl-7-phenylindole-2-carboxamide

5-fluoro-7- (4-fluoro-3-methylphenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- (3, 4, 5-trifluorophenyl) -1H-indole-2-carboxamide

5-cyano-1-methyl-7- (3, 4, 5-trifluorophenyl) indole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-1H-indole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-1-methylindole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1H-indole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1-methylindole-2-carboxamide

5-cyano-1, 3-dimethyl-7- (3, 4, 5-trifluorophenyl) indole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -1, 3-dimethylindole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2, 4-difluorophenyl) -1, 3-dimethylindole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -1, 3-dimethylindole-2-carboxamide

5-cyano-3-methyl-7- (3, 4, 5-trifluorophenyl) -1H-indole-2-carboxamide

5-cyano-7- (4-fluoro-3-methylphenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-7- (2, 4-dichlorophenyl) -3-methyl-1H-indole-2-carboxamide

5-cyano-7- [4- (hydroxymethyl) phenyl ] -3-methyl-1H-indole-2-carboxamide

7- (4-chloro-3-fluorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide

7- (4-chloro-2-fluorophenyl) -5-cyano-3-methyl-1H-indole-2-carboxamide, or

5-cyano-7- (2, 4-difluorophenyl) -3-methyl-1H-indole-2-carboxamide.

5. A compound of formula I according to claim 1 or 2, wherein R¹Is a pyridyl group optionally substituted by one, two or three groups selected from C_1-4Alkyl, halogen substituted C_1-4Alkyl, hydroxy-substituted C_1-4Alkyl radical, C_1-4Alkoxy, halogen substituted C_1-4Alkoxy, cyano or nitro.

6. A compound of formula I according to claim 2, which is

7- (2-chloropyridin-4-yl) -5-cyano-1-methylindole-2-carboxamide

7- (2-chloropyridin-4-yl) -5-cyano-1H-indole-2-carboxamide

5-fluoro-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

5-cyano-7- (6-fluoropyridin-3-yl) -1H-indole-2-carboxamide

5-fluoro-1, 3-dimethyl-7-pyridin-4-ylindole-2-carboxamide

5-cyano-7-pyridin-4-yl-1H-indole-2-carboxamide

5-cyano-1-methyl-7-pyridin-4-ylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -1-methylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -1H-indole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-1H-indole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-1-methylindole-2-carboxamide

7- (2-chloropyridin-4-yl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -1, 3-dimethylindole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-1, 3-dimethylindole-2-carboxamide

5-cyano-7- (6-fluoropyridin-3-yl) -1, 3-dimethylindole-2-carboxamide

5-cyano-3-methyl-7-pyridin-4-yl-1H-indole-2-carboxamide

5-cyano-1, 3-dimethyl-7-pyridin-4-ylindole-2-carboxamide

5-cyano-7- (2-fluoropyridin-4-yl) -3-methyl-1H-indole-2-carboxamide

7- (6-chloropyridin-3-yl) -5-cyano-3-methyl-1H-indole-2-carboxamide

5-cyano-7- (6-fluoropyridin-3-yl) -3-methyl-1H-indole-2-carboxamide, or

7- (2-chloropyridin-4-yl) -5-cyano-3-methyl-1H-indole-2-carboxamide.

7. A process for the preparation of a compound of formula I as claimed in claim 1, which process comprises:

a) reacting a compound of formula 1 with a compound of formula 2

To form a compound of formula I

Wherein the definitions of the substituents are given in claim 1, and, if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt, or

b) Reacting a compound of formula 3 with a compound of formula 4

To form a compound of formula I

Wherein the definitions of the substituents are given in claim 1 and, if desired, converting the obtained compound into a pharmaceutically acceptable acid addition salt.

8. A compound of formula I according to any one of claims 1 to 6 for use as therapeutically active substance.

9. A compound of formula I according to any one of claims 1 to 6 for use in the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, parkinson's disease, cognitive impairment, down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs selected from alcohol, opiates, methamphetamine, phencyclidine and cocaine.

10. A compound of formula I according to any one of claims 1 to 6 for use in the treatment of cognitive dysfunction caused by dementia or chemotherapy.

11. A compound of formula I according to any one of claims 1 to 6 for use in the treatment of alzheimer's disease.

12. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

13. Use of a compound of formula I according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of schizophrenia, obsessive-compulsive personality disorder, depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, parkinson's disease, cognitive impairment, down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs selected from alcohol, opiates, methamphetamine, phencyclidine and cocaine.

14. Use of a compound of formula I according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of cognitive dysfunction caused by dementia or chemotherapy.

15. Use of a compound of formula I according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of alzheimer's disease.