HK1206721B - 2-oxo-2,3-dihydro-indoles for the treatment of cns disorders - Google Patents

Description

2-oxo-2, 3-dihydro-indoles for the treatment of CNS disorders

The invention relates to 2-oxo-2, 3-dihydro-indoles of general formula (I),

wherein

Is phenyl or heteroaryl, said heteroaryl being selected from pyridyl, pyrimidinyl, imidazolyl, isoheteroarylAzolyl or pyrazolyl;

is phenyl or pyridyl, wherein the N atom in the pyridyl may be in all free positions;

R¹is hydrogen, lower alkyl substituted by halogen, lower alkoxy or halogen;

n is 1 or 2; if n is 2, R¹May be the same or different;

R²/R^2’independently of one another, are lower alkyl or, together with the carbon atom to which they are attached, form C_3-6-a cycloalkyl ring;

R³is lower alkyl, C_3-6-cycloalkyl, CH₂-C_3-6Cycloalkyl, C in which one ring carbon atom is replaced by-O-_3-6-cycloalkyl, (CH)₂)₃-O-C_3-6Cycloalkyl, lower alkyl substituted by hydroxy, lower alkyl substituted by halogen, (CH)₂)₃-S(O)₂-C_3-6-cycloalkyl or (CH)₂)₂-S(O)₂-a lower alkyl group;

R⁴is hydrogen, halogen or lower alkyl;

m is 1 or 2; if m is 2, R⁴May be the same or different;

and pharmaceutically acceptable salts thereof, racemic mixtures thereof, or the corresponding enantiomers and/or optical isomers and/or stereoisomers thereof,

and is

Relates to compounds of formula I-1

Wherein

Is phenyl or heteroaryl, said heteroaryl being selected from pyridyl, pyrimidinyl, imidazolyl, isoheteroarylAzolyl or pyrazolyl;

is phenyl or pyridyl, wherein the N atom in the pyridyl may be in all free positions;

R¹is hydrogen, lower alkyl substituted by halogen, lower alkoxy or halogen;

n is 1 or 2; if n is 2, R¹May be the same or different;

R²/R^2’independently of one another, are lower alkyl or, together with the carbon atom to which they are attached, form C_3-6-a cycloalkyl ring;

R³is hydrogen, lower alkyl, C_3-6-cycloalkyl, CH₂-C_3-6Cycloalkyl, C in which one ring carbon atom is replaced by-O-_3-6-cycloalkyl, (CH)₂)₃-O-C_3-6Cycloalkyl, lower alkyl substituted by hydroxy, lower alkyl substituted by halogen, (CH)₂)₃-S(O)₂-C_3-6-cycloalkyl or (CH)₂)₂-S(O)₂-a lower alkyl group;

R⁴is hydrogen, halogen or lower alkyl;

m is 1 or 2; if m is 2, R⁴May be the same or different;

and pharmaceutically acceptable salts thereof, racemic mixtures thereof, or the corresponding enantiomers and/or optical isomers and/or stereoisomers thereof,

it is useful for the treatment of certain central nervous system diseases which are positive (psychosis) and negative symptoms of schizophrenia (schizophrenia), substance abuse (substential abuse), alcohol and drug addiction (alcohol and drug addition), obsessive-compulsive disorders (obsessive-complex disorders), cognitive impairment (cognitive impairment), bipolar disorders (bipolar disorders), mood disorders (mood disorders), major depression (major depression), refractory depression (refractory depression), anxiety disorders (anxiety disorders), Alzheimer's disease (Alzheimer's disease), autism (autism), Parkinson's disease (Parkinson's disease), chronic pain (neuropathic pain), borderline disorder (metabolic disorder), sleep disturbance (distress syndrome), chronic fatigue syndrome (distress syndrome), and chronic fatigue syndrome (distress syndrome).

Structurally similar compounds are described, for example, in WO2007063925(Astellas Pharma/Japan), wherein the active compounds described have NHR-substitution on the left phenyl or heteroaryl group, which are useful for the treatment of pain; WO0056709 and WO0008202(Sugen, inc./USA) describe compounds which are not substituted on the 2-oxo-2.3-dihydro-indole ring, for use in the treatment of cancer, hepatitis, ocular diseases and cardiovascular diseases; DE 3925584, EP0344634, DE 3803775, US4835280, US 4810801, DE 3501497, EP0161632 and DE 3417643(Boehringer Mannheim/DE) describe 2-oxo-2, 3-dihydro-indole derivatives which are not substituted in the 1-position (N-atom) and which are useful as intermediates or for the treatment of diseases of the heart and circulatory system, for influencing platelet function and for the treatment of cardiovascular diseases.

It has now been found that compounds of formula I and I-1 can be used for the treatment of CNS disorders. The described compounds have been shown to reverse L-687, 414((3R, 4R) -3-amino-1-hydroxy-4-methyl-pyrrolidin-2-one, an NMDA glycine site antagonist) induced hyperlocomotion (hypercocontoon), a behavioral pharmacokinetic mouse model for schizophrenia prediction of efficacy in human patients, described by d.alberti et al in Pharmacology, Biochemistry and Behavior (Pharmacology, Biochemistry and Behavior), 97(2010), 185-. The authors describe that the excessive movements induced by L-687, 414 are inhibited by a range of known antipsychotic drugs. The compounds of formula I and I-1 exhibited significant activity in this model. These findings are predictive of antipsychotic activity of the compounds of the present invention, making them useful in the treatment of schizophrenia and other diseases as described above. The results are shown in Table 1.

In addition to the reverse L-687, 414-induced hypermobility assay described above, some compounds of the present invention have been shownIn a test, theIs an automated system in which compound-treated mice's behavior in response to a variety of challenges is captured by digital video and analyzed with computer algorithms (robeds et al, Frontiersin Neuroscience, 2011, vol.5, art.103, 1-4). In this way, the neuro-pharmacological effects of test compounds can be predicted by their similarity to a broad class of compounds such as antipsychotics, anxiolytics and antidepressants. Examples 29 and 30 show similarities to atypical antipsychotics, whereby similar efficacy to atypical antipsychotics is expected in human patients. The results are shown in Table 2.

Schizophrenia is a complex mental disorder, typically occurring in late adolescence or early adulthood with a worldwide prevalence of about 1% of the adult population, with a tremendous social and economic impact. The criteria of the European psychiatric Association (ICD) and american psychiatric Association (DSM) for the diagnosis of schizophrenia require the presence of two or more characteristic symptoms: delusions (delusions), hallucinations (hallucinations), speech disturbances (disordered speech), severe disturbances or tonic behavior (positive symptoms), or negative symptoms (aphasia), affective chill (negative striking), lack of motivation (lack of motivation), loss of interest (anhedonia)). In general, people with schizophrenia have functional deficits that may begin in childhood, persist throughout adult life and render most patients unable to maintain normal work or otherwise have normal social function. They also have a shortened lifespan compared to the general population and suffer from an increased prevalence of a wide variety of other neuropsychiatric syndromes, including substance abuse, obsessive-compulsive syndrome, and abnormal involuntary movements prior to antipsychotic treatment. Schizophrenia is also associated with a wide range of the following diseases: cognitive impairment, bipolar disorder, major depression and anxiety disorders, the severity of which limits the functioning of patients even when the psychotic symptoms are well controlled. The primary treatment for schizophrenia is the administration of antipsychotics. However, antipsychotics, such as risperidone (risperidone), olanzapine (olanzapine), do not significantly alleviate the negative symptoms and cognitive dysfunction.

The treatment of antipsychotic drugs has shown clinical efficacy for the following diseases:

fibromyalgia (Fibromyalgia)It is a syndrome characterized by chronic general pain associated with different somatic symptoms such as sleep disorders, fatigue, stiffness, balance problems, hypersensitivity to physical and physiological environmental stimuli, depression and anxiety (CNS Drugs, 2012, 26 (2): 135-53).

Schizoaffective disorder (Schizoafffective disorders): including psychosis and affective symptoms, which fall within the range between bipolar disorder (with depressive and manic episodes, alcohol and drug addiction, substance abuse) and schizophrenia.

J.Clin.Psychiatry，2010，71，Suppl.2，14-9，

Pediatr.Drugs 2011，13(5)，291-302

Major depressive disorder:BMC Psychiatry 2011，11，86

refractory depression：Journal of Psychopharmacology，0(0)1-16

Anxiety disorders:European Neuropsychopharmacology，2011，21，429-449

bipolar disorder:Encephale，International J.of Neuropsychopharmacology，2011，14，1029-1049

international J.of Neuropsychopharmacology, 2012, pages 1-12

J.of Neuropsychopharmacology，2011，0(0)，1-15

Mood disorder：J.Psychopharmacol.2012，Jan 11

CNS Drugs，2010，Feb.24(2)，131-61

Autism:Current opinion in pediatrics，2011，23：621-627；

J.Clin.Psychiatry，2011，72(9)，1270-1276

alzheimer's disease：J.Clin.Psychiatry，2012，73(1)，121-128

Parkinson's disease：Movement Disorders，Vol.26，No.6，2011

Chronic fatigue syndrome：European Neuropsychopharmacology，2011，21，282-286

Borderline personality disorder：J.Clin.Psychiatry，2011，72(10)，1363-1365

J.Clin.Psychiatry，2011，72(10)，1353-1362

Anti-inflammatory effects in arthritis：European J.of Pharmacology，678，2012，55-60

Objects of the present invention are novel compounds of formula I and the use of compounds of formula I and I-1 and their pharmaceutically acceptable salts for the treatment of CNS diseases involving positive (psychosis) and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, sleep disorders, chronic fatigue syndrome, stiffness, anti-inflammatory effects in arthritis and balance problems. Further objects of the invention are medicaments containing such novel compounds as well as processes for the preparation of compounds of formula I, combinations of compounds of formula I or I-1 with commercially available antipsychotics, antidepressants, anxiolytics or mood stabilizers, and methods for the treatment of the above-mentioned CNS disorders.

The present invention encompasses the corresponding prodrugs of the compounds of formula I and I-1.

One common antipsychotic used to treat schizophrenia is olanzapine. Olanzapine (Zyprexa) belongs to a class of drugs known as atypical antipsychotics. Other members of this class include, for example, clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify), and ziprasidone (Geodon).

Olanzapine is approved for the treatment of psychiatric disorders, chronic treatment of bipolar disorders and in combination with fluoxetine for the treatment of depressive episodes associated with bipolar disorders and for the treatment of treatment-resistant depression.

The compounds of the invention may be combined with antipsychotics such as olanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify), amisulpride (Solian), asenapine (asenapine) (Saphris), blonanserin (Lonasen), chlorothiazine (Entumine), iloperidone (Fanapt), lurasidone (lurasidone) (lada), mosapamide (Cremin), paliperidone (Invega), peropiropiroctone (lulan), quetiapine (Seroquel), remoxiam (roxam), sellindole (serotidole) (serdol), sulpiride (sulpiride) (sulpiride, egonyl), ziprasidone (geodone, zeoxepin), tezophil (pololazine), ziprasidone (sedafluorine), trifluraline (chlorphenirazine), chlorphenirazine (chlorphenirazine), trifluoropropylamine (Vesprin), levomepromazine (Nozinan), promethazine (Phenergan), pimozide (Orap) and cyanomesalamine (Tercian).

A preferred embodiment of the present invention is a combination wherein the marketed antipsychotic drug is olanzapine (Zyprexa), clozapine (Clozaril), risperidone (Risperdal), aripiprazole (Abilify) or ziprasidone.

In addition, the compounds of the invention may be combined with antidepressants such as selective 5-hydroxytryptamine reuptake inhibitors [ citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), fluvoxamine (Luvox), sertraline (Zoloft, Lustral) ], 5-hydroxytryptamine norepinephrine reuptake inhibitors [ duloxetine (Cymbalta), milnacipran (Ixel, Savella), venlafaxine (Effexor), desvenlafaxine (Pristq), tramadol (Tramal, Ultram), sibutramine (Meridia, Reducil) ], 5-hydroxytryptamine antagonists and reuptake inhibitors [ etoperidone (Iopamin, Etonin), Lubazodone (Lubazode) (YM-992, Reducrex), nevirapine [ fax ] reuptake inhibitors (Edoxazalone, Redox), nefazodone (Dexperzine), viloxazine (Vivalan), tomoxetine (Strattera) ], norepinephrine-dopamine reuptake inhibitor [ bupropion (Wellbutrin, Zyban), Dexmethylphenidate (Dexmethylphenidate) (Focalin), methylphenidate (Ritalin, certa) ], norepinephrine-dopamine releasing agent [ amphetamine (Adderall), dextroamphetamine (dexaine), Dextromethamphetamine (dexmethylamphetamine) (Desoxyn), lisdexamphetamine (Lisdexamfetamine) (Vyvanse) ], tricyclic antidepressants [ amitriptyline (Elavil, Endep), clomipramine (Anafranil), desipramine (norpramine, perfrrame), polysuflippine [ Dothiepin (prothia), doxepin (adoxin, doxepin), doxepin (luteine), methotrexate (luteine), luteolin (luteolin, luteolin (luteolin), lutepinine (lutepinine, lutepinine (lutepinine), lutepinine (lutepinine, lute, norval, tollon), mirtazapine (Remeron) ], monoamine oxidase inhibitors [ isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), selegiline [ L-diprenil ] (eldryl, Zelapar, Emsam), tranylcypropylammonium (Parnate), pirlindole (Pirazidol) ], 5-HT1A receptor agonists [ buspirone (Buspar), tandospirone (sediell), vilazodone (vilbiyd) ], 5-HT2 receptor antagonists [ agomelatine (Valdoxan), nefazodone (Nefadar, Serzone ], selective 5-hydroxytryptamine reuptake promoters [ Tianeptine (tianepene) ].

A preferred embodiment of the invention is a combination wherein the marketed antidepressant is citalopram (Celexa), escitalopram (Lexapro, Cipralex), paroxetine (Paxil, Seroxat), fluoxetine (Prozac), sertraline (Zoloft, Lustral) duloxetine (Cymbalta), milnacipran (Ixel, Savella), venlafaxine (Effexor), or Miltazapine (Remeron).

The compounds may also be combined with anxiolytics such as alprazolam (Helex, Xanax, Xanor, Onax, Alprox, Restyl, Tafil, Paxal), bromotacrine, bromodiazepam (Lectopam, Lexotanil, Lexotan, Bromam), brotizolam (Lendormin, Dormex, sinonal, noctlan), chlordiazepoxide (Librium, Risolid, Elenium), cinozepam (geodorm), clonazepam (Rivotril, Klonopin, Iktorivil, Paxam), loratadine (Tranxene, nxilium), chlorthiazepam (veratranan, Clozan, Rize), chlorambucil (Veratran, Rize), chlorambucil (loran, loram), chlorambucil), and the likeAzolam (Sepazon, Olcadil), diazepam (Dadumir), diazepam (Antenex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolidid, Stedon, Valium, Vival, Valaxona), estazolam (ProSom), etizolam (Etilaam, Pasaden, Depas), Flunitrazepam (Rohypnol, Fluscan, Fluunipam, Ronal, Rohydorm), Fluzepam (Dalmadorm, Dalman), Flutopetapam (Restas), Halazepam (Paxipam), diazepam (Daxipam), and optionally, for example, the salts thereof, such as sodium, potassium, magnesium) Katazalam (Anxon), chlorprozolam (dorminoct), lorazepam (Ativan, Temesta, Tavor, Lorabenz), chlordiazepam (Loramet, noctamamid, pronocotan), metazepam (nobium), midazolam (Dormicum, Versed, Hypnovel, dormonnid), nimetapam (Erimin), nitrazepam (mogandon, Alodorm, pacison, Dumolid, nizadon), desmetham (padar, Stilny), oxazepam (serestata, serrax, Serenid, serreix, Sobril, oxbenz, Oxapax), fennacetapam (phenozepam), clonazepam (stolazine, lopraz), lopraz (clavam, roxiranib, rox, naprox, naproxen, naproxepam, naproxen, naphazoline (naproxen, naphazelyne, naproxen, naphazelyne, naphazoline, naproxen, nap; zileze; zimoclone; zirnovane; zopitan; zorclone), pregabalin (Lyrica) and gabapentin (Fanatrex, Gabarone, Gralise, Neurontin, Nupentin).

A preferred embodiment of the invention is a combination wherein the commercially available anxiolytic is alprazolam (Helex, Xanax, Xanor, Omax, Alprox, Restyl, Tafil, Paxal), chlordiazepoxide (Librium, Risolid, Elenium), clonazepam (Rivotril, Klonopin, Iktorivi, Paxam), diazepam (Antehex, Apaurin, Apzepam, Apozepam, Hexalid, Pax, Stesolid, Stedon, Valium, Vival, Valaxona), estazolam (ProSom), Eszopiclone (Lunesta), Zaleplon (Sonata, Starnoc), zolpidan (Ambien, Nytame, Stilnoct, Stilnox, Zollin (Zollin, or Facaritin (Gapenoldione, Gasterone, or Gasterone).

Another object of the invention is the combination with mood stabilizers such as carbamazepine (Tegretol), lamotrigine (Lamictal), lithium (Eskalith, Lithane, Lithobid) and valproic acid (Depakote).

The compounds may also be combined with cognition enhancing compounds (cognitive compounds) such as donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon) and memantine (Namenda).

Preferred indications for use of the compounds of the invention are psychiatric disorders such as schizophrenia.

As used herein, the term "lower alkyl" denotes a saturated straight or branched chain group containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred alkyl groups are those having 1 to 4 carbon atoms.

As used herein, the term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above and which is attached via an oxygen atom.

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

The term "pharmaceutically acceptable acid addition salts" includes 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.

A preferred embodiment of the present invention relates to compounds of the formula I, in which

Is a pyridyl group andis phenyl, for example the following compounds:

n- (3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide (known)

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -isonicotinamide

N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indolin ] -6' -yl) isonicotinamide

N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

4-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

6-methoxy-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-methoxy-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

4-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

2-chloro-N- (1, 3, 3, 7-tetramethyl-2-oxoindolin-6-yl) isonicotinamide

2-chloro-6-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

3-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

3-fluoro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

3-chloro-N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -6-methylnicotinamide

5-fluoro-2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (5-chloro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (5-chloro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-isopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

3-chloro-N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1-isopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

4-fluoro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) benzamide

3-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) picolinamide

N- (1-cyclopentyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -isonicotinamide

3-fluoro-N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

3-chloro-N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (cyclopropylmethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (cyclopropylmethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -5-fluoro-2-methylisonicotinamide

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) isonicotinamide

3-chloro-N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) isonicotinamide

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) -3-fluoroisonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) -2-methylisonicotinamide

3-chloro-N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

3-chloro-N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) nicotinamide

N- (1- (3-Cyclopropoxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1- (3-Cyclopropoxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-fluoro-N- (1- (hydroxymethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-fluoro-N- (1- (2-hydroxyethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-fluoro-N- (1- (3-hydroxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (3- (cyclopropylsulfonyl) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (3- (cyclopropylsulfonyl) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

3-chloro-N- (1- (3-hydroxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-2-oxo-1- (2, 2, 2-trifluoroethyl) indolin-6-yl) -3-fluoroisonicotinamide, or

N- (3, 3-dimethyl-1- (2- (methylsulfonyl) ethyl) -2-oxoindolin-6-yl) -3-fluoroisonicotinamide.

Another preferred embodiment of the present invention relates to compounds of the formula I, in whichIs pyrimidinyl or imidazolyl, andis phenyl, for example the following compounds:

2, 6-dimethyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-4-carboxamide

1-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) -1H-imidazole-2-carboxamide

2, 4-dimethyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-5-carboxamide, or

2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-5-carboxamide.

Another preferred embodiment of the present invention relates to compounds of the formula I, in whichIs pyrimidinyl, isoAzolyl or pyrazolyl, andis a pyridyl group, such as the following compounds:

n- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methylpyrimidine-5-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-6-yl) isoAzole-5-carboxamides

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -1-methyl-1H-pyrazole-5-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -1-methyl-1H-pyrazole-3-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methoxypyrimidine-5-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-6-yl) -3-methyliso-ylOxazole-4-carboxamide, or

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2- (trifluoromethyl) pyrimidine-5-carboxamide.

Another preferred embodiment of the present invention relates to compounds of the formula I, in which

Andare all pyridyl, such as the following compounds:

n- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) nicotinamide

2-methyl-N- (], 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) nicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methylisonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide, or

2-chloro-N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide.

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

Reacting a compound of formula 2

With a compound of formula 3

Reaction to give the compound of formula I

Wherein X is hydroxy or chloro and the other groups have the meaning as described above, and,

if desired, the compound obtained is converted 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 invention is shown in the following scheme. The skill required to carry out the reaction and the purification of the resulting product is known to those skilled in the art. Unless indicated to the contrary, the substituents and indices used in the following description of the process have the meanings given herein before.

In more detail, the compounds of formula I can be prepared by the methods given below, by the methods given in the examples, or by analogous methods. The appropriate reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is then not limited to the sequence shown in the scheme, which depends on the starting materials and their respective reactivities, the order of the reaction steps can be freely varied. The starting materials are commercially available or can be prepared by methods analogous to those given below, by the methods described in the examples, or by methods known in the art.

According to the inventionCompounds of formula I and pharmaceutically acceptable salts thereof may be prepared by2Of the formula3By acylation of the activated acid of (a) (see scheme 1). Acid chlorides (wherein X ═ Cl) are commercially available or can be prepared from the corresponding acids (X ═ OH) by generally known procedures, for example, reaction with thionyl chloride or oxalyl chloride. Acyl chloride3(wherein X ═ Cl) can be reacted with aniline in the presence of a base (e.g., triethylamine, diisopropylethylamine)2The reaction provides the amide of formula I. Alternatively, the amide of formula I may be obtained by: with commonly known amide coupling agents such as 1-chloro-N, N, 2-trimethylpropenylamine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) or (2- (7-aza-1H-benzotriazol-1-yl) -1, 1, 3, 3-tetramethylureaHexafluorophosphate (HATU) in-situ activation general formula3(X ═ OH) acids with anilines2And (4) reacting.

General formula (VII)2The anilines of (a) are commercially available or the corresponding nitro compounds can be obtained by methods known to the person skilled in the art, for example hydrogenation in the presence of a catalyst, for example palladium on charcoal, or by chemical reduction with, for example, sodium dithionite6Reduction (see scheme 2). Alternatively, a halide4Can be coupled with ammonia bearing a protecting group such as benzyl to form substituted anilines7. This reaction can be accomplished using generally known procedures, such as a metathesis reaction under catalytic conditions (such as, for example, palladium (O) or copper (II) catalysis) or under thermal conditions or under basic conditions. Cleavage of the protecting group (e.g. for hydrogenation of benzyl) provides aniline2. Alternatively, a compound of formula2Can be prepared by reacting an aniline of the general formula4Is coupled with ammonia.

For R²＝R^2’＝R³General formula (II)4Can be prepared, for example, by reacting R with a base such as sodium hydride in the presence of a base such as sodium hydride^2，2’，3-LG tri-alkylated 6-halo-oxindoles8Where LG is a leaving group such as iodine, bromine, chlorine, tosylate (see scheme 3).

For R²＝R^2’≠R³General formula (II)4The compounds of (A) can be prepared, for example, by reacting R with a base such as potassium tert-butoxide and in the presence of a copper (I) -dimethyl sulfide bromide complex^2，2’Dialkylated 6-halo-oxindoles (LG is a leaving group such as iodine, bromine, chlorine, tosylate)8And then the preparation. Then dialkylating the product9Can be prepared by using R in the presence of a base such as sodium hydride or cesium carbonate³LG alkylation or by coupling of boronic acids R in the presence of a base such as, for example, sodium bis (trimethylsilyl) amide or sodium carbonate, under metal catalysis (such as, for example, palladium (O) or copper (II) catalysis)³-B(OH)₂Or boronic acid esters R³-B(OR)₂(e.g. R)³-4, 4, 5, 5-tetramethyl- [1, 3, 2 [ ]]Dioxaborolane) to the compound4。

For Y ═ I, R⁴＝F，Is phenyl and R⁴' H or F, formula4aThe compounds of (a) can be prepared, for example, by the following method: alkylated oxindoles analogous to scheme 310Followed by n-silylation by treatment with LDA and trimethylsilyl chloride followed by exchange of the silyl group with iodine using iodine monochloride (see scheme 4).

General formula (VII)8The compounds of (a) can be prepared, for example, by reducing isatin derivatives with, for example, hydrazine13And prepared (see scheme 5).

Alternatively, a compound of formula8aThe compound of (1) (wherein Y ═ Br,═ phenyl) can be prepared, for example, from 4-bromo-1-fluoro-2-nitro-benzene derivatives14Initially, they are prepared by nucleophilic substitution of a fluoride with a malonate in the presence of a base such as, for example, sodium hydride (see scheme 6). Hydrolysis and decarboxylation of the ester can be accomplished, for example, by heating in the presence of hydrochloric acid to provide the acid16. Reduction of the nitro group with iron, for example in acetic acid, followed by cyclization to give the lactam8a。

EXAMPLE 1 (known)

N- (3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

a)6-amino-3, 3-dimethylindolin-2-ones

Activated carbon-supported palladium (10%, 129mg, 121 μmol) was added to 3, 3-dimethyl-6-nitroindolin-2-one (j. -P).Et al, 1987, US 4666923A 1; 500mg, 2.42mmol) in ethyl acetate (100 ml). The mixture was stirred under hydrogen atmosphere (balloon) at 70 ℃ for 48 hours. The catalyst was filtered off, washed with ethyl acetate and the solvent was evaporated. ObtainTitle compound was obtained as an orange powder (427 mg).

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.75(s，1H)，7.92-7.89(m，1H)，7.62-7.58(m，2H)，1.30(s，6H)。

b)N- (3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

To a suspension of 2-methylisonicotinic acid (175mg, 1.28mmol) in dry toluene (12.8ml) under argon atmosphere was added SOCl₂(167mg, 103. mu.l, 1.4mmol) and anhydrous DMF (9.33mg, 9.89. mu.l, 128. mu. mol). The mixture was heated at reflux for 2 hours and the solvent was evaporated under reduced pressure. The residue was suspended in anhydrous dichloromethane (3.51ml) and a suspension of 6-amino-3, 3-dimethylindolin-2-one (0.15g, 851. mu. mol) and DIPEA (330mg, 446. mu.l, 2.55mmol) in anhydrous dichloromethane (5ml) was added portionwise. The suspension was stirred at room temperature under argon for 16 hours and then diluted with dichloromethane, water and 1M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a brown solid (99 mg).

MS ESI(m/z)：296.3[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.38(s，2H)，8.64-8.62(m，1H)，7.71(m，1H)，7.64-7.62(m，1H)，7.49(m，1H)，7.31-7.23(m，2H)，2.57(s，3H)，1.24(s，6H)。

Example 2

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -isonicotinamide

To a solution of 6-amino-1, 3, 3-trimethylindolin-2-one (W.von der Saal et al, J.Med.chem.1989, 32(7), 1481-one 1491; 500mg, 2.63mmol) in anhydrous dichloromethane (13ml) were added triethylamine (798mg, 1.1ml, 7.88mmol) and isonicotinoyl chloride hydrochloride (724mg, 3.94 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, water and 1M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a brown solid (661 mg).

MS ESI(m/z)：296.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.83-8.81(m，2H)，8.03(bs，1H)，7.74-7.72(m，2H)，7.55(m，1H)，7.20-7.17(m，1H)，7.06-7.02(m，1H)，3.24(s，3H)，1.37(s，6H)。

Example 3

N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indolin ] -6' -yl) isonicotinamide

Prepared in analogy to example 2, using 6 '-amino-1' -methyl-spiro [ cyclopentane-1, 3 '-indolin ] -2' -one (prepared analogously to the procedure described in W.von der Saal et al, J.Med.chem.1989, 32(7), 1481-indolin ] -2 '-one for the preparation of 6-amino-1, 3, 3-trimethylindolin-2-one by methylation and nitro reduction of 6' -nitro-spiro [ cyclopentane-1, 3 '-indolin ] -2' -one (A.Mertens et al, J.Med.chem.1987, 30(8), 1279-indolin-2-one) in section I.R.C.R.R.C.C.C.1287). The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：322.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.84-8.82(m，2H)，7.90(bs，1H)，7.75-7.73(m，2H)，7.50(m，1H)，7.19-7.16(m，1H)，7.04-7.00(m，1H)，3.24(s，3H)，2.20-1.80(m，8H)。

Example 4

N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 1b from nicotinic acid and 6-amino-1, 3, 3-trimethylindolin-2-one (W.von der Saal et al, J.Med.chem.1989, 32(7), 1481-1491). The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：296.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.12-9.11(m，1H)，8.81-8.79(m，1H)，8.25-8.21(m，1H)，7.96(bs，1H)，7.56-7.55(m，1H)，7.49-7.45(m，1H)，7.20-7.17(m，1H)，7.06-7.02(m，1H)，3.25(s，3H)，1.38(s，6H)。

Example 5

2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 1b from 6-amino-1, 3, 3-trimethylindolin-2-one (W.von der Saal et al, J.Med.chem.1989, 32(7), 1481-1491). The title compound was obtained as a light brown solid.

MS ESI(m/z)：310.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.70-8.68(m，1H)，7.88(bs，1H)，7.59-7.54(m，1H)，7.51-7.49(m，1H)，7.20-7.17(m，1H)，7.04-7.01(m，1H)，3.24(s，3H)，2.68(s，3H)，1.37(s，6H)。

Example 6

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide

Prepared in analogy to examples 20d, 37b, 37c and 2 from 6-chloro-1, 3-dihydro-pyrrolo [3, 2-c ] pyridin-2-one (p. eastwood et al, bioorg.med.chem.lett.2011, 21(18), 5270-. The title compound was obtained as a yellow powder.

MS ESI(m/z)：297.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.23(bs，1H)，8.86-8.84(m，2H)，8.03-7.98(m，2H)，7.81-7.79(m，2H)，3.29(s，3H)，1.44(s，6H)。

Example 7

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 2 from 6-amino-1-ethyl-3, 3-dimethylindolin-2-one (g. georges et al, US2006/142247a 1). The title compound was obtained as an off-white powder.

MS ESI(m/z)：310.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.81-8.79(m，2H)，8.23(bs，1H)，7.75-7.73(m，2H)，7.58(m，1H)，7.20-7.17(m，1H)，7.07-7.04(m，1H)，3.78(q，J＝7.27Hz，2H)，1.36(s，6H)，1.27(t，J＝7.27Hz，3H)。

Example 8

2, 6-dimethyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-4-carboxamide

Prepared in analogy to example 1b from 6-amino-1, 3, 3-trimethylindolin-2-one and 2, 6-dimethylpyrimidine-4-carboxylic acid. The title compound was obtained as a white foam.

MS ESI(m/z)：325.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.98(bs，1H)，7.88(m，1H)，7.65(m，1H)，7.20(m，2H)，3.27(s，3H)，2.81(s，3H)，2.64(s，3H)，1.38(s，6H)。

Example 9

4-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 1b from 6-amino-1, 3, 3-trimethylindolin-2-one and 4-methyl-nicotinic acid. The title compound was obtained as a red oil.

MS ESI(m/z)：310.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.65(m，1H)，8.57(m，1H)，8.48-8.46(m，1H)，7.88(m，1H)，7.60(m，1H)，7.21-7.16(m，2H)，7.10-7.07(m，1H)，3.23(s，3H)，2.53(s，3H)，1.36(s，6H)。

Example 10

6-methoxy-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 1b from 6-amino-1, 3, 3-trimethylindolin-2-one and 6-methoxynicotinic acid. The title compound was obtained as a light yellow foam.

MS ESI(m/z)：326.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.71-8.70(m，1H)，8.11-8.07(m，1H)，7.74(bs，1H)，7.55(m，1H)，7.18-7.15(m，1H)，7.00-6.97(m，1H)，6.86-6.84(m，1H)，4.02(s，3H)，3.24(s，3H)，1.37(s，6H)。

Example 11

1-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) -1H-imidazole-2-carboxamide

To a solution of 1-methyl-1H-imidazole-2-carboxylic acid (99.4mg, 788. mu. mol) and 6-amino-1, 3, 3-trimethylindolin-2-one (100mg, 526. mu. mol) in DMF (3ml) were added HATU (400mg, 1.05mmol) and DIPEA (347mg, 468. mu.l, 2.63 mmol). The reaction mixture was stirred at room temperature for 3 hours and then poured into ethyl acetate and 1M aqueous sodium carbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography using ethyl acetate/heptane as eluent followed by reverse phase preparative HPLC. The title compound was obtained as off-white crystals (135 mg).

MS ESI(m/z)：299.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.30(bs，1H)，7.53-7.52(m，1H)，7.17-7.14(m，1H)，7.09-7.04(m，3H)，4.12(s，3H)，3.24(s，3H)，1.37(s，6H)。

Example 12

2, 4-dimethyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-5-carboxamide

Prepared in analogy to example 11 from 2, 4-dimethylpyrimidine-5-carboxylic acid. The title compound was obtained as a white foam.

MS ESI(m/z)：325.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.72(m，1H)，7.56-7.52(m，2H)，7.20-7.17(m，1H)，6.99-6.96(m，1H)，3.25(s，3H)，2.76(s，3H)，2.71(s，3H)，1.37(s，6H)。

Example 13

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

a)7-fluoro-1, 3, 3-trimethylindolin-2-one

To a suspension of NaH (8.79g, 220mmol) in tetrahydrofuran (100ml) was added 7-fluoroindolin-2-one (8.30g, 54.9mmol) portionwise over 20 min. The reaction mixture was stirred for 30 minutes. MeI (31.2g, 13.7ml, 220mmol) was added dropwise over 1.5 hours at 24-27 ℃. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched very carefully with 20ml of saturated aqueous ammonium chloride solution at 10-15 ℃ and then diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as orange crystals (9.91 g).

MS ESI(m/z)：194.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.99-6.97(m，3H)，3.43(d，J＝2.62Hz，3H)，1.37(s，6H)。

b)7-fluoro-1, 3, 3-trimethyl-6- (trimethylsilyl) indolin-2-one

A solution of diisopropylamine (5.4g, 7.6ml, 52.8mmol) in dry tetrahydrofuran (23ml) was cooled to-40 ℃ under argon and a solution of n-BuLi (1.6M in hexane, 31.6ml, 50.5mmol) was added dropwise. The mixture was stirred at-40 ℃ for 30 minutes and then added at-75 ℃ to a solution of 7-fluoro-1, 3, 3-trimethylindolin-2-one (8.875g, 45.9mmol) and trimethylsilyl chloride (5.49g, 6.46ml, 50.5mmol) in anhydrous tetrahydrofuran (69 ml). The reaction mixture was warmed to room temperature over 16 hours. The reaction mixture was carefully quenched with water (2ml) and diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as a pale yellow oil (8.55 g).

MS ESI(m/z)：266.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.06-7.02(m，1H)，6.99-6.96(m，1H)，3.44(d，J＝3.03Hz，3H)，1.36(s，6H)，0.33(s，9H)。

c)7-fluoro-6-iodo-1, 3, 3-trimethylindolin-2-one

To a solution of 7-fluoro-1, 3, 3-trimethyl-6- (trimethylsilyl) indolin-2-one (9.9g, 37.3mmol) in dichloromethane (500ml) was added iodine monochloride (37.3ml, 37.3mmol) at 0 ℃. The reaction mixture was warmed to room temperature and stirred for 16 hours. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as off-white crystals (9.82 g).

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.43-7.39(m，1H)，6.77-6.75(m，1H)，3.42(d，J＝3.23Hz，3H)，1.36(s，6H)。

d)6-amino-7-fluoro-1, 3, 3-trimethylindolin-2-one

Prepared in analogy to examples 20e and 37c from 7-fluoro-6-iodo-1, 3, 3-trimethylindolin-2-one. The title compound was obtained as white crystals.

MS ESI(m/z)：209.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.75-6.73(m，1H)，6.45-6.40(m，1H)，3.73(bs，2H)，3.42-3.41(m，3H)，1.32(s，6H)。

e)N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 2 from 6-amino-7-fluoro-1, 3, 3-trimethylindolin-2-one. The title compound was obtained as a white solid.

MS ESI(m/z)：314.0[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.86-8.84(m，2H)，8.01-8.00(m，2H)，7.74-7.72(m，2H)，7.05-7.02(m，1H)，3.45-3.44(m，3H)，1.39(s，6H)。

Example 14

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

a)6-bromo-3, 3-dimethyl-1, 3-dihydro-indol-2-ones

To a suspension of potassium tert-butoxide (12.8g, 114mmol) in dry THF (80ml) under argon at 0 ℃ was added 6-bromoindolin-2-one (5.0g, 22.9mmol) portionwise, followed by copper (I) bromide-dimethylsulfide complex (470mg, 2.29 mmol). MeI (6.82g, 3.00ml, 48.0mmol) was added dropwise over 45 minutes, maintaining the temperature of the reaction mixture below 8 ℃. The reaction mixture was warmed to room temperature and held at that temperature for 16 hours. The reaction mixture was again cooled to 0 ℃ and saturated aqueous ammonium chloride solution was carefully added. The mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as a pale yellow solid (5.17 g).

MS ESI(m/z)：240.0/242.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.12(m，1H)，7.20-7.16(m，1H)，7.09-7.08(m，1H)，7.06-7.04(m，1H)，1.39(s，6H)。

b)6-bromo-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one

To a suspension of 6-bromo-3, 3-dimethylindolin-2-one (4.85g, 20.2mmol), cyclopropylboronic acid (3.47g, 40.4mmol), DMAP (7.55g, 60.6mmol) and copper (II) acetate (3.85g, 21.2mmol) in dry toluene (400ml) was added a 2M solution of sodium bis (trimethylsilyl) amide in THF (10.6ml, 21.2 mmol). The reaction mixture was heated to 95 ℃ while dry air was bubbled through the mixture for 16 hours.

The reaction mixture was diluted with tert-butyl methyl ether, quenched with water and acidified with 1M HCl. The aqueous phase was extracted with tert-butyl methyl ether. The combined organic layers were washed with 1M HCl and brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as a red solid (5.12 g).

MS ESI(m/z)：280.1/282.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.24(m，1H)，7.20-7.17(m，1H)，7.04-7.02(m，1H)，2.66-2.58(m，1H)，1.32(s，6H)，1.11-1.04(m，2H)，0.92-0.86(m，2H)。

c)6-amino-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one

Prepared in analogy to example 37b-c from 6-bromo-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one. The title compound was obtained as a brown solid.

MS ESI(m/z)：217.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.95-6.92(m，1H)，6.49(m，1H)，6.37-6.34(m，1H)，3.72(bs，2H)，2.63-2.56(m，1H)，1.29(s，6H)，1.06-0.99(m，2H)，0.91-0.86(m，2H)。

d)N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 2 from 6-amino-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one. The title compound was obtained as a brown powder.

MS ESI(m/z)：322.2[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.54(s，1H)，8.81-8.79(m，2H)，7.88-7.86(m，2H)，7.69(m，1H)，7.46-7.43(m，1H)，7.31-7.28(m，1H)，2.73-2.66(m，1H)，1.23(s，6H)，1.04-0.97(m，2H)，0.81-0.76(m，2H)。

Example 15

3-methoxy-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 11 from 3-methoxyisonicotinic acid. The title compound was obtained as off-white crystals.

MS ESI(m/z)：326.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.69(bs，1H)，8.55(m，1H)，8.50-8.49(m，1H)，8.10-8.09(m，1H)，7.63(m，1H)，7.18-7.16(m，1H)，7.00-6.97(m，1H)，4.21(s，3H)，3.26(s，3H)，1.38(s，6H)。

Example 16

2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-5-carboxamide

Prepared in analogy to example 11 from 2-methylpyrimidine-5-carboxylic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：311.4[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.12(m，2H)，7.88(bs，1H)，7.52-7.51(m，1H)，7.20-7.18(m，1H)，7.05-7.02(m，1H)，3.24(s，3H)，2.84(s，3H)，1.38(s，6H)。

Example 17

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

To a solution of 2-methylisonicotinic acid (95.1mg, 694. mu. mol) in anhydrous dichloromethane (3.64ml) was added a solution of 1-chloro-N, N, 2-trimethylpropenylamine (104mg, 763. mu. mol) in anhydrous dichloromethane (1ml) at 0 ℃ under argon. After 2 hours 6-amino-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one (example 14c, 150mg, 694. mu. mol) and triethylamine (140mg, 193. mu.l, 1.39mmol) were added at 0 ℃. The reaction mixture was warmed to room temperature, held at that temperature for 16 hours, and then diluted with dichloromethane, water and 1M aqueous sodium carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with 1M aqueous sodium carbonate solution, dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a pale yellow oil (207 mg).

MS ESI(m/z)：336.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.68-8.67(m，1H)，8.05(bs，1H)，7.69(m，1H)，7.61(m，1H)，7.53-7.51(m，1H)，7.18-7.10(m，2H)，2.70-2.62(m，1H)，2.67(s，3H)，1.34(s，6H)，1.12-1.06(m，2H)，0.95-0.89(m，2H)。

Example 18

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared analogously to example 17 from nicotinic acid. The title compound was obtained as a yellow solid.

MS ESI(m/z)：322.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.13-9.12(m，1H)，8.79-8.77(m，1H)，8.27-8.23(m，2H)，7.70(m，1H)，7.48-7.44(m，1H)，7.18-7.15(m，2H)，2.70-2.63(m，1H)，1.34(s，6H)，1.12-1.06(m，2H)，0.95-0.89(m，2H)。

Example 19

4-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 1b from 4-chloronicotinic acid. The title compound was obtained as a light brown solid.

MS ESI(m/z)：330.2/332.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.96(s，1H)，8.62-8.61(m，1H)，8.01(bs，1H)，7.57-7.56(m，1H)，7.45-7.43(m，1H)，7.20-7.17(m，1H)，7.04-7.00(m，1H)，3.25(s，3H)，1.37(s，6H)。

Example 20

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

a)2- (4-bromo-5-fluoro-2-nitro-phenyl) -malonic acid dimethyl ester/2- (2-bromo-5-fluoro-4-nitro-phenyl) -propane Diacid dimethyl ester

NaH (60% in mineral oil, 20.2g, 504mmol) was dissolved in dioxaneThe suspension in alkane (233ml) was cooled to 11 ℃. 1-bromo-2, 4-difluoro-5-nitrobenzene (50g, 26.5ml, 210mmol) and dimethyl malonate (33.3g, 28.9ml, 242mmol) were added carefully to the solution over a period of 45 minutes at 11-14 deg.CSolution in alkane (467ml) (gas evolution). After the addition was complete, the reaction mixture was held at 12 ℃ for an additional hour and then warmed to room temperature. After 16 hours, the reaction mixture was cooled to 10 ℃ and 100ml of saturated aqueous ammonium chloride solution was added. The reaction mixture was diluted with tert-butyl methyl ether, water and saturated aqueous ammonium chloride solution. The aqueous phase is extracted with tert-butyl methyl ether and the combined organic phases are saturated withAqueous ammonium chloride solution and brine were washed and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as a yellow liquid (53.7g) as a 2.6: 1 mixture and used in the next reaction without further purification.

MS ESI(m/z)：348.1/350.3[(M-H)^-]。

Process for preparation of dimethyl 2- (4-bromo-5-fluoro-2-nitro-phenyl) -malonate¹H NMR(CDCl₃，400MHz)：(ppm)＝8.37-8.35(m，1H)，7.36-7.33(m，1H)，5.36(s，1H)，3.82(s，6H)。

Process for preparation of dimethyl 2- (2-bromo-5-fluoro-4-nitro-phenyl) -malonate¹H NMR(CDCl₃，400MHz)：(ppm)＝8.33-8.30(m，1H)，7.60-7.56(m，1H)，5.27(s，1H)，3.76(s，6H)。

b)(4-bromo-5-fluoro-2-nitrophenyl) -acetic acid/(2-bromo-5-fluoro-4-nitro-phenyl) -acetic acid

A mixture of 2- (4-bromo-5-fluoro-2-nitro-phenyl) -malonic acid dimethyl ester/2- (2-bromo-5-fluoro-4-nitro-phenyl) -malonic acid dimethyl ester (2.6: 1 mixture, 53.7g, 153mmol) and 6M aqueous hydrochloric acid (767ml) was heated to reflux for 7 hours and then cooled to 5 ℃. The precipitate was filtered, washed with water and n-pentane and then co-evaporated 3 times with toluene to give 25.9g of a mixture of the title compounds as a white solid. The mother liquor was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate. The solvent was evaporated and the residue triturated with n-pentane and then co-evaporated with toluene to give 11.42g of a mixture of the title compounds as an off-white solid. This material was combined with the first product to give a total of 37.32g of the title compound, 2.6: 1 mixture, which was used without further purification for the next reaction.

MS ESI(m/z)：232.0/233.9[(M-CO₂-H)^-]。

Process for preparing 2- (4-bromo-5-fluoro-2-nitrophenyl) acetic acid¹H NMR(DMSO-D₆，400MHz)：(ppm)＝8.50-8.47(m，1H)，7.70-7.67(m，1H)，4.00(s，2H)。

Process for preparation of (2-bromo-5-fluoro-4-nitro-phenyl) -acetic acid¹H NMR(DMSO-D₆，400MHz)：(ppm)＝8.40-8.37(m，1H)，7.78-7.74(m，1H)，3.87(s，2H)。

c)6-bromo-5-fluoroindolin-2-ones

A suspension of (4-bromo-5-fluoro-2-nitrophenyl) -acetic acid/(2-bromo-5-fluoro-4-nitro-phenyl) -acetic acid (2.6: 1 mixture, 37.3g, 134mmol) and iron (30.0g, 537mmol) in acetic acid (671ml) was heated to 100 ℃ for 7 hours and then cooled to room temperature. The residual elementary iron is removed by a magnetic bar. Ice water (900ml) was added to the reaction mixture. The precipitate was filtered off, washed four times with water and then suspended in an ice-cold aqueous solution of 25% HCl (300ml) and concentrated HCl (50 ml). After stirring for 10 minutes, the precipitate was filtered off and washed four times with water.

Suspending the precipitate in 1MNa₂CO₃(400ml) aqueous solution and 0.1M NaOH (100ml) and stirred for 40 minutes. The precipitate was filtered off and washed four times with 0.1M aqueous NaOH, three times with water and once with diisopropyl ether to give the title compound as a pale grey solid (20.5 g).

MS ESI(m/z)：228.0/230.0[(M-H)^-]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.47(bs，1H)，7.31-7.28(m，1H)，7.01-6.99(m，1H)，3.49(s，2H)。

d)6-bromo-5-fluoro-1, 3, 3-trimethylindolin-2-one

To a suspension of NaH (5.04g, 126mmol) in tetrahydrofuran (105ml) was added 6-bromo-5-fluoroindolin-2-one (7.24g, 31.5mmol) portionwise under argon atmosphere. After the evolution of gas had ceased, methyl iodide (17.9g, 7.88ml, 126mmol) was added dropwise over 50 minutes by means of a syringe pump (exothermic reaction), maintaining the temperature of the reaction mixture at 24 ℃ to 26 ℃. The reaction mixture was kept at room temperature for 4 hours and then carefully quenched with aqueous ammonium chloride.

The reaction mixture was diluted with tert-butyl methyl ether, water and saturated aqueous ammonium chloride solution. The aqueous phase was extracted with tert-butyl methyl ether and the combined organic phases were washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate. The solvent was evaporated and the residue triturated with heptane to give the title compound as a light brown solid (7.87 g).

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.02-6.97(m，2H)，3.19(s，3H)，1.36(s，6H)。

e)6- (benzylamino) -5-fluoro-1, 3, 3-trimethylindolin-2-one

To a solution of 6-bromo-5-fluoro-1, 3, 3-trimethylindolin-2-one (2.8g, 10.3mmol) in tetrahydrofuran (280ml) was added 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (320mg, 514. mu. mol), tris (dibenzylideneacetone) dipalladium (0) (471mg, 514. mu. mol), benzylamine (2.21g, 2.25ml, 20.6mmol) and 1M lithium bis (trimethylsilyl) amide solution (25.7ml, 25.7mmol) under argon. The reaction mixture was heated to 80 ℃ for 45 minutes in a microwave and then washed with ethyl acetate, water and 2N Na₂CO₃And (5) diluting the aqueous solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as a pale yellow powder (1.57 g).

MS ESI(m/z)：299.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.41-7.29(m，5H)，6.89-6.85(m，1H)，6.20-6.18(m，1H)，4.40(s，2H)，4.38(bs，1H)，3.11(s，3H)，1.31(s，6H)。

f)6-amino-5-fluoro-1, 3, 3-trimethylindolin-2-one

Prepared in analogy to example 37c from 6- (benzylamino) -5-fluoro-1, 3, 3-trimethylindolin-2-one. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：209.1[(M+H)⁺]。

g)N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 17 from 6-amino-5-fluoro-1, 3, 3-trimethylindolin-2-one and isonicotinic acid. The title compound was obtained as a white powder.

MS ESI(m/z)：314.0[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.87-8.85(m，2H)，8.13(bs，1H)，8.06-8.04(m，1H)，7.75-7.73(m，2H)，7.07-7.03(m，1H)，3.26(s，3H)，1.37(s，6H)。

Example 21

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 17 from 6-amino-1-ethyl-3, 3-dimethylindolin-2-one (g. georges et al, US2006/142247a1) and nicotinic acid. The title compound was obtained as a white solid.

MS ESI(m/z)：310.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.81-8.79(m，2H)，8.23(bs，1H)，7.75-7.73(m，2H)，7.58(m，1H)，7.20-7.17(m，1H)，7.07-7.04(m，lH)，3.78(q，J＝7.27Hz，2H)，1.36(s，6H)，1.27(t，J＝7.27Hz，3H)。

Example 22

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

Prepared in analogy to example 17 from 6-amino-5-fluoro-1, 3, 3-trimethylindolin-2-one (example 20 f). The title compound was obtained as a white powder.

MS ESI(m/z)：328.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.73-8.71(m，1H)，8.10(bs，1H)，8.06-8.04(m，1H)，7.59(m，1H)，7.52-7.50(m，1H)，7.06-7.03(m，1H)，3.26(s，3H)，2.69(s，3H)，1.37(s，6H)。

Example 23

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 26 from 6-amino-7-fluoro-1, 3, 3-trimethylindolin-2-one (example 13d) and nicotinic acid. The title compound was obtained as off-white crystals.

MS ESI(m/z)：314.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.13(m，1H)，8.83-8.81(m，1H)，8.25-8.21(m，1H)，8.02-7.97(m，2H)，7.51-7.46(m，1H)，7.04-7.02(m，1H)，3.45(m，3H)，1.39(s，6H)。

Example 24

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 17 from 6-amino-5-fluoro-1, 3, 3-trimethylindolin-2-one (example 20f) and nicotinic acid. The title compound was obtained as an off-white solid.

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.14(m，1H)，8.84-8.82(m，1H)，8.24-8.21(m，1H)，8.09(bs，1H)，8.06-8.04(m，1H)，7.52-7.47(m，1H)，7.06-7.03(m，1H)，3.26(s，3H)，1.37(s，6H)。

Example 25

2-chloro-N- (1, 3, 3, 7-tetramethyl-2-oxoindolin-6-yl) isonicotinamide

a)6-bromo-7-methyl-1, 3-dihydro-indol-2-ones

6-bromo-7-methylindoline-2, 3-dione (G.W.Rewcastle et al, J.Med.chem.1991, 34(1), 217-222; 7.65g, 31.9mmol) and hydrazine monohydrate (35.9g, 35ml, 718mmol) were heated to 130 ℃ for 3h and then cooled to 10 ℃. 37% HCl (72.2g, 60.2ml, 733mmol) was added slowly. The precipitate was filtered through sintered glass, washed thoroughly with water, then with a small amount of heptane, and dried under high vacuum. The title compound was obtained as yellow crystals and used in the next reaction without further purification.

b)6-amino-1, 3, 3, 7-tetramethyl-1, 3-dihydro-indol-2-one

Prepared in analogy to example 20d-f from 6-bromo-7-methyl-1, 3-dihydro-indol-2-one. The title compound was obtained as a grey foam.

MS ESI(m/z)：205.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.87-6.84(m，1H)，6.43-6.41(m，1H)，3.62(bs，2H)，3.50(s，3H)，2.37(s，3H)，1.31(s，6H)。

c)2-chloro-N- (1, 3, 3, 7-tetramethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 2-chloroisonicotinic acid and 6-amino-1, 3, 3, 7-tetramethyl-1, 3-dihydro-indol-2-one. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：344.1/346.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.60-8.59(m，1H)，7.80-7.67(m，3H)，7.17-7.08(m，2H)，3.54(s，3H)，2.50(s，3H)，1.36(s，6H)。

Example 26

2-chloro-6-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

Mixing 6-amino-1, 3, 3-trimethylindolin-2-one (120mg, 631. mu. mol), 2-chloro-6-methylnicotinic acid (108mg, 631. mu. mol) and 2- (3H- [1, 2, 3)]Triazolo [4, 5-b]Pyridin-3-yl) -1, 1, 3, 3-tetramethylisoureaA suspension of hexafluorophosphate (V) (480mg, 1.26mmol) and N, N-diisopropylethylamine (408mg, 536. mu.l, 3.15mmol) in DMF (3ml) was stirred at room temperature for 16 h. Adding intoNa₂CO₃An aqueous solution of (a). The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as a white solid (167 mg).

MS ESI(m/z)：344.2/346.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.33(bs，1H)，8.17-8.14(m，1H)，7.54(m，1H)，7.28-7.25(m，1H)，7.20-7.17(m，1H)，7.05-7.02(m，1H)，3.25(s，3H)，2.62(s，3H)，1.37(s，6H)。

Example 27

3-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 3-chloroisonicotinic acid. The title compound was obtained as a white solid.

MS ESI(m/z)：330.2/332.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.74(s，1H)，8.67-8.66(m，1H)，8.00(bs，1H)，7.70-7.68(m，1H)，7.54-7.53(m，1H)，7.20-7.18(m，1H)，7.04-7.01(m，1H)，3.25(s，3H)，1.38(s，6H)。

Example 28

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

Prepared in analogy to example 26 from 6-amino-7-fluoro-1, 3, 3-trimethylindolin-2-one (example 13d) and 2-methylisonicotinic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：328.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.72-8.70(m，1H)，8.02-7.97(m，2H)，7.60(m，1H)，7.51-7.50(m，1H)，7.04-7.02(m，1H)，3.45-3.44(m，2.69(s，3H)，1.38(s，6H)。

Example 29

3-fluoro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 3-fluoroisonicotinic acid. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：314.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.68-8.65(m，2H)，8.46-8.41(m，1H)，8.05-8.01(m，1H)，7.54-7.53(m，1H)，7.21-7.18(m，1H)，7.07-7.04(m，1H)，3.25(s，3H)，1.38(s，6H)。

Example 30

3-chloro-N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 3-chloroisonicotinic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one (example 14 c). The title compound was obtained as a white foam.

MS ESI(m/z)：356.3/358.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.75(m，1H)，8.68-8.66(m，1H)，7.95(m，1H)，7.71-7.69(m，1H)，7.67(m，1H)，7.19-7.16(m，1H)，7.12-7.09(m，1H)，2.72-2.65(m，1H)，1.34(s，6H)，1.14-1.07(m，2H)，0.96-0.91(m，2H)。

Example 31

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one (example 14 c). The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：340.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.69-8.68(m，1H)，8.67-8.65(m，1H)，8.44-8.39(m，1H)，8.06-8.02(m，1H)，7.69-7.68(m，1H)，7.19-7.16(m，1H)，7.14-7.10(m，1H)，2.72-2.65(m，1H)，1.34(s，6H)，1.15-1.08(m，2H)，0.96-0.91(m，2H)

Example 32

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -6-methylnicotinamide

Prepared in analogy to example 1b from 6-amino-7-fluoro-1, 3, 3-trimethylindolin-2-one (example 13d) and 6-methylnicotinic acid. The title compound was obtained as a dark red foam.

MS ESI(m/z)：328.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.01-9.00(m，1H)，8.13-8.09(m，1H)，8.02-7.93(m，2H)，7.34-7.31(m，1H)，7.03-7.01(m，1H)，3.45-3.44(m，3H)，2.67(s，3H)，1.38(s，6H)。

Example 33

5-fluoro-2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 5-fluoro-2-methyl-isonicotinic acid (prepared according to u.abel et al, WO 200645514). The title compound was obtained as a white solid.

MS ESI(m/z)：326.3[(M-H)^-]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.54-8.53(m，1H)，8.45-8.41(m，1H)，7.86-7.84(m，1H)，7.53-7.52(m，1H)，7.20-7.18(m，1H)，7.07-7.04(m，1H)，3.25(s，3H)，2.64(s，3H)，1.38(s，6H)。

Example 34

N- (5-chloro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 2 from 6-amino-5-chloro-1, 3, 3-trimethyl-1, 3-dihydro-indol-2-one (which was prepared in analogy to examples 20a-f starting from 1-bromo-2-chloro-4-fluoro-5-nitrobenzene). The title compound was obtained as light yellow crystals.

MS ESI(m/z)：330.2/332.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.88-8.86(m，2H)，8.52(bs，1H)，8.17(m，1H)，7.77-7.75(m，2H)，7.25(m，1H)，3.26(s，3H)，1.38(s，6H)。

Example 35

N- (5-chloro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

Prepared in analogy to example 26 from 2-methylisonicotinic acid and 6-amino-5-chloro-1, 3, 3-trimethyl-1, 3-dihydro-indol-2-one (which was prepared in analogy to examples 20a-f starting from 1-bromo-2-chloro-4-fluoro-5-nitrobenzene). The title compound was obtained as a white foam.

MS ESI(m/z)：344.1/346.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.74-8.72(m，1H)，8.49(bs，1H)，8.16(m，1H)，7.62(m，1H)，7.54-7.52(m，1H)，7.24(m，1H)，3.26(s，3H)，2.70(s，3H)，1.38(s，6H)。

Example 36

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

a)6-bromo-5-fluoro-3, 3-dimethylindolin-2-one

To a solution of potassium tert-butoxide (9.27g, 82.6mmol) in anhydrous THF (50ml) was added 6-bromo-5-fluoroindolin-2-one (example 20c, 3.8g, 16.5mmol) in portions, followed by copper (I) bromide-dimethylsulfide complex (340mg, 1.65mmol) with ice-bath cooling. After cooling to 2 ℃, methyl iodide (4.92g, 2.17ml, 34.7mmol) was added slowly over a period of 30 minutes. The reaction mixture was warmed to room temperature, stirred for 16 hours, then cooled to 0 ℃ and carefully quenched with saturated ammonium chloride solution.

The mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue was purified by chromatography on silica gel using ethyl acetate/heptane as eluent, followed by trituration with diethyl ether. The title compound was obtained as a yellow solid (3.6 g).

MS ESI(m/z)：258.0/260.0[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝10.44(bs，1H)，7.48-7.45(m，1H)，7.05-7.04(m，1H)，1.25(s，6H)。

b)6-bromo-1-cyclopropyl-5-fluoro-3, 3-dimethyl-1, 3-dihydro-indol-2-one

Prepared in analogy to example 14b from 6-bromo-5-fluoro-3, 3-dimethylindolin-2-one.

MS ESI(m/z)：298.1/300.0[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.24-7.22(m，1H)，6.98-6.96(m，1H)，2.65-2.58(m，1H)，1.32(s，6H)，1.11-1.04(m，2H)，0.92-0.86(m，2H)。

c)N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 20 e-g. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：340.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.87-8.85(m，2H)，8.28-8.26(m，1H)，8.11-8.10(m，1H)，7.75-7.73(m，2H)，7.03-7.00(m，1H)，2.72-2.65(m，1H)，1.34(s，6H)，1.16-1.09(m，2H)，0.96-0.90(m，2H)。

Example 37

N- (1-isopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

a)6-bromo-1-isopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one

To a suspension of 6-bromo-3, 3-dimethylindolin-2-one (example 14a, 1.68g, 7.00mmol) in DMF (30ml) were added 2-bromopropane (2.15g, 1.64ml, 17.5mmol) and cesium carbonate (5.02g, 15.4 mmol). The reaction mixture was heated to 80 ℃ for 18 hours. The reaction mixture was treated with 1M HCl and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄The solvent was dried and evaporated. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as an orange solid (2.00g, 70% purity) and used in the next reaction without further purification.

b)6-benzylamino-1-isopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one

To a solution of 6-bromo-1-isopropyl-3, 3-dimethylindolin-2-one (1.99g, 7.08mmol, 70%) in THF (20.0ml) under argon was added BINAP (227mg, 354. mu. mol) and sodium tert-butoxide (1.74g, 17.7mmol), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (378mg, 354. mu. mol) and benzylamine (766mg, 782. mu.l, 7.08 mmol). The reaction mixture was heated to 70 ℃ for 18 hours. To the reaction mixture was added Na at room temperature₂CO₃The aqueous phase is extracted with tert-butyl methyl ether, the combined organic phases are dried over sodium sulfate, the solvent is evaporated and the residue is purified by chromatography on silica gel using ethyl acetate/heptane as eluent. The title compound was obtained as a yellow foam (1.60 g).

MS ESI(m/z)：309.4[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.42-7.28(m，5H)，6.98-6.97(m，1H)，6.33-6.28(m，2H)，4.58(hep，J＝7.06Hz，1H)，4.35-4.33(m，2H)，4.11(m，1H)，1.39(d，J＝7.06Hz，6H)，1.29(s，6H)。

c)6-amino-1-isopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one

Palladium on activated carbon (10%, 276mg, 259. mu. mol) was added to a solution of 6- (benzylamino) -1-isopropyl-3, 3-dimethylindolin-2-one (1.60g, 5.18mmol) in ethanol (75 ml). The mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 16 hours. Since the reaction was incomplete, the catalyst was filtered off and washed with ethanol. The solvent was evaporated and ethanol (75ml) was added to the residue. Activated carbon supported palladium (276mg, 259 μmol) was added and hydrogenated (balloon) at 50 ℃ for 6 hours and at room temperature for 12 hours. The catalyst was filtered off, washed with ethanol and the solvent was evaporated. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as a pale yellow solid (892 mg).

MS ESI(m/z)：219.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.98-6.95(m，1H)，6.40-6.39(m，1H)，6.36-6.33(m，1H)，4.59(hep，J＝7.06Hz，1H)，3.69(bs，2H)，1.46(d，J＝7.06Hz，6H)，1.30(s，6H)。

d)N- (1-isopropyl-3, 3-dimethyl-2-hydroindolinon-6-yl) nicotinamide

Prepared in analogy to example 26 from 6-amino-1-isopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one and nicotinic acid. The title compound was obtained as a white foam.

MS ESI(m/z)：324.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.11(m，1H)，8.82-8.79(m，1H)，8.25-8.21(m，1H)，7.87(bs，1H)，7.76(m，1H)，7.50-7.45(m，1H)，7.20-7.17(m，1H)，7.02-6.98(m，1H)，4.66(hep，J＝7.06Hz，1H)，1.52(d，J＝7.06Hz，6H)，1.35(s，6H)。

Example 38

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to examples 20e, 20f and 26 from 6-bromo-1-cyclopropyl-5-fluoro-3, 3-dimethyl-1, 3-dihydro-indol-2-one (example 36b) and nicotinic acid. The title compound was obtained as a light yellow foam.

MS ESI(m/z)：340.1[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝9.15-9.14(m，1H)，8.84-8.82(m，1H)，8.28-8.21(m，2H)，8.06-8.05(m，1H)，7.51-7.47(m，1H)，7.03-7.00(m，1H)，2.73-2.65(m，1H)，1.34(s，6H)，1.16-1.09(m，2H)，0.96-0.91(m，2H)。

Example 39

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

Prepared in analogy to example 1b from 6-amino-1-ethyl-3, 3-dimethylindolin-2-one (g. georges et al, US2006/142247a 1). The title compound was obtained as an off-white foam.

MS ESI(m/z)：324.4[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.70-8.69(m，1H)，7.87(bs，1H)，7.59-7.56(m，2H)，7.51-7.49(m，1H)，7.20-7.17(m，1H)，7.04-7.00(m，1H)，3.79(q，J＝7.27Hz，2H)，2.68(s，3H)，1.37(s，6H)，1.29(t，J＝7.27Hz，3H)。

Example 40

3-chloro-N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 3-chloroisonicotinic acid and 6-amino-1-ethyl-3, 3-dimethylindolin-2-one (g. georges et al, US2006/142247a 1). The title compound was obtained as a white solid.

MS ESI(m/z)：344.2/346.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.75(m，1H)，8.68-8.66(m，1H)，7.97(bs，1H)，7.70-7.69(m，1H)，7.55(m，1H)，7.21-7.18(m，1H)，7.03-6.99(m，1H)，3.80(q，J＝7.27Hz，2H)，1.37(s，6H)，1.30(t，J＝7.27Hz，3H)。

EXAMPLE 41

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-ethyl-3, 3-dimethylindolin-2-one (g. georges et al, US2006/142247a 1). The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：328.3[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.68(m，1H)，8.67-8.65(m，1H)，8.44-8.40(m，1H)，8.05-8.01(m，1H)，7.56(m，1H)，7.21-7.18(m，1H)，7.06-7.02(m，1H)，3.80(q，J＝7.27Hz，2H)，1.37(s，6H)，1.30(t，J＝7.27Hz，3H)。

Example 42

N- (1-isopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

Prepared in analogy to example 37d from 2-methylisonicotinic acid. The title compound was obtained as a white solid.

MS ESI(m/z)：338.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.70-8.68(m，1H)，7.91(m，1H)，7.77-7.76(m，1H)，7.60(m，1H)，7.51-7.49(m，1H)，7.19-7.17(m，1H)，7.01-6.98(m，1H)，4.66(hep，J＝7.06Hz，1H)，2.67(s，3H)，1.51(d，J＝6.86Hz，6H)，1.35(s，6H)。

Example 43

4-fluoro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) benzamide

Prepared in analogy to example 26 from 4-fluorobenzoic acid. The title compound was obtained as a white solid.

MS ESI(m/z)：313.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝7.93-7.88(m，2H)，7.82(bs，1H)，7.56-7.55(m，1H)，7.22-7.15(m，3H)，7.01-6.98(m，1H)，3.24(s，3H)，1.37(s，6H)。

Example 44

3-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) picolinamide

Prepared in analogy to example 26 from 3-chloropyridine-2-carboxylic acid. The title compound was obtained as a white solid.

MS ESI(m/z)：330.5/332.4[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.55-8.53(m，1H)，8.24-8.20(m，2H)，7.54(m，1H)，7.43-7.41(m，1H)，7.20-7.18(m，1H)，7.06-7.02(m，1H)，3.25(s，3H)，1.38(s，6H)。

Example 45

N- (1-cyclopentyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

a)6-amino-1-cyclopentyl-3, 3-dimethyl-1, 3-indolin-2-one

Prepared in analogy to examples 37a-c from bromocyclopentane. The title compound was obtained as a yellow waxy solid.

MS ESI(m/z)：245.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.98-6.95(m，1H)，6.37-6.33(m，1H)，6.31(m，1H)，4.80-4.68(m，1H)，3.69(bs，2H)，2.10-1.69(m，8H)，1.30(s，6H)。

b)N- (1-cyclopentyl-3, 3-dimethyl-2-hydroindolino-6-yl) -3-fluoroisonicotinamide

Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-cyclopentyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one. The title compound was obtained as a yellow foam.

MS ESI(m/z)：368.6[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.68-8.67(m，1H)，8.66-8.64(m，1H)，8.42-8.36(m，1H)，8.05-8.01(m，1H)，7.75-7.74(m，1H)，7.20-7.18(m，1H)，6.98-6.95(m，1H)，4.84-4.78(m，1H)，2.15-1.71(m，8H)，1.36(s，6H)。

Example 46

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

a)6-amino-1-cyclopropyl-5-fluoro-3, 3-dimethyl-1, 3-dihydro-indol-2-one

To a solution of 6-bromo-1-cyclopropyl-5-fluoro-3, 3-dimethylindolin-2-one (example 36b, 400mg, 1.34mmol) in NMP (7ml) were added ammonium hydroxide (6.3g, 7ml, 44.9mmol) and copper (I) oxide (38.4mg, 268. mu. mol). The reaction mixture was heated to 110 ℃ for 24 hours in a sealed tube and then poured into dichloromethane (20 ml). The organic phase is washed with 1M aqueous sodium bicarbonate solution and with water, dried over sodium sulfate and concentrated in vacuo. NMP was removed by kugelrohr distillation. The residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as grey self-colored crystals (257 mg).

MS ESI(m/z)：235.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.84-6.81(m，1H)，6.57-6.54(m，1H)，3.75(bs，2H)，2.62-2.54(m，1H)，1.28(s，6H)，1.06-0.99(m，2H)，0.90-0.85(m，2H)。

b)N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

Prepared in analogy to example 26 from 6-amino-1-cyclopropyl-5-fluoro-3, 3-dimethyl-1, 3-dihydro-indol-2-one and 2-methylisonicotinic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：354.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.72-8.71(m，1H)，8.28-8.26(m，1H)，8.09(m，1H)，7.61(m，1H)，7.53-7.51(m，1H)，7.03-6.99(m，1H)，2.72-2.65(m，1H)，2.69(s，3H)，1.33(s，6H)，1.16-1.09(m，2H)，0.96-0.90(m，2H)。

Example 47

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -isonicotinamide

a)5, 7-difluoro-6-iodo-1, 3, 3-trimethyl-1, 3-indolin-2-one

Prepared in analogy to examples 13a-c from 5, 7-difluoro-1, 3-dihydro-indol-2-one. The title compound was obtained as an off-white solid.

MS ESI(m/z)：338[(M+H)⁺]。

b)6-amino-5, 7-difluoro-1, 3, 3-trimethyl-1, 3-dihydro-indol-2-one

Prepared in analogy to example 46a from 5, 7-difluoro-6-iodo-1, 3, 3-trimethyl-1, 3-dihydro-indol-2-one. The title compound was obtained as a yellow solid.

MS ESI(m/z)：227[(M+H)⁺]。

c)N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 2, 3-dihydro-1H-indol-6-yl) -isonicotinamide

To a solution of isonicotinic acid (70mg, 0.569mmol) in DMF (2ml) were added triethylamine (0.24ml, 1.7mmol) and Mukaiyama reagent (312mg, 1.13mmol), followed by 6-amino-5, 7Difluoro-1, 3, 3-trimethyl-1, 3-dihydro-indol-2-one (154mg, 0.682 mmol). The resulting reaction mixture was stirred at 25 ℃ for 12 hours. The mixture was saturated NaHCO₃Aqueous solution (10ml) was diluted and extracted with dichloromethane (2 × 20 ml). The combined organic layers were washed with brine (15ml) and anhydrous Na₂SO₄The solvent was dried and evaporated. The crude material was purified by column chromatography over amine-functionalized silica gel using ethyl acetate/heptane as eluent, followed by preparative HPLC. The title compound was obtained as an off-white solid (45 mg).

MS ESI(m/z)：332[(M+H)⁺]。

Example 48

3-fluoro-N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 6-amino-5-fluoro-1, 3, 3-trimethylindolin-2-one (example 20f) and 3-fluoroisonicotinic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：332.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.81-8.76(m，1H)，8.71-8.66(m，2H)，8.08-8.01(m，2H)，7.07-7.04(m，1H)，3.26(s，3H)，1.37(s，6H)。

Example 49

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

Prepared in analogy to example 47 using 2-methylisonicotinic acid. The title compound was obtained as an off-white solid.

MS ESI(m/z)：346[(M+H)⁺]。

Example 50

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -nicotinamide

Prepared in analogy to example 47, using nicotinic acid. The title compound was obtained as an off-white solid.

MS ESI(m/z)：332[(M+H)⁺]。

Example 51

3-chloro-N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 6-amino-5-fluoro-1, 3, 3-trimethylindolin-2-one (example 20f) and 3-chloroisonicotinic acid. The title compound was obtained as white crystals.

MS ESI(m/z)：348.4/350.4[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.77(m，1H)，8.70-8.68(m，1H)，8.37(m，1H)，8.06-8.04(m，1H)，7.74-7.73(m，1H)，7.06-7.03(m，1H)，3.26(s，3H)，1.37(s，6H)。

Example 52

N- (1- (cyclopropylmethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to examples 37a, 46a and 26 using (bromomethyl) cyclopropane and isonicotinic acid. The title compound was obtained as a white solid.

MS ESI(m/z)：336.2[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.82-8.81(m，2H)，8.05(m，1H)，7.73-7.72(m，2H)，7.67(m，1H)，7.19-7.18(m，1H)，7.03-7.01(m，1H)，3.62(d，J＝6.95Hz，2H)，1.37(s，6H)，1.23-1.19(m，1H)，0.54-0.51(m，2H)，0.42-0.39(m，2H)。

Example 53

N- (1- (cyclopropylmethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

Prepared in analogy to examples 37a, 46a and 26 using (bromomethyl) cyclopropane and 3-fluoroisonicotinic acid. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：354.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.69-8.65(m，2H)，8.44-8.40(m，1H)，8.06-8.02(m，1H)，7.67-7.66(m，1H)，7.21-7.19(m，1H)，7.04-7.00(m，1H)，3.64(d，J＝6.86Hz，2H)，1.38(s，6H)，1.26-1.19(m，1H)，0.57-0.51(m，2H)，0.45-0.39(m，2H)。

Example 54

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -5-fluoro-2-methylisonicotinamide

Prepared in analogy to example 26 from 6-amino-1-cyclopropyl-3, 3-dimethyl-1, 3-dihydro-indol-2-one (example 14c) and 5-fluoro-2-methyl-isonicotinic acid (prepared according to u.abel et al, WO 200645514). The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：354.4[(M+H)⁺]。

¹H NMR(CD₃OD，400MHz)：(ppm)＝8.50(m，1H)，7.76(m，1H)，7.60-7.58(m，1H)，7.35-7.32(m，1H)，7.29-7.26(m，1H)，2.77-2.70(m，1H)，2.61(s，3H)，1.33(s，6H)，1.14-1.08(m，2H)，0.92-0.86(m，2H)。

Example 55

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) isonicotinamide

a)6 '-Bromospiro [ cyclopropane-1, 3' -indoline]-2' ketones

A solution of 6-bromoindolin-2-one (2g, 9.43mmol) and diisopropylamine (2.00g, 2.82ml, 19.8mmol) in tetrahydrofuran (16ml) was cooled to-25 ℃ and a solution of nBuLi (1.6M in hexane, 23.6ml, 37.7mmol) was added dropwise. The reaction mixture was warmed to 0 ℃ and a solution of 1, 2-dibromoethane (5.32g, 2.44ml, 28.3mmol) in tetrahydrofuran (2ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 20 h and quenched carefully with brine (2ml) and concentrated HCl (2ml, ice bath). The reaction mixture was diluted with tert-butyl methyl ether and water. The aqueous phase was extracted with tert-butyl methyl ether and the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as red crystals (1.11 g).

MS ESI(m/z)：238.3/240.3[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.67(bs，1H)，7.12-7.09(m，1H)，7.03(m，1H)，6.95-6.92(m，1H)，1.61-1.57(m，2H)，1.49-1.45(m，2H)。

b)6 ' -amino-1 ' -cyclopropylspiro [ cyclopropane-1, 3 ' -indoline]-2' -ketones

Prepared in analogy to examples 14b and 46a from 6 ' -bromospiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one. The title compound was obtained as light brown crystals.

MS ESI(m/z)：215.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝6.60-6.57(m，2H)，6.35-6.32(m，1H)，3.72(bs，2H)，2.69-2.61(m，1H)，1.61-1.58(m，2H)，1.37-1.33(m，2H)，1.07-0.98(m，2H)，0.96-0.91(m，2H)。

c)N- (1 ' -cyclopropyl-2 ' -hydro-spiro [ cyclopropane-1, 3 ' -indoline)]-6' -yl) isonicotinamide

Prepared in analogy to example 26 from 6 ' -amino-1 f-cyclopropylspiro [ cyclopropane-1, 3 ' -indolin ] -2 ' -one and isonicotinic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：320.4[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.54(s，1H)，8.80-8.78(m，2H)，7.89-7.87(m，2H)，7.77-7.76(m，1H)，7.44-7.41(m，1H)，7.00-6.97(m，1H)，2.78-2.71(m，1H)，1.56-1.53(m，2H)，1.48-1.44(m，2H)，1.05-0.99(m，2H)，0.86-0.80(m，2H)。

Example 56

3-chloro-N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) isonicotinamide

Prepared in analogy to example 55, using 3-chloroisonicotinic acid. The title compound was obtained as light brown crystals.

MS ESI(m/z)：354.4/356.4[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.74(s，1H)，8.80(m，1H)，8.68-8.66(m，1H)，7.70-7.66(m，2H)，7.32-7.29(m 1H)，6.99-6.96(m，1H)，2.78-2.71(m，1H)，1.56-1.52(m，2H)，1.48-1.44(m，2H)，1.04-0.97(m，2H)，0.85-0.79(m，2H)。

Example 57

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) -3-fluoroisonicotinamide

Prepared in analogy to example 55, using 3-fluoroisonicotinic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：338.4[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)：(ppm)＝10.73(s，1H)，8.77(m，1H)，8.61-8.59(m，1H)，7.74-7.70(m，2H)，7.34-7.31(m 1H)，6.99-6.97(m，1H)，2.77-2.72(m，1H)，1.56-1.53(m，2H)，1.48-1.44(m，2H)，1.04-0.97(m，2H)，0.85-0.79(m，2H)。

Example 58

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to examples 37a, 46a and 26, using 3-bromooxetane and isonicotinic acid. The title compound was obtained as a white foam.

MS ESI(m/z)：338.5[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.85-8.83(m，2H)，7.93-7.92(m，2H)，7.75-7.73(m，2H)，7.45-7.42(m，1H)，7.29-7.24(m，1H)，5.65-5.56(m，1H)，5.17-5.08(m，4H)，1.39(s，6H)。

Example 59

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to examples 37a and 46a and 26 using 3-bromooxetane and 3-fluoroisonicotinic acid. The title compound was obtained as a white foam.

MS ESI(m/z)：356.4[(M+H)⁺]。

¹H NMR(CDCl₃，400MHz)：(ppm)＝8.69-8.68(m，1H)，8.66-8.64(m，1H)，8.46-8.42(m，1H)，8.06-8.03(m，2H)，7.29-7.25(m，2H)，5.63-5.54(m，1H)，5.19-5.07(m，4H)，1.39(s，6H)。

Example 60

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) -2-methylisonicotinamide

Prepared in analogy to example 55 using 2-methylisonicotinic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：334.5[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)＝10.49(s，1H)，8.64(d，J＝4.8Hz，1H)，7.76-7.75(m，2H)，7.67(d，J＝5.0Hz，1H)，7.43(dd，J＝1.8，8.1Hz，1H)，6.98(d，J＝8.1Hz，1H)，2.78-2.72(m，1H)，2.58(s，3H)，1.56-1.44(m，4H)，1.05-0.80(m，4H)。

Example 61

3-chloro-N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 23 using 3-chloroisonicotinic acid. The title compound was obtained as yellow crystals.

MS ESI(m/z)：348.4/350.4[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)＝10.58(s，1H)，8.79(s，1H)，8.67(d，J＝4.8Hz，1H)，7.64(d，J＝4.6Hz，1H)，7.39-7.34(m，1H)，7.22(d，J＝7.9Hz，1H)，3.32(s，3H)，1.30(s，6H)。

Example 62

3-chloro-N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 59, using 3-chloroisonicotinic acid. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：372.5/374.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.75(s，1H)，8.66(d，J＝4.6Hz，1H)，8.02(s，1H)，7.92(d，J＝1.8Hz，1H)，7.70(d，J＝4.8Hz，1H)，7.39(dd，J＝1.9，8.0Hz，1H)，7.29-7.26(m，1H)，5.62-5.53(m，1H)，5.17-5.06(m，4H)，1.39(s，6H)。

Example 63

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) -2-methylisonicotinamide

Prepared in analogy to example 59 using 2-methylisonicotinic acid. The title compound was obtained as a white foam.

MS ESI(m/z)：352.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.70(d，J＝5.0Hz，1H)，7.93(s，1H)，7.90(d，J＝1.8Hz，1H)，7.62(s，1H)，7.53(d，J＝5.2Hz，1H)，7.47(dd，J＝1.9，8.0Hz，1H)，7.28-7.26(m，1H)，5.60(tt，J＝5.9，7.9Hz，1H)，5.18-5.07(m，4H)，2.68(s，3H)，1.39(s，6H)。

Example 64

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) nicotinamide

Prepared in analogy to example 59 using 2-methylisonicotinic acid. The title compound was obtained as a light yellow foam.

MS ESI(m/z)：338.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝9.15(d，J＝1.8Hz，1H)，8.77(dd，J＝1.6，4.8Hz，1H)，8.31(br s，1H)，8.26(td，J＝2.0，7.9Hz，1H)，7.93(d，J＝1.6Hz，1H)，7.51-7.41(m，2H)，7.28-7.26(m，1H)，5.65-5.56(m，1H)，5.18-5.07(m，4H)，1.38(s，6H)。

Example 65

N- (1- (3-Cyclopropoxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

a)(3-Bromopropoxy) cyclopropane

To 3-Cyclopropoxyprop-propan-1-ol (J. -W. Huang et al, Tetrahedron Letters, 1999, 40(49), 8647-8650; 350mg, 3.01mmol) and CBr₄(1.2g, 3.62mmol) to a solution in pentane (4ml) triphenylphosphine (948mg, 3.62mmol) was added in portions. The reaction mixture was stirred at room temperature for 18 hours, then filtered through sintered glass and washed with pentane. The pentane layers were combined and concentrated in vacuo. The title compound was obtained as a colorless liquid (586mg, purity-90%).

¹H NMR(CDCl₃，300MHz)＝3.62(t，J＝6.0Hz，2H)，3.47(t，J＝6.5Hz，2H)，3.31-3.25(m，1H)，2.08(quin，J＝6.2Hz，2H)，0.59-0.43(m，4H)。

b)6-bromo-1- (3-cyclopropoxypropyl) -3, 3-dimethylindolin-2-one

To 6-bromo-3, 3-dimethylindolin-2-one (example 14a, 300mg, 1.25mmol) and Cs₂CO₃(814mg, 2.5mmol) to a suspension in DMF (2ml) was added a solution of (3-bromopropoxy) cyclopropane (447mg, 2.5mmol) in DMF (0.5 ml). The reaction mixture was heated to 70 ℃ for 3 hours. The reaction mixture was filtered through sintered glass and concentrated. The crude material was purified by flash chromatography on silica gel using ethyl acetate as eluent. The title compound was obtained as an orange viscous oil (360 mg).

MS ESI(m/z)：338.4/340.4[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝7.17(dd，J＝1.8，7.9Hz，1H)，7.06-7.03(m，2H)，3.75(t，J＝6.9Hz，2H)，3.49(t，J＝6.0Hz，2H)，3.24(tt，J＝3.0，6.1Hz，1H)，1.92(quin，J＝6.4Hz，2H)，1.35(s，6H)，0.59-0.41(m，4H)。

c)6-amino-1- (3-ring)Propoxypropyl) -3, 3-dimethylindolin-2-one

To 6-bromo-1- (3-cyclopropyloxypropyl) -3, 3-dimethylindolin-2-one (360mg, 1.06mmol) and K₂CO₃(441mg, 3.19mmol) to a suspension in DMSO (2ml) were added L-proline (49.0mg, 426. mu. mol), copper (I) iodide (40.5mg, 213. mu. mol) and ammonium hydroxide (373mg, 414. mu.l, 2.66 mmol). The tube was sealed and heated to 90 ℃ for 7 hours. The reaction mixture was poured into TBME (50ml) and extracted with 1M HCl. The combined aqueous layers were washed with 2M Na₂CO₃Alkalizing. The aqueous phase was extracted twice with TBME. The combined organic layers were washed with Na₂SO₄Dried and concentrated under vacuum. The title compound was obtained as a brown viscous oil (228 mg).

MS ESI(m/z)：275.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝6.95(d，J＝7.9Hz，1H)，6.34(dd，J＝2.1，7.8Hz，1H)，6.27(d，J＝2.0Hz，1H)，3.71(t，J＝6.9Hz，2H)，3.50(t，J＝6.2Hz，2H)，3.25(tt，J＝3.1，6.0Hz，1H)，1.91(quin，J＝6.6Hz，2H)，1.31(s，6H)，0.59-0.41(m，4H)。

d)N- (1- (3-Cyclopropoxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

Prepared in analogy to example 26 from 6-amino-1- (3-cyclopropyloxypropyl) -3, 3-dimethylindolin-2-one and 3-fluoroisonicotinic acid. The title compound was obtained as a yellow oil.

MS ESI(m/z)：398.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.68(d，J＝2.8Hz，1H)，8.65(dd，J＝1.4，5.0Hz，1H)，8.40(d，J＝13.5Hz，1H)，8.03(dd，J＝4.9，6.6Hz，1H)，7.45(d，J＝1.4Hz，1H)，7.21-7.14(m，2H)，3.81(t，J＝6.9Hz，2H)，3.52(t，J＝6.1Hz，2H)，3.25(tt，J＝3.0，6.1Hz，1H)，1.96(quin，J＝6.5Hz，2H)，1.37(s，6H)，0.59-0.39(m，4H)。

Example 66

N- (1- (3-Cyclopropoxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared similarly to example 65 using isonicotinic acid. The title compound was obtained as light yellow crystals.

MS ESI(m/z)：380.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.84-8.82(m，2H)，7.85(s，1H)，7.73-7.71(m，2H)，7.44(d，J＝1.6Hz，1H)，7.19(d，J＝8.1Hz，1H)，7.13(dd，J＝1.8，8.1Hz，1H)，3.80(t，J＝6.9Hz，2H)，3.53(t，J＝6.1Hz，2H)，3.25(tt，J＝3.1，6.0Hz，1H)，1.96(quin，J＝6.5Hz，2H)，1.37(s，6H)，0.58-0.39(m，4H)。

Example 67

3-fluoro-N- (1- (hydroxymethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

a)6-bromo-3, 3-dimethyl-1- ((2- (trimethylsilyl) ethoxy) methyl) indolin-2-one

A solution of 6-bromo-3, 3-dimethylindolin-2-one (example 14a, 4.87g, 20.3mmol) in THF (135ml) was cooled to 0 deg.C and a solution of sodium bis (trimethylsilyl) amide in THF (1M, 24.3ml, 24.3mmol) was added over a period of 15 minutes. A solution of (2- (chloromethoxy) ethyl) trimethylsilane (4.27g, 4.54ml, 24.3mmol) in THF (5ml) was then added over a period of 15 minutes. After 4 hours, the reaction mixture was poured into ice water at 0 ℃.

The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with Na₂SO₄The solvent was dried and evaporated. The crude product was purified by flash chromatography on silica gel using EtOAc/heptane as eluent. The title compound was obtained as a pale yellow liquid (7.76g, 70% purity).

MS ESI(m/z)：370.0/372.0[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝7.24-7.21(m，2H)，7.07(d，J＝8.5Hz，1H)，5.13(s，2H)，3.57-3.51(m，2H)，1.37(s，6H)，0.95-0.92(m，2H)，-0.04(s，9H)。

b)3-fluoro-N- (1- (hydroxymethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

To a solution of N- (3, 3-dimethyl-2-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) indolin-6-yl) -3-fluoroisonicotinamide (prepared from 6-bromo-3, 3-dimethyl-1- ((2- (trimethylsilyl) ethoxy) methyl) indolin-2-one and 3-fluoroisonicotinic acid in analogy to examples 37b, 37c and 26; 110mg, 256. mu. mol) in chloroform (2ml) was added TFA (1.7g, 1.14ml, 14.9 mmol). After 5 hours at room temperature, the reaction mixture was washed with NaHCO₃Treating with a saturated aqueous solution. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄Dried and concentrated under vacuum. The crude material was purified by flash chromatography on silica gel using ethyl acetate/heptane as eluent.

The title compound was obtained as a pale yellow solid (42 mg).

MS ESI(m/z)：330.4[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)＝10.71(s，1H)，8.76(d，J＝1.4Hz，1H)，8.59(dd，J＝1.3，4.7Hz，1H)，7.70-7.67(m，1H)，7.56(s，1H)，7.33(m，2H)，6.23(t，J＝6.9Hz，1H)，5.05(d，J＝6.9Hz，2H)，1.28(s，6H)。

Example 68

3-fluoro-N- (1- (2-hydroxyethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

a)6-bromo-1- (2- (tert-butyldimethylsilyloxy) ethyl) -3, 3-dimethylindolin-2-one

To a solution of 6-bromo-3, 3-dimethylindolin-2-one (example 14a, 500mg, 2.08mmol) in DMF (16.7ml) under argon was added (2-bromoethoxy) (tert-butyl) dimethylsilane (996mg, 894. mu.l, 4.16mmol) and cesium carbonate (1.36g, 4.16 mmol). After 1h, at 80 ℃, the reaction mixture was treated with water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using heptane/ethyl acetate as eluent. The title compound was obtained as an orange liquid (740 mg).

MS ESI(m/z)：398.5/400.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝7.19(d，J＝1.6Hz，1H)，7.15(dd，J＝1.6，7.9Hz，1H)，7.02(d，J＝7.9Hz，1H)，3.87-3.78(m，4H)，1.35(s，6H)，0.81(s，9H)，-0.04(s，6H)。

b)3-fluoro-N- (1- (2-hydroxyethyl) -33-dimethyl-2-oxoindolin-6-yl) isonicotinamide

To N- (1- (2- (tert-butyldimethylsilyloxy) ethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide (prepared from 6-bromo-1 in analogy to examples 65c and 26)- (2- (tert-butyldimethylsilyloxy) ethyl) -3, 3-dimethylindolin-2-one and 3-fluoroisonicotinic acid; 195mg, 426. mu. mol) in THF (10ml) was added a solution of TBAF in THF (1M, 639. mu.l, 639. mu. mol). After 2 hours at room temperature, the reaction mixture was treated with water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as a pale yellow solid (151 mg).

MS ESI(m/z)：344.5[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)＝10.69(s，1H)，8.76(d，J＝1.2Hz，1H)，8.60(dd，J＝1.1，4.7Hz，1H)，7.71-7.67(m，1H)，7.51(s，1H)，7.33-7.29(m，2H)，4.90(t，J＝5.4Hz，1H)，3.72-3.68(m，2H)，3.62-3.57(m，2H)，1.27(s，6H)。

Example 69

3-fluoro-N- (1- (3-hydroxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 68 using (3-bromopropoxy) (tert-butyl) dimethylsilane. The title compound was obtained as a light yellow foam.

MS ESI(m/z)：358.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.68(d，J＝2.8Hz，1H)，8.66(dd，J＝1.4，4.8Hz，1H)，8.43(d，J＝14.5Hz，1H)，8.02(dd，J＝4.9，6.6Hz，1H)，7.63(d，J＝1.8Hz，1H)，7.22(d，J＝7.9Hz，1H)，7.04(dd，J＝1.8，7.9Hz，1H)，3.95-3.91(m，2H)，3.59-3.53(m，2H)，3.16-3.11(m，1H)，1.91(td，J＝6.0，11.7Hz，2H)，1.40(s，6H)。

Example 70

N- (1- (3- (cyclopropylsulfonyl) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

a)3- (Cyclopropylthio) propan-1-ol

A solution of 3-mercaptopropan-1-ol (1.15g, 1.08ml, 12.5mmol), potassium tert-butoxide (1.4g, 12.5mmol) and bromocyclopropane (1.51g, 1ml, 12.5mmol) in DMSO (30ml) was heated to 80 ℃ for 15 h. The reaction mixture was poured into 75mL of saturated NaHCO₃In aqueous solution and extracted with diethyl ether and washed with water. The combined organic layers were dried over sodium sulfate, filtered and the resulting solution was concentrated in vacuo. The title compound was obtained as a red liquid (1.24g) and used without further purification.

¹H NMR(CDCl₃，300MHz)：＝3.78(q，J＝5.9Hz，2H)，2.70(t，J＝7.1Hz，2H)，2.00-1.81(m，3H)，0.95-0.75(m，2H)，0.61-0.47(m，2H)。

b)(3-bromopropyl) (cyclopropyl) sulfane

To 3- (cyclopropylthio) propan-1-ol (1.68g, 12.7mmol) and CBr under ice-cooling₄To a suspension of (5.06g, 15.2mmol) in pentane (13ml) was added triphenylphosphine (4.00g, 15.2mmol) in portions. Dichloromethane (7ml) was added and the suspension was stirred for 4 hours. The reaction mixture was filtered and washed with pentane. The solution obtained was concentrated in vacuo. The title compound was obtained as a mixture with TPPO, brown semi-solid (6.66 g). This material was used without further purification.

c)6-amino-1- (3- (cyclopropylthio) propyl) 3-,3-dimethylindolin-2-ones

Prepared in analogy to examples 65b and 65c using (3-bromopropyl) (cyclopropyl) sulfane. The title compound was obtained as a brown viscous oil.

MS ESI(m/z)：291.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝6.96(d，J＝7.9Hz，1H)，6.35(dd，J＝2.0，7.9Hz，1H)，6.28(d，J＝2.0Hz，1H)，3.76(t，J＝7.1Hz，2H)，3.71(br s，2H)，2.632.58(m，2H)，2.00(quin，J＝7.2Hz，2H)，1.89(tt，J＝4.3，7.4Hz，1H)，1.32(s，6H)，0.86-0.80(m，2H)，0.57-0.51(m，2H)。

d)N- (1- (3- (cyclopropylthio) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

A solution of 6-amino-1- (3- (cyclopropylthio) propyl) -3, 3-dimethylindolin-2-one (160mg, 496. mu. mol), isonicotinoyl chloride (84.2mg, 595. mu. mol) and DIPEA (192mg, 260. mu.l, 1.49mmol) in dichloromethane (3ml) was stirred at room temperature for 3 hours. The crude material was purified by flash chromatography on silica gel using EtOAc/heptane as eluent. The title compound was obtained as a yellow viscous oil (131 mg).

MS ESI(m/z)：396.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.84-8.82(m，2H)，7.89(s，1H)，7.73-7.71(m，2H)，7.54(d，J＝1.8Hz，1H)，7.19(d，J＝7.9Hz，1H)，7.08(dd，J＝1.8，7.9Hz，1H)，3.85(t，J＝7.1Hz，2H)，2.62(t，J＝7.4Hz，2H)，2.06(quin，J＝7.2Hz，2H)，1.91(tt，J＝4.4，7.4Hz，1H)，1.37(s，6H)，0.86-0.80(m，2H)，0.56-0.51(m，2H)。

e)N- (1- (3- (cyclopropylsulfonyl) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

To N- (1- (3- (cyclopropylthio) propyl) -3, 3-dimethyl-2-oxodihydroTo a solution of indol-6-yl) isonicotinamide (130mg, 329 μmol) in methanol (1ml) was added dropwise a solution of potassium persulfate formulation (oxone) (303mg, 493 μmol) in water (1.00 ml). After 2 hours, at room temperature, the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with saturated NaHCO₃Washing with Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent. The title compound was obtained as a white foam (91 mg).

MS ESI(m/z)：428.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.84-8.82(m，2H)，7.93(s，1H)，7.73-7.71(m，2H)，7.47(d，J＝1.6Hz，1H)，7.22(d，J＝7.9Hz，1H)，7.17(dd，J＝1.6，7.9Hz，1H)，3.92(t，J＝7.0Hz，2H)，3.14-3.09(m，2H)，2.42(tt，J＝4.8，7.9Hz，1H)，2.34-2.25(m，2H)，1.38(s，6H)，1.28-1.22(m，2H)，1.09-1.02(m，2H)。

Example 71

N- (1- (3- (cyclopropylsulfonyl) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to examples 70a-c, 26 and 70e, using 3-fluoroisonicotinic acid. The title compound was obtained as a white foam.

MS ESI(m/z)：446.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.68(d，J＝2.6Hz，1H)，8.66(d，J＝4.8Hz，1H)，8.43(d，J＝13.7Hz，1H)，8.01(dd，J＝5.0，6.5Hz，1H)，7.54(d，J＝1.8Hz，1H)，7.22(d，J＝8.0Hz，1H)，7.13(dd，J＝1.8，8.0Hz，1H)，3.93(t，J＝6.8Hz，2H)，3.14-3.09(m，2H)，2.42(tt，J＝4.8，8.0Hz，1H)，2.36-2.26(m，2H)，1.38(s，6H)，1.28-1.22(m，2H)，1.09-1.02(m，2H)。

Example 72

N- (3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

Prepared in analogy to example 1 using 3-fluoroisonicotinic acid. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：300.5[(M+H)⁺]。

¹H NMR(DMSO-D₆，400MHz)＝10.65(s，1H)，10.38(s，1H)，8.76(d，J＝1.1Hz，1H)，8.59(dd，J＝1.3，4.8Hz，1H)，7.69-7.67(m，1H)，7.44(d，J＝1.9Hz，1H)，7.28-7.22(m，1H)，7.21-7.12(m，1H)，1.24(s，6H)。

Example 73

3-chloro-N- (1- (3-hydroxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

Prepared in analogy to example 69, using 3-chloroisonicotinic acid. The title compound was obtained as a white solid.

MS ESI(m/z)：374.5/376.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.74(s，1H)，8.66(d，J＝5.0Hz，1H)，8.11(s，1H)，7.67(d，J＝4.8Hz，1H)，7.61(d，J＝1.8Hz，1H)，7.21(d，J＝7.9Hz，1H)，7.04(dd，J＝1.8，7.9Hz，1H)，3.94-3.90(m，2H)，3.57-3.51(m，2H)，3.18(t，J＝6.7Hz，1H)，1.90(quin，J＝5.9Hz，2H)，1.39(s，6H)。

Example 74

N- (3, 3-dimethyl-2-oxo-1- (2, 2, 2-trifluoroethyl) indolin-6-yl) -3-fluoroisonicotinamide

To a solution of N- (3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide (example 72, 78mg, 261. mu. mol) in DMF (700. mu.l) was added 2, 2, 2-trifluoroethyl triflate (66.5mg, 39.6. mu.l, 287. mu. mol) and cesium carbonate (93.4mg, 287. mu. mol) under argon atmosphere. After 3 hours, at room temperature, the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄The solvent was dried and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by trituration with diethyl ether/heptane. The title compound was obtained as a white foam (36 mg).

MS ESI(m/z)：382.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.68(d，J＝2.6Hz，1H)，8.66(dd，J＝1.4，4.8Hz，1H)，8.43(d，J＝13.3Hz，1H)，8.03(dd，J＝4.9，6.6Hz，1H)，7.64(s，1H)，7.23(d，J＝7.9Hz，1H)，7.13(dd，J＝1.9，7.9Hz，1H)，4.36(q，J＝8.7Hz，2H)，1.42(s，6H)。

Example 75

N- (3, 3-dimethyl-1- (2- (methylsulfonyl) ethyl) -2-oxoindolin-6-yl) -3-fluoroisonicotinamide

To a solution of N- (3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide (example 72, 100mg, 334. mu. mol) in DMF (1.67ml) under argon atmosphere was added methylsulfonylethylene (35.5mg, 31.6. mu.l, 334. mu. mol) and cesium carbonate (109mg, 334. mu. mol). After 3 hours at room temperature, the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with Na₂SO₄The solvent was dried and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by preparative HPLC. The title compound was obtained as an off-white solid (60 mg).

MS ESI(m/z)：406.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.68(d，J＝2.6Hz，1H)，8.65(dd，J＝1.3，4.9Hz，1H)，8.45(d，J＝13.1Hz，1H)，8.02(dd，J＝4.8，6.5Hz，1H)，7.56(d，J＝1.6Hz，1H)，7.23(d，J＝7.9Hz，1H)，7.18(dd，J＝1.8，7.9Hz，1H)，4.24(t，J＝6.8Hz，2H)，3.43(t，J＝6.8Hz，2H)，3.01(s，3H)，1.39(s，6H)。

Example 76

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide

a)6-chloro-1, 3, 3-trimethyl-pyrrolo [2, 3-b]Pyridin-2-ones

Under argon, reacting 6-chloro-1H-pyrrolo [2, 3-b ]]A suspension of pyridin-2 (3H) -one (300mg, 1.78mmol) in dry THF (4.19ml) was added portionwise over a period of 10 minutes to a suspension of NaH (60% in mineral oil, 285mg, 7.12mmol) in dry THF (1.74ml) and the reaction mixture was stirred for 20 minutes. MeI (1.01g, 445. mu.l, 7.12mmol) was added dropwise carefully during 30 minutes at 23-26 ℃ and the mixture was stirred for a further 3 hours. The reaction mixture was carefully diluted with 10ml of saturated NH₄Aqueous Cl solution was quenched and washed with EtOAc, water and saturated NaHCO₃And (5) diluting the aqueous solution. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with saturated NaHCO₃The aqueous solution was washed, dried over sodium sulfate and the solvent was evaporated. The crude material was purified by silica gel chromatography using heptane/ethyl acetate as eluent. The title compound was isolated as a red solid (149 mg).

MS ESI(m/z)：211.1/213.3[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝7.36(d，J＝7.5Hz，1H)，6.98(d，J＝7.7Hz，1H)，3.28(s，3H)，1.38(s，6H)。

b)6- (benzylamino) -1, 3, 3-trimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-2 (3H) -ones

To a mixture of 6-chloro-1, 3, 3-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-2-one (500mg, 2.37mmol), benzylamine (763mg, 778. mu.l, 7.12mmol) and sodium tert-butoxide (388mg, 4.03mmol) in toluene (10ml) was added tris (dibenzylideneacetone) dipalladium (O) chloroform adduct (49.1mg, 47.5. mu. mol) and BINAP (29.6mg, 47.5. mu. mol). The reaction mixture was heated to 115 ℃ and stirred for 48 hours. The reaction mixture was diluted with EtOAc, silica gel was added and the mixture was concentrated in vacuo. The obtained material was purified by silica gel chromatography using heptane/ethyl acetate as eluent. The title compound was obtained as a pale yellow solid (616 mg).

MS ESI(m/z)：282.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝7.41-7.27(m，5H)，7.17(d，J＝7.9Hz，1H)，5.97(d，J＝7.9Hz，1H)，4.85(br t，J＝5.4Hz，1H)，4.48(d，J＝5.9Hz，2H)，3.21(s，3H)，1.32(s，6H)。

c)6-amino-1, 3, 3-trimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-2 (3H) -one hydrochloride

A mixture of 6- (benzylamino) -1, 3, 3-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-2 (3H) -one (610mg, 2.17mmol) and 25% aqueous HCl (1.2g, 1ml, 8.23mmol) in ethanol (20ml) was evacuated three times and flushed with argon. Pd (10%, on activated carbon, 231mg, 217. mu. mol) was added. Degassing was repeated, then evacuated three times and flushed with hydrogen. The reaction mixture was heated to 40 ℃ and stirred at this temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through a glass fiber filter, washed with EtOH and the solvent was evaporated. The title compound was obtained as a grey solid (388mg) and used without further purification.

MS ESI(m/z)：192.5[(M+H)⁺]。

¹H NMR(DMSO-D₆，300MHz)＝7.33(d，J＝7.9Hz，1H)，6.10(d，J＝8.1Hz，1H)，3.06(s，3H)，1.21(s，6H)。

d)N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) isonicotinamides

Prepared in analogy to example 2 from 6-amino-1, 3, 3-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-2 (3H) -one hydrochloride and isonicotinoyl chloride hydrochloride. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：297.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.88-8.80(m，2H)，8.39(br s，1H)，8.01(d，J＝7.9Hz，1H)，7.80-7.74(m，2H)，7.50(d，J＝8.1Hz，1H)，3.25(s，3H)，1.40(s，6H)。

Example 77

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) nicotinamide

Prepared in analogy to example 2, using 6-amino-1, 3, 3-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-2-one hydrochloride (example 76c) and nicotinoyl chloride hydrochloride. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：297.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝9.17(d，J＝1.8Hz，1H)，8.82(dd，J＝1.6，4.8Hz，1H)，8.38(br s，1H)，8.30-8.21(m，1H)，8.01(d，J＝7.9Hz，1H)，7.53-7.44(m，2H)，3.25(s，3H)，1.40(s，6H)。

Example 78

2-methyl-N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide

Prepared in analogy to example 26 using 6-amino-1, 3, 3-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-2 (3H) -one hydrochloride (example 76c) and 2-methylisonicotinic acid. The title compound was obtained as a light brown viscous oil.

MS ESI(m/z)：311.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.71(d，J＝5.0Hz，1H)，8.36(br s，1H)，8.01(d，J＝7.9Hz，1H)，7.63(s，1H)，7.55(d，J＝5.2Hz，1H)，7.50(d，J＝7.9Hz，1H)，3.25(s，3H)，2.69(s，3H)，1.40(s，6H)。

Example 79

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide

a)6-chloro-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-2 (3H) -ones

Prepared in analogy to examples 14a and 14b from 6-chloro-1, 3-dihydro-pyrrolo [3, 2-c ] pyridin-2-one (p. eastwood et al, bioorg.med.chem.lett.2011, 21(18), 5270-. The title compound was obtained as yellow crystals.

MS ESI(m/z)：237.4[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.04(s，1H)，7.04(d，J＝0.6Hz，1H)，2.65(tt，J＝3.7，7.1Hz，1H)，1.38(s，6H)，1.14-1.07(m，2H)，0.91-0.86(m，2H)。

b)1-cyclopropyl-6- (diphenylmethyleneamino) -3, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridine-2 (3H) -ketones

To a suspension of 6-chloro-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (1.789g, 7.56mmol), diphenylmethanimine (2.05g, 1.9ml, 11.3mmol, Eq: 1.5), and sodium tert-butoxide (1.23g, 12.8mmol) in toluene (48ml) were added the tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (156mg, 151. mu. mol) and BINAP (94.1mg, 151. mu. mol). The reaction mixture was heated to 100 ℃ for 18 hours and then diluted with dichloromethane. Silica gel was added and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel using heptane/EtOAc as eluent. The title compound was obtained as brown crystals (2.31 g).

MS ESI(m/z)：382.6[(M+H)⁺]。

c)6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c)]Pyridin-2 (3H) -ones

A suspension of 1-cyclopropyl-6- (diphenylmethyleneamino) -3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (2.31g, 6.06mmol), sodium acetate (1.49g, 18.2mmol) and hydroxylamine hydrochloride (926mg, 13.3mmol) in methanol (60ml) was heated to 50 ℃ for 3 hours. The reaction mixture was diluted with methanol, silica gel was added and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent. The title compound was obtained as off-white crystals (1.1 g).

MS ESI(m/z)：218.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝7.73(s，1H)，6.23(s，1H)，4.60(br s，2H)，2.63-2.56(m，1H)，1.33(s，6H)，1.07-1.01(m，2H)，0.89-0.84(m，2H)

d)N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-6-yl) iso Nicotinamide

Prepared in analogy to example 2 from 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one. The title compound was obtained as white crystals.

MS ESI(m/z)：323.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.86-8.84(m，2H)，8.65(br s，1H)，8.19(s，1H)，7.97(s，1H)，7.77-7.75(m，2H)，2.72(tt，J＝3.6，7.1Hz，1H)，1.39(s，6H)，1.20-1.13(m，2H)，0.96-0.91(m，2H)。

Example 80

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) nicotinamide

Prepared in analogy to example 2 from nicotinoyl chloride hydrochloride and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79 c). The title compound was obtained as light yellow crystals.

MS ESI(m/z)：323.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝9.18(d，J＝2.2Hz，1H)，8.82(dd，J＝1.5，4.7Hz，1H)，8.62(br s，1H)，8.24(td，J＝2.0，7.9Hz，1H)，8.19(s，1H)，7.97(s，1H)，7.48(dd，J＝4.8，8.1Hz，1H)，2.72(tt，J＝3.7，7.1Hz，1H)，1.39(s，6H)，1.19-1.13(m，2H)，0.97-0.91(m，2H)。

Example 81

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methylisonicotinamide

Prepared in analogy to example 26 from 2-methylisonicotinic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79 c). The title compound was obtained as an off-white foam.

MS ESI(m/z)：337.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.70(d，J＝5.2Hz，1H)，8.70(br s，1H)，8.20(s，1H)，7.95(s，1H)，7.63(s，1H)，7.54(dd，J＝1.2，5.0Hz，1H)，2.76-2.68(m，1H)，2.67(s，3H)，1.39(s，6H)，1.19-1.12(m，2H)，0.96-0.91(m，2H)。

Example 82

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide

a)6-chloro-3, 3-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-2 (3H) -ones

To a suspension of potassium tert-butoxide (3.2g, 28.0mmol) in anhydrous THF (10.5ml) under ice-cooling and argon atmosphere was added 6-chloro-1H-pyrrolo [2, 3-b ]]A suspension of pyridin-2 (3H) -one (1g, 5.59mmol) in dry THF (8.1 ml). Copper (I) bromide-dimethyl sulfide complex (116mg, 559. mu. mol) was added. MeI (1.59g, 699. mu.l, 11.2mmol) in THF (1ml) was added dropwise carefully during 15 min at the same temperature. The cooling bath was removed. After 30 minutes at room temperature, the reaction mixture was cooled to 0 ℃ and saturated NH was added₄Aqueous Cl solution (20 ml). The aqueous phase was extracted with EtOAc. The combined organic layers were washed with water and Na₂SO₄The solvent was dried and evaporated. The crude material was purified by silica gel chromatography using heptane/ethyl acetate as eluent. The title compound was obtained as a pink solid (470 mg).

MS ESI(m/z)：197.1/199.2[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.13(br s，1H)，7.39(d，J＝7.9Hz，1H)，7.00(d，J＝7.7Hz，1H)，1.42(s，6H)。

b)6-chloro-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-2 (3H) -ones

To 6-chloro-3, 3-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridine-2(3H) -one (150mg, 763. mu. mol), cyclopropylboronic acid (131mg, 1.53mmol), copper (II) acetate (145mg, 801. mu. mol) and DMAP (280mg, 2.29mmol) in toluene (15ml) were added sodium bis (trimethylsilyl) amide (2M in THF, 400. mu.l, 801. mu. mol). While dry air was bubbled through the reaction mixture, it was heated to 95 ℃ and stirred for 16 hours. The reaction mixture was poured into 1M aqueous HCl (20ml) and extracted with tBuOMe. The organic layer was washed with 1M aqueous HCl and brine, Na₂SO₄Dried and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/ethyl acetate as eluent. The title compound was obtained as a yellow viscous oil (178 mg).

MS ESI(m/z)：237.5，239.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝7.34(d，J＝7.7Hz，1H)，6.97(d，J＝7.7Hz，1H)，2.89-2.77(m，1H)，1.34(s，6H)，1.10-1.03(m，4H)。

c)6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-2 (3H) -one hydrochloride

Prepared in analogy to examples 76b and 76 c. The title compound was obtained as a grey solid. MS ESI (m/z): 218.5[ (M + H)⁺]。

¹H NMR(DMSO-D₆，300MHz)＝7.37(d，J＝7.9Hz，1H)，6.16(d，J＝8.1Hz，1H)，2.78-2.68(m，1H)，1.18(s，6H)，0.98-0.86(m，4H)

d)N- (1-cyclopropyl-3, 3-dimethyl-2-hydro-2, 3-dihydro-1H-pyrrolo [2, 3-b)]Pyridin-6-yl) iso Nicotinamide

Prepared in analogy to example 2, using 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-2 (3H) -one hydrochloride. The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：323.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.92-8.79(m，2H)，8.46(br s，1H)，8.02(d，J＝7.9Hz，1H)，7.83-7.74(m，2H)，7.49(d，J＝7.9Hz，1H)，2.83-2.72(m，1H)，1.36(s，6H)，1.08-1.01(m，4H)。

Example 83

2-chloro-N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide

Prepared in analogy to example 26 from 2-chloroisonicotinic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79 c). The title compound was obtained as a light yellow foam.

MS ESI(m/z)：357.5/359.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.61(dd，J＝0.6，5.0Hz，1H)，8.59(br s，1H)，8.15(brs，1H)，7.98(s，1H)，7.82(s，1H)，7.68(dd，J＝1.4，5.2Hz，1H)，2.72(tt，J＝3.7，7.1Hz，1H)，1.40(s，6H)，1.20-1.13(m，2H)，0.96-0.90(m，2H)。

Example 84

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methylpyrimidine-5-carboxamide

Prepared in analogy to example 26 from 2-methylpyrimidine-5-carboxylic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79 c). The title compound was obtained as light yellow crystals.

MS ESI(m/z)：338.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝9.17(s，2H)，8.15(s，1H)，7.97(s，1H)，2.85(s，3H)，2.72(tt，J＝3.8，7.0Hz，1H)，1.39(s，6H)，1.20-1.13(m，2H)，0.96-0.91(m，2H)。

Example 85

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-6-yl) isoAzole-5-carboxamides

Prepared analogously to example 26 fromAzole-5-carboxylic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridin-2 (3H) -one (example 79 c). The title compound was obtained as a pale yellow solid.

MS ESI(m/z)：313.4[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.93(br s，1H)，8.41(d，J＝1.8Hz，1H)，8.11(s，1H)，8.02(s，1H)，7.07(d，J＝2.0Hz，1H)，2.71(tt，J＝3.7，7.1Hz，1H)，1.40(s，6H)，1.18-1.11(m，2H)，0.95-0.90(m，2H)。

Example 86

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -1-methyl-1H-pyrazole-5-carboxamide

Prepared in analogy to example 26 from 1-methyl-1H-pyrazole-5-carboxylic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79 c). The title compound was obtained as a white foam.

MS ESI(m/z)：326.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.36(br s，1H)，8.09(d，J＝0.6Hz，1H)，7.97(d，J＝0.8Hz，1H)，7.52(d，J＝2.0Hz，1H)，6.73(d，J＝2.2Hz，1H)，4.26(s，3H)，2.72(tt，J＝3.6，7.1Hz，1H)，1.39(s，6H)，1.19-1.13(m，2H)，0.96-0.92(m，2H)。

Example 87

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -1-methyl-1H-pyrazole-3-carboxamide

Prepared in analogy to example 26 from 1-methyl-1H-pyrazole-3-carboxylic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79 c). The title compound was obtained as white crystals.

MS ESI(m/z)：326.5[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝9.36(s，1H)，8.22(d，J＝0.8Hz，1H)，7.98(d，J＝0.6Hz，1H)，7.42(d，J＝2.2Hz，1H)，6.89(d，J＝2.4Hz，1H)，3.97(s，3H)，2.70(tt，J＝3.6，7.1Hz，1H)，1.38(s，6H)，1.17-1.10(m，2H)，0.95-0.90(m，2H)。

Example 88

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methoxypyrimidine-5-carboxamide

A solution of 2-methoxypyrimidine-5-carboxylic acid (70.9mg, 460. mu. mol) and CDI (82.1mg, 506. mu. mol) in DMF (2ml) was heated to 60 ℃ for 30 minutes and then cooled to room temperature. 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79c, 100mg, 460. mu. mol) was added and the mixture was heated to 60 ℃ for 18 hours. 2-Methoxypyrimidine-5-carboxylic acid (70.9mg, 460. mu. mol) and CDI (82.1mg, 506. mu. mol) were also added to the reaction. After 2 hours, citric acid (460 μ l, 460 μmol) was added to the reaction mixture at 60 ℃ and stirred at room temperature for 30 minutes.

Water (25ml) was added and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with Na₂SO₄The solvent was dried and evaporated. The crude product was purified by flash chromatography on silica gel using heptane/EtOAc as eluent, followed by preparative HPLC, followed by flash chromatography on silica gel using EtOAc/DCM as eluent. The title compound was obtained as a white solid (27 mg).

MS ESI(m/z)：354.2[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝9.08(s，2H)，8.61(br s，1H)，8.14(s，1H)，7.95(s，1H)，4.12(s，3H)，2.72(tt，J＝3.6，7.1Hz，1H)，1.39(s，6H)，1.19-1.12(m，2H)，0.96-0.90(m，2H)。

Example 89

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-6-yl) -3-methyliso-ylAzole-4-carboxamides

Prepared from 3-methylisoxazo-l-ene in analogy to example 26Azole-4-carboxylic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c]Pyridin-2 (3H) -one (example 79 c). The title compound was obtained as a light brown viscous oil.

MS ESI(m/z)：327.6[(M+H)⁺]。

¹H NMR(CDCl₃，300MHz)＝8.84(s，1H)，8.22(br s，1H)，8.05(s，1H)，7.94(s，1H)，2.70(tt，J＝3.7，7.1Hz，1H)，2.61(s，3H)，1.38(s，6H)，1.18-1.12(m，2H)，0.95-0.89(m，2H)。

Example 90

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2- (trifluoromethyl) pyrimidine-5-carboxamide

Prepared in analogy to example 26 from 2- (trifluoromethyl) pyrimidine-5-carboxylic acid and 6-amino-1-cyclopropyl-3, 3-dimethyl-1H-pyrrolo [3, 2-c ] pyridin-2 (3H) -one (example 79 c). The title compound was obtained as an off-white solid.

MS ESI(m/z)：392.1[(M+H)⁺]。

¹H NMR(DMSO-D₆，600MHz)＝11.49(s，1H)，9.53(s，2H)，8.25(s，1H)，8.08(s，1H)，2.77(tt，J＝3.7，7.1Hz，1H)，1.31(s，6H)，1.05-1.01(m，2H)，0.82-0.79(m，2H)。

Biological assays and data

It has now been found that compounds of formula I and I-1 can be used for the treatment of CNS disorders.

The compounds of formula I and I-1 described reduce L-687, 414-induced hyperlocomotion. This is evaluated by: a computerized Digiscan 16 animal activity monitoring system (Omnitech Electronics, Columbus, Ohio) was used to quantify the movement activity. Animals were kept in a 12h light/black cycle and the experiment was performed during the dosing period. Each activity monitoring room is made up of a Plexiglas box (41X 28 em; W X L X H) with sawdust embedded in the floor, surrounded by invisible horizontal and vertical infrared sensor bundles. The test chambers were separated by Plexiglas crosses, providing each mouse with a 20X 20cm activity space. The cage was connected to a Digiscan analyzer, which was connected to a computer that constantly collected the beam status information. The recording of the photo-beam interruption for individual animals was performed every 5 minutes for the duration of the experimental period and the sum of the first 6 periods was used as final parameter. The compound is administered orally 15 minutes prior to subcutaneous injection of 50mg/kg of L-687, 414, or by intraperitoneal injection simultaneously with subcutaneous injection of 50mg/kg of L-687, 414. The mice were then transferred from their home cages to the recording chamber for a 15-min acclimation period, allowing free exploration of the new environment. Horizontal activity was then recorded for a period of 30-min. The% inhibition of L-687, 414-induced hyperlocomotion was calculated according to the following formula:

((vehicle (Veh) + L-687, 414 horizontal Activity-drug + L-687, 414 horizontal Activity)/vehicle + L-687, 414 horizontal Activity) x 100

ID₅₀The value of the one or more of,it was defined as the dose of each compound that produced 50% inhibition of L-687, 414-induced hypermotility, calculated by linear regression analysis of dose-response data using an Excel-based computer fitting program.

When the data do not assume a normal distribution, the group treated with the test compound is statistically compared to the control (vehicle-treated) group using a one-sided (one-tailed) Mann-Whitney U-test. Statistically, the Mann-Whitney U test (also known as the Mann-Whitney-Wilcoxon (mww) or Wilcoxon rank-sum test) is a non-parametric statistical hypothesis test used to assess whether one of two samples of independent observations tends to have a greater value than the other. It is one of the best known non-parametric significance tests. The p-value gives the probability that the two groups differ significantly from each other and a value of < 0.05 is generally accepted as a criterion, which means that there is a > 95% chance that the two groups actually differ from each other.

The p values given in Table 1 are one-sided, in that only a decrease in motility is expected and tested (Mann, H.B., Whitney, D.R. (1947), "On a Test of one of Two Random Variables issochastopically Large target the Other," Annals of chemical statics, 18(1), 50-60).

TABLE 1

Effect of Compounds of formula I on L-687, 414-induced hyperlocomotion

As mentioned above, some compounds have been described(an analytical system developed by PsychoGenics Inc.).

To compare the behavioral characteristics of the test compounds with a database of behavioral characteristics (grouped by indication) obtained from a large group of clinically approved reference compounds. In this way, the neuro-pharmacological effects of test compounds can be predicted by their similarity to a broad class of compounds such as antipsychotics, anxiolytics and antidepressants. This approach is ideally suited to screening a collection of existing drugs or drug candidates with previously unknown neuropharmacologies, which can expedite the development of new and unexpected treatments for psychiatric diseases.

Some compounds of the invention were injected intraperitoneally at various doses for 15 minutes prior to the test. At least 8 mice were used per treatment group. The digital video of the subject was processed with a computer version of the algorithm to extract over 2000 correlation metrics, including the frequency and duration of many different behavioral states. The results of the classification are presented as a bar graph for each dose (mg/kg) and the Y-axis represents the relative probability that the test compound will show efficacy in a particular CNS indication.

The bar diagrams of example compounds 29 and 30 are shown in figures 1 and 2. For comparison, the behavioral profile of the atypical antipsychotic risperidone is shown in figure 3 (for the behavioral profiles of other atypical antipsychotics, such as clozapine, olanzapine, see also robeds et al, Frontiers in Neuroscience, 2011, vol.5, art.103, 1-4). The compounds of the present invention exhibit characteristics similar to those of atypical antipsychotics. The unclassified data were analyzed independently to determine the similarity of the active doses of the example compounds to known atypical antipsychotics. For this analysis, we used the recognition rate as a measure of the separability between two drugs, i.e., "distinguishability" of one drug from the other. A rating equal to 50% (or 0.5) corresponds to zero distinguishability. Empirical data has shown that two drugs with threshold levels below 70% for reliable separation, i.e. showing discrimination levels below 70%, are considered similar, whereas discrimination levels above 70% indicate that the two drugs are not similar. The following table shows the similarity analysis of selected compounds of the present invention to several atypical antipsychotics. In most cases, the example compounds showed similarities to risperidone, clozapine, and olanzapine with a discrimination rating ≦ 0.70.

Table 2:in thatData for compounds of formula I showing effects

	Clozapine	Olanzapine	Risperidone
				Example 29	0.63	0.58	0.56
Example 30	0.68	0.67	0.72

Thus, it is believed that the compounds of the present invention have similar efficacy in human patients as known atypical antipsychotics.

FIG. 1: method for preparing compound 29 showing a distribution similar to that of atypical antipsychoticsAnd (5) characterizing.

FIG. 2: methods of Compound 30 exhibiting a similar profile as an atypical antipsychoticAnd (5) characterizing.

FIG. 3: method for treating atypical antipsychotic risperidoneAnd (5) characterizing.

The compounds of formula (I) and (I-1) and their pharmaceutically acceptable salts can be used as medicaments, for example 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, the administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formulae (I) and (I-1) and their pharmaceutically acceptable salts can be processed 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, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like may be used in the aqueous injection solutions of the water-soluble salts of the compounds of formula (I), but are generally not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

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

As mentioned before, medicaments containing a compound of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as are processes for the manufacture of such medicaments, which comprise bringing one or more compounds of formula (I) or (I-1) or a pharmaceutically acceptable salt thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers. The active compounds may also be used in their prodrug form.

As also mentioned before, the use of the compounds of formulae (I) and (I-1) for the preparation of medicaments useful for the prevention and/or treatment of the above-mentioned diseases is also an object of the present invention.

The dosage may vary within wide limits and will of course be adapted to the individual requirements in each particular case. In general, an effective dose for oral or parenteral administration is 0.01-20 mg/kg/day, with a dose of 0.1-10 mg/kg/day being preferred for all such indications. The daily dose for an adult human weighing 70kg is accordingly between 0.7 and 1400 mg/day, preferably between 7 and 700 mg/day.

Preparation of pharmaceutical compositions comprising the compounds of the invention:

example A

Tablets having the following composition were produced in a conventional manner:

Claims (12)

1. A compound of formula I

Wherein

Is phenyl or heteroaryl, said heteroaryl being selected from pyridyl, pyrimidinyl, imidazolyl, isoheteroarylAzolyl or pyrazolyl;

is phenyl or pyridyl, wherein the N atom in the pyridyl may be in all free positions;

R¹is hydrogen, C_1-7Alkyl, C substituted by halogen_1-7-alkyl radical, C_1-7-alkoxy or halogen; n is 1 or 2; if n is 2, R¹May be the same or different;

R²/R^2’independently of one another is C_1-7-alkyl, or together with the carbon atom to which they are attached form C_3-6-a cycloalkyl ring;

R³is C_1-7-alkyl radical, C_3-6-cycloalkyl, CH₂-C_3-6Cycloalkyl, C in which one ring carbon atom is replaced by-O-_3-6-cycloalkyl, (CH)₂)₃-O-C_3-6Cycloalkyl, C substituted by hydroxy_1-7Alkyl, C substituted by halogen_1-7-alkyl, (CH)₂)₃-S(O)₂-C_3-6-cycloalkyl or (CH)₂)₂-S(O)₂-C_1-7-an alkyl group;

R⁴is hydrogen, halogen or C_1-7-an alkyl group;

and pharmaceutically acceptable salts thereof or racemic mixtures thereof.

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

Is a pyridyl group andis phenyl.

3. The compound according to any one of claims 1 or 2, wherein said compound is

N- (3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -isonicotinamide

N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indolin ] -6' -yl) isonicotinamide

N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

4-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

6-methoxy-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-methoxy-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

4-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

2-chloro-N- (1, 3, 3, 7-tetramethyl-2-oxoindolin-6-yl) isonicotinamide

2-chloro-6-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) nicotinamide

3-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

3-fluoro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

3-chloro-N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -6-methylnicotinamide

5-fluoro-2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (5-chloro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (5-chloro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-isopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) nicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

3-chloro-N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1-ethyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1-isopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

4-fluoro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) benzamide

3-chloro-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) picolinamide

N- (1-cyclopentyl-3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1-cyclopropyl-5-fluoro-3, 3-dimethyl-2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -isonicotinamide

3-fluoro-N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

N- (5, 7-difluoro-1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) -2-methyl-isonicotinamide

3-chloro-N- (5-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (cyclopropylmethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (cyclopropylmethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxoindolin-6-yl) -5-fluoro-2-methylisonicotinamide

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) isonicotinamide

3-chloro-N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) isonicotinamide

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) -3-fluoroisonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

N- (1 '-cyclopropyl-2' -oxospiro [ cyclopropane-1, 3 '-indolin ] -6' -yl) -2-methylisonicotinamide

3-chloro-N- (7-fluoro-1, 3, 3-trimethyl-2-oxoindolin-6-yl) isonicotinamide

3-chloro-N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) -2-methylisonicotinamide

N- (3, 3-dimethyl-1- (oxetan-3-yl) -2-oxoindolin-6-yl) nicotinamide

N- (1- (3-Cyclopropoxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

N- (1- (3-Cyclopropoxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-fluoro-N- (1- (hydroxymethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-fluoro-N- (1- (2-hydroxyethyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

3-fluoro-N- (1- (3-hydroxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (3- (cyclopropylsulfonyl) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (1- (3- (cyclopropylsulfonyl) propyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-2-oxoindolin-6-yl) -3-fluoroisonicotinamide

3-chloro-N- (1- (3-hydroxypropyl) -3, 3-dimethyl-2-oxoindolin-6-yl) isonicotinamide

N- (3, 3-dimethyl-2-oxo-1- (2, 2, 2-trifluoroethyl) indolin-6-yl) -3-fluoroisonicotinamide, or

N- (3, 3-dimethyl-1- (2- (methylsulfonyl) ethyl) -2-oxoindolin-6-yl) -3-fluoroisonicotinamide.

4. A compound of formula I according to claim 1, whereinIs pyrimidinyl or imidazolyl, andis phenyl.

5. A compound of formula I according to any one of claims 1 or 4, wherein the compound is

2, 6-dimethyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-4-carboxamide

1-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) -1H-imidazole-2-carboxamide

2, 4-dimethyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-5-carboxamide, or

2-methyl-N- (1, 3, 3-trimethyl-2-oxoindolin-6-yl) pyrimidine-5-carboxamide.

6. A compound of formula I according to claim 1, whereinIs pyrimidinyl, isoAzolyl or pyrazolyl, andis a pyridyl group.

7. A compound of formula I according to any one of claims 1 or 6, wherein the compound is

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methylpyrimidine-5-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-6-yl) isoAzole-5-carboxamides

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -1-methyl-1H-pyrazole-5-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -1-methyl-1H-pyrazole-3-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methoxypyrimidine-5-carboxamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c)]Pyridin-6-yl) -3-methyliso-ylOxazole-4-carboxamide, or

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2- (trifluoromethyl) pyrimidine-5-carboxamide.

8. A compound of formula I according to claim 1, wherein

Andare all pyridyl.

9. A compound of formula I according to any one of claims 1 or 8, wherein the compound is

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide

N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) nicotinamide

2-methyl-N- (1, 3, 3-trimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) nicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) -2-methylisonicotinamide

N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [2, 3-b ] pyridin-6-yl) isonicotinamide, or

2-chloro-N- (1-cyclopropyl-3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo [3, 2-c ] pyridin-6-yl) isonicotinamide.

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

reacting a compound of formula 2

With a compound of formula 3

Reaction to give the compound of formula I

Wherein X is hydroxy or chlorine and the other groups have the meaning as defined in claim 1, and,

if desired, the compound obtained is converted into a pharmaceutically acceptable acid addition salt.

11. A pharmaceutical composition comprising a compound according to any one of claims 1-9 and a therapeutically active carrier for the treatment of certain central nervous system disorders which are positive and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, sleep disorders, chronic fatigue syndrome, stiffness, anti-inflammatory effects in arthritis and balance problems.

12. The use of a compound of formula I-1 and pharmaceutically acceptable salts or racemic mixtures thereof for the preparation of a medicament,

wherein

Is phenyl or heteroaryl, said heteroaryl being selected from pyridyl, pyrimidinyl, imidazolyl, isoheteroarylAzolyl or pyrazolyl;

is phenyl or pyridyl, wherein the N atom in the pyridyl may be in all free positions;

R¹is hydrogen, C_1-7Alkyl, C substituted by halogen_1-7-alkyl radical, C_1-7-alkoxy or halogen; n is 1 or 2; if n is 2, R¹May be the same or different;

R²/R^2’independently of one another is C_1-7-alkyl, or together with the carbon atom to which they are attached form C_3-6-a cycloalkyl ring;

R³is hydrogen, C_1-7-alkyl radical, C_3-6-cycloalkyl, CH₂-C_3-6Cycloalkyl, C in which one ring carbon atom is replaced by-O-_3-6-cycloalkyl, (CH)₂)₃-O-C_3-6Cycloalkyl, C substituted by hydroxy_1-7Alkyl, C substituted by halogen_1-7-alkyl, (CH)₂)₃-S(O)₂-C_3-6-cycloalkyl or (CH)₂)₂-S(O)₂-C_1-7-an alkyl group;

R⁴is hydrogen, halogen or C_1-7-an alkyl group;

the medicament is for the treatment of central nervous system disorders which are positive and negative symptoms of schizophrenia, substance abuse, alcohol and drug addiction, obsessive-compulsive disorders, cognitive impairment, bipolar disorders, mood disorders, major depression, treatment-resistant depression, anxiety disorders, alzheimer's disease, autism, parkinson's disease, chronic pain, borderline personality disorder, sleep disorders, chronic fatigue syndrome, stiffness, anti-inflammatory effects in arthritis and balance problems.